The U.S. Food and Drug Administration has approved brexucabtagene autoleucel (Tecartus) for the treatment of adult patients (18 years and older) with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).

The therapy is the first chimeric antigen receptor (CAR) T-cell treatment approved for adults with ALL.

This is a “meaningful advance,” because “roughly half of all adults with B-ALL will relapse on currently available therapies,” said Bijal Shah, MD, of Moffitt Cancer Center, Tampa, Fla., in a press statement from the manufacturer, Kite.

“A single infusion of Tecartus has demonstrated durable responses, suggesting the potential for long-term remission and a new approach to care,” he added.

“Roughly half of all cases actually occur in adults, and unlike pediatric ALL, adult ALL has historically had a poor prognosis,” said Lee Greenberger, PhD, chief scientific officer at the Leukemia & Lymphoma Society, in the statement. The median overall survival (OS) is only about 8 months in this setting with current treatments, according to the company.

The new FDA approval, which is the fourth indication for brexucabtagene autoleucel, is based on results from ZUMA-3, a multicenter, single-arm study of 71 patients, with 54 efficacy-evaluable patients.

Efficacy was established on the basis of complete remission (CR) rate within 3 months after infusion and the duration of CR (DOCR). Twenty-eight (51.9%) of evaluable patients achieved CR, with a median follow-up for responders of 7.1 months. The median DOCR was not reached.

The median time to CR was 56 days. All 54 efficacy-evaluable patients had potential follow-up for 10 or more months with a median actual follow-up time of 12.3 months.

Among the 54 patients, the median time from leukapheresis to product delivery was 16 days and the median time from leukapheresis to infusion was 29 days.

Of the 17 study patients who did reach efficacy evaluation, 6 did not receive the agent because of manufacturing failure, 8 were not treated because of adverse events following leukapheresis, 2 underwent leukapheresis and received lymphodepleting chemotherapy but were not treated with the drug, and 1 treated patient was not evaluable for efficacy, per the prescribing information.

Among all patients treated with brexucabtagene autoleucel at its target dose, grade 3 or higher cytokine release syndrome (CRS) and neurologic events occurred in 26% and 35% of patients, respectively, and were generally well managed, according to the company.

The most common adverse reactions (≥20%) among ALL patients are fever, CRS, hypotension, encephalopathy, tachycardia, nausea, chills, headache, fatigue, febrile neutropenia, diarrhea, musculoskeletal pain, hypoxia, rash, edema, tremor, infection with pathogen unspecified, constipation, decreased appetite, and vomiting.

The prescribing information includes a boxed warning about the risks of CRS and neurologic toxicities; the drug is approved with a Risk Evaluation and Mitigation Strategy (REMS) because of these risks.

A version of this article first appeared on Medscape.com.

The U.S. Food and Drug Administration has approved brexucabtagene autoleucel (Tecartus) for the treatment of adult patients (18 years and older) with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).

The therapy is the first chimeric antigen receptor (CAR) T-cell treatment approved for adults with ALL.

This is a “meaningful advance,” because “roughly half of all adults with B-ALL will relapse on currently available therapies,” said Bijal Shah, MD, of Moffitt Cancer Center, Tampa, Fla., in a press statement from the manufacturer, Kite.

“A single infusion of Tecartus has demonstrated durable responses, suggesting the potential for long-term remission and a new approach to care,” he added.

“Roughly half of all cases actually occur in adults, and unlike pediatric ALL, adult ALL has historically had a poor prognosis,” said Lee Greenberger, PhD, chief scientific officer at the Leukemia & Lymphoma Society, in the statement. The median overall survival (OS) is only about 8 months in this setting with current treatments, according to the company.

The new FDA approval, which is the fourth indication for brexucabtagene autoleucel, is based on results from ZUMA-3, a multicenter, single-arm study of 71 patients, with 54 efficacy-evaluable patients.

Efficacy was established on the basis of complete remission (CR) rate within 3 months after infusion and the duration of CR (DOCR). Twenty-eight (51.9%) of evaluable patients achieved CR, with a median follow-up for responders of 7.1 months. The median DOCR was not reached.

The median time to CR was 56 days. All 54 efficacy-evaluable patients had potential follow-up for 10 or more months with a median actual follow-up time of 12.3 months.

Among the 54 patients, the median time from leukapheresis to product delivery was 16 days and the median time from leukapheresis to infusion was 29 days.

Of the 17 study patients who did reach efficacy evaluation, 6 did not receive the agent because of manufacturing failure, 8 were not treated because of adverse events following leukapheresis, 2 underwent leukapheresis and received lymphodepleting chemotherapy but were not treated with the drug, and 1 treated patient was not evaluable for efficacy, per the prescribing information.

Among all patients treated with brexucabtagene autoleucel at its target dose, grade 3 or higher cytokine release syndrome (CRS) and neurologic events occurred in 26% and 35% of patients, respectively, and were generally well managed, according to the company.

The most common adverse reactions (≥20%) among ALL patients are fever, CRS, hypotension, encephalopathy, tachycardia, nausea, chills, headache, fatigue, febrile neutropenia, diarrhea, musculoskeletal pain, hypoxia, rash, edema, tremor, infection with pathogen unspecified, constipation, decreased appetite, and vomiting.

The prescribing information includes a boxed warning about the risks of CRS and neurologic toxicities; the drug is approved with a Risk Evaluation and Mitigation Strategy (REMS) because of these risks.

A version of this article first appeared on Medscape.com.

The U.S. Food and Drug Administration has approved brexucabtagene autoleucel (Tecartus) for the treatment of adult patients (18 years and older) with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).

The therapy is the first chimeric antigen receptor (CAR) T-cell treatment approved for adults with ALL.

This is a “meaningful advance,” because “roughly half of all adults with B-ALL will relapse on currently available therapies,” said Bijal Shah, MD, of Moffitt Cancer Center, Tampa, Fla., in a press statement from the manufacturer, Kite.

“A single infusion of Tecartus has demonstrated durable responses, suggesting the potential for long-term remission and a new approach to care,” he added.

“Roughly half of all cases actually occur in adults, and unlike pediatric ALL, adult ALL has historically had a poor prognosis,” said Lee Greenberger, PhD, chief scientific officer at the Leukemia & Lymphoma Society, in the statement. The median overall survival (OS) is only about 8 months in this setting with current treatments, according to the company.

The new FDA approval, which is the fourth indication for brexucabtagene autoleucel, is based on results from ZUMA-3, a multicenter, single-arm study of 71 patients, with 54 efficacy-evaluable patients.

Efficacy was established on the basis of complete remission (CR) rate within 3 months after infusion and the duration of CR (DOCR). Twenty-eight (51.9%) of evaluable patients achieved CR, with a median follow-up for responders of 7.1 months. The median DOCR was not reached.

The median time to CR was 56 days. All 54 efficacy-evaluable patients had potential follow-up for 10 or more months with a median actual follow-up time of 12.3 months.

Among the 54 patients, the median time from leukapheresis to product delivery was 16 days and the median time from leukapheresis to infusion was 29 days.

Of the 17 study patients who did reach efficacy evaluation, 6 did not receive the agent because of manufacturing failure, 8 were not treated because of adverse events following leukapheresis, 2 underwent leukapheresis and received lymphodepleting chemotherapy but were not treated with the drug, and 1 treated patient was not evaluable for efficacy, per the prescribing information.

Among all patients treated with brexucabtagene autoleucel at its target dose, grade 3 or higher cytokine release syndrome (CRS) and neurologic events occurred in 26% and 35% of patients, respectively, and were generally well managed, according to the company.

The most common adverse reactions (≥20%) among ALL patients are fever, CRS, hypotension, encephalopathy, tachycardia, nausea, chills, headache, fatigue, febrile neutropenia, diarrhea, musculoskeletal pain, hypoxia, rash, edema, tremor, infection with pathogen unspecified, constipation, decreased appetite, and vomiting.

The prescribing information includes a boxed warning about the risks of CRS and neurologic toxicities; the drug is approved with a Risk Evaluation and Mitigation Strategy (REMS) because of these risks.

A version of this article first appeared on Medscape.com.

The Diagnosis: Drug-Induced Hyperpigmentation

Additional history provided by the patient’s caretaker elucidated an extensive list of medications including chlorpromazine and minocycline, among several others. The caretaker revealed that the patient began treatment for acne vulgaris 2 years prior; despite the acne resolving, therapy was not discontinued. The blue-gray and brown pigmentation on our patient’s shins likely was attributed to a medication he was taking.

Both chlorpromazine and minocycline, among many other medications, are known to cause abnormal pigmentation of the skin.¹ Minocycline is a tetracycline antibiotic prescribed for acne and other inflammatory cutaneous conditions. It is highly lipophilic, allowing it to reach high drug concentrations in the skin and nail unit.² Patients taking minocycline long term and at high doses are at greatest risk for pigment deposition.^3,4

Minocycline-induced hyperpigmentation is classified into 3 types. Type I describes blue-black deposition of pigment in acne scars and areas of inflammation, typically on facial skin.^1,5 Histologically, type I stains positive for Perls Prussian blue, indicating an increased deposition of iron as hemosiderin,¹ which likely occurs because minocycline is thought to play a role in defective clearance of hemosiderin from the dermis of injured tissue.⁵ Type II hyperpigmentation presents as bluegray pigment on the lower legs and occasionally the arms.^6,7 Type II stains positive for both Perls Prussian blue and Fontana-Masson, demonstrating hemosiderin and melanin, respectively.⁶ The third form of hyperpigmentation results in diffuse, dark brown to gray pigmentation with a predilection for sun-exposed areas.⁸ Histology of type III shows increased pigment in the basal portion of the epidermis and brown-black pigment in macrophages of the dermis. Type III stains positive for Fontana-Masson and negative for Perls Prussian blue. The etiology of hyperpigmentation has been suspected to be caused by minocycline stimulating melanin production and/or deposition of minocycline-melanin complexes in dermal macrophages after a certain drug level; this largely is seen in patients receiving 100 to 200 mg daily as early as 1 year into treatment.⁸

Chlorpromazine is a typical antipsychotic that causes abnormal skin pigmentation in sun-exposed areas due to increased melanogenesis.⁹ Similar to type III minocyclineinduced hyperpigmentation, a histologic specimen may stain positive for Fontana-Masson yet negative for Perls Prussian blue. Lal et al10 demonstrated complete resolution of abnormal skin pigmentation within 5 years after stopping chlorpromazine. In contrast, minocyclineinduced hyperpigmentation may be permanent in some cases. There is substantial clinical and histologic overlap for drug-induced hyperpigmentation etiologies; it would behoove the clinician to focus on the most common locations affected and the generalized coloration.

Treatment of minocycline-induced hyperpigmentation includes the use of Q-switched lasers, specifically Q-switched ruby and Q-switched alexandrite.¹¹ The use of the Q-switched Nd:YAG laser appears to be ineffective at clearing minocycline-induced pigmentation.^7,11 In our patient, minocycline was discontinued immediately. Due to the patient’s critical condition, he deferred all other therapy. Erythema dyschromicum perstans, also referred to as ashy dermatosis, is an idiopathic form of hyperpigmentation.¹² Lesions start as blue-gray to ashy gray macules, occasionally surrounded by a slightly erythematous, raised border.

Erythema dyschromicum perstans typically presents on the trunk, face, and arms of patients with Fitzpatrick skin types III and IV; it is considered a variant of lichen planus actinicus.¹² Histologically, erythema dyschromicum perstans may mimic lichen planus pigmentosus (LPP); however, subtle differences exist to distinguish the 2 conditions. Erythema dyschromicum perstans demonstrates a mild lichenoid infiltrate, focal basal vacuolization at the dermoepidermal junction, and melanophage deposition.¹³ In contrast, LPP demonstrates pigmentary incontinence and a more severe inflammatory infiltrate. A perifollicular infiltrate and fibrosis also can be seen in LPP, which may explain the frontal fibrosing alopecia that often precedes LPP.¹³

Addison disease, also known as primary adrenal insufficiency, can cause diffuse hyperpigmentation in the skin, mucosae, and nail beds. The pigmentation is prominent in regions of naturally increased pigmentation, such as the flexural surfaces and intertriginous areas.¹⁴ Patients with adrenal insufficiency will have accompanying weight loss, hypotension, and fatigue, among other symptoms related to deficiency of cortisol and aldosterone. Skin biopsy shows acanthosis, hyperkeratosis, focal parakeratosis, spongiosis, superficial perivascular lymphocytic infiltrate, basal melanin deposition, and superficial dermal macrophages.¹⁵

Confluent and reticulated papillomatosis is an uncommon dermatosis that presents with multiple hyperpigmented macules and papules that coalesce to form patches and plaques centrally with reticulation in the periphery.¹⁶ Confluent and reticulated papillomatosis commonly presents on the upper trunk, axillae, and neck, though involvement can include flexural surfaces as well as the lower trunk and legs.^16,17 Biopsy demonstrates undulating hyperkeratosis, papillomatosis, acanthosis, and negative fungal staining.¹⁶

Pretibial myxedema most commonly is associated with Graves disease and presents as well-defined thickening and induration with overlying pink or purple-brown papules in the pretibial region.¹⁸ An acral surface and mucin deposition within the entire dermis may be appreciated on histology with staining for colloidal iron or Alcian blue.

The Diagnosis: Drug-Induced Hyperpigmentation

Additional history provided by the patient’s caretaker elucidated an extensive list of medications including chlorpromazine and minocycline, among several others. The caretaker revealed that the patient began treatment for acne vulgaris 2 years prior; despite the acne resolving, therapy was not discontinued. The blue-gray and brown pigmentation on our patient’s shins likely was attributed to a medication he was taking.

Both chlorpromazine and minocycline, among many other medications, are known to cause abnormal pigmentation of the skin.¹ Minocycline is a tetracycline antibiotic prescribed for acne and other inflammatory cutaneous conditions. It is highly lipophilic, allowing it to reach high drug concentrations in the skin and nail unit.² Patients taking minocycline long term and at high doses are at greatest risk for pigment deposition.^3,4

Minocycline-induced hyperpigmentation is classified into 3 types. Type I describes blue-black deposition of pigment in acne scars and areas of inflammation, typically on facial skin.^1,5 Histologically, type I stains positive for Perls Prussian blue, indicating an increased deposition of iron as hemosiderin,¹ which likely occurs because minocycline is thought to play a role in defective clearance of hemosiderin from the dermis of injured tissue.⁵ Type II hyperpigmentation presents as bluegray pigment on the lower legs and occasionally the arms.^6,7 Type II stains positive for both Perls Prussian blue and Fontana-Masson, demonstrating hemosiderin and melanin, respectively.⁶ The third form of hyperpigmentation results in diffuse, dark brown to gray pigmentation with a predilection for sun-exposed areas.⁸ Histology of type III shows increased pigment in the basal portion of the epidermis and brown-black pigment in macrophages of the dermis. Type III stains positive for Fontana-Masson and negative for Perls Prussian blue. The etiology of hyperpigmentation has been suspected to be caused by minocycline stimulating melanin production and/or deposition of minocycline-melanin complexes in dermal macrophages after a certain drug level; this largely is seen in patients receiving 100 to 200 mg daily as early as 1 year into treatment.⁸

Chlorpromazine is a typical antipsychotic that causes abnormal skin pigmentation in sun-exposed areas due to increased melanogenesis.⁹ Similar to type III minocyclineinduced hyperpigmentation, a histologic specimen may stain positive for Fontana-Masson yet negative for Perls Prussian blue. Lal et al10 demonstrated complete resolution of abnormal skin pigmentation within 5 years after stopping chlorpromazine. In contrast, minocyclineinduced hyperpigmentation may be permanent in some cases. There is substantial clinical and histologic overlap for drug-induced hyperpigmentation etiologies; it would behoove the clinician to focus on the most common locations affected and the generalized coloration.

Treatment of minocycline-induced hyperpigmentation includes the use of Q-switched lasers, specifically Q-switched ruby and Q-switched alexandrite.¹¹ The use of the Q-switched Nd:YAG laser appears to be ineffective at clearing minocycline-induced pigmentation.^7,11 In our patient, minocycline was discontinued immediately. Due to the patient’s critical condition, he deferred all other therapy. Erythema dyschromicum perstans, also referred to as ashy dermatosis, is an idiopathic form of hyperpigmentation.¹² Lesions start as blue-gray to ashy gray macules, occasionally surrounded by a slightly erythematous, raised border.

Erythema dyschromicum perstans typically presents on the trunk, face, and arms of patients with Fitzpatrick skin types III and IV; it is considered a variant of lichen planus actinicus.¹² Histologically, erythema dyschromicum perstans may mimic lichen planus pigmentosus (LPP); however, subtle differences exist to distinguish the 2 conditions. Erythema dyschromicum perstans demonstrates a mild lichenoid infiltrate, focal basal vacuolization at the dermoepidermal junction, and melanophage deposition.¹³ In contrast, LPP demonstrates pigmentary incontinence and a more severe inflammatory infiltrate. A perifollicular infiltrate and fibrosis also can be seen in LPP, which may explain the frontal fibrosing alopecia that often precedes LPP.¹³

Addison disease, also known as primary adrenal insufficiency, can cause diffuse hyperpigmentation in the skin, mucosae, and nail beds. The pigmentation is prominent in regions of naturally increased pigmentation, such as the flexural surfaces and intertriginous areas.¹⁴ Patients with adrenal insufficiency will have accompanying weight loss, hypotension, and fatigue, among other symptoms related to deficiency of cortisol and aldosterone. Skin biopsy shows acanthosis, hyperkeratosis, focal parakeratosis, spongiosis, superficial perivascular lymphocytic infiltrate, basal melanin deposition, and superficial dermal macrophages.¹⁵

Confluent and reticulated papillomatosis is an uncommon dermatosis that presents with multiple hyperpigmented macules and papules that coalesce to form patches and plaques centrally with reticulation in the periphery.¹⁶ Confluent and reticulated papillomatosis commonly presents on the upper trunk, axillae, and neck, though involvement can include flexural surfaces as well as the lower trunk and legs.^16,17 Biopsy demonstrates undulating hyperkeratosis, papillomatosis, acanthosis, and negative fungal staining.¹⁶

Pretibial myxedema most commonly is associated with Graves disease and presents as well-defined thickening and induration with overlying pink or purple-brown papules in the pretibial region.¹⁸ An acral surface and mucin deposition within the entire dermis may be appreciated on histology with staining for colloidal iron or Alcian blue.

The Diagnosis: Drug-Induced Hyperpigmentation

Additional history provided by the patient’s caretaker elucidated an extensive list of medications including chlorpromazine and minocycline, among several others. The caretaker revealed that the patient began treatment for acne vulgaris 2 years prior; despite the acne resolving, therapy was not discontinued. The blue-gray and brown pigmentation on our patient’s shins likely was attributed to a medication he was taking.

Both chlorpromazine and minocycline, among many other medications, are known to cause abnormal pigmentation of the skin.¹ Minocycline is a tetracycline antibiotic prescribed for acne and other inflammatory cutaneous conditions. It is highly lipophilic, allowing it to reach high drug concentrations in the skin and nail unit.² Patients taking minocycline long term and at high doses are at greatest risk for pigment deposition.^3,4

Minocycline-induced hyperpigmentation is classified into 3 types. Type I describes blue-black deposition of pigment in acne scars and areas of inflammation, typically on facial skin.^1,5 Histologically, type I stains positive for Perls Prussian blue, indicating an increased deposition of iron as hemosiderin,¹ which likely occurs because minocycline is thought to play a role in defective clearance of hemosiderin from the dermis of injured tissue.⁵ Type II hyperpigmentation presents as bluegray pigment on the lower legs and occasionally the arms.^6,7 Type II stains positive for both Perls Prussian blue and Fontana-Masson, demonstrating hemosiderin and melanin, respectively.⁶ The third form of hyperpigmentation results in diffuse, dark brown to gray pigmentation with a predilection for sun-exposed areas.⁸ Histology of type III shows increased pigment in the basal portion of the epidermis and brown-black pigment in macrophages of the dermis. Type III stains positive for Fontana-Masson and negative for Perls Prussian blue. The etiology of hyperpigmentation has been suspected to be caused by minocycline stimulating melanin production and/or deposition of minocycline-melanin complexes in dermal macrophages after a certain drug level; this largely is seen in patients receiving 100 to 200 mg daily as early as 1 year into treatment.⁸

Chlorpromazine is a typical antipsychotic that causes abnormal skin pigmentation in sun-exposed areas due to increased melanogenesis.⁹ Similar to type III minocyclineinduced hyperpigmentation, a histologic specimen may stain positive for Fontana-Masson yet negative for Perls Prussian blue. Lal et al10 demonstrated complete resolution of abnormal skin pigmentation within 5 years after stopping chlorpromazine. In contrast, minocyclineinduced hyperpigmentation may be permanent in some cases. There is substantial clinical and histologic overlap for drug-induced hyperpigmentation etiologies; it would behoove the clinician to focus on the most common locations affected and the generalized coloration.

Treatment of minocycline-induced hyperpigmentation includes the use of Q-switched lasers, specifically Q-switched ruby and Q-switched alexandrite.¹¹ The use of the Q-switched Nd:YAG laser appears to be ineffective at clearing minocycline-induced pigmentation.^7,11 In our patient, minocycline was discontinued immediately. Due to the patient’s critical condition, he deferred all other therapy. Erythema dyschromicum perstans, also referred to as ashy dermatosis, is an idiopathic form of hyperpigmentation.¹² Lesions start as blue-gray to ashy gray macules, occasionally surrounded by a slightly erythematous, raised border.

Erythema dyschromicum perstans typically presents on the trunk, face, and arms of patients with Fitzpatrick skin types III and IV; it is considered a variant of lichen planus actinicus.¹² Histologically, erythema dyschromicum perstans may mimic lichen planus pigmentosus (LPP); however, subtle differences exist to distinguish the 2 conditions. Erythema dyschromicum perstans demonstrates a mild lichenoid infiltrate, focal basal vacuolization at the dermoepidermal junction, and melanophage deposition.¹³ In contrast, LPP demonstrates pigmentary incontinence and a more severe inflammatory infiltrate. A perifollicular infiltrate and fibrosis also can be seen in LPP, which may explain the frontal fibrosing alopecia that often precedes LPP.¹³

Addison disease, also known as primary adrenal insufficiency, can cause diffuse hyperpigmentation in the skin, mucosae, and nail beds. The pigmentation is prominent in regions of naturally increased pigmentation, such as the flexural surfaces and intertriginous areas.¹⁴ Patients with adrenal insufficiency will have accompanying weight loss, hypotension, and fatigue, among other symptoms related to deficiency of cortisol and aldosterone. Skin biopsy shows acanthosis, hyperkeratosis, focal parakeratosis, spongiosis, superficial perivascular lymphocytic infiltrate, basal melanin deposition, and superficial dermal macrophages.¹⁵

Confluent and reticulated papillomatosis is an uncommon dermatosis that presents with multiple hyperpigmented macules and papules that coalesce to form patches and plaques centrally with reticulation in the periphery.¹⁶ Confluent and reticulated papillomatosis commonly presents on the upper trunk, axillae, and neck, though involvement can include flexural surfaces as well as the lower trunk and legs.^16,17 Biopsy demonstrates undulating hyperkeratosis, papillomatosis, acanthosis, and negative fungal staining.¹⁶

Pretibial myxedema most commonly is associated with Graves disease and presents as well-defined thickening and induration with overlying pink or purple-brown papules in the pretibial region.¹⁸ An acral surface and mucin deposition within the entire dermis may be appreciated on histology with staining for colloidal iron or Alcian blue.

Even third-degree relatives of people with early-onset colorectal cancer (CRC) are at elevated risk for the disease, according to a study that researchers say could influence screening recommendations.

Among first-degree relatives, there was a sixfold increased risk of developing the malignancy before age 50 in comparison with the general population. Among second- and third-degree relatives, the risk was 1.5 times higher.

Family history is a recognized risk factor for CRC. Roughly 1 in 10 cases of CRC in the United States occurs in people younger than 50 years. It has not been clear to what extent having relatives with early-onset CRC contributes to risk beyond familial syndromes and whether risk extends beyond first-degree relatives, according to study author Lisa A. Cannon-Albright, PhD, of the University of Utah, Salt Lake City, and colleagues.

The new findings suggest “that extended family history should be part of the discussion when making cancer screening decisions,” the researchers write. Their study appears in the August issue of Cancer Epidemiology.

The authors used the Utah Population Data Base (UPDB) to examine genealogies in which more than three generations were linked to the Utah Cancer Registry. The analysis comprised all CRC cases for which there were linked genealogy data.

Of the 1,510 cases of early-onset CRC that the team identified, the risk for CRC was 6.00, 3.09, and 1.56 times higher than expected on the basis of UPDB disease rates for first-, second-, and third-degree relatives, respectively. All results were statistically significant.

The authors also found that individuals with a first-degree relative with early-onset CRC were at 2.64-fold higher risk for CRC at any age. The risk was 1.96-fold higher risk with a second-degree relative and 1.3-fold higher with a third-degree relative. In other words, “the risk for [early-onset] CRC is higher than the risk for CRC at any age, for all degrees of relatives shown,” the team writes.

“Significantly elevated risk for CRC at both locations (left or right) was observed for all degrees of relationship; however the confidence intervals are overlapping, suggesting no difference in risk of left- vs. right-sided CRC,” they state.

The findings held up when the researchers used a genealogic index of familiality test instead of calculating relative risk. Although the authors were unable to exclude from the analysis people with inherited syndromes, they say that it is not likely that Lynch syndrome is driving the results, given that more than three-quarters of the early-onset CRC cases were left-sided, “and Lynch primarily occurs in the proximal colon.”

The authors caution, however, that the majority of the study population were of Northern European ancestry, which could limit generalizability to other groups.

Currently, there are no screening guidelines for second- or third-degree relatives of persons with early-onset CRC unless Lynch syndrome or another genetic condition is identified, the researchers write.

The authors note that their findings suggest that early colonoscopy screening may be considered not only for first-degree relatives, but also for second- and possibly third-degree relatives of persons who have early-onset CRC and that the findings could “influence future CRC screening recommendations.

“Relatives may also benefit from an evaluation with genetic counseling to assess underlying inherited conditions,” they write. “However, we note that there are important considerations in the need for resources to accomplish earlier population-based CRC screening.”

The study was supported by the Utah Cancer Registry, which is funded by the National Cancer Institute’s SEER Program, and the U.S. Centers for Disease Control and Prevention’s National Program of Cancer Registries. Additional support was provided by the University of Utah and Huntsman Cancer Foundation. The authors have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Even third-degree relatives of people with early-onset colorectal cancer (CRC) are at elevated risk for the disease, according to a study that researchers say could influence screening recommendations.

Among first-degree relatives, there was a sixfold increased risk of developing the malignancy before age 50 in comparison with the general population. Among second- and third-degree relatives, the risk was 1.5 times higher.

Family history is a recognized risk factor for CRC. Roughly 1 in 10 cases of CRC in the United States occurs in people younger than 50 years. It has not been clear to what extent having relatives with early-onset CRC contributes to risk beyond familial syndromes and whether risk extends beyond first-degree relatives, according to study author Lisa A. Cannon-Albright, PhD, of the University of Utah, Salt Lake City, and colleagues.

The new findings suggest “that extended family history should be part of the discussion when making cancer screening decisions,” the researchers write. Their study appears in the August issue of Cancer Epidemiology.

The authors used the Utah Population Data Base (UPDB) to examine genealogies in which more than three generations were linked to the Utah Cancer Registry. The analysis comprised all CRC cases for which there were linked genealogy data.

Of the 1,510 cases of early-onset CRC that the team identified, the risk for CRC was 6.00, 3.09, and 1.56 times higher than expected on the basis of UPDB disease rates for first-, second-, and third-degree relatives, respectively. All results were statistically significant.

The authors also found that individuals with a first-degree relative with early-onset CRC were at 2.64-fold higher risk for CRC at any age. The risk was 1.96-fold higher risk with a second-degree relative and 1.3-fold higher with a third-degree relative. In other words, “the risk for [early-onset] CRC is higher than the risk for CRC at any age, for all degrees of relatives shown,” the team writes.

“Significantly elevated risk for CRC at both locations (left or right) was observed for all degrees of relationship; however the confidence intervals are overlapping, suggesting no difference in risk of left- vs. right-sided CRC,” they state.

The findings held up when the researchers used a genealogic index of familiality test instead of calculating relative risk. Although the authors were unable to exclude from the analysis people with inherited syndromes, they say that it is not likely that Lynch syndrome is driving the results, given that more than three-quarters of the early-onset CRC cases were left-sided, “and Lynch primarily occurs in the proximal colon.”

The authors caution, however, that the majority of the study population were of Northern European ancestry, which could limit generalizability to other groups.

Currently, there are no screening guidelines for second- or third-degree relatives of persons with early-onset CRC unless Lynch syndrome or another genetic condition is identified, the researchers write.

The authors note that their findings suggest that early colonoscopy screening may be considered not only for first-degree relatives, but also for second- and possibly third-degree relatives of persons who have early-onset CRC and that the findings could “influence future CRC screening recommendations.

“Relatives may also benefit from an evaluation with genetic counseling to assess underlying inherited conditions,” they write. “However, we note that there are important considerations in the need for resources to accomplish earlier population-based CRC screening.”

The study was supported by the Utah Cancer Registry, which is funded by the National Cancer Institute’s SEER Program, and the U.S. Centers for Disease Control and Prevention’s National Program of Cancer Registries. Additional support was provided by the University of Utah and Huntsman Cancer Foundation. The authors have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Even third-degree relatives of people with early-onset colorectal cancer (CRC) are at elevated risk for the disease, according to a study that researchers say could influence screening recommendations.

Among first-degree relatives, there was a sixfold increased risk of developing the malignancy before age 50 in comparison with the general population. Among second- and third-degree relatives, the risk was 1.5 times higher.

Family history is a recognized risk factor for CRC. Roughly 1 in 10 cases of CRC in the United States occurs in people younger than 50 years. It has not been clear to what extent having relatives with early-onset CRC contributes to risk beyond familial syndromes and whether risk extends beyond first-degree relatives, according to study author Lisa A. Cannon-Albright, PhD, of the University of Utah, Salt Lake City, and colleagues.

The new findings suggest “that extended family history should be part of the discussion when making cancer screening decisions,” the researchers write. Their study appears in the August issue of Cancer Epidemiology.

The authors used the Utah Population Data Base (UPDB) to examine genealogies in which more than three generations were linked to the Utah Cancer Registry. The analysis comprised all CRC cases for which there were linked genealogy data.

Of the 1,510 cases of early-onset CRC that the team identified, the risk for CRC was 6.00, 3.09, and 1.56 times higher than expected on the basis of UPDB disease rates for first-, second-, and third-degree relatives, respectively. All results were statistically significant.

The authors also found that individuals with a first-degree relative with early-onset CRC were at 2.64-fold higher risk for CRC at any age. The risk was 1.96-fold higher risk with a second-degree relative and 1.3-fold higher with a third-degree relative. In other words, “the risk for [early-onset] CRC is higher than the risk for CRC at any age, for all degrees of relatives shown,” the team writes.

“Significantly elevated risk for CRC at both locations (left or right) was observed for all degrees of relationship; however the confidence intervals are overlapping, suggesting no difference in risk of left- vs. right-sided CRC,” they state.

The findings held up when the researchers used a genealogic index of familiality test instead of calculating relative risk. Although the authors were unable to exclude from the analysis people with inherited syndromes, they say that it is not likely that Lynch syndrome is driving the results, given that more than three-quarters of the early-onset CRC cases were left-sided, “and Lynch primarily occurs in the proximal colon.”

The authors caution, however, that the majority of the study population were of Northern European ancestry, which could limit generalizability to other groups.

Currently, there are no screening guidelines for second- or third-degree relatives of persons with early-onset CRC unless Lynch syndrome or another genetic condition is identified, the researchers write.

The authors note that their findings suggest that early colonoscopy screening may be considered not only for first-degree relatives, but also for second- and possibly third-degree relatives of persons who have early-onset CRC and that the findings could “influence future CRC screening recommendations.

“Relatives may also benefit from an evaluation with genetic counseling to assess underlying inherited conditions,” they write. “However, we note that there are important considerations in the need for resources to accomplish earlier population-based CRC screening.”

The study was supported by the Utah Cancer Registry, which is funded by the National Cancer Institute’s SEER Program, and the U.S. Centers for Disease Control and Prevention’s National Program of Cancer Registries. Additional support was provided by the University of Utah and Huntsman Cancer Foundation. The authors have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Discovery of substantial atrial fibrillation (AFib) is usually an indication to start oral anticoagulation (OAC) for stroke prevention, but it’s far from settled whether such AFib is actually a direct cause of thromboembolic stroke. And that has implications for whether patients with occasional bouts of the arrhythmia need to be on continuous OAC.  

It’s possible that some with infrequent paroxysmal AFib can get away with OAC maintained only about as long as the arrhythmia persists, and then go off the drugs, say researchers based on their study, which, they caution, would need the support of prospective trials before such a strategy could be considered.

But importantly, in their patients who had been continuously monitored by their cardiac implantable electronic devices (CIEDs) prior to experiencing a stroke, the 30-day risk of that stroke more than tripled if their AFib burden on 1 day reached at least 5-6 hours. The risk jumped especially high within the first few days after accumulating that amount of AFib in a day, but then fell off sharply over the next few days.

Based on the study, “Your risk of stroke goes up acutely when you have an episode of AFib, and it decreases rapidly, back to baseline – certainly by 30 days and it looked like in our data by 5 days,” Daniel E. Singer, MD, of Massachusetts General Hospital, Boston, said in an interview.

Increasingly, he noted, “there’s a widespread belief that AFib is a risk marker, not a causal risk factor.” In that scenario, most embolic strokes are caused by thrombi formed as a result of an atrial myopathy, characterized by fibrosis and inflammation, that also happens to trigger AFib.

But the current findings are, “from a mechanistic point of view, very much in favor of AFib being a causal risk factor, acutely raising the risk of stroke,” said Dr. Singer, who is lead author on the analysis published online Sept. 29 in JAMA Cardiology.

Some studies have “shown that anticoagulants seem to lower stroke risk even in patients without atrial fib, and even from sources not likely to be coming from the atrium,” Mintu P. Turakhia, MD, of Stanford (Calif.) University, Palo Alto, said in an interview. Collectively they point to “atrial fibrillation as a cause of and a noncausal marker for stroke.”

For example, Dr. Turakhia pointed out in an editorial accompanying the current report that stroke in patients with CIEDs “may occur during prolonged periods of sinus rhythm.”

The current study, he said in an interview, doesn’t preclude atrial myopathy as one direct cause of stroke-associated thrombus, because probably both the myopathy and AFib can be culprits. Still, AFib itself it may bear more responsibility for strokes in patients with fewer competing risks for stroke.

In such patients at lower vascular risk, who may have a CHA2DS2-VASc score of only 1 or 2, for example, “AFib can become a more important cause” of ischemic stroke, Dr. Turakhia said. That’s when AFib is more likely to be temporally related to stroke as the likely culprit, the mechanism addressed by Dr. Singer and associates.

“I think we’re all trying to grapple with what the truth is,” Dr. Singer observed. Still, the current study was unusual for primarily looking at the temporal relationship between AFib and stroke, rather than stroke risk. “And once again, as we found in our earlier study, but now a much larger study, it’s a tight relationship.”

Based on the current results, he said, the risk is “high when you have AFib, and it decreases very rapidly after the AFib is over.” And, “it takes multiple hours of AFib to raise stroke risk.” Inclusion in the analysis required accumulation of at least 5.5 hours of AFib on at least 1 day in a month, the cut point at which stroke risk started to climb significantly in an earlier trial.  

In the current analysis, however, the 30-day odds ratio for stroke was a nonsignificant 2.75 for an AFib burden of 6-23 hours in a day and jumped to a significant 5.0 for a burden in excess of 23 hours in a day. “That’s a lot of AFib” before the risk actually goes up, and supports AFib as causative, Dr. Singer said. If it were the myopathy itself triggering stroke in these particular patients, the risk would be ongoing and not subject to a threshold of AFib burden.
 

Implications for noncontinuous OAC

“The hope is that there are people who have very little AFib: They may have several hours, and then they have nothing for 6 months. Do they have to be anticoagulated or not?” Dr. Singer asked.

“If you believe the risk-marker story, you might say they have to be anticoagulated. But if you believe our results, you would certainly think there’s a good chance they don’t have to be anticoagulated,” he said.

“So it is logical to think, if you have the right people and continuous monitoring, that you could have time-delimited anticoagulation.” That is, patients might start right away on a direct OAC once reaching the AFib threshold in a day, Dr. Singer said, “going on and off anticoagulants in parallel with their episodes of AFib.”

The strategy wouldn’t be feasible in patients who often experience AFib, Dr. Singer noted, “but it might work for people who have infrequent paroxysmal AFib.” It certainly would first have to be tested in prospective trials, he said. Such trials would be more practical than ever to carry out given the growing availability of continuous AFib monitoring by wearables.

“We need a trial to make the case whether it’s safe or not,” Dr. Turakhia said of such a rhythm-guided approach to OAC for AFib. The population to start with, he said, would be patients with paroxysmal AFib and low CHA2DS2-VASc scores. “If you think CHA2DS2-VASc as an integrated score of vascular risk, such patients would have a lot fewer reasons to have strokes. And if they do have a stroke, it’s more reasonable to assume that it’s likely caused by atrial fib and not just a marker.”

Importantly, such a strategy could well be safer than continuous OAC for some patients – those at the lowest vascular risk and with the most occasional AFib and lowest AFib burden “who are otherwise doing fine,” Dr. Turakhia said. In such patients on continuous OAC, he proposed, the risks of bleeding and intracranial hemorrhage could potentially exceed the expected degree of protection from ischemic events.
 

Discordant periods of AFib burden

Dr. Singer and his colleagues linked a national electronic health record database with Medtronic CareLink records covering 10 years to identify 891 patients who experienced an ischemic stroke preceded by at least 120 days of continuous heart-rhythm monitoring.

The patients were then categorized by their pattern of AFib, if any, within each of two prestroke periods: the most recent 30 days, which was the test period, and the preceding 91-120 days, the control period.

The analysis then excluded any patients who reached an AFib-burden threshold of at least 5.5 hours on any day during both the test and control periods, and those who did not attain that threshold in either period.

“The ones who had AFib in both periods mostly had permanent AFib, and ones that didn’t have AFib in either period mostly were in sinus rhythm,” Dr. Singer said. It was “close to 100%” in both cases.

Those exclusions left 66 patients, 7.4% of the total, who reached the AFib-burden threshold on at least 1 day during either the test or control periods, but not both. They included 52 and 14 patients, respectively, with “discordant” periods, that is, at least that burden of AFib in a day during either the test or control period, but not both.

Comparing AFib burden at test versus control periods among patients for whom the two periods were discordant yielded an OR for stroke of 3.71 (95% confidence interval, 2.06-6.70).

Stroke risk levels were not evenly spread throughout the 24-hour periods that met the AFib-burden threshold or the 30 days preceding the patients’ strokes. The OR for stroke was 5.00 (95% CI, 2.62-9.55) during days 1-5 following the day in which the AFib-burden threshold was met. And it was 5.00 (95% CI, 2.08-12.01) over 30 days if the AFib burden exceeded 23 hours on any day of the test period.

The study’s case-crossover design, in which each patient served as their own control, is one of its advantages, Dr. Singer observed. Most patient features, including CHA2DS2-VASc score and comorbidities, did not change appreciably from earliest to the latest 30-day period, which strengthens the comparison of the two because “you don’t have to worry about long-term confounding.”

Dr. Singer was supported by the Eliot B. and Edith C. Shoolman fund of the Massachusetts General Hospital. He discloses receiving grants from Boehringer Ingelheim and Bristol-Myers Squibb; personal fees from Boehringer Ingelheim, Bristol-Myers Squibb, Fitbit, Johnson & Johnson, Merck, and Pfizer; and royalties from UpToDate.

Dr. Turakhia discloses personal fees from Medtronic, Abbott, Sanofi, Pfizer, Myokardia, Johnson & Johnson, Milestone Pharmaceuticals, InCarda Therapeutics, 100Plus, Forward Pharma, and AliveCor; and grants from Bristol-Myers Squibb, the American Heart Association, Apple, and Bayer.

A version of this article first appeared on Medscape.com.

Discovery of substantial atrial fibrillation (AFib) is usually an indication to start oral anticoagulation (OAC) for stroke prevention, but it’s far from settled whether such AFib is actually a direct cause of thromboembolic stroke. And that has implications for whether patients with occasional bouts of the arrhythmia need to be on continuous OAC.  

It’s possible that some with infrequent paroxysmal AFib can get away with OAC maintained only about as long as the arrhythmia persists, and then go off the drugs, say researchers based on their study, which, they caution, would need the support of prospective trials before such a strategy could be considered.

But importantly, in their patients who had been continuously monitored by their cardiac implantable electronic devices (CIEDs) prior to experiencing a stroke, the 30-day risk of that stroke more than tripled if their AFib burden on 1 day reached at least 5-6 hours. The risk jumped especially high within the first few days after accumulating that amount of AFib in a day, but then fell off sharply over the next few days.

Based on the study, “Your risk of stroke goes up acutely when you have an episode of AFib, and it decreases rapidly, back to baseline – certainly by 30 days and it looked like in our data by 5 days,” Daniel E. Singer, MD, of Massachusetts General Hospital, Boston, said in an interview.

Increasingly, he noted, “there’s a widespread belief that AFib is a risk marker, not a causal risk factor.” In that scenario, most embolic strokes are caused by thrombi formed as a result of an atrial myopathy, characterized by fibrosis and inflammation, that also happens to trigger AFib.

But the current findings are, “from a mechanistic point of view, very much in favor of AFib being a causal risk factor, acutely raising the risk of stroke,” said Dr. Singer, who is lead author on the analysis published online Sept. 29 in JAMA Cardiology.

Some studies have “shown that anticoagulants seem to lower stroke risk even in patients without atrial fib, and even from sources not likely to be coming from the atrium,” Mintu P. Turakhia, MD, of Stanford (Calif.) University, Palo Alto, said in an interview. Collectively they point to “atrial fibrillation as a cause of and a noncausal marker for stroke.”

For example, Dr. Turakhia pointed out in an editorial accompanying the current report that stroke in patients with CIEDs “may occur during prolonged periods of sinus rhythm.”

The current study, he said in an interview, doesn’t preclude atrial myopathy as one direct cause of stroke-associated thrombus, because probably both the myopathy and AFib can be culprits. Still, AFib itself it may bear more responsibility for strokes in patients with fewer competing risks for stroke.

In such patients at lower vascular risk, who may have a CHA2DS2-VASc score of only 1 or 2, for example, “AFib can become a more important cause” of ischemic stroke, Dr. Turakhia said. That’s when AFib is more likely to be temporally related to stroke as the likely culprit, the mechanism addressed by Dr. Singer and associates.

“I think we’re all trying to grapple with what the truth is,” Dr. Singer observed. Still, the current study was unusual for primarily looking at the temporal relationship between AFib and stroke, rather than stroke risk. “And once again, as we found in our earlier study, but now a much larger study, it’s a tight relationship.”

Based on the current results, he said, the risk is “high when you have AFib, and it decreases very rapidly after the AFib is over.” And, “it takes multiple hours of AFib to raise stroke risk.” Inclusion in the analysis required accumulation of at least 5.5 hours of AFib on at least 1 day in a month, the cut point at which stroke risk started to climb significantly in an earlier trial.  

In the current analysis, however, the 30-day odds ratio for stroke was a nonsignificant 2.75 for an AFib burden of 6-23 hours in a day and jumped to a significant 5.0 for a burden in excess of 23 hours in a day. “That’s a lot of AFib” before the risk actually goes up, and supports AFib as causative, Dr. Singer said. If it were the myopathy itself triggering stroke in these particular patients, the risk would be ongoing and not subject to a threshold of AFib burden.
 

Implications for noncontinuous OAC

“The hope is that there are people who have very little AFib: They may have several hours, and then they have nothing for 6 months. Do they have to be anticoagulated or not?” Dr. Singer asked.

“If you believe the risk-marker story, you might say they have to be anticoagulated. But if you believe our results, you would certainly think there’s a good chance they don’t have to be anticoagulated,” he said.

“So it is logical to think, if you have the right people and continuous monitoring, that you could have time-delimited anticoagulation.” That is, patients might start right away on a direct OAC once reaching the AFib threshold in a day, Dr. Singer said, “going on and off anticoagulants in parallel with their episodes of AFib.”

The strategy wouldn’t be feasible in patients who often experience AFib, Dr. Singer noted, “but it might work for people who have infrequent paroxysmal AFib.” It certainly would first have to be tested in prospective trials, he said. Such trials would be more practical than ever to carry out given the growing availability of continuous AFib monitoring by wearables.

“We need a trial to make the case whether it’s safe or not,” Dr. Turakhia said of such a rhythm-guided approach to OAC for AFib. The population to start with, he said, would be patients with paroxysmal AFib and low CHA2DS2-VASc scores. “If you think CHA2DS2-VASc as an integrated score of vascular risk, such patients would have a lot fewer reasons to have strokes. And if they do have a stroke, it’s more reasonable to assume that it’s likely caused by atrial fib and not just a marker.”

Importantly, such a strategy could well be safer than continuous OAC for some patients – those at the lowest vascular risk and with the most occasional AFib and lowest AFib burden “who are otherwise doing fine,” Dr. Turakhia said. In such patients on continuous OAC, he proposed, the risks of bleeding and intracranial hemorrhage could potentially exceed the expected degree of protection from ischemic events.
 

Discordant periods of AFib burden

Dr. Singer and his colleagues linked a national electronic health record database with Medtronic CareLink records covering 10 years to identify 891 patients who experienced an ischemic stroke preceded by at least 120 days of continuous heart-rhythm monitoring.

The patients were then categorized by their pattern of AFib, if any, within each of two prestroke periods: the most recent 30 days, which was the test period, and the preceding 91-120 days, the control period.

The analysis then excluded any patients who reached an AFib-burden threshold of at least 5.5 hours on any day during both the test and control periods, and those who did not attain that threshold in either period.

“The ones who had AFib in both periods mostly had permanent AFib, and ones that didn’t have AFib in either period mostly were in sinus rhythm,” Dr. Singer said. It was “close to 100%” in both cases.

Those exclusions left 66 patients, 7.4% of the total, who reached the AFib-burden threshold on at least 1 day during either the test or control periods, but not both. They included 52 and 14 patients, respectively, with “discordant” periods, that is, at least that burden of AFib in a day during either the test or control period, but not both.

Comparing AFib burden at test versus control periods among patients for whom the two periods were discordant yielded an OR for stroke of 3.71 (95% confidence interval, 2.06-6.70).

Stroke risk levels were not evenly spread throughout the 24-hour periods that met the AFib-burden threshold or the 30 days preceding the patients’ strokes. The OR for stroke was 5.00 (95% CI, 2.62-9.55) during days 1-5 following the day in which the AFib-burden threshold was met. And it was 5.00 (95% CI, 2.08-12.01) over 30 days if the AFib burden exceeded 23 hours on any day of the test period.

The study’s case-crossover design, in which each patient served as their own control, is one of its advantages, Dr. Singer observed. Most patient features, including CHA2DS2-VASc score and comorbidities, did not change appreciably from earliest to the latest 30-day period, which strengthens the comparison of the two because “you don’t have to worry about long-term confounding.”

Dr. Singer was supported by the Eliot B. and Edith C. Shoolman fund of the Massachusetts General Hospital. He discloses receiving grants from Boehringer Ingelheim and Bristol-Myers Squibb; personal fees from Boehringer Ingelheim, Bristol-Myers Squibb, Fitbit, Johnson & Johnson, Merck, and Pfizer; and royalties from UpToDate.

Dr. Turakhia discloses personal fees from Medtronic, Abbott, Sanofi, Pfizer, Myokardia, Johnson & Johnson, Milestone Pharmaceuticals, InCarda Therapeutics, 100Plus, Forward Pharma, and AliveCor; and grants from Bristol-Myers Squibb, the American Heart Association, Apple, and Bayer.

A version of this article first appeared on Medscape.com.

Discovery of substantial atrial fibrillation (AFib) is usually an indication to start oral anticoagulation (OAC) for stroke prevention, but it’s far from settled whether such AFib is actually a direct cause of thromboembolic stroke. And that has implications for whether patients with occasional bouts of the arrhythmia need to be on continuous OAC.  

It’s possible that some with infrequent paroxysmal AFib can get away with OAC maintained only about as long as the arrhythmia persists, and then go off the drugs, say researchers based on their study, which, they caution, would need the support of prospective trials before such a strategy could be considered.

But importantly, in their patients who had been continuously monitored by their cardiac implantable electronic devices (CIEDs) prior to experiencing a stroke, the 30-day risk of that stroke more than tripled if their AFib burden on 1 day reached at least 5-6 hours. The risk jumped especially high within the first few days after accumulating that amount of AFib in a day, but then fell off sharply over the next few days.

Based on the study, “Your risk of stroke goes up acutely when you have an episode of AFib, and it decreases rapidly, back to baseline – certainly by 30 days and it looked like in our data by 5 days,” Daniel E. Singer, MD, of Massachusetts General Hospital, Boston, said in an interview.

Increasingly, he noted, “there’s a widespread belief that AFib is a risk marker, not a causal risk factor.” In that scenario, most embolic strokes are caused by thrombi formed as a result of an atrial myopathy, characterized by fibrosis and inflammation, that also happens to trigger AFib.

But the current findings are, “from a mechanistic point of view, very much in favor of AFib being a causal risk factor, acutely raising the risk of stroke,” said Dr. Singer, who is lead author on the analysis published online Sept. 29 in JAMA Cardiology.

Some studies have “shown that anticoagulants seem to lower stroke risk even in patients without atrial fib, and even from sources not likely to be coming from the atrium,” Mintu P. Turakhia, MD, of Stanford (Calif.) University, Palo Alto, said in an interview. Collectively they point to “atrial fibrillation as a cause of and a noncausal marker for stroke.”

For example, Dr. Turakhia pointed out in an editorial accompanying the current report that stroke in patients with CIEDs “may occur during prolonged periods of sinus rhythm.”

The current study, he said in an interview, doesn’t preclude atrial myopathy as one direct cause of stroke-associated thrombus, because probably both the myopathy and AFib can be culprits. Still, AFib itself it may bear more responsibility for strokes in patients with fewer competing risks for stroke.

In such patients at lower vascular risk, who may have a CHA2DS2-VASc score of only 1 or 2, for example, “AFib can become a more important cause” of ischemic stroke, Dr. Turakhia said. That’s when AFib is more likely to be temporally related to stroke as the likely culprit, the mechanism addressed by Dr. Singer and associates.

“I think we’re all trying to grapple with what the truth is,” Dr. Singer observed. Still, the current study was unusual for primarily looking at the temporal relationship between AFib and stroke, rather than stroke risk. “And once again, as we found in our earlier study, but now a much larger study, it’s a tight relationship.”

Based on the current results, he said, the risk is “high when you have AFib, and it decreases very rapidly after the AFib is over.” And, “it takes multiple hours of AFib to raise stroke risk.” Inclusion in the analysis required accumulation of at least 5.5 hours of AFib on at least 1 day in a month, the cut point at which stroke risk started to climb significantly in an earlier trial.  

In the current analysis, however, the 30-day odds ratio for stroke was a nonsignificant 2.75 for an AFib burden of 6-23 hours in a day and jumped to a significant 5.0 for a burden in excess of 23 hours in a day. “That’s a lot of AFib” before the risk actually goes up, and supports AFib as causative, Dr. Singer said. If it were the myopathy itself triggering stroke in these particular patients, the risk would be ongoing and not subject to a threshold of AFib burden.
 

Implications for noncontinuous OAC

“The hope is that there are people who have very little AFib: They may have several hours, and then they have nothing for 6 months. Do they have to be anticoagulated or not?” Dr. Singer asked.

“If you believe the risk-marker story, you might say they have to be anticoagulated. But if you believe our results, you would certainly think there’s a good chance they don’t have to be anticoagulated,” he said.

“So it is logical to think, if you have the right people and continuous monitoring, that you could have time-delimited anticoagulation.” That is, patients might start right away on a direct OAC once reaching the AFib threshold in a day, Dr. Singer said, “going on and off anticoagulants in parallel with their episodes of AFib.”

The strategy wouldn’t be feasible in patients who often experience AFib, Dr. Singer noted, “but it might work for people who have infrequent paroxysmal AFib.” It certainly would first have to be tested in prospective trials, he said. Such trials would be more practical than ever to carry out given the growing availability of continuous AFib monitoring by wearables.

“We need a trial to make the case whether it’s safe or not,” Dr. Turakhia said of such a rhythm-guided approach to OAC for AFib. The population to start with, he said, would be patients with paroxysmal AFib and low CHA2DS2-VASc scores. “If you think CHA2DS2-VASc as an integrated score of vascular risk, such patients would have a lot fewer reasons to have strokes. And if they do have a stroke, it’s more reasonable to assume that it’s likely caused by atrial fib and not just a marker.”

Importantly, such a strategy could well be safer than continuous OAC for some patients – those at the lowest vascular risk and with the most occasional AFib and lowest AFib burden “who are otherwise doing fine,” Dr. Turakhia said. In such patients on continuous OAC, he proposed, the risks of bleeding and intracranial hemorrhage could potentially exceed the expected degree of protection from ischemic events.
 

Discordant periods of AFib burden

Dr. Singer and his colleagues linked a national electronic health record database with Medtronic CareLink records covering 10 years to identify 891 patients who experienced an ischemic stroke preceded by at least 120 days of continuous heart-rhythm monitoring.

The patients were then categorized by their pattern of AFib, if any, within each of two prestroke periods: the most recent 30 days, which was the test period, and the preceding 91-120 days, the control period.

The analysis then excluded any patients who reached an AFib-burden threshold of at least 5.5 hours on any day during both the test and control periods, and those who did not attain that threshold in either period.

“The ones who had AFib in both periods mostly had permanent AFib, and ones that didn’t have AFib in either period mostly were in sinus rhythm,” Dr. Singer said. It was “close to 100%” in both cases.

Those exclusions left 66 patients, 7.4% of the total, who reached the AFib-burden threshold on at least 1 day during either the test or control periods, but not both. They included 52 and 14 patients, respectively, with “discordant” periods, that is, at least that burden of AFib in a day during either the test or control period, but not both.

Comparing AFib burden at test versus control periods among patients for whom the two periods were discordant yielded an OR for stroke of 3.71 (95% confidence interval, 2.06-6.70).

Stroke risk levels were not evenly spread throughout the 24-hour periods that met the AFib-burden threshold or the 30 days preceding the patients’ strokes. The OR for stroke was 5.00 (95% CI, 2.62-9.55) during days 1-5 following the day in which the AFib-burden threshold was met. And it was 5.00 (95% CI, 2.08-12.01) over 30 days if the AFib burden exceeded 23 hours on any day of the test period.

The study’s case-crossover design, in which each patient served as their own control, is one of its advantages, Dr. Singer observed. Most patient features, including CHA2DS2-VASc score and comorbidities, did not change appreciably from earliest to the latest 30-day period, which strengthens the comparison of the two because “you don’t have to worry about long-term confounding.”

Dr. Singer was supported by the Eliot B. and Edith C. Shoolman fund of the Massachusetts General Hospital. He discloses receiving grants from Boehringer Ingelheim and Bristol-Myers Squibb; personal fees from Boehringer Ingelheim, Bristol-Myers Squibb, Fitbit, Johnson & Johnson, Merck, and Pfizer; and royalties from UpToDate.

Dr. Turakhia discloses personal fees from Medtronic, Abbott, Sanofi, Pfizer, Myokardia, Johnson & Johnson, Milestone Pharmaceuticals, InCarda Therapeutics, 100Plus, Forward Pharma, and AliveCor; and grants from Bristol-Myers Squibb, the American Heart Association, Apple, and Bayer.

A version of this article first appeared on Medscape.com.

Medtronic has updated a previous recall of its MiniMed 600 series insulin pumps to include all with a potentially problematic clear retainer ring, not just those that appear damaged.

The U.S. Food and Drug Administration announced on Oct. 5 that Medtronic will now replace any MiniMed 600 series pump that has a clear retainer ring with an updated pump that includes a black retainer ring at no extra charge, regardless of warranty status.

In November 2019, Medtronic first advised patients to examine their pumps for potential damage to the ring, and to contact the company if it appeared to be loose, damaged, or missing. In February 2020, the FDA designated the recall as class 1, “the most serious type of recall,” for which use of the devices “may cause serious injuries or death.”

In this case, one potential risk is hyperglycemia. This can occur if the reservoir isn’t properly locked into place by the retainer ring, and insulin isn’t infused into the body. That, in turn, can lead to diabetic ketoacidosis. Another risk is hypoglycemia, which could result from over-delivery of insulin if the retainer ring breaks or detaches and the user inserts the reservoir back into the pump with the infusion set still connected to the body.

While serious injuries and deaths have been reported with the use of Minimed series 600 insulin pumps, “those adverse events may not have been directly related to the damaged clear retainer rings that are the basis for this recall,” according to the FDA notice. Nonetheless, lawsuits have reportedly been filed.

The new update is not a result of any new issues, Medtronic spokesperson Pamela Reese told this news organization. “Medtronic will proactively replace all MiniMed 600 series insulin pumps with the clear retainer ring design with an equivalent pump that has an updated black retainer ring design, which is designed to better withstand damage sustained by an accidental drop or bump on a hard surface.”

She added, “As we analyze the information that we continuously collect on the safety and performance of our insulin pumps, we recognize that patients who are still using the clear retainer ring could potentially encounter future problems. Therefore, we are currently accelerating our replacement as inventory allows over the coming months to eliminate any potential performance concerns and optimize patient safety and experience.”

The company has replaced nearly half of the clear retainer ring pumps that were in use since November 2019, she said.

The specific insulin pump products are the model 630G, distributed between September 2016 and February 2020; and the 670G, distributed between May 2015 and December 2020. The 630G is approved for people aged 16 years and older, and the 670G – which works with a continuous glucose monitor in a “hybrid closed-loop system – is available for people with type 1 diabetes as young as 7 years of age.

Medtronic has updated a previous recall of its MiniMed 600 series insulin pumps to include all with a potentially problematic clear retainer ring, not just those that appear damaged.

The U.S. Food and Drug Administration announced on Oct. 5 that Medtronic will now replace any MiniMed 600 series pump that has a clear retainer ring with an updated pump that includes a black retainer ring at no extra charge, regardless of warranty status.

In November 2019, Medtronic first advised patients to examine their pumps for potential damage to the ring, and to contact the company if it appeared to be loose, damaged, or missing. In February 2020, the FDA designated the recall as class 1, “the most serious type of recall,” for which use of the devices “may cause serious injuries or death.”

In this case, one potential risk is hyperglycemia. This can occur if the reservoir isn’t properly locked into place by the retainer ring, and insulin isn’t infused into the body. That, in turn, can lead to diabetic ketoacidosis. Another risk is hypoglycemia, which could result from over-delivery of insulin if the retainer ring breaks or detaches and the user inserts the reservoir back into the pump with the infusion set still connected to the body.

While serious injuries and deaths have been reported with the use of Minimed series 600 insulin pumps, “those adverse events may not have been directly related to the damaged clear retainer rings that are the basis for this recall,” according to the FDA notice. Nonetheless, lawsuits have reportedly been filed.

The new update is not a result of any new issues, Medtronic spokesperson Pamela Reese told this news organization. “Medtronic will proactively replace all MiniMed 600 series insulin pumps with the clear retainer ring design with an equivalent pump that has an updated black retainer ring design, which is designed to better withstand damage sustained by an accidental drop or bump on a hard surface.”

She added, “As we analyze the information that we continuously collect on the safety and performance of our insulin pumps, we recognize that patients who are still using the clear retainer ring could potentially encounter future problems. Therefore, we are currently accelerating our replacement as inventory allows over the coming months to eliminate any potential performance concerns and optimize patient safety and experience.”

The company has replaced nearly half of the clear retainer ring pumps that were in use since November 2019, she said.

The specific insulin pump products are the model 630G, distributed between September 2016 and February 2020; and the 670G, distributed between May 2015 and December 2020. The 630G is approved for people aged 16 years and older, and the 670G – which works with a continuous glucose monitor in a “hybrid closed-loop system – is available for people with type 1 diabetes as young as 7 years of age.

Medtronic has updated a previous recall of its MiniMed 600 series insulin pumps to include all with a potentially problematic clear retainer ring, not just those that appear damaged.

The U.S. Food and Drug Administration announced on Oct. 5 that Medtronic will now replace any MiniMed 600 series pump that has a clear retainer ring with an updated pump that includes a black retainer ring at no extra charge, regardless of warranty status.

In November 2019, Medtronic first advised patients to examine their pumps for potential damage to the ring, and to contact the company if it appeared to be loose, damaged, or missing. In February 2020, the FDA designated the recall as class 1, “the most serious type of recall,” for which use of the devices “may cause serious injuries or death.”

In this case, one potential risk is hyperglycemia. This can occur if the reservoir isn’t properly locked into place by the retainer ring, and insulin isn’t infused into the body. That, in turn, can lead to diabetic ketoacidosis. Another risk is hypoglycemia, which could result from over-delivery of insulin if the retainer ring breaks or detaches and the user inserts the reservoir back into the pump with the infusion set still connected to the body.

While serious injuries and deaths have been reported with the use of Minimed series 600 insulin pumps, “those adverse events may not have been directly related to the damaged clear retainer rings that are the basis for this recall,” according to the FDA notice. Nonetheless, lawsuits have reportedly been filed.

The new update is not a result of any new issues, Medtronic spokesperson Pamela Reese told this news organization. “Medtronic will proactively replace all MiniMed 600 series insulin pumps with the clear retainer ring design with an equivalent pump that has an updated black retainer ring design, which is designed to better withstand damage sustained by an accidental drop or bump on a hard surface.”

She added, “As we analyze the information that we continuously collect on the safety and performance of our insulin pumps, we recognize that patients who are still using the clear retainer ring could potentially encounter future problems. Therefore, we are currently accelerating our replacement as inventory allows over the coming months to eliminate any potential performance concerns and optimize patient safety and experience.”

The company has replaced nearly half of the clear retainer ring pumps that were in use since November 2019, she said.

The specific insulin pump products are the model 630G, distributed between September 2016 and February 2020; and the 670G, distributed between May 2015 and December 2020. The 630G is approved for people aged 16 years and older, and the 670G – which works with a continuous glucose monitor in a “hybrid closed-loop system – is available for people with type 1 diabetes as young as 7 years of age.

Methylphenidate is safe and effective for treating apathy in patients with Alzheimer’s disease (AD), new research suggests.

Dundanim/shutterstock.com

Results from a phase 3 randomized trial showed that, after 6 months of treatment, mean score on the Neuropsychiatric Inventory (NPI) apathy subscale decreased by 4.5 points for patients who received methylphenidate vs. a decrease of 3.1 points for those who received placebo.

In addition, the safety profile showed no significant between-group differences.

“Methylphenidate offers a treatment approach providing a modest but potentially clinically significant benefit for patients and caregivers,” said the investigators, led by Jacobo E. Mintzer, MD, MBA, professor of health studies at the Medical University of South Carolina in Charleston.

The findings were published online Sept. 27 in JAMA Neurology.
 

Common problem

Apathy, which is common among patients with AD, is associated with increased risk for mortality, financial burden, and caregiver burden. No treatment has proved effective for apathy in this population.

Two trials of methylphenidate, a catecholaminergic agent, have provided preliminary evidence of efficacy. Findings from the Apathy in Dementia Methylphenidate trial (ADMET) suggested the drug was associated with improved cognition and few adverse events. However, both trials had small patient populations and short durations.

The current investigators conducted ADMET 2, a 6-month, phase 3 trial, to investigate methylphenidate further. They recruited 200 patients (mean age, 76 years; 66% men; 90% White) at nine clinical centers that specialized in dementia care in the United States and one in Canada.

Eligible patients had a diagnosis of possible or probable AD and a Mini-Mental State Examination (MMSE) score between 10 and 28. They also had clinically significant apathy for at least 4 weeks and an available caregiver who spent more than 10 hours a week with the patient.

The researchers randomly assigned patients to receive methylphenidate (n = 99) or placebo (n = 101). For 3 days, participants in the active group received 10 mg/day of methylphenidate. After that point, they received 20 mg/day of methylphenidate for the rest of the study.

Patients in both treatment groups were given the same number of identical-appearing capsules each day.

In-person follow-up visits took place monthly for 6 months. Participants also were contacted by telephone at days 15, 45, and 75 after treatment assignment.

Participants underwent cognitive testing at baseline and at 2, 4, and 6 months. The battery of tests included the MMSE, Hopkins Verbal Learning Test, and Wechsler Adult Intelligence Scale – Revised Digit Span.

The trial’s two primary outcomes were mean change in NPI apathy score from baseline to 6 months and the odds of an improved rating on the Alzheimer’s Disease Cooperative Study Clinical Global Impression of Change (ADCS-CGIC) between baseline and 6 months.

Significant change on either outcome was to be considered a signal of effective treatment.
 

Treatment-specific benefit

Ten patients in the methylphenidate group and seven in the placebo group withdrew during the study.

Mean MMSE score at baseline was 19.2 in the methylphenidate group vs. 18.5 in the placebo group, indicating moderately severe dementia. Mean baseline score on the NPI apathy subscale was 8.0 vs. 7.6, respectively.

In an adjusted, longitudinal model, mean between-group difference in change in NPI apathy score at 6 months was –1.25 (P = .002). The mean NPI apathy score decreased by 4.5 points in the methylphenidate group vs. 3.1 points in the placebo group.

The largest change in apathy score occurred during the first 2 months of treatment. At 6 months, 27% of the methylphenidate group vs. 14% of the placebo group had an NPI apathy score of 0.

In addition, 43.8% of the methylphenidate group had improvement on the ADCS-CGIC compared with 35.2% of the placebo group. The odds ratio (OR) for improvement on ADCS-CGIC for methylphenidate vs. placebo was 1.90 (P = .07).

There was also a strong association between score improvement on the NPI apathy subscale and improvement on the ADCS-CGIC subscale (OR, 2.95; P = .002).

“It is important to note that there were no group differences in any of the cognitive measures, suggesting that the effect of the treatment is specific to the treatment of apathy and not a secondary effect of improvement in cognition,” the researchers wrote.

In all, 17 serious adverse events occurred in the methylphenidate group and 10 occurred in the placebo group. However, all events were found to be hospitalizations for events not related to treatment.
 

‘Enduring effect’

Commenting on the findings, Jeffrey L. Cummings, MD, ScD, professor of brain sciences at the University of Nevada, Las Vegas, noted that the reduction in NPI apathy subscale score of more than 50% was clinically meaningful.

A more robust outcome on the ADCS-CGIC would have been desirable, he added, although that instrument is not designed specifically for apathy.

Methylphenidate’s effect on apathy observed at 2 months and remaining stable throughout the study makes it appear to be “an enduring effect, and not something that the patient accommodates to,” said Dr. Cummings, who was not involved with the research. Such a change may manifest itself in a patient’s greater willingness to help voluntarily with housework or to suggest going for a walk, he noted.

“These are not dramatic changes in cognition, of course, but they are changes in initiative and that is very important,” Dr. Cummings said. Decreased apathy also may improve quality of life for the patient’s caregiver, he added.

Overall, the findings raise the question of whether the Food and Drug Administration should recognize apathy as an indication for which drugs can be approved, said Dr. Cummings.

“For me, that would be the next major step in this line of investigation,” he concluded.

The study was funded by the National Institute on Aging. Dr. Mintzer has served as an adviser to Praxis Bioresearch and Cerevel Therapeutics on matters unrelated to this study. Dr. Cummings is the author of the Neuropsychiatric Inventory but does not receive payments for it from academic trials such as ADMET 2.
 

A version of this article first appeared on Medscape.com.

Methylphenidate is safe and effective for treating apathy in patients with Alzheimer’s disease (AD), new research suggests.

Dundanim/shutterstock.com

Results from a phase 3 randomized trial showed that, after 6 months of treatment, mean score on the Neuropsychiatric Inventory (NPI) apathy subscale decreased by 4.5 points for patients who received methylphenidate vs. a decrease of 3.1 points for those who received placebo.

In addition, the safety profile showed no significant between-group differences.

“Methylphenidate offers a treatment approach providing a modest but potentially clinically significant benefit for patients and caregivers,” said the investigators, led by Jacobo E. Mintzer, MD, MBA, professor of health studies at the Medical University of South Carolina in Charleston.

The findings were published online Sept. 27 in JAMA Neurology.
 

Common problem

Apathy, which is common among patients with AD, is associated with increased risk for mortality, financial burden, and caregiver burden. No treatment has proved effective for apathy in this population.

Two trials of methylphenidate, a catecholaminergic agent, have provided preliminary evidence of efficacy. Findings from the Apathy in Dementia Methylphenidate trial (ADMET) suggested the drug was associated with improved cognition and few adverse events. However, both trials had small patient populations and short durations.

The current investigators conducted ADMET 2, a 6-month, phase 3 trial, to investigate methylphenidate further. They recruited 200 patients (mean age, 76 years; 66% men; 90% White) at nine clinical centers that specialized in dementia care in the United States and one in Canada.

Eligible patients had a diagnosis of possible or probable AD and a Mini-Mental State Examination (MMSE) score between 10 and 28. They also had clinically significant apathy for at least 4 weeks and an available caregiver who spent more than 10 hours a week with the patient.

The researchers randomly assigned patients to receive methylphenidate (n = 99) or placebo (n = 101). For 3 days, participants in the active group received 10 mg/day of methylphenidate. After that point, they received 20 mg/day of methylphenidate for the rest of the study.

Patients in both treatment groups were given the same number of identical-appearing capsules each day.

In-person follow-up visits took place monthly for 6 months. Participants also were contacted by telephone at days 15, 45, and 75 after treatment assignment.

Participants underwent cognitive testing at baseline and at 2, 4, and 6 months. The battery of tests included the MMSE, Hopkins Verbal Learning Test, and Wechsler Adult Intelligence Scale – Revised Digit Span.

The trial’s two primary outcomes were mean change in NPI apathy score from baseline to 6 months and the odds of an improved rating on the Alzheimer’s Disease Cooperative Study Clinical Global Impression of Change (ADCS-CGIC) between baseline and 6 months.

Significant change on either outcome was to be considered a signal of effective treatment.
 

Treatment-specific benefit

Ten patients in the methylphenidate group and seven in the placebo group withdrew during the study.

Mean MMSE score at baseline was 19.2 in the methylphenidate group vs. 18.5 in the placebo group, indicating moderately severe dementia. Mean baseline score on the NPI apathy subscale was 8.0 vs. 7.6, respectively.

In an adjusted, longitudinal model, mean between-group difference in change in NPI apathy score at 6 months was –1.25 (P = .002). The mean NPI apathy score decreased by 4.5 points in the methylphenidate group vs. 3.1 points in the placebo group.

The largest change in apathy score occurred during the first 2 months of treatment. At 6 months, 27% of the methylphenidate group vs. 14% of the placebo group had an NPI apathy score of 0.

In addition, 43.8% of the methylphenidate group had improvement on the ADCS-CGIC compared with 35.2% of the placebo group. The odds ratio (OR) for improvement on ADCS-CGIC for methylphenidate vs. placebo was 1.90 (P = .07).

There was also a strong association between score improvement on the NPI apathy subscale and improvement on the ADCS-CGIC subscale (OR, 2.95; P = .002).

“It is important to note that there were no group differences in any of the cognitive measures, suggesting that the effect of the treatment is specific to the treatment of apathy and not a secondary effect of improvement in cognition,” the researchers wrote.

In all, 17 serious adverse events occurred in the methylphenidate group and 10 occurred in the placebo group. However, all events were found to be hospitalizations for events not related to treatment.
 

‘Enduring effect’

Commenting on the findings, Jeffrey L. Cummings, MD, ScD, professor of brain sciences at the University of Nevada, Las Vegas, noted that the reduction in NPI apathy subscale score of more than 50% was clinically meaningful.

A more robust outcome on the ADCS-CGIC would have been desirable, he added, although that instrument is not designed specifically for apathy.

Methylphenidate’s effect on apathy observed at 2 months and remaining stable throughout the study makes it appear to be “an enduring effect, and not something that the patient accommodates to,” said Dr. Cummings, who was not involved with the research. Such a change may manifest itself in a patient’s greater willingness to help voluntarily with housework or to suggest going for a walk, he noted.

“These are not dramatic changes in cognition, of course, but they are changes in initiative and that is very important,” Dr. Cummings said. Decreased apathy also may improve quality of life for the patient’s caregiver, he added.

Overall, the findings raise the question of whether the Food and Drug Administration should recognize apathy as an indication for which drugs can be approved, said Dr. Cummings.

“For me, that would be the next major step in this line of investigation,” he concluded.

The study was funded by the National Institute on Aging. Dr. Mintzer has served as an adviser to Praxis Bioresearch and Cerevel Therapeutics on matters unrelated to this study. Dr. Cummings is the author of the Neuropsychiatric Inventory but does not receive payments for it from academic trials such as ADMET 2.
 

A version of this article first appeared on Medscape.com.

Methylphenidate is safe and effective for treating apathy in patients with Alzheimer’s disease (AD), new research suggests.

Dundanim/shutterstock.com

Results from a phase 3 randomized trial showed that, after 6 months of treatment, mean score on the Neuropsychiatric Inventory (NPI) apathy subscale decreased by 4.5 points for patients who received methylphenidate vs. a decrease of 3.1 points for those who received placebo.

In addition, the safety profile showed no significant between-group differences.

“Methylphenidate offers a treatment approach providing a modest but potentially clinically significant benefit for patients and caregivers,” said the investigators, led by Jacobo E. Mintzer, MD, MBA, professor of health studies at the Medical University of South Carolina in Charleston.

The findings were published online Sept. 27 in JAMA Neurology.
 

Common problem

Apathy, which is common among patients with AD, is associated with increased risk for mortality, financial burden, and caregiver burden. No treatment has proved effective for apathy in this population.

Two trials of methylphenidate, a catecholaminergic agent, have provided preliminary evidence of efficacy. Findings from the Apathy in Dementia Methylphenidate trial (ADMET) suggested the drug was associated with improved cognition and few adverse events. However, both trials had small patient populations and short durations.

The current investigators conducted ADMET 2, a 6-month, phase 3 trial, to investigate methylphenidate further. They recruited 200 patients (mean age, 76 years; 66% men; 90% White) at nine clinical centers that specialized in dementia care in the United States and one in Canada.

Eligible patients had a diagnosis of possible or probable AD and a Mini-Mental State Examination (MMSE) score between 10 and 28. They also had clinically significant apathy for at least 4 weeks and an available caregiver who spent more than 10 hours a week with the patient.

The researchers randomly assigned patients to receive methylphenidate (n = 99) or placebo (n = 101). For 3 days, participants in the active group received 10 mg/day of methylphenidate. After that point, they received 20 mg/day of methylphenidate for the rest of the study.

Patients in both treatment groups were given the same number of identical-appearing capsules each day.

In-person follow-up visits took place monthly for 6 months. Participants also were contacted by telephone at days 15, 45, and 75 after treatment assignment.

Participants underwent cognitive testing at baseline and at 2, 4, and 6 months. The battery of tests included the MMSE, Hopkins Verbal Learning Test, and Wechsler Adult Intelligence Scale – Revised Digit Span.

The trial’s two primary outcomes were mean change in NPI apathy score from baseline to 6 months and the odds of an improved rating on the Alzheimer’s Disease Cooperative Study Clinical Global Impression of Change (ADCS-CGIC) between baseline and 6 months.

Significant change on either outcome was to be considered a signal of effective treatment.
 

Treatment-specific benefit

Ten patients in the methylphenidate group and seven in the placebo group withdrew during the study.

Mean MMSE score at baseline was 19.2 in the methylphenidate group vs. 18.5 in the placebo group, indicating moderately severe dementia. Mean baseline score on the NPI apathy subscale was 8.0 vs. 7.6, respectively.

In an adjusted, longitudinal model, mean between-group difference in change in NPI apathy score at 6 months was –1.25 (P = .002). The mean NPI apathy score decreased by 4.5 points in the methylphenidate group vs. 3.1 points in the placebo group.

The largest change in apathy score occurred during the first 2 months of treatment. At 6 months, 27% of the methylphenidate group vs. 14% of the placebo group had an NPI apathy score of 0.

In addition, 43.8% of the methylphenidate group had improvement on the ADCS-CGIC compared with 35.2% of the placebo group. The odds ratio (OR) for improvement on ADCS-CGIC for methylphenidate vs. placebo was 1.90 (P = .07).

There was also a strong association between score improvement on the NPI apathy subscale and improvement on the ADCS-CGIC subscale (OR, 2.95; P = .002).

“It is important to note that there were no group differences in any of the cognitive measures, suggesting that the effect of the treatment is specific to the treatment of apathy and not a secondary effect of improvement in cognition,” the researchers wrote.

In all, 17 serious adverse events occurred in the methylphenidate group and 10 occurred in the placebo group. However, all events were found to be hospitalizations for events not related to treatment.
 

‘Enduring effect’

Commenting on the findings, Jeffrey L. Cummings, MD, ScD, professor of brain sciences at the University of Nevada, Las Vegas, noted that the reduction in NPI apathy subscale score of more than 50% was clinically meaningful.

A more robust outcome on the ADCS-CGIC would have been desirable, he added, although that instrument is not designed specifically for apathy.

Methylphenidate’s effect on apathy observed at 2 months and remaining stable throughout the study makes it appear to be “an enduring effect, and not something that the patient accommodates to,” said Dr. Cummings, who was not involved with the research. Such a change may manifest itself in a patient’s greater willingness to help voluntarily with housework or to suggest going for a walk, he noted.

“These are not dramatic changes in cognition, of course, but they are changes in initiative and that is very important,” Dr. Cummings said. Decreased apathy also may improve quality of life for the patient’s caregiver, he added.

Overall, the findings raise the question of whether the Food and Drug Administration should recognize apathy as an indication for which drugs can be approved, said Dr. Cummings.

“For me, that would be the next major step in this line of investigation,” he concluded.

The study was funded by the National Institute on Aging. Dr. Mintzer has served as an adviser to Praxis Bioresearch and Cerevel Therapeutics on matters unrelated to this study. Dr. Cummings is the author of the Neuropsychiatric Inventory but does not receive payments for it from academic trials such as ADMET 2.
 

A version of this article first appeared on Medscape.com.

The continuing decline in COVID-19 incidence suggests the latest surge has peaked as new cases in children dropped for the 4th consecutive week, based on data from the American Academy of Pediatrics and the Children’s Hospital Association.

Preliminary data from the Centers for Disease Control and Prevention, however, show an uptick in new cases in late September, largely among younger children, that may indicate otherwise. Those data have a potential 2-week reporting delay, the CDC said on its COVID Data Tracker, so the most recent points on the graph (see above) could still go up.

The AAP and the CHA said that 173,000 new cases were reported for the week of Sept. 24-30, down 16% from the week before and 31% from the peak in early September. Those new cases made up almost 27% of all cases for the week, and the nearly 5.9 million child cases that have been reported since the start of the pandemic represent 16.2% of cases among Americans of all ages, the two groups said in their weekly COVID-19 report.

The CDC data on new cases by age group suggest that younger children have borne a heavier burden in the summer surge of COVID than they did last winter. The rate of new cases was not as high for 16- and 17-year-olds in the summer, but the other age groups all reached higher peaks than in the winter, including the 12- to 15-year-olds, who have been getting vaccinated since May, according to the COVID Data Tracker.

With vaccination approval getting closer for children under age 12 years, initiation in those already eligible continues to slide. Those aged 12-15 made up just 6.9% of new vaccinations during the 2 weeks from Sept. 21 to Oct. 4, and that figure has been dropping since July 13-26, when it was 14.1%. Vaccine initiation among 16- and 17-year-olds over that time has dropped by almost half, from 5.4% to 2.9%, the CDC data show.

All the vaccinations so far add up to this: Almost 55% of those aged 12-15 have gotten at least one dose of COVID vaccine, as have over 62% of those aged 16-17, and 52% of the older group is fully vaccinated, as is 44% of the younger group. Altogether, 10.8 million children were fully vaccinated as of Oct. 4, including those under 12 who may be participating in clinical trials or had a birth date entered incorrectly, the CDC said.

[email protected]

The continuing decline in COVID-19 incidence suggests the latest surge has peaked as new cases in children dropped for the 4th consecutive week, based on data from the American Academy of Pediatrics and the Children’s Hospital Association.

Preliminary data from the Centers for Disease Control and Prevention, however, show an uptick in new cases in late September, largely among younger children, that may indicate otherwise. Those data have a potential 2-week reporting delay, the CDC said on its COVID Data Tracker, so the most recent points on the graph (see above) could still go up.

The AAP and the CHA said that 173,000 new cases were reported for the week of Sept. 24-30, down 16% from the week before and 31% from the peak in early September. Those new cases made up almost 27% of all cases for the week, and the nearly 5.9 million child cases that have been reported since the start of the pandemic represent 16.2% of cases among Americans of all ages, the two groups said in their weekly COVID-19 report.

The CDC data on new cases by age group suggest that younger children have borne a heavier burden in the summer surge of COVID than they did last winter. The rate of new cases was not as high for 16- and 17-year-olds in the summer, but the other age groups all reached higher peaks than in the winter, including the 12- to 15-year-olds, who have been getting vaccinated since May, according to the COVID Data Tracker.

With vaccination approval getting closer for children under age 12 years, initiation in those already eligible continues to slide. Those aged 12-15 made up just 6.9% of new vaccinations during the 2 weeks from Sept. 21 to Oct. 4, and that figure has been dropping since July 13-26, when it was 14.1%. Vaccine initiation among 16- and 17-year-olds over that time has dropped by almost half, from 5.4% to 2.9%, the CDC data show.

All the vaccinations so far add up to this: Almost 55% of those aged 12-15 have gotten at least one dose of COVID vaccine, as have over 62% of those aged 16-17, and 52% of the older group is fully vaccinated, as is 44% of the younger group. Altogether, 10.8 million children were fully vaccinated as of Oct. 4, including those under 12 who may be participating in clinical trials or had a birth date entered incorrectly, the CDC said.

[email protected]

The continuing decline in COVID-19 incidence suggests the latest surge has peaked as new cases in children dropped for the 4th consecutive week, based on data from the American Academy of Pediatrics and the Children’s Hospital Association.

Preliminary data from the Centers for Disease Control and Prevention, however, show an uptick in new cases in late September, largely among younger children, that may indicate otherwise. Those data have a potential 2-week reporting delay, the CDC said on its COVID Data Tracker, so the most recent points on the graph (see above) could still go up.

The AAP and the CHA said that 173,000 new cases were reported for the week of Sept. 24-30, down 16% from the week before and 31% from the peak in early September. Those new cases made up almost 27% of all cases for the week, and the nearly 5.9 million child cases that have been reported since the start of the pandemic represent 16.2% of cases among Americans of all ages, the two groups said in their weekly COVID-19 report.

The CDC data on new cases by age group suggest that younger children have borne a heavier burden in the summer surge of COVID than they did last winter. The rate of new cases was not as high for 16- and 17-year-olds in the summer, but the other age groups all reached higher peaks than in the winter, including the 12- to 15-year-olds, who have been getting vaccinated since May, according to the COVID Data Tracker.

With vaccination approval getting closer for children under age 12 years, initiation in those already eligible continues to slide. Those aged 12-15 made up just 6.9% of new vaccinations during the 2 weeks from Sept. 21 to Oct. 4, and that figure has been dropping since July 13-26, when it was 14.1%. Vaccine initiation among 16- and 17-year-olds over that time has dropped by almost half, from 5.4% to 2.9%, the CDC data show.

All the vaccinations so far add up to this: Almost 55% of those aged 12-15 have gotten at least one dose of COVID vaccine, as have over 62% of those aged 16-17, and 52% of the older group is fully vaccinated, as is 44% of the younger group. Altogether, 10.8 million children were fully vaccinated as of Oct. 4, including those under 12 who may be participating in clinical trials or had a birth date entered incorrectly, the CDC said.

[email protected]

Third-year medical student Liz Groesbeck was like other excited Las Vegas Raiders fans recently headed to the first full-capacity game in the new Allegiant Stadium since the team moved to “Sin City.” She was in an Uber on a first date just blocks from the game that would pit her Raiders against the Seattle Seahawks when she saw a man on the ground and people gathered around him.

Abandoning her keys, cellphone, and date in the Uber, Ms. Groesbeck popped out to see if she could help. The Uber had been stuck in traffic, so Ms. Groesbeck thought she’d still be able to jump back in the car if she wasn’t needed. 

Then she heard screams. “That didn’t concern me. People scream whenever anything unexpected happens,” said the 28-year-old student from the Kirk Kerkorian School of Medicine at the University of Nevada, Las Vegas (UNLV). But the screams were only a small indication of what she would discover on closer inspection. The arm of the middle-aged man lying on the ground was detached. An abandoned gold SUV remained on the curb nearby. It would turn out to be a hit-and-run of pedestrians by a driver later charged by police with DUI. 

“I was one of the first people there,” Ms. Groesbeck recounted for this news organization. “I knew this guy did not just fall. I told someone to call EMS and I got someone to take his wife somewhere else [away from the bloody scene]. She was obviously very distraught. …At a couple of points she was hysterical.” 

Next, Ms. Groesbeck, who, ironically, had finished her emergency general surgery rotation the day before, focused on the patient. Kneeling beside him, she determined that the immediate priorities were to stop the bleeding and clear his airway. “He was barely breathing,” she recounted. Another student who Ms. Groesbeck believes was pursuing a medical degree — there wasn’t time for formal introductions — offered to help, along with bystanders headed to the game. 

“The crowd was very energetic. It was a beautiful thing.” Ms. Groesbeck cited the spirit of saving lives that developed from the October 1, 2017, Las Vegas country music festival shooting. “People are very willing to try to help others in any way they can.” 

MS. Groesbeck, leading the effort, asked for belts, “and bystanders immediately provided that,” and the other student followed Ms. Groesbeck’s directions to apply tourniquets with the help of those around her. With the blood loss being stemmed, Ms. Groesbeck’s next priority was making sure the patient could breathe. 

Appealing for clothing to clear the man’s airway, “five shirts were handed in a circle to me.” She only needed one jersey to scoop the blood out of his mouth manually to free his airway. 

She overruled well-meaning suggestions to lay the man on his side — which she was concerned could paralyze him — or use a straw to help him breathe. “I did not want to stick anything down his throat.” Meanwhile, there was so much traffic that night around Allegiant Stadium that when the ambulance couldn’t get any closer the firefighters and paramedics exited the vehicle and ran to the scene. 
 

From training to practice

The decisions Ms. Groesbeck made until they could arrive called upon her years of training to be a doctor, and specifically an EMT certification course she had to pass before beginning medical school, she said.

She credits the life-saving methods she learned in that course to Douglas Fraser, MD, FACS, associate professor of surgery at UNLV and University Medical Center (UMC) trauma medical director. He happened to be the attending physician when the accident victim was admitted to the hospital that night in critical condition. The man’s wife also was injured, but not to the extent of her husband.

Dr. Fraser said he didn’t know at the time that his student had been involved in saving the man’s life until Ms. Groesbeck reached out to say thanks for teaching her what to do in an emergency. “I [first] was overly impressed that she did that. Students are so busy; they move after they graduate or finish their rotations. You don’t get to see them time and time again; your short time with them could have a lasting impact and that is my goal,” Dr. Fraser told this news organization.

“They rarely thank you or reflect back. It renewed my sense that I want to teach more, to see the positive impact it had on Elizabeth” and other students, he said.

In terms of the emergency situation she navigated, Dr. Fraser said he was very proud of his student, but was also concerned she could have gotten hurt herself in the middle of a busy intersection. “She was selfless and put herself in harm’s way to help someone.” He also noted it was the first time he knew of a student putting her skills to the test so soon after learning them. “It was a good outcome and she truly provided lifesaving care to this victim.”

He attributed her training to the Stop the Bleed program, which began after the Sandy Hook tragedy in 2012. UNLV requires new med students to complete the American College of Surgeons’ first aid program to learn how to stop the bleeding of a severely injured person by applying tourniquets and pressure. “You have to stop the bleeding right away…and look to see whether their airway is open and if it’s not, open their airway or you won’t have a patient very long. I know she did that. These are the two most important lifesaving skills that she did.” 

Medical students are often called upon as doctors by their family and friends, Dr. Fraser continued. “Everyone looks to you. It can happen on an airplane; you can be anywhere. She heard a person was in need and jumped to action and was able to use the training her school provided and was able to put it to good use.” 
 

Not her first call to action

Just the week before the incident, Ms. Groesbeck was on clinical rotations at UMC helping in the emergency and operating rooms. “She was always very engaged and mature beyond her years,” Dr. Fraser said. “She definitely had that ‘it’ factor. She was sincere with patients and their families and performed well in the operating room. …She was very comfortable around the patients; very comfortable in stressful situations.” 

He added, “I look forward to her participating in trauma surgery rotations in the near future.”

In the meantime, Ms. Groesbeck was pleased to learn that the man she saved survived and thrilled to be part of that effort. As of press time, he had not contacted her. Nor has the other student who helped save his life. 

“A lot of people stepped up and donated their time to help. He got lucky on a very unlucky day,” Ms. Groesbeck said.

She recalled a previous accident victim years ago who wasn’t as lucky. On the way to pick up her white coat for the ceremony before her first year of medical school, she came upon a car that had flipped upside down. “It sheared the roof away. I checked on the restrained passenger. He was partially scalped. The windows were broken and I climbed in next to him.” This time, she used her own shirt to hold pressure on the wound. “He, unfortunately did not make it.” There was nothing she could have done, she was told. 

“That one got me mentally. Very graphic imaging was stuck in my head,” Ms. Groesbeck said. With a masters in neuroscience, she was accustomed to seeing the brain, “but not like this. I felt sad he passed in such a violent way.” So the more recent life-saving experience was redemptive, she said. “I’ve been through hell and back.”

And she’s still on track to become the doctor she envisioned as a child, mummifying her cats with gauze wraps and covering her little sister with adhesive bandages. “It felt good knowing what I could do,” Ms. Groesbeck said. “I’m glad this [man] made it. He got lucky and he could go home to his family. I was not positive when he left in the ambulance. It was a huge relief.” 

Of her role in the episode and her future career ambitions, Ms. Groesbeck noted: “We are studying all the time. It’s not very rewarding. But this, not thinking but having sprung into action, doing the right thing and he could go home to his family a week later. It’s things like this that make the endless hours of studying worth it. I feel like I accomplished something.”

A version of this article first appeared on Medscape.com.

Third-year medical student Liz Groesbeck was like other excited Las Vegas Raiders fans recently headed to the first full-capacity game in the new Allegiant Stadium since the team moved to “Sin City.” She was in an Uber on a first date just blocks from the game that would pit her Raiders against the Seattle Seahawks when she saw a man on the ground and people gathered around him.

Abandoning her keys, cellphone, and date in the Uber, Ms. Groesbeck popped out to see if she could help. The Uber had been stuck in traffic, so Ms. Groesbeck thought she’d still be able to jump back in the car if she wasn’t needed. 

Then she heard screams. “That didn’t concern me. People scream whenever anything unexpected happens,” said the 28-year-old student from the Kirk Kerkorian School of Medicine at the University of Nevada, Las Vegas (UNLV). But the screams were only a small indication of what she would discover on closer inspection. The arm of the middle-aged man lying on the ground was detached. An abandoned gold SUV remained on the curb nearby. It would turn out to be a hit-and-run of pedestrians by a driver later charged by police with DUI. 

“I was one of the first people there,” Ms. Groesbeck recounted for this news organization. “I knew this guy did not just fall. I told someone to call EMS and I got someone to take his wife somewhere else [away from the bloody scene]. She was obviously very distraught. …At a couple of points she was hysterical.” 

Next, Ms. Groesbeck, who, ironically, had finished her emergency general surgery rotation the day before, focused on the patient. Kneeling beside him, she determined that the immediate priorities were to stop the bleeding and clear his airway. “He was barely breathing,” she recounted. Another student who Ms. Groesbeck believes was pursuing a medical degree — there wasn’t time for formal introductions — offered to help, along with bystanders headed to the game. 

“The crowd was very energetic. It was a beautiful thing.” Ms. Groesbeck cited the spirit of saving lives that developed from the October 1, 2017, Las Vegas country music festival shooting. “People are very willing to try to help others in any way they can.” 

MS. Groesbeck, leading the effort, asked for belts, “and bystanders immediately provided that,” and the other student followed Ms. Groesbeck’s directions to apply tourniquets with the help of those around her. With the blood loss being stemmed, Ms. Groesbeck’s next priority was making sure the patient could breathe. 

Appealing for clothing to clear the man’s airway, “five shirts were handed in a circle to me.” She only needed one jersey to scoop the blood out of his mouth manually to free his airway. 

She overruled well-meaning suggestions to lay the man on his side — which she was concerned could paralyze him — or use a straw to help him breathe. “I did not want to stick anything down his throat.” Meanwhile, there was so much traffic that night around Allegiant Stadium that when the ambulance couldn’t get any closer the firefighters and paramedics exited the vehicle and ran to the scene. 
 

From training to practice

The decisions Ms. Groesbeck made until they could arrive called upon her years of training to be a doctor, and specifically an EMT certification course she had to pass before beginning medical school, she said.

She credits the life-saving methods she learned in that course to Douglas Fraser, MD, FACS, associate professor of surgery at UNLV and University Medical Center (UMC) trauma medical director. He happened to be the attending physician when the accident victim was admitted to the hospital that night in critical condition. The man’s wife also was injured, but not to the extent of her husband.

Dr. Fraser said he didn’t know at the time that his student had been involved in saving the man’s life until Ms. Groesbeck reached out to say thanks for teaching her what to do in an emergency. “I [first] was overly impressed that she did that. Students are so busy; they move after they graduate or finish their rotations. You don’t get to see them time and time again; your short time with them could have a lasting impact and that is my goal,” Dr. Fraser told this news organization.

“They rarely thank you or reflect back. It renewed my sense that I want to teach more, to see the positive impact it had on Elizabeth” and other students, he said.

In terms of the emergency situation she navigated, Dr. Fraser said he was very proud of his student, but was also concerned she could have gotten hurt herself in the middle of a busy intersection. “She was selfless and put herself in harm’s way to help someone.” He also noted it was the first time he knew of a student putting her skills to the test so soon after learning them. “It was a good outcome and she truly provided lifesaving care to this victim.”

He attributed her training to the Stop the Bleed program, which began after the Sandy Hook tragedy in 2012. UNLV requires new med students to complete the American College of Surgeons’ first aid program to learn how to stop the bleeding of a severely injured person by applying tourniquets and pressure. “You have to stop the bleeding right away…and look to see whether their airway is open and if it’s not, open their airway or you won’t have a patient very long. I know she did that. These are the two most important lifesaving skills that she did.” 

Medical students are often called upon as doctors by their family and friends, Dr. Fraser continued. “Everyone looks to you. It can happen on an airplane; you can be anywhere. She heard a person was in need and jumped to action and was able to use the training her school provided and was able to put it to good use.” 
 

Not her first call to action

Just the week before the incident, Ms. Groesbeck was on clinical rotations at UMC helping in the emergency and operating rooms. “She was always very engaged and mature beyond her years,” Dr. Fraser said. “She definitely had that ‘it’ factor. She was sincere with patients and their families and performed well in the operating room. …She was very comfortable around the patients; very comfortable in stressful situations.” 

He added, “I look forward to her participating in trauma surgery rotations in the near future.”

In the meantime, Ms. Groesbeck was pleased to learn that the man she saved survived and thrilled to be part of that effort. As of press time, he had not contacted her. Nor has the other student who helped save his life. 

“A lot of people stepped up and donated their time to help. He got lucky on a very unlucky day,” Ms. Groesbeck said.

She recalled a previous accident victim years ago who wasn’t as lucky. On the way to pick up her white coat for the ceremony before her first year of medical school, she came upon a car that had flipped upside down. “It sheared the roof away. I checked on the restrained passenger. He was partially scalped. The windows were broken and I climbed in next to him.” This time, she used her own shirt to hold pressure on the wound. “He, unfortunately did not make it.” There was nothing she could have done, she was told. 

“That one got me mentally. Very graphic imaging was stuck in my head,” Ms. Groesbeck said. With a masters in neuroscience, she was accustomed to seeing the brain, “but not like this. I felt sad he passed in such a violent way.” So the more recent life-saving experience was redemptive, she said. “I’ve been through hell and back.”

And she’s still on track to become the doctor she envisioned as a child, mummifying her cats with gauze wraps and covering her little sister with adhesive bandages. “It felt good knowing what I could do,” Ms. Groesbeck said. “I’m glad this [man] made it. He got lucky and he could go home to his family. I was not positive when he left in the ambulance. It was a huge relief.” 

Of her role in the episode and her future career ambitions, Ms. Groesbeck noted: “We are studying all the time. It’s not very rewarding. But this, not thinking but having sprung into action, doing the right thing and he could go home to his family a week later. It’s things like this that make the endless hours of studying worth it. I feel like I accomplished something.”

A version of this article first appeared on Medscape.com.

Third-year medical student Liz Groesbeck was like other excited Las Vegas Raiders fans recently headed to the first full-capacity game in the new Allegiant Stadium since the team moved to “Sin City.” She was in an Uber on a first date just blocks from the game that would pit her Raiders against the Seattle Seahawks when she saw a man on the ground and people gathered around him.

Abandoning her keys, cellphone, and date in the Uber, Ms. Groesbeck popped out to see if she could help. The Uber had been stuck in traffic, so Ms. Groesbeck thought she’d still be able to jump back in the car if she wasn’t needed. 

Then she heard screams. “That didn’t concern me. People scream whenever anything unexpected happens,” said the 28-year-old student from the Kirk Kerkorian School of Medicine at the University of Nevada, Las Vegas (UNLV). But the screams were only a small indication of what she would discover on closer inspection. The arm of the middle-aged man lying on the ground was detached. An abandoned gold SUV remained on the curb nearby. It would turn out to be a hit-and-run of pedestrians by a driver later charged by police with DUI. 

“I was one of the first people there,” Ms. Groesbeck recounted for this news organization. “I knew this guy did not just fall. I told someone to call EMS and I got someone to take his wife somewhere else [away from the bloody scene]. She was obviously very distraught. …At a couple of points she was hysterical.” 

Next, Ms. Groesbeck, who, ironically, had finished her emergency general surgery rotation the day before, focused on the patient. Kneeling beside him, she determined that the immediate priorities were to stop the bleeding and clear his airway. “He was barely breathing,” she recounted. Another student who Ms. Groesbeck believes was pursuing a medical degree — there wasn’t time for formal introductions — offered to help, along with bystanders headed to the game. 

“The crowd was very energetic. It was a beautiful thing.” Ms. Groesbeck cited the spirit of saving lives that developed from the October 1, 2017, Las Vegas country music festival shooting. “People are very willing to try to help others in any way they can.” 

MS. Groesbeck, leading the effort, asked for belts, “and bystanders immediately provided that,” and the other student followed Ms. Groesbeck’s directions to apply tourniquets with the help of those around her. With the blood loss being stemmed, Ms. Groesbeck’s next priority was making sure the patient could breathe. 

Appealing for clothing to clear the man’s airway, “five shirts were handed in a circle to me.” She only needed one jersey to scoop the blood out of his mouth manually to free his airway. 

She overruled well-meaning suggestions to lay the man on his side — which she was concerned could paralyze him — or use a straw to help him breathe. “I did not want to stick anything down his throat.” Meanwhile, there was so much traffic that night around Allegiant Stadium that when the ambulance couldn’t get any closer the firefighters and paramedics exited the vehicle and ran to the scene. 
 

From training to practice

The decisions Ms. Groesbeck made until they could arrive called upon her years of training to be a doctor, and specifically an EMT certification course she had to pass before beginning medical school, she said.

She credits the life-saving methods she learned in that course to Douglas Fraser, MD, FACS, associate professor of surgery at UNLV and University Medical Center (UMC) trauma medical director. He happened to be the attending physician when the accident victim was admitted to the hospital that night in critical condition. The man’s wife also was injured, but not to the extent of her husband.

Dr. Fraser said he didn’t know at the time that his student had been involved in saving the man’s life until Ms. Groesbeck reached out to say thanks for teaching her what to do in an emergency. “I [first] was overly impressed that she did that. Students are so busy; they move after they graduate or finish their rotations. You don’t get to see them time and time again; your short time with them could have a lasting impact and that is my goal,” Dr. Fraser told this news organization.

“They rarely thank you or reflect back. It renewed my sense that I want to teach more, to see the positive impact it had on Elizabeth” and other students, he said.

In terms of the emergency situation she navigated, Dr. Fraser said he was very proud of his student, but was also concerned she could have gotten hurt herself in the middle of a busy intersection. “She was selfless and put herself in harm’s way to help someone.” He also noted it was the first time he knew of a student putting her skills to the test so soon after learning them. “It was a good outcome and she truly provided lifesaving care to this victim.”

He attributed her training to the Stop the Bleed program, which began after the Sandy Hook tragedy in 2012. UNLV requires new med students to complete the American College of Surgeons’ first aid program to learn how to stop the bleeding of a severely injured person by applying tourniquets and pressure. “You have to stop the bleeding right away…and look to see whether their airway is open and if it’s not, open their airway or you won’t have a patient very long. I know she did that. These are the two most important lifesaving skills that she did.” 

Medical students are often called upon as doctors by their family and friends, Dr. Fraser continued. “Everyone looks to you. It can happen on an airplane; you can be anywhere. She heard a person was in need and jumped to action and was able to use the training her school provided and was able to put it to good use.” 
 

Not her first call to action

Just the week before the incident, Ms. Groesbeck was on clinical rotations at UMC helping in the emergency and operating rooms. “She was always very engaged and mature beyond her years,” Dr. Fraser said. “She definitely had that ‘it’ factor. She was sincere with patients and their families and performed well in the operating room. …She was very comfortable around the patients; very comfortable in stressful situations.” 

He added, “I look forward to her participating in trauma surgery rotations in the near future.”

In the meantime, Ms. Groesbeck was pleased to learn that the man she saved survived and thrilled to be part of that effort. As of press time, he had not contacted her. Nor has the other student who helped save his life. 

“A lot of people stepped up and donated their time to help. He got lucky on a very unlucky day,” Ms. Groesbeck said.

She recalled a previous accident victim years ago who wasn’t as lucky. On the way to pick up her white coat for the ceremony before her first year of medical school, she came upon a car that had flipped upside down. “It sheared the roof away. I checked on the restrained passenger. He was partially scalped. The windows were broken and I climbed in next to him.” This time, she used her own shirt to hold pressure on the wound. “He, unfortunately did not make it.” There was nothing she could have done, she was told. 

“That one got me mentally. Very graphic imaging was stuck in my head,” Ms. Groesbeck said. With a masters in neuroscience, she was accustomed to seeing the brain, “but not like this. I felt sad he passed in such a violent way.” So the more recent life-saving experience was redemptive, she said. “I’ve been through hell and back.”

And she’s still on track to become the doctor she envisioned as a child, mummifying her cats with gauze wraps and covering her little sister with adhesive bandages. “It felt good knowing what I could do,” Ms. Groesbeck said. “I’m glad this [man] made it. He got lucky and he could go home to his family. I was not positive when he left in the ambulance. It was a huge relief.” 

Of her role in the episode and her future career ambitions, Ms. Groesbeck noted: “We are studying all the time. It’s not very rewarding. But this, not thinking but having sprung into action, doing the right thing and he could go home to his family a week later. It’s things like this that make the endless hours of studying worth it. I feel like I accomplished something.”

A version of this article first appeared on Medscape.com.

People with insulin-treated type 1 diabetes who had problems avoiding hypoglycemic episodes despite optimal care were helped significantly by a new psychoeducational program called HARPdoc, it was reported at the annual meeting of the European Association for the Study of Diabetes.

In a randomized controlled trial (RCT), both HARPdoc and the more established Blood Glucose Awareness Training (BGAT) were effective at reducing the number of severe hypoglycemia episodes seen, from five episodes at baseline to one at 1 year in both groups, and one and none at 2-years’ follow-up, respectively.

“HARPdoc is not superior to BGAT in its ability to restore hypoglycemia awareness and reduce severe hypoglycemia,” said Stephanie Amiel, MD, FRCP, the chief investigator for the trial. However, “it does reduce cognitive barriers to hypoglycemia avoidance, so it achieves what it set out to do.”

Dr. Amiel, professor of diabetes research at Kings College London, added that it was important to note that HARPdoc was better than BGAT at improving participants’ mental health, “producing a clinically important and sustainable reduction in diabetes distress, anxiety, and depression.”
 

What’s HARPdoc?

The Hypoglycaemia Awareness Restoration Programme for people with type 1 diabetes and problematic hypoglycaemia persisting despite optimised self-care (HARPdoc) was designed to specifically address why some people with type 1 diabetes find it difficult to avoid recurrent hypoglycemia.

“It’s a psychoeducational program with clinical knowledge about hypoglycemia and group learning, but also explicit topics on mindset and behavior change,” explained Nicole de Zoysa, DClinPsych, one of the clinical psychologists involved in the trial.

Over the course of the 6-week program, there are four group sessions (weeks 1-3, and week 6) and two individual sessions (weeks 4 and 5) ­that address important “cognitive barriers” or “thinking traps” to avoiding hypoglycemia that were identified during prior qualitative research.

HARPdoc is thus “an attempt to make sense of people’s reluctance or seeming reluctance to take action around hypoglycemia, Dr. de Zoysa said. The intervention draws on both cognitive behavioral theory “to work with the beliefs” and motivational interviewing “to work with the resistance.”
 

The HARPdoc RCT

Starting in 2017 and ending earlier this year, the HARPdoc RCT was a parallel group study conducted at three specialist diabetes centers in the United Kingdom and one in the United States.

A total of 99 adults with insulin-treated type 1 diabetes and impaired hypoglycemia awareness were enrolled – with 49 randomized to the HARPdoc arm and 50 to the BGAT arm. All had been offered technologies to help them potentially bring their hypoglycemia under better control, such as continuous glucose monitoring, insulin pumps, or closed loop systems, and received structured education on flexible insulin dosing.

The aim was to show superiority of the HARPdoc program over BGAT, in helping people avoid episodes of severe hypoglycemia, defined as episodes that needed other people’s intervention to help resolve.

BGAT is also a psychoeducation program that has been around since the 1980s but barely used in the United Kingdom, Dr. Amiel noted.

Baseline demographic characteristics were similar for the HARPdoc and BGAT arms: The mean age was 57 versus 52 years, there was a long (30+ years) duration of diabetes, over half of the participants were male, and almost all were White.
 

Primary endpoint not met, but still ‘impressive’

Although the primary endpoint of the trial was not met, the reductions in severe hypoglycemia seen are still “impressive,” said Ramzi Ajjan, MD, FRCP, of Leeds (England) University and Leeds Teaching Hospitals Trust.

“I was really blown away,” by the improvement in both study arms, said Dr. Ajjan, who was not involved in the trial. “These people have had proper clinical input,” he stressed, noting that both interventions worked, with no difference between them in terms of severe hypoglycemia.

Dr. Ajjan was not surprised by the better cognition scores measured using the A2A questionnaire seen with HARPdoc versus BGAT, as “this is what the intervention was designed to address.”

In terms of the mental health benefits seen, HARPdoc significantly reduced the level of diabetes distress as measured using the Problem Areas In Diabetes (PAID) questionnaire versus the BGAT intervention.

The PAID score was around 30 in both groups at baseline, this fell to about 26 at 1 year, and around 20 at 2 years in the HARPdoc group, which was significantly lower than the score seen in the BGAT group which rose slightly then fell back to baseline levels.

A similar pattern was seen in the levels of depression and anxiety, which were measured by the HADS-D and HADS-A instruments. So HARPdoc was more effective at improving psychological and mental health outcomes than BGAT, Dr. Ajjan observed.

The HARPdoc project is funded by the Juvenile Diabetes Research Foundation with additional support from the UK’s National Institute of Health Research. The HARPdoc RCT was jointly sponsored by King’s College London and King’s College Hospital NHS Foundation Trust. Dr. Amiel has served on advisory panels for Roche, Medtronic, and Novo Nordisk. Dr. de Zoysa did not state having any conflicts of interest. Dr. Ajjan disclosed that he has financial relationships with multiple pharmaceutical companies.

People with insulin-treated type 1 diabetes who had problems avoiding hypoglycemic episodes despite optimal care were helped significantly by a new psychoeducational program called HARPdoc, it was reported at the annual meeting of the European Association for the Study of Diabetes.

In a randomized controlled trial (RCT), both HARPdoc and the more established Blood Glucose Awareness Training (BGAT) were effective at reducing the number of severe hypoglycemia episodes seen, from five episodes at baseline to one at 1 year in both groups, and one and none at 2-years’ follow-up, respectively.

“HARPdoc is not superior to BGAT in its ability to restore hypoglycemia awareness and reduce severe hypoglycemia,” said Stephanie Amiel, MD, FRCP, the chief investigator for the trial. However, “it does reduce cognitive barriers to hypoglycemia avoidance, so it achieves what it set out to do.”

Dr. Amiel, professor of diabetes research at Kings College London, added that it was important to note that HARPdoc was better than BGAT at improving participants’ mental health, “producing a clinically important and sustainable reduction in diabetes distress, anxiety, and depression.”
 

What’s HARPdoc?

The Hypoglycaemia Awareness Restoration Programme for people with type 1 diabetes and problematic hypoglycaemia persisting despite optimised self-care (HARPdoc) was designed to specifically address why some people with type 1 diabetes find it difficult to avoid recurrent hypoglycemia.

“It’s a psychoeducational program with clinical knowledge about hypoglycemia and group learning, but also explicit topics on mindset and behavior change,” explained Nicole de Zoysa, DClinPsych, one of the clinical psychologists involved in the trial.

Over the course of the 6-week program, there are four group sessions (weeks 1-3, and week 6) and two individual sessions (weeks 4 and 5) ­that address important “cognitive barriers” or “thinking traps” to avoiding hypoglycemia that were identified during prior qualitative research.

HARPdoc is thus “an attempt to make sense of people’s reluctance or seeming reluctance to take action around hypoglycemia, Dr. de Zoysa said. The intervention draws on both cognitive behavioral theory “to work with the beliefs” and motivational interviewing “to work with the resistance.”
 

The HARPdoc RCT

Starting in 2017 and ending earlier this year, the HARPdoc RCT was a parallel group study conducted at three specialist diabetes centers in the United Kingdom and one in the United States.

A total of 99 adults with insulin-treated type 1 diabetes and impaired hypoglycemia awareness were enrolled – with 49 randomized to the HARPdoc arm and 50 to the BGAT arm. All had been offered technologies to help them potentially bring their hypoglycemia under better control, such as continuous glucose monitoring, insulin pumps, or closed loop systems, and received structured education on flexible insulin dosing.

The aim was to show superiority of the HARPdoc program over BGAT, in helping people avoid episodes of severe hypoglycemia, defined as episodes that needed other people’s intervention to help resolve.

BGAT is also a psychoeducation program that has been around since the 1980s but barely used in the United Kingdom, Dr. Amiel noted.

Baseline demographic characteristics were similar for the HARPdoc and BGAT arms: The mean age was 57 versus 52 years, there was a long (30+ years) duration of diabetes, over half of the participants were male, and almost all were White.
 

Primary endpoint not met, but still ‘impressive’

Although the primary endpoint of the trial was not met, the reductions in severe hypoglycemia seen are still “impressive,” said Ramzi Ajjan, MD, FRCP, of Leeds (England) University and Leeds Teaching Hospitals Trust.

“I was really blown away,” by the improvement in both study arms, said Dr. Ajjan, who was not involved in the trial. “These people have had proper clinical input,” he stressed, noting that both interventions worked, with no difference between them in terms of severe hypoglycemia.

Dr. Ajjan was not surprised by the better cognition scores measured using the A2A questionnaire seen with HARPdoc versus BGAT, as “this is what the intervention was designed to address.”

In terms of the mental health benefits seen, HARPdoc significantly reduced the level of diabetes distress as measured using the Problem Areas In Diabetes (PAID) questionnaire versus the BGAT intervention.

The PAID score was around 30 in both groups at baseline, this fell to about 26 at 1 year, and around 20 at 2 years in the HARPdoc group, which was significantly lower than the score seen in the BGAT group which rose slightly then fell back to baseline levels.

A similar pattern was seen in the levels of depression and anxiety, which were measured by the HADS-D and HADS-A instruments. So HARPdoc was more effective at improving psychological and mental health outcomes than BGAT, Dr. Ajjan observed.

The HARPdoc project is funded by the Juvenile Diabetes Research Foundation with additional support from the UK’s National Institute of Health Research. The HARPdoc RCT was jointly sponsored by King’s College London and King’s College Hospital NHS Foundation Trust. Dr. Amiel has served on advisory panels for Roche, Medtronic, and Novo Nordisk. Dr. de Zoysa did not state having any conflicts of interest. Dr. Ajjan disclosed that he has financial relationships with multiple pharmaceutical companies.

People with insulin-treated type 1 diabetes who had problems avoiding hypoglycemic episodes despite optimal care were helped significantly by a new psychoeducational program called HARPdoc, it was reported at the annual meeting of the European Association for the Study of Diabetes.

In a randomized controlled trial (RCT), both HARPdoc and the more established Blood Glucose Awareness Training (BGAT) were effective at reducing the number of severe hypoglycemia episodes seen, from five episodes at baseline to one at 1 year in both groups, and one and none at 2-years’ follow-up, respectively.

“HARPdoc is not superior to BGAT in its ability to restore hypoglycemia awareness and reduce severe hypoglycemia,” said Stephanie Amiel, MD, FRCP, the chief investigator for the trial. However, “it does reduce cognitive barriers to hypoglycemia avoidance, so it achieves what it set out to do.”

Dr. Amiel, professor of diabetes research at Kings College London, added that it was important to note that HARPdoc was better than BGAT at improving participants’ mental health, “producing a clinically important and sustainable reduction in diabetes distress, anxiety, and depression.”
 

What’s HARPdoc?

The Hypoglycaemia Awareness Restoration Programme for people with type 1 diabetes and problematic hypoglycaemia persisting despite optimised self-care (HARPdoc) was designed to specifically address why some people with type 1 diabetes find it difficult to avoid recurrent hypoglycemia.

“It’s a psychoeducational program with clinical knowledge about hypoglycemia and group learning, but also explicit topics on mindset and behavior change,” explained Nicole de Zoysa, DClinPsych, one of the clinical psychologists involved in the trial.

Over the course of the 6-week program, there are four group sessions (weeks 1-3, and week 6) and two individual sessions (weeks 4 and 5) ­that address important “cognitive barriers” or “thinking traps” to avoiding hypoglycemia that were identified during prior qualitative research.

HARPdoc is thus “an attempt to make sense of people’s reluctance or seeming reluctance to take action around hypoglycemia, Dr. de Zoysa said. The intervention draws on both cognitive behavioral theory “to work with the beliefs” and motivational interviewing “to work with the resistance.”
 

The HARPdoc RCT

Starting in 2017 and ending earlier this year, the HARPdoc RCT was a parallel group study conducted at three specialist diabetes centers in the United Kingdom and one in the United States.

A total of 99 adults with insulin-treated type 1 diabetes and impaired hypoglycemia awareness were enrolled – with 49 randomized to the HARPdoc arm and 50 to the BGAT arm. All had been offered technologies to help them potentially bring their hypoglycemia under better control, such as continuous glucose monitoring, insulin pumps, or closed loop systems, and received structured education on flexible insulin dosing.

The aim was to show superiority of the HARPdoc program over BGAT, in helping people avoid episodes of severe hypoglycemia, defined as episodes that needed other people’s intervention to help resolve.

BGAT is also a psychoeducation program that has been around since the 1980s but barely used in the United Kingdom, Dr. Amiel noted.

Baseline demographic characteristics were similar for the HARPdoc and BGAT arms: The mean age was 57 versus 52 years, there was a long (30+ years) duration of diabetes, over half of the participants were male, and almost all were White.
 

Primary endpoint not met, but still ‘impressive’

Although the primary endpoint of the trial was not met, the reductions in severe hypoglycemia seen are still “impressive,” said Ramzi Ajjan, MD, FRCP, of Leeds (England) University and Leeds Teaching Hospitals Trust.

“I was really blown away,” by the improvement in both study arms, said Dr. Ajjan, who was not involved in the trial. “These people have had proper clinical input,” he stressed, noting that both interventions worked, with no difference between them in terms of severe hypoglycemia.

Dr. Ajjan was not surprised by the better cognition scores measured using the A2A questionnaire seen with HARPdoc versus BGAT, as “this is what the intervention was designed to address.”

In terms of the mental health benefits seen, HARPdoc significantly reduced the level of diabetes distress as measured using the Problem Areas In Diabetes (PAID) questionnaire versus the BGAT intervention.

The PAID score was around 30 in both groups at baseline, this fell to about 26 at 1 year, and around 20 at 2 years in the HARPdoc group, which was significantly lower than the score seen in the BGAT group which rose slightly then fell back to baseline levels.

A similar pattern was seen in the levels of depression and anxiety, which were measured by the HADS-D and HADS-A instruments. So HARPdoc was more effective at improving psychological and mental health outcomes than BGAT, Dr. Ajjan observed.

The HARPdoc project is funded by the Juvenile Diabetes Research Foundation with additional support from the UK’s National Institute of Health Research. The HARPdoc RCT was jointly sponsored by King’s College London and King’s College Hospital NHS Foundation Trust. Dr. Amiel has served on advisory panels for Roche, Medtronic, and Novo Nordisk. Dr. de Zoysa did not state having any conflicts of interest. Dr. Ajjan disclosed that he has financial relationships with multiple pharmaceutical companies.

In the fall of 1980, my parents made me take a high school class that I was REALLY angry over. It was a waste of time. It was beneath my dignity. It was something I never was going to use. It was embarrassing.

It was ... typing.

And I was completely wrong.

Looking back from 2021, I have to say that, of all the things I learned in high school, it’s probably the skill I depend on the most every day. It’s probably been at least 25 years since I had a day when I didn’t type something.

Some of it is the rise of the Internet and computers, but a lot of it is also the way I run my practice. My schedule isn’t as busy as those of my colleagues in general practice, and I don’t use one of those new-fangled EMRs (my charts are on computer, but not in a specialized program per se).

I’ve always been my own transcriptionist. I type roughly 40 words a minute; certainly not blazing speed, but enough to get the job done. For a few years I used voice dictation, but the only speech program I really liked folded up years ago (yes, ViaVoice, I still miss you).

So now I just type, and proofread, all my own notes. Old-school maybe, certainly not efficient as far as time goes, but it works for me. My thoughts go through my fingers directly into the chart, occasionally pausing to think something through before I put it in or hitting backspace if I think of a better way to phrase it. Typing my own notes lets me turn the case over as I’m hitting the keys, working my way through the differential and what needs to be done.

Writing the notes myself allows me to tell the patient’s story, and think about it in the process. It allows me to work through it again the next time I open the chart, months, or even years, later. Hopefully it shows my thought process and why I did things the way I did for myself, the colleague I’m sending the note to, and any physicians down the line.

I could probably save time with a system that lets me just check boxes or circle pertinent positives and negatives in a template, but that’s not how my thought process works. I feel like I’d be missing something if I did.

And, 41 years later, it’s still a reminder of how much of my parents’ advice was correct. Because at the time, I was pretty sure they were wrong.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

In the fall of 1980, my parents made me take a high school class that I was REALLY angry over. It was a waste of time. It was beneath my dignity. It was something I never was going to use. It was embarrassing.

It was ... typing.

And I was completely wrong.

Looking back from 2021, I have to say that, of all the things I learned in high school, it’s probably the skill I depend on the most every day. It’s probably been at least 25 years since I had a day when I didn’t type something.

Some of it is the rise of the Internet and computers, but a lot of it is also the way I run my practice. My schedule isn’t as busy as those of my colleagues in general practice, and I don’t use one of those new-fangled EMRs (my charts are on computer, but not in a specialized program per se).

I’ve always been my own transcriptionist. I type roughly 40 words a minute; certainly not blazing speed, but enough to get the job done. For a few years I used voice dictation, but the only speech program I really liked folded up years ago (yes, ViaVoice, I still miss you).

So now I just type, and proofread, all my own notes. Old-school maybe, certainly not efficient as far as time goes, but it works for me. My thoughts go through my fingers directly into the chart, occasionally pausing to think something through before I put it in or hitting backspace if I think of a better way to phrase it. Typing my own notes lets me turn the case over as I’m hitting the keys, working my way through the differential and what needs to be done.

Writing the notes myself allows me to tell the patient’s story, and think about it in the process. It allows me to work through it again the next time I open the chart, months, or even years, later. Hopefully it shows my thought process and why I did things the way I did for myself, the colleague I’m sending the note to, and any physicians down the line.

I could probably save time with a system that lets me just check boxes or circle pertinent positives and negatives in a template, but that’s not how my thought process works. I feel like I’d be missing something if I did.

And, 41 years later, it’s still a reminder of how much of my parents’ advice was correct. Because at the time, I was pretty sure they were wrong.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

In the fall of 1980, my parents made me take a high school class that I was REALLY angry over. It was a waste of time. It was beneath my dignity. It was something I never was going to use. It was embarrassing.

It was ... typing.

And I was completely wrong.

Looking back from 2021, I have to say that, of all the things I learned in high school, it’s probably the skill I depend on the most every day. It’s probably been at least 25 years since I had a day when I didn’t type something.

Some of it is the rise of the Internet and computers, but a lot of it is also the way I run my practice. My schedule isn’t as busy as those of my colleagues in general practice, and I don’t use one of those new-fangled EMRs (my charts are on computer, but not in a specialized program per se).

I’ve always been my own transcriptionist. I type roughly 40 words a minute; certainly not blazing speed, but enough to get the job done. For a few years I used voice dictation, but the only speech program I really liked folded up years ago (yes, ViaVoice, I still miss you).

So now I just type, and proofread, all my own notes. Old-school maybe, certainly not efficient as far as time goes, but it works for me. My thoughts go through my fingers directly into the chart, occasionally pausing to think something through before I put it in or hitting backspace if I think of a better way to phrase it. Typing my own notes lets me turn the case over as I’m hitting the keys, working my way through the differential and what needs to be done.

Writing the notes myself allows me to tell the patient’s story, and think about it in the process. It allows me to work through it again the next time I open the chart, months, or even years, later. Hopefully it shows my thought process and why I did things the way I did for myself, the colleague I’m sending the note to, and any physicians down the line.

I could probably save time with a system that lets me just check boxes or circle pertinent positives and negatives in a template, but that’s not how my thought process works. I feel like I’d be missing something if I did.

And, 41 years later, it’s still a reminder of how much of my parents’ advice was correct. Because at the time, I was pretty sure they were wrong.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.