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The Naming Project: Renaming Schizophrenia
One in 100 people worldwide experience a condition called schizophrenia. There is widespread disagreement regarding what should be the appropriate name for this condition. Raquelle Mesholam-Gately, PhD, Matcheri Keshavan, MD, the Consumer Advisory Board, and associated members of the research team at Beth Israel Deaconess Medical Center are conducting a study about renaming schizophrenia.
They are requesting your opinion on this matter. If you choose to be in the study, you will complete this survey, which will take 5 to 10 minutes. The survey is anonymous, and no one will be able to link your answers back to you. Please do not include your name or other information that could be used to identify you in the survey responses. Participation in this study is voluntary.
Take the survey: https://forms.gle/fBVvrkGbVSU3H7Cz8
One in 100 people worldwide experience a condition called schizophrenia. There is widespread disagreement regarding what should be the appropriate name for this condition. Raquelle Mesholam-Gately, PhD, Matcheri Keshavan, MD, the Consumer Advisory Board, and associated members of the research team at Beth Israel Deaconess Medical Center are conducting a study about renaming schizophrenia.
They are requesting your opinion on this matter. If you choose to be in the study, you will complete this survey, which will take 5 to 10 minutes. The survey is anonymous, and no one will be able to link your answers back to you. Please do not include your name or other information that could be used to identify you in the survey responses. Participation in this study is voluntary.
Take the survey: https://forms.gle/fBVvrkGbVSU3H7Cz8
One in 100 people worldwide experience a condition called schizophrenia. There is widespread disagreement regarding what should be the appropriate name for this condition. Raquelle Mesholam-Gately, PhD, Matcheri Keshavan, MD, the Consumer Advisory Board, and associated members of the research team at Beth Israel Deaconess Medical Center are conducting a study about renaming schizophrenia.
They are requesting your opinion on this matter. If you choose to be in the study, you will complete this survey, which will take 5 to 10 minutes. The survey is anonymous, and no one will be able to link your answers back to you. Please do not include your name or other information that could be used to identify you in the survey responses. Participation in this study is voluntary.
Take the survey: https://forms.gle/fBVvrkGbVSU3H7Cz8
FCC backs designating 988 as suicide prevention hotline
A Federal Communications Commission report recommends that 988 be designated as a nationwide suicide and mental health crisis support hotline, because a three-digit number “could be more effective” than the current 10-digit number, according to an FCC release.
The report was prepared by the FCC’s Wireline Competition Bureau and Office of Economics and Analytics at the direction of the National Suicide Hotline Improvement Act of 2018. The current service, known as the National Suicide Prevention Lifeline, uses the 10-digit number of 800-273-8255 (TALK). The report noted that the hotline has proved effective: The service answered 2.2 million calls in 2018 and various assessments have shown significant reductions in hopelessness and suicidal ideation among callers.
However, based on data and conclusions from some of those assessments, the report determined “that the Lifeline could be more effective in preventing suicides and providing crisis intervention if it were accessible via a simple, easy-to-remember, 3-digit dialing code.” The report examined the feasibility of three-digit options, including N11 options such as 211 and 511, but based on an analysis by the North American Numbering Council, it found that “technical and operational concerns related to the 988 code could be more easily and quickly addressed and resolved than any re-education efforts related to repurposing a N11 code.”
Suicide and mental health crises have been on the rise, according to numbers from the Centers for Disease Control and Prevention cited by the FCC report. Among the 50 states, 49 saw increases during 1999-2016, and more than half saw increases greater than 20%. The report describes how some groups, such as veterans and LGBTQ youth, are at especially high risk:
A Federal Communications Commission report recommends that 988 be designated as a nationwide suicide and mental health crisis support hotline, because a three-digit number “could be more effective” than the current 10-digit number, according to an FCC release.
The report was prepared by the FCC’s Wireline Competition Bureau and Office of Economics and Analytics at the direction of the National Suicide Hotline Improvement Act of 2018. The current service, known as the National Suicide Prevention Lifeline, uses the 10-digit number of 800-273-8255 (TALK). The report noted that the hotline has proved effective: The service answered 2.2 million calls in 2018 and various assessments have shown significant reductions in hopelessness and suicidal ideation among callers.
However, based on data and conclusions from some of those assessments, the report determined “that the Lifeline could be more effective in preventing suicides and providing crisis intervention if it were accessible via a simple, easy-to-remember, 3-digit dialing code.” The report examined the feasibility of three-digit options, including N11 options such as 211 and 511, but based on an analysis by the North American Numbering Council, it found that “technical and operational concerns related to the 988 code could be more easily and quickly addressed and resolved than any re-education efforts related to repurposing a N11 code.”
Suicide and mental health crises have been on the rise, according to numbers from the Centers for Disease Control and Prevention cited by the FCC report. Among the 50 states, 49 saw increases during 1999-2016, and more than half saw increases greater than 20%. The report describes how some groups, such as veterans and LGBTQ youth, are at especially high risk:
A Federal Communications Commission report recommends that 988 be designated as a nationwide suicide and mental health crisis support hotline, because a three-digit number “could be more effective” than the current 10-digit number, according to an FCC release.
The report was prepared by the FCC’s Wireline Competition Bureau and Office of Economics and Analytics at the direction of the National Suicide Hotline Improvement Act of 2018. The current service, known as the National Suicide Prevention Lifeline, uses the 10-digit number of 800-273-8255 (TALK). The report noted that the hotline has proved effective: The service answered 2.2 million calls in 2018 and various assessments have shown significant reductions in hopelessness and suicidal ideation among callers.
However, based on data and conclusions from some of those assessments, the report determined “that the Lifeline could be more effective in preventing suicides and providing crisis intervention if it were accessible via a simple, easy-to-remember, 3-digit dialing code.” The report examined the feasibility of three-digit options, including N11 options such as 211 and 511, but based on an analysis by the North American Numbering Council, it found that “technical and operational concerns related to the 988 code could be more easily and quickly addressed and resolved than any re-education efforts related to repurposing a N11 code.”
Suicide and mental health crises have been on the rise, according to numbers from the Centers for Disease Control and Prevention cited by the FCC report. Among the 50 states, 49 saw increases during 1999-2016, and more than half saw increases greater than 20%. The report describes how some groups, such as veterans and LGBTQ youth, are at especially high risk:
Windshield and UV exposure
As the summer draws to a close and I have finished my 20th road trip with my three children who frequently complain of “being too hot” or that the “sun is in my eyes” while in the car, I would like to particularly for passengers. As thoughtful parents, we lather our kids with sunscreen before going to the pool or beach, but do we really remember to do this, or to provide sunglasses before embarking on a 5-hour car ride? Many people do not. We must raise awareness of the risk of UV light in cars, and take better care of both our children and ourselves.
Windshield glass is federally regulated to allow in a maximum amount of light for visibility, but has no requirements for sun protection. Many people do not understand the difference between UVA and UVB protection, let alone that UVB radiation is blocked by the window glass, but UVA radiation is not, and reaches the skin and eyes through glass. By law, windshields must be made of laminated glass, which includes two 2.1-mm layers of glass separated by a 0.8-mm piece of plastic. The glass is made to break easily upon impact and the plastic then stretches to absorb the impact. The thin layer of plastic also helps windshields absorb nearly all of the sun’s UVA and UVB rays. Sunroofs also contain UV-protective technology, which blocks UVA and UVB radiation while also keeping the car cool and protecting against direct sun exposure. However, rear windows do not offer the same protection.
Side and rear windows are made of a cheaper tempered glass that does not include a plastic layer, thereby offering no UVA protection. In a study by Butler et al. reviewing 900 head and neck cancers, 53% were found on the left side, and those who spent more hours driving each week had a higher chance of getting a left-side skin cancer (J Am Acad Dermatol. 2010 Dec;63[6]:1006-10). Many automakers have not helped this problem; while there is higher-SPF glass that can be used, it is more costly for automobile manufacturers – and ultimately for consumers. A cheaper and more practical alternative is a UV film that can be applied to the glass; these films both improve UV protection and cool the car. In addition to providing sun protection, it can be assumed that the subsequent reduction of temperature within a car decreases the usage of air conditioners, thus improving both fuel economy and the environment.
Aftermarket window tinting and UV films can also be applied by glass-tinting companies and auto dealers for $150-$200. Companies like Solar Gard, LLUMAr, and 3M offer window films that can block UV rays. While these are available, the legal allowable tint limit varies from state to state. Visible light transmission (VLT) is the measurement of the percent of visible light that gets through a car’s window. The lower the VLT, the darker the tint. Most states prohibit less than 50% VLT for the driver and front passenger window, and 35% for the rear passenger, side, and rear windows.
To mitigate this, I offer patients with severe photo-dermitides a letter of medical necessity to the DMV to allow a higher percentage of tinting and recommend that they get aftermarket UV-protective films or tints on their vehicles. Regardless of whether higher tints are an option for them, sun protection of the skin and eyes is recommended for all passengers. Sunscreen with broad-spectrum coverage is recommended regardless of how long a car ride might be, and it is recommended that individuals keep the sunroof closed while driving for added UV protection. The use of polarized sunglasses for adults and children is also recommended to avoid UV damage to the eyes. Sunscreens and glasses with protection against blue light are also recommended for passengers who stare at screens and tablets during long car rides.
Dr. Talakoub and Dr. Wesley are cocontributors to this column. Dr. Talakoub is in private practice in McLean, Va. Dr. Wesley practices dermatology in Beverly Hills, Calif. This month’s column is by Dr. Talakoub. Write to them at [email protected]. They had no relevant disclosures.
As the summer draws to a close and I have finished my 20th road trip with my three children who frequently complain of “being too hot” or that the “sun is in my eyes” while in the car, I would like to particularly for passengers. As thoughtful parents, we lather our kids with sunscreen before going to the pool or beach, but do we really remember to do this, or to provide sunglasses before embarking on a 5-hour car ride? Many people do not. We must raise awareness of the risk of UV light in cars, and take better care of both our children and ourselves.
Windshield glass is federally regulated to allow in a maximum amount of light for visibility, but has no requirements for sun protection. Many people do not understand the difference between UVA and UVB protection, let alone that UVB radiation is blocked by the window glass, but UVA radiation is not, and reaches the skin and eyes through glass. By law, windshields must be made of laminated glass, which includes two 2.1-mm layers of glass separated by a 0.8-mm piece of plastic. The glass is made to break easily upon impact and the plastic then stretches to absorb the impact. The thin layer of plastic also helps windshields absorb nearly all of the sun’s UVA and UVB rays. Sunroofs also contain UV-protective technology, which blocks UVA and UVB radiation while also keeping the car cool and protecting against direct sun exposure. However, rear windows do not offer the same protection.
Side and rear windows are made of a cheaper tempered glass that does not include a plastic layer, thereby offering no UVA protection. In a study by Butler et al. reviewing 900 head and neck cancers, 53% were found on the left side, and those who spent more hours driving each week had a higher chance of getting a left-side skin cancer (J Am Acad Dermatol. 2010 Dec;63[6]:1006-10). Many automakers have not helped this problem; while there is higher-SPF glass that can be used, it is more costly for automobile manufacturers – and ultimately for consumers. A cheaper and more practical alternative is a UV film that can be applied to the glass; these films both improve UV protection and cool the car. In addition to providing sun protection, it can be assumed that the subsequent reduction of temperature within a car decreases the usage of air conditioners, thus improving both fuel economy and the environment.
Aftermarket window tinting and UV films can also be applied by glass-tinting companies and auto dealers for $150-$200. Companies like Solar Gard, LLUMAr, and 3M offer window films that can block UV rays. While these are available, the legal allowable tint limit varies from state to state. Visible light transmission (VLT) is the measurement of the percent of visible light that gets through a car’s window. The lower the VLT, the darker the tint. Most states prohibit less than 50% VLT for the driver and front passenger window, and 35% for the rear passenger, side, and rear windows.
To mitigate this, I offer patients with severe photo-dermitides a letter of medical necessity to the DMV to allow a higher percentage of tinting and recommend that they get aftermarket UV-protective films or tints on their vehicles. Regardless of whether higher tints are an option for them, sun protection of the skin and eyes is recommended for all passengers. Sunscreen with broad-spectrum coverage is recommended regardless of how long a car ride might be, and it is recommended that individuals keep the sunroof closed while driving for added UV protection. The use of polarized sunglasses for adults and children is also recommended to avoid UV damage to the eyes. Sunscreens and glasses with protection against blue light are also recommended for passengers who stare at screens and tablets during long car rides.
Dr. Talakoub and Dr. Wesley are cocontributors to this column. Dr. Talakoub is in private practice in McLean, Va. Dr. Wesley practices dermatology in Beverly Hills, Calif. This month’s column is by Dr. Talakoub. Write to them at [email protected]. They had no relevant disclosures.
As the summer draws to a close and I have finished my 20th road trip with my three children who frequently complain of “being too hot” or that the “sun is in my eyes” while in the car, I would like to particularly for passengers. As thoughtful parents, we lather our kids with sunscreen before going to the pool or beach, but do we really remember to do this, or to provide sunglasses before embarking on a 5-hour car ride? Many people do not. We must raise awareness of the risk of UV light in cars, and take better care of both our children and ourselves.
Windshield glass is federally regulated to allow in a maximum amount of light for visibility, but has no requirements for sun protection. Many people do not understand the difference between UVA and UVB protection, let alone that UVB radiation is blocked by the window glass, but UVA radiation is not, and reaches the skin and eyes through glass. By law, windshields must be made of laminated glass, which includes two 2.1-mm layers of glass separated by a 0.8-mm piece of plastic. The glass is made to break easily upon impact and the plastic then stretches to absorb the impact. The thin layer of plastic also helps windshields absorb nearly all of the sun’s UVA and UVB rays. Sunroofs also contain UV-protective technology, which blocks UVA and UVB radiation while also keeping the car cool and protecting against direct sun exposure. However, rear windows do not offer the same protection.
Side and rear windows are made of a cheaper tempered glass that does not include a plastic layer, thereby offering no UVA protection. In a study by Butler et al. reviewing 900 head and neck cancers, 53% were found on the left side, and those who spent more hours driving each week had a higher chance of getting a left-side skin cancer (J Am Acad Dermatol. 2010 Dec;63[6]:1006-10). Many automakers have not helped this problem; while there is higher-SPF glass that can be used, it is more costly for automobile manufacturers – and ultimately for consumers. A cheaper and more practical alternative is a UV film that can be applied to the glass; these films both improve UV protection and cool the car. In addition to providing sun protection, it can be assumed that the subsequent reduction of temperature within a car decreases the usage of air conditioners, thus improving both fuel economy and the environment.
Aftermarket window tinting and UV films can also be applied by glass-tinting companies and auto dealers for $150-$200. Companies like Solar Gard, LLUMAr, and 3M offer window films that can block UV rays. While these are available, the legal allowable tint limit varies from state to state. Visible light transmission (VLT) is the measurement of the percent of visible light that gets through a car’s window. The lower the VLT, the darker the tint. Most states prohibit less than 50% VLT for the driver and front passenger window, and 35% for the rear passenger, side, and rear windows.
To mitigate this, I offer patients with severe photo-dermitides a letter of medical necessity to the DMV to allow a higher percentage of tinting and recommend that they get aftermarket UV-protective films or tints on their vehicles. Regardless of whether higher tints are an option for them, sun protection of the skin and eyes is recommended for all passengers. Sunscreen with broad-spectrum coverage is recommended regardless of how long a car ride might be, and it is recommended that individuals keep the sunroof closed while driving for added UV protection. The use of polarized sunglasses for adults and children is also recommended to avoid UV damage to the eyes. Sunscreens and glasses with protection against blue light are also recommended for passengers who stare at screens and tablets during long car rides.
Dr. Talakoub and Dr. Wesley are cocontributors to this column. Dr. Talakoub is in private practice in McLean, Va. Dr. Wesley practices dermatology in Beverly Hills, Calif. This month’s column is by Dr. Talakoub. Write to them at [email protected]. They had no relevant disclosures.
Flying solo
Recently, a stiff-white-coat family medicine resident showed up eager for his first day in dermatology. Working with him reminded me how exciting the journey is from resident to attending. It also reminded me how slow residents are – we’re 10 minutes into a visit and not yet done injecting anesthesia. A simple biopsy and electrodesiccation of a basal cell carcinoma would take 3 minutes – easy, rote, like driving home and being surprised when you arrive. But this task is making my resident so fraught with fear he’s barely moving. He won’t be crawling for long; his journey from novice to confident physician will be quick. Like a student pilot learning to fly, in a few hundred hours he’ll be flying solo.
After a year, most residents are adept, exuding the temerity of an attending. But as any practicing physician knows, medicine can make cowards of us all without warning. An experienced pilot facing an unexpected gusty 25-knot crosswind landing can find himself or herself a trembling beginner just as an excellent clinician can be overwhelmed facing an unexpectedly sick patient.
Not long after my visiting resident, I was back to my own packed clinic. With one swoop of a dermablade, I intended to quickly extirpate a keratoacanthoma on the back of an elderly man’s hand. I hardly had to think about it. However, when I lifted the blade, dark blood pooled where a dorsal saphenous vein used to live. After much electrodesiccation (and sutures) this particular biopsy was safely landed. But it wasn’t without a bit of blood loss and inconvenience for the patient. What might I have done differently? Injected 5-fluorouracil instead? Done an incisional biopsy? Used a different blade? More importantly, what will I do next time?
To avoid adverse outcomes, it might seem like the best strategy is to avoid deteriorating conditions, whether flying or in clinic. That would be a mistake. The journey from apprehension to mastery must pass through discomfort. It is only by working through unease and successfully managing complications that expertise is forged. Our days are mostly routine and the longer the period without adversity, the greater the risk of complacency. Consider seeking difficulty once in awhile and learn how to work through it. No pilot wants to be in a situation he or she hasn’t practiced managing.
For some physicians and residents, an unexpected complication or adverse outcome can make them apprehensive and defensive. I’ve seen doctors choose not to treat complicated diseases or dire lesions because of a previous bad experience or adverse outcome. It is sometimes appropriate to transfer a patient to a different service, but as physicians, it’s also our job to take care of our patient. When it’s your plane, you’ll have to land it.
Much later (or so it seemed), my resident finally finished the electrodesiccation and curettage. He had a look of relief knowing he has landed safely. I hope he realizes that this is a trip that he must take over and over again. One is never done learning to fly.
Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on Twitter. Write to him at [email protected].
Recently, a stiff-white-coat family medicine resident showed up eager for his first day in dermatology. Working with him reminded me how exciting the journey is from resident to attending. It also reminded me how slow residents are – we’re 10 minutes into a visit and not yet done injecting anesthesia. A simple biopsy and electrodesiccation of a basal cell carcinoma would take 3 minutes – easy, rote, like driving home and being surprised when you arrive. But this task is making my resident so fraught with fear he’s barely moving. He won’t be crawling for long; his journey from novice to confident physician will be quick. Like a student pilot learning to fly, in a few hundred hours he’ll be flying solo.
After a year, most residents are adept, exuding the temerity of an attending. But as any practicing physician knows, medicine can make cowards of us all without warning. An experienced pilot facing an unexpected gusty 25-knot crosswind landing can find himself or herself a trembling beginner just as an excellent clinician can be overwhelmed facing an unexpectedly sick patient.
Not long after my visiting resident, I was back to my own packed clinic. With one swoop of a dermablade, I intended to quickly extirpate a keratoacanthoma on the back of an elderly man’s hand. I hardly had to think about it. However, when I lifted the blade, dark blood pooled where a dorsal saphenous vein used to live. After much electrodesiccation (and sutures) this particular biopsy was safely landed. But it wasn’t without a bit of blood loss and inconvenience for the patient. What might I have done differently? Injected 5-fluorouracil instead? Done an incisional biopsy? Used a different blade? More importantly, what will I do next time?
To avoid adverse outcomes, it might seem like the best strategy is to avoid deteriorating conditions, whether flying or in clinic. That would be a mistake. The journey from apprehension to mastery must pass through discomfort. It is only by working through unease and successfully managing complications that expertise is forged. Our days are mostly routine and the longer the period without adversity, the greater the risk of complacency. Consider seeking difficulty once in awhile and learn how to work through it. No pilot wants to be in a situation he or she hasn’t practiced managing.
For some physicians and residents, an unexpected complication or adverse outcome can make them apprehensive and defensive. I’ve seen doctors choose not to treat complicated diseases or dire lesions because of a previous bad experience or adverse outcome. It is sometimes appropriate to transfer a patient to a different service, but as physicians, it’s also our job to take care of our patient. When it’s your plane, you’ll have to land it.
Much later (or so it seemed), my resident finally finished the electrodesiccation and curettage. He had a look of relief knowing he has landed safely. I hope he realizes that this is a trip that he must take over and over again. One is never done learning to fly.
Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on Twitter. Write to him at [email protected].
Recently, a stiff-white-coat family medicine resident showed up eager for his first day in dermatology. Working with him reminded me how exciting the journey is from resident to attending. It also reminded me how slow residents are – we’re 10 minutes into a visit and not yet done injecting anesthesia. A simple biopsy and electrodesiccation of a basal cell carcinoma would take 3 minutes – easy, rote, like driving home and being surprised when you arrive. But this task is making my resident so fraught with fear he’s barely moving. He won’t be crawling for long; his journey from novice to confident physician will be quick. Like a student pilot learning to fly, in a few hundred hours he’ll be flying solo.
After a year, most residents are adept, exuding the temerity of an attending. But as any practicing physician knows, medicine can make cowards of us all without warning. An experienced pilot facing an unexpected gusty 25-knot crosswind landing can find himself or herself a trembling beginner just as an excellent clinician can be overwhelmed facing an unexpectedly sick patient.
Not long after my visiting resident, I was back to my own packed clinic. With one swoop of a dermablade, I intended to quickly extirpate a keratoacanthoma on the back of an elderly man’s hand. I hardly had to think about it. However, when I lifted the blade, dark blood pooled where a dorsal saphenous vein used to live. After much electrodesiccation (and sutures) this particular biopsy was safely landed. But it wasn’t without a bit of blood loss and inconvenience for the patient. What might I have done differently? Injected 5-fluorouracil instead? Done an incisional biopsy? Used a different blade? More importantly, what will I do next time?
To avoid adverse outcomes, it might seem like the best strategy is to avoid deteriorating conditions, whether flying or in clinic. That would be a mistake. The journey from apprehension to mastery must pass through discomfort. It is only by working through unease and successfully managing complications that expertise is forged. Our days are mostly routine and the longer the period without adversity, the greater the risk of complacency. Consider seeking difficulty once in awhile and learn how to work through it. No pilot wants to be in a situation he or she hasn’t practiced managing.
For some physicians and residents, an unexpected complication or adverse outcome can make them apprehensive and defensive. I’ve seen doctors choose not to treat complicated diseases or dire lesions because of a previous bad experience or adverse outcome. It is sometimes appropriate to transfer a patient to a different service, but as physicians, it’s also our job to take care of our patient. When it’s your plane, you’ll have to land it.
Much later (or so it seemed), my resident finally finished the electrodesiccation and curettage. He had a look of relief knowing he has landed safely. I hope he realizes that this is a trip that he must take over and over again. One is never done learning to fly.
Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on Twitter. Write to him at [email protected].
Immune Checkpoint Inhibitors for Urothelial Cancer: An Update on New Therapies (FULL)
An essential feature of cancer is its ability to evade the immune system. Multiple mechanisms are used for this purpose, including the disruption of antigen presentation and suppression of the immune response. The latter mechanism involves the activation of T-cell inhibition by recruiting regulatory T cells that weaken this response. Recent progress in understanding the ability of cancer to evade the immune system has paved the way to develop strategies to reverse this process and reactivate the immune system. Particularly, immune checkpoint signaling between T cells and tumor cells has been targeted with a new class of drug, immune checkpoint inhibitors. Immunotherapy has been an established and effective treatment in bladder cancer since 1976 when Morales and colleagues demonstrated that intravesical treatments with bacillus Calmette-Guérin can treat carcinoma in situ and prevent nonmuscle invasive urothelial cancer recurrence.1,2 This treatment elicits a cytotoxic response via antigenic presentation by bladder tumor cells.
Cytotoxic T-lymphocyte-associated protein (CTLA)-4, programmed death-1 (PD-1) and programmed death-ligand-1 (PD-L1) are molecules that downregulate the immune response and are targets of therapeutic antibodies that have demonstrated clinical efficacy across a wide range of malignancies. Five such agents—pembrolizumab, atezolizumab, nivolumab, avelumab and durvalumab—were recently approved by the US Food and Drug Administration (FDA) for clinical use in patients with advanced urothelial cancers.3 This class of agents also has been approved for several other malignancies, most notably in melanoma, non-small cell lung cancer, and renal cell carcinoma.3
Immune Biology
CTLA-4 is expressed on activated CD4 and CD8 T cells and competes with CD28 on T cells to interact with the costimulatory B7 proteins on antigen presenting cells. The CD28/B7 interaction promotes T-cell activation and effector functions, and the CTLA-4/B7 interaction inhibits them. In addition, PD-1 is a receptor expressed on CD4 and CD8 T cells, T regulatory (Treg) cells, B cells and natural killer (NK) cells that interacts with its ligand PD-L1 to suppress the immune response. Urothelial cancer possesses features that make it an adequate target for immunotherapeutic agents. Primarily, it is characterized by a high-mutation load, which lends itself to an increased expression of immunogenic antigens on tumor cells.4
Immunotherapy Treatments in Cisplatin-Ineligible Patients
Cisplatin-based chemotherapy is the first-line treatment and standard of care in unresectable or metastatic urothelial cancer. However, many patients are unable to receive cisplatin secondary to renal dysfunction, poor performance status, or other comorbidities. Alternative cytotoxic therapies in the first-line setting such as carboplatin-based regimens are associated with inferior outcomes and poor tolerability. There is, therefore, a need for effective and well-tolerated therapies in cisplatin-ineligible patients (Table).
In the phase 2 Keynote-052 trial, 370 cisplatin-ineligible patients were treated with the anti-PD-1 antibody pembrolizumab 200 mg every 3 weeks for up to 2 years.5At a median follow-up of 9.5 months, the objective response rate (+ORR) was 29% for the entire cohort, with a 7% complete response (CR) rate, and a 22% partial response (PR) rate.5 The median duration of response had not been reached at the time of analysis. Responses were seen regardless of PD-L1 expression, although high response rates were noted in patients whose tumors had PD-L1 expression > 10%. Pembrolizumab had an acceptable tolerability profile in this population. The most common grade 3 or 4 treatment-related adverse event (AE) was fatigue at 2%; 5% of patients discontinued therapy due to treatment related AEs, whereas 17% of patients had immune-mediated AEs.5
Similarly, in a single-arm phase 2 trial, atezolizumab, an anti-PD-L1 antibody, dosed at 1,200 mg every 3 weeks was used as first-line therapy in 119 patients with advanced urothelial cancer who were cisplatin ineligible. At a median follow-up of 17 months, the ORR was 23%, with a 9% CR rate. The median duration of response had not been reached. Median progression free survival (PFS) was 2.7 months, whereas overall survival (OS) was 16 months. Eight percent of patients had an AE leading to treatment discontinuation, and 17% had immune-mediated AEs.6 Both pembrolizumab and atezolizumab were granted FDA approval in 2017 for patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-based chemotherapy.3
Immunotherapy Treatments After Progression With Cisplatin
Cytotoxic chemotherapy in the second-line setting with disease progression following platinum-based treatment has shown dismal responses, with a median OS of about 6 to 7 months.7 Immunotherapy provides an effective and a much-needed option in this scenario.
Five antibodies targeting the PD-1/PD-L1 pathway, pembrolizumab, nivolumab, atezolizumab, avelumab and durvalumab, have been granted FDA approval for patients who have progressed during or after platinum-based therapy (Table).3 In the phase 3 Keynote-045 trial, 542 patients were randomly assigned to receive either pembrolizumab 200 mg administered every 3 weeks or investigator’s choice chemotherapy (paclitaxel, docetaxel, or vinflunine).7 Median OS was 10.3 months in the pembrolizumab group and 7.4 months in the chemotherapy group (hazard ratio for death, 0.73; P = .002). Serious (grade 3 or above) treatment-related AEs were significantly less frequent with pembrolizumab (15% vs 49.4%).7 In a phase 2 trial, 270 patients were treated with nivolumab, a PD-1 inhibitor, at a dose of 3 mg/kg given every 2 weeks.8 The ORR was 19.6%, while the median OS for the entire cohort was 7 months. Responses were seen at all levels of PD-L1 expression, although in patients whose tumor expressed PD-L1 ≥1%, median OS was 11.3 months.8
It should be noted that in a large phase 3 trial comparing atezolizumab with chemotherapy in the second-line setting, ORR and OS were not statistically different between the 2 groups, although the duration of response was longer with atezolizumab.9 In early phase trials, avelumab and durvalumab, both PD-L1 inhibitors showed an ORR of about 17%, with higher ORR seen in patients with tumors positive for PD-L1 expression.10,11 The AE profile of immune checkpoint inhibitors is relatively favorable in clinical trials. The American Society of Clinical Oncology and National Comprehensive Cancer Network have jointly published evidence-based guidelines for the management of their immune related AEs.12
Future Directions
Several challenges have emerged with immunotherapy treatments. One issue is the relatively low ORRs for immune checkpoint inhibitors, ranging from 13.4% to 24% depending on the trial. Therefore, there is a need to identify reliable biomarkers and selection criteria to predict their efficacy and improve patient selection. Although tumor PD-L1 expression has shown some usefulness in this setting, responses have been noted in patients whose tumors have low or no expression of PD-L1. This low predictive accuracy is caused by several factors, including PD-L1 intratumor expression heterogeneity, primary vs metastatic site PD-L1 expression heterogeneity, lack of consensus on which PD-L1 assays and which value cutoffs to use, and the differences seen in marker expression depending on the freshness of the tissue specimen.
Other predictive biomarkers with potential include tumor gene expression profiles/tumor mutational load, T-cell and B-cell signatures. The optimal imaging modality and timing of this imaging for response assessment also is uncertain. So-called tumor pseudo-progression seen on imaging after treatment with these agents as a result of the immune/inflammatory response to the tumor is now a well-recognized phenomenon, but it can be challenging to differentiate from true disease progression. Other challenges include deciding on which immune checkpoint inhibitor to use given a lack of head-to-head comparisons of these immunotherapeutic agents, finding the proper drug doses to maximize efficacy, as well as determining the optimal duration of treatment in patients with continued response to immunotherapy. Many oncologists continue these treatments for up to 2 years in the setting of a significant or complete response.
Conclusion
Immune checkpoint inhibitors have emerged as pivotal treatments for patients with advanced urothelial cancer who are unfit to receive cisplatin in the first-line setting or who experience disease progression after cisplatin-based chemotherapy. This field continues to expand at a rapid pace due to multiple ongoing clinical trials assessing these agents, whether alone, in combination with cytotoxic, targeted, radiation therapies, or with other immune checkpoint inhibitors, both in the advanced as well as the neoadjuvant/adjuvant settings.
1. Morales A, Eidinger D, Bruce AW. Intracavitary bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J Urol. 1976;116(2):180-183.
2. Morales A. Treatment of carcinoma in situ of the bladder with BCG. Cancer Immunol Immunother. 1980;9 (1-2):69-72.
3. US Food and drug administration. FDA approved drug products. www.accessdata.fda.gov/scripts/cder/daf/index.cfm. Accessed July 5, 2018.
4. Farina MS, Lundgren KT, Bellmunt J. Immunotherapy in urothelial cancer: recent results and future perspectives. Drugs. 2017;77(10):1077-1089.
5. Balar AV, Castellano DE, O’Donnell PH, et al. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol. 2017;18(11):1483-1492.
6. Balar AV, Galsky MD, Rosenberg JE, et al; IMvigor210 Study Group. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet. 2017;389(10064):67-76.
7. Bellmunt J, de Wit R, Vaughn DJ, et al; KEYNOTE-045 Investigators. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017;376(11):1015-1026.
8. Sharma P, Retz M, Siefker-Radtke A, et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2017;18(3):312-322.
9. Powles T, Durán I, van der Heijden MS, et al. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2018;391(10122):748-757.
10. Patel MR, Ellerton J, Infante JR, et al. Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial. Lancet Oncol. 2018;19(1):51-64.
11. Powles T, O’Donnell PH, Massard C, et al. Efficacy and safety of durvalumab in locally advanced or metastatic urothelial carcinoma: updated results from a phase 1/2 open-label study. JAMA Oncol. 2017;3(9):e172411.
12. Brahmer JR, Lacchetti C, Schneider BJ, et al; National Comprehensive Cancer Network. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2018;36(17):1714-1768.
An essential feature of cancer is its ability to evade the immune system. Multiple mechanisms are used for this purpose, including the disruption of antigen presentation and suppression of the immune response. The latter mechanism involves the activation of T-cell inhibition by recruiting regulatory T cells that weaken this response. Recent progress in understanding the ability of cancer to evade the immune system has paved the way to develop strategies to reverse this process and reactivate the immune system. Particularly, immune checkpoint signaling between T cells and tumor cells has been targeted with a new class of drug, immune checkpoint inhibitors. Immunotherapy has been an established and effective treatment in bladder cancer since 1976 when Morales and colleagues demonstrated that intravesical treatments with bacillus Calmette-Guérin can treat carcinoma in situ and prevent nonmuscle invasive urothelial cancer recurrence.1,2 This treatment elicits a cytotoxic response via antigenic presentation by bladder tumor cells.
Cytotoxic T-lymphocyte-associated protein (CTLA)-4, programmed death-1 (PD-1) and programmed death-ligand-1 (PD-L1) are molecules that downregulate the immune response and are targets of therapeutic antibodies that have demonstrated clinical efficacy across a wide range of malignancies. Five such agents—pembrolizumab, atezolizumab, nivolumab, avelumab and durvalumab—were recently approved by the US Food and Drug Administration (FDA) for clinical use in patients with advanced urothelial cancers.3 This class of agents also has been approved for several other malignancies, most notably in melanoma, non-small cell lung cancer, and renal cell carcinoma.3
Immune Biology
CTLA-4 is expressed on activated CD4 and CD8 T cells and competes with CD28 on T cells to interact with the costimulatory B7 proteins on antigen presenting cells. The CD28/B7 interaction promotes T-cell activation and effector functions, and the CTLA-4/B7 interaction inhibits them. In addition, PD-1 is a receptor expressed on CD4 and CD8 T cells, T regulatory (Treg) cells, B cells and natural killer (NK) cells that interacts with its ligand PD-L1 to suppress the immune response. Urothelial cancer possesses features that make it an adequate target for immunotherapeutic agents. Primarily, it is characterized by a high-mutation load, which lends itself to an increased expression of immunogenic antigens on tumor cells.4
Immunotherapy Treatments in Cisplatin-Ineligible Patients
Cisplatin-based chemotherapy is the first-line treatment and standard of care in unresectable or metastatic urothelial cancer. However, many patients are unable to receive cisplatin secondary to renal dysfunction, poor performance status, or other comorbidities. Alternative cytotoxic therapies in the first-line setting such as carboplatin-based regimens are associated with inferior outcomes and poor tolerability. There is, therefore, a need for effective and well-tolerated therapies in cisplatin-ineligible patients (Table).
In the phase 2 Keynote-052 trial, 370 cisplatin-ineligible patients were treated with the anti-PD-1 antibody pembrolizumab 200 mg every 3 weeks for up to 2 years.5At a median follow-up of 9.5 months, the objective response rate (+ORR) was 29% for the entire cohort, with a 7% complete response (CR) rate, and a 22% partial response (PR) rate.5 The median duration of response had not been reached at the time of analysis. Responses were seen regardless of PD-L1 expression, although high response rates were noted in patients whose tumors had PD-L1 expression > 10%. Pembrolizumab had an acceptable tolerability profile in this population. The most common grade 3 or 4 treatment-related adverse event (AE) was fatigue at 2%; 5% of patients discontinued therapy due to treatment related AEs, whereas 17% of patients had immune-mediated AEs.5
Similarly, in a single-arm phase 2 trial, atezolizumab, an anti-PD-L1 antibody, dosed at 1,200 mg every 3 weeks was used as first-line therapy in 119 patients with advanced urothelial cancer who were cisplatin ineligible. At a median follow-up of 17 months, the ORR was 23%, with a 9% CR rate. The median duration of response had not been reached. Median progression free survival (PFS) was 2.7 months, whereas overall survival (OS) was 16 months. Eight percent of patients had an AE leading to treatment discontinuation, and 17% had immune-mediated AEs.6 Both pembrolizumab and atezolizumab were granted FDA approval in 2017 for patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-based chemotherapy.3
Immunotherapy Treatments After Progression With Cisplatin
Cytotoxic chemotherapy in the second-line setting with disease progression following platinum-based treatment has shown dismal responses, with a median OS of about 6 to 7 months.7 Immunotherapy provides an effective and a much-needed option in this scenario.
Five antibodies targeting the PD-1/PD-L1 pathway, pembrolizumab, nivolumab, atezolizumab, avelumab and durvalumab, have been granted FDA approval for patients who have progressed during or after platinum-based therapy (Table).3 In the phase 3 Keynote-045 trial, 542 patients were randomly assigned to receive either pembrolizumab 200 mg administered every 3 weeks or investigator’s choice chemotherapy (paclitaxel, docetaxel, or vinflunine).7 Median OS was 10.3 months in the pembrolizumab group and 7.4 months in the chemotherapy group (hazard ratio for death, 0.73; P = .002). Serious (grade 3 or above) treatment-related AEs were significantly less frequent with pembrolizumab (15% vs 49.4%).7 In a phase 2 trial, 270 patients were treated with nivolumab, a PD-1 inhibitor, at a dose of 3 mg/kg given every 2 weeks.8 The ORR was 19.6%, while the median OS for the entire cohort was 7 months. Responses were seen at all levels of PD-L1 expression, although in patients whose tumor expressed PD-L1 ≥1%, median OS was 11.3 months.8
It should be noted that in a large phase 3 trial comparing atezolizumab with chemotherapy in the second-line setting, ORR and OS were not statistically different between the 2 groups, although the duration of response was longer with atezolizumab.9 In early phase trials, avelumab and durvalumab, both PD-L1 inhibitors showed an ORR of about 17%, with higher ORR seen in patients with tumors positive for PD-L1 expression.10,11 The AE profile of immune checkpoint inhibitors is relatively favorable in clinical trials. The American Society of Clinical Oncology and National Comprehensive Cancer Network have jointly published evidence-based guidelines for the management of their immune related AEs.12
Future Directions
Several challenges have emerged with immunotherapy treatments. One issue is the relatively low ORRs for immune checkpoint inhibitors, ranging from 13.4% to 24% depending on the trial. Therefore, there is a need to identify reliable biomarkers and selection criteria to predict their efficacy and improve patient selection. Although tumor PD-L1 expression has shown some usefulness in this setting, responses have been noted in patients whose tumors have low or no expression of PD-L1. This low predictive accuracy is caused by several factors, including PD-L1 intratumor expression heterogeneity, primary vs metastatic site PD-L1 expression heterogeneity, lack of consensus on which PD-L1 assays and which value cutoffs to use, and the differences seen in marker expression depending on the freshness of the tissue specimen.
Other predictive biomarkers with potential include tumor gene expression profiles/tumor mutational load, T-cell and B-cell signatures. The optimal imaging modality and timing of this imaging for response assessment also is uncertain. So-called tumor pseudo-progression seen on imaging after treatment with these agents as a result of the immune/inflammatory response to the tumor is now a well-recognized phenomenon, but it can be challenging to differentiate from true disease progression. Other challenges include deciding on which immune checkpoint inhibitor to use given a lack of head-to-head comparisons of these immunotherapeutic agents, finding the proper drug doses to maximize efficacy, as well as determining the optimal duration of treatment in patients with continued response to immunotherapy. Many oncologists continue these treatments for up to 2 years in the setting of a significant or complete response.
Conclusion
Immune checkpoint inhibitors have emerged as pivotal treatments for patients with advanced urothelial cancer who are unfit to receive cisplatin in the first-line setting or who experience disease progression after cisplatin-based chemotherapy. This field continues to expand at a rapid pace due to multiple ongoing clinical trials assessing these agents, whether alone, in combination with cytotoxic, targeted, radiation therapies, or with other immune checkpoint inhibitors, both in the advanced as well as the neoadjuvant/adjuvant settings.
An essential feature of cancer is its ability to evade the immune system. Multiple mechanisms are used for this purpose, including the disruption of antigen presentation and suppression of the immune response. The latter mechanism involves the activation of T-cell inhibition by recruiting regulatory T cells that weaken this response. Recent progress in understanding the ability of cancer to evade the immune system has paved the way to develop strategies to reverse this process and reactivate the immune system. Particularly, immune checkpoint signaling between T cells and tumor cells has been targeted with a new class of drug, immune checkpoint inhibitors. Immunotherapy has been an established and effective treatment in bladder cancer since 1976 when Morales and colleagues demonstrated that intravesical treatments with bacillus Calmette-Guérin can treat carcinoma in situ and prevent nonmuscle invasive urothelial cancer recurrence.1,2 This treatment elicits a cytotoxic response via antigenic presentation by bladder tumor cells.
Cytotoxic T-lymphocyte-associated protein (CTLA)-4, programmed death-1 (PD-1) and programmed death-ligand-1 (PD-L1) are molecules that downregulate the immune response and are targets of therapeutic antibodies that have demonstrated clinical efficacy across a wide range of malignancies. Five such agents—pembrolizumab, atezolizumab, nivolumab, avelumab and durvalumab—were recently approved by the US Food and Drug Administration (FDA) for clinical use in patients with advanced urothelial cancers.3 This class of agents also has been approved for several other malignancies, most notably in melanoma, non-small cell lung cancer, and renal cell carcinoma.3
Immune Biology
CTLA-4 is expressed on activated CD4 and CD8 T cells and competes with CD28 on T cells to interact with the costimulatory B7 proteins on antigen presenting cells. The CD28/B7 interaction promotes T-cell activation and effector functions, and the CTLA-4/B7 interaction inhibits them. In addition, PD-1 is a receptor expressed on CD4 and CD8 T cells, T regulatory (Treg) cells, B cells and natural killer (NK) cells that interacts with its ligand PD-L1 to suppress the immune response. Urothelial cancer possesses features that make it an adequate target for immunotherapeutic agents. Primarily, it is characterized by a high-mutation load, which lends itself to an increased expression of immunogenic antigens on tumor cells.4
Immunotherapy Treatments in Cisplatin-Ineligible Patients
Cisplatin-based chemotherapy is the first-line treatment and standard of care in unresectable or metastatic urothelial cancer. However, many patients are unable to receive cisplatin secondary to renal dysfunction, poor performance status, or other comorbidities. Alternative cytotoxic therapies in the first-line setting such as carboplatin-based regimens are associated with inferior outcomes and poor tolerability. There is, therefore, a need for effective and well-tolerated therapies in cisplatin-ineligible patients (Table).
In the phase 2 Keynote-052 trial, 370 cisplatin-ineligible patients were treated with the anti-PD-1 antibody pembrolizumab 200 mg every 3 weeks for up to 2 years.5At a median follow-up of 9.5 months, the objective response rate (+ORR) was 29% for the entire cohort, with a 7% complete response (CR) rate, and a 22% partial response (PR) rate.5 The median duration of response had not been reached at the time of analysis. Responses were seen regardless of PD-L1 expression, although high response rates were noted in patients whose tumors had PD-L1 expression > 10%. Pembrolizumab had an acceptable tolerability profile in this population. The most common grade 3 or 4 treatment-related adverse event (AE) was fatigue at 2%; 5% of patients discontinued therapy due to treatment related AEs, whereas 17% of patients had immune-mediated AEs.5
Similarly, in a single-arm phase 2 trial, atezolizumab, an anti-PD-L1 antibody, dosed at 1,200 mg every 3 weeks was used as first-line therapy in 119 patients with advanced urothelial cancer who were cisplatin ineligible. At a median follow-up of 17 months, the ORR was 23%, with a 9% CR rate. The median duration of response had not been reached. Median progression free survival (PFS) was 2.7 months, whereas overall survival (OS) was 16 months. Eight percent of patients had an AE leading to treatment discontinuation, and 17% had immune-mediated AEs.6 Both pembrolizumab and atezolizumab were granted FDA approval in 2017 for patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-based chemotherapy.3
Immunotherapy Treatments After Progression With Cisplatin
Cytotoxic chemotherapy in the second-line setting with disease progression following platinum-based treatment has shown dismal responses, with a median OS of about 6 to 7 months.7 Immunotherapy provides an effective and a much-needed option in this scenario.
Five antibodies targeting the PD-1/PD-L1 pathway, pembrolizumab, nivolumab, atezolizumab, avelumab and durvalumab, have been granted FDA approval for patients who have progressed during or after platinum-based therapy (Table).3 In the phase 3 Keynote-045 trial, 542 patients were randomly assigned to receive either pembrolizumab 200 mg administered every 3 weeks or investigator’s choice chemotherapy (paclitaxel, docetaxel, or vinflunine).7 Median OS was 10.3 months in the pembrolizumab group and 7.4 months in the chemotherapy group (hazard ratio for death, 0.73; P = .002). Serious (grade 3 or above) treatment-related AEs were significantly less frequent with pembrolizumab (15% vs 49.4%).7 In a phase 2 trial, 270 patients were treated with nivolumab, a PD-1 inhibitor, at a dose of 3 mg/kg given every 2 weeks.8 The ORR was 19.6%, while the median OS for the entire cohort was 7 months. Responses were seen at all levels of PD-L1 expression, although in patients whose tumor expressed PD-L1 ≥1%, median OS was 11.3 months.8
It should be noted that in a large phase 3 trial comparing atezolizumab with chemotherapy in the second-line setting, ORR and OS were not statistically different between the 2 groups, although the duration of response was longer with atezolizumab.9 In early phase trials, avelumab and durvalumab, both PD-L1 inhibitors showed an ORR of about 17%, with higher ORR seen in patients with tumors positive for PD-L1 expression.10,11 The AE profile of immune checkpoint inhibitors is relatively favorable in clinical trials. The American Society of Clinical Oncology and National Comprehensive Cancer Network have jointly published evidence-based guidelines for the management of their immune related AEs.12
Future Directions
Several challenges have emerged with immunotherapy treatments. One issue is the relatively low ORRs for immune checkpoint inhibitors, ranging from 13.4% to 24% depending on the trial. Therefore, there is a need to identify reliable biomarkers and selection criteria to predict their efficacy and improve patient selection. Although tumor PD-L1 expression has shown some usefulness in this setting, responses have been noted in patients whose tumors have low or no expression of PD-L1. This low predictive accuracy is caused by several factors, including PD-L1 intratumor expression heterogeneity, primary vs metastatic site PD-L1 expression heterogeneity, lack of consensus on which PD-L1 assays and which value cutoffs to use, and the differences seen in marker expression depending on the freshness of the tissue specimen.
Other predictive biomarkers with potential include tumor gene expression profiles/tumor mutational load, T-cell and B-cell signatures. The optimal imaging modality and timing of this imaging for response assessment also is uncertain. So-called tumor pseudo-progression seen on imaging after treatment with these agents as a result of the immune/inflammatory response to the tumor is now a well-recognized phenomenon, but it can be challenging to differentiate from true disease progression. Other challenges include deciding on which immune checkpoint inhibitor to use given a lack of head-to-head comparisons of these immunotherapeutic agents, finding the proper drug doses to maximize efficacy, as well as determining the optimal duration of treatment in patients with continued response to immunotherapy. Many oncologists continue these treatments for up to 2 years in the setting of a significant or complete response.
Conclusion
Immune checkpoint inhibitors have emerged as pivotal treatments for patients with advanced urothelial cancer who are unfit to receive cisplatin in the first-line setting or who experience disease progression after cisplatin-based chemotherapy. This field continues to expand at a rapid pace due to multiple ongoing clinical trials assessing these agents, whether alone, in combination with cytotoxic, targeted, radiation therapies, or with other immune checkpoint inhibitors, both in the advanced as well as the neoadjuvant/adjuvant settings.
1. Morales A, Eidinger D, Bruce AW. Intracavitary bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J Urol. 1976;116(2):180-183.
2. Morales A. Treatment of carcinoma in situ of the bladder with BCG. Cancer Immunol Immunother. 1980;9 (1-2):69-72.
3. US Food and drug administration. FDA approved drug products. www.accessdata.fda.gov/scripts/cder/daf/index.cfm. Accessed July 5, 2018.
4. Farina MS, Lundgren KT, Bellmunt J. Immunotherapy in urothelial cancer: recent results and future perspectives. Drugs. 2017;77(10):1077-1089.
5. Balar AV, Castellano DE, O’Donnell PH, et al. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol. 2017;18(11):1483-1492.
6. Balar AV, Galsky MD, Rosenberg JE, et al; IMvigor210 Study Group. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet. 2017;389(10064):67-76.
7. Bellmunt J, de Wit R, Vaughn DJ, et al; KEYNOTE-045 Investigators. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017;376(11):1015-1026.
8. Sharma P, Retz M, Siefker-Radtke A, et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2017;18(3):312-322.
9. Powles T, Durán I, van der Heijden MS, et al. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2018;391(10122):748-757.
10. Patel MR, Ellerton J, Infante JR, et al. Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial. Lancet Oncol. 2018;19(1):51-64.
11. Powles T, O’Donnell PH, Massard C, et al. Efficacy and safety of durvalumab in locally advanced or metastatic urothelial carcinoma: updated results from a phase 1/2 open-label study. JAMA Oncol. 2017;3(9):e172411.
12. Brahmer JR, Lacchetti C, Schneider BJ, et al; National Comprehensive Cancer Network. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2018;36(17):1714-1768.
1. Morales A, Eidinger D, Bruce AW. Intracavitary bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J Urol. 1976;116(2):180-183.
2. Morales A. Treatment of carcinoma in situ of the bladder with BCG. Cancer Immunol Immunother. 1980;9 (1-2):69-72.
3. US Food and drug administration. FDA approved drug products. www.accessdata.fda.gov/scripts/cder/daf/index.cfm. Accessed July 5, 2018.
4. Farina MS, Lundgren KT, Bellmunt J. Immunotherapy in urothelial cancer: recent results and future perspectives. Drugs. 2017;77(10):1077-1089.
5. Balar AV, Castellano DE, O’Donnell PH, et al. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol. 2017;18(11):1483-1492.
6. Balar AV, Galsky MD, Rosenberg JE, et al; IMvigor210 Study Group. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet. 2017;389(10064):67-76.
7. Bellmunt J, de Wit R, Vaughn DJ, et al; KEYNOTE-045 Investigators. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017;376(11):1015-1026.
8. Sharma P, Retz M, Siefker-Radtke A, et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2017;18(3):312-322.
9. Powles T, Durán I, van der Heijden MS, et al. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2018;391(10122):748-757.
10. Patel MR, Ellerton J, Infante JR, et al. Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial. Lancet Oncol. 2018;19(1):51-64.
11. Powles T, O’Donnell PH, Massard C, et al. Efficacy and safety of durvalumab in locally advanced or metastatic urothelial carcinoma: updated results from a phase 1/2 open-label study. JAMA Oncol. 2017;3(9):e172411.
12. Brahmer JR, Lacchetti C, Schneider BJ, et al; National Comprehensive Cancer Network. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2018;36(17):1714-1768.
Short-term parenteral antibiotics effective for bacteremic UTI in young infants
according to a study.
While previous studies have shown short-term parenteral antibiotic therapy to be safe and equally effective in uncomplicated urinary tract infections (UTIs), short-term therapy safety in bacteremic UTI had not been established, Sanyukta Desai, MD, of the University of Cincinnati and Cincinnati Children’s Hospital and associates wrote in Pediatrics.
“As a result, infants with bacteremic UTI often receive prolonged courses of parenteral antibiotics, which can lead to long hospitalizations and increased costs,” they said.
In a multicenter, retrospective cohort study, Dr. Desai and associates analyzed a group of 115 infants aged 60 days or younger who were admitted to a group of 11 participating EDs between July 1, 2011, and June 30, 2016, if they had a UTI caused by a bacterial pathogen. Half of the infants were administered parenteral antibiotics for 7 days or less before being switched to oral antibiotics, and the rest were given parenteral antibiotics for more than 7 days before switching to oral. Infants were more likely to receive long-term parenteral treatment if they were ill appearing and had growth of a non–Escherichia coli organism.
Six infants (two in the short-term group, four in the long-term group) had a recurrent UTI, each one diagnosed between 15 and 30 days after discharge; the adjusted risk difference between the two groups was 3% (95% confidence interval, –5.8 to 12.7). Two of the infants in the long-term group with a recurrent UTI had a different organism than during the index infection. When comparing only the infants with growth of the same pathogen that caused the index UTI, the adjusted risk difference between the two groups was 0.2% (95% CI, –7.8 to 8.3).
A total of 15 infants (6 in the short-term group, 9 in the long-term group) had 30-day all-cause reutilization, with no significant difference between groups (adjusted risk difference, 3%; 95% CI, –14.6 to 20.4).
Mean length of stay was significantly longer in the long-term treatment group, compared with the short-term group (11 days vs. 5 days; adjusted mean difference, 6 days; 95% CI, 4.0-8.8).
No infants experienced a serious adverse event such as ICU readmission, need for mechanical ventilation or vasopressor use, or signs of neurologic sequelae within 30 days of discharge from the index hospitalization, the investigators noted. Peripherally inserted central catheters were required in 13 infants; of these, 1 infant had to revisit an ED because of a related mechanical complication.
“Researchers in future prospective studies should seek to establish the bioavailability and optimal dosing of oral antibiotics in young infants and assess if there are particular subpopulations of infants with bacteremic UTI who may benefit from longer courses of parenteral antibiotic therapy,” Dr. Desai and associates concluded.
In a related editorial, Natalia V. Leva, MD, and Hillary L. Copp, MD, of the University of California, San Francisco, noted that the study represents a “critical piece of a complicated puzzle that not only includes minimum duration of parenteral antibiotic treatment but also involves bioavailability of antimicrobial agents in infants and total treatment duration, which includes parenteral and oral antibiotic therapy.”
The question that remains is how long a duration of parenteral antibiotic is necessary, Dr. Leva and Dr. Copp wrote. “Desai et al. used a relatively arbitrary cutoff of 7 days on the basis of the distribution of antibiotic course among their patient population; however, this is likely more a reflection of clinical practice than it is evidence based.” They concluded that this study provided evidence that a “short course of parenteral antibiotics in infants [aged 60 days or younger] with bacteremic UTI is safe and effective. Although the current study does not address total duration of antibiotics [parenteral and oral], it does shine a light on where we should focus future research endeavors.”
The study authors reported that they had no conflicts of interest. The study was supported in part by a National Center for Advancing Translational Sciences grant and an Agency for Healthcare Research and Quality grant. The editorialists had no relevant conflicts of interest and received no external funding.
SOURCEs: Desai S et al. Pediatrics. 2019 Aug 20. doi: 10.1542/peds.2018-3844; Leva et al. 2019 Aug 20. doi: 10.1542/peds.2019-1611.
according to a study.
While previous studies have shown short-term parenteral antibiotic therapy to be safe and equally effective in uncomplicated urinary tract infections (UTIs), short-term therapy safety in bacteremic UTI had not been established, Sanyukta Desai, MD, of the University of Cincinnati and Cincinnati Children’s Hospital and associates wrote in Pediatrics.
“As a result, infants with bacteremic UTI often receive prolonged courses of parenteral antibiotics, which can lead to long hospitalizations and increased costs,” they said.
In a multicenter, retrospective cohort study, Dr. Desai and associates analyzed a group of 115 infants aged 60 days or younger who were admitted to a group of 11 participating EDs between July 1, 2011, and June 30, 2016, if they had a UTI caused by a bacterial pathogen. Half of the infants were administered parenteral antibiotics for 7 days or less before being switched to oral antibiotics, and the rest were given parenteral antibiotics for more than 7 days before switching to oral. Infants were more likely to receive long-term parenteral treatment if they were ill appearing and had growth of a non–Escherichia coli organism.
Six infants (two in the short-term group, four in the long-term group) had a recurrent UTI, each one diagnosed between 15 and 30 days after discharge; the adjusted risk difference between the two groups was 3% (95% confidence interval, –5.8 to 12.7). Two of the infants in the long-term group with a recurrent UTI had a different organism than during the index infection. When comparing only the infants with growth of the same pathogen that caused the index UTI, the adjusted risk difference between the two groups was 0.2% (95% CI, –7.8 to 8.3).
A total of 15 infants (6 in the short-term group, 9 in the long-term group) had 30-day all-cause reutilization, with no significant difference between groups (adjusted risk difference, 3%; 95% CI, –14.6 to 20.4).
Mean length of stay was significantly longer in the long-term treatment group, compared with the short-term group (11 days vs. 5 days; adjusted mean difference, 6 days; 95% CI, 4.0-8.8).
No infants experienced a serious adverse event such as ICU readmission, need for mechanical ventilation or vasopressor use, or signs of neurologic sequelae within 30 days of discharge from the index hospitalization, the investigators noted. Peripherally inserted central catheters were required in 13 infants; of these, 1 infant had to revisit an ED because of a related mechanical complication.
“Researchers in future prospective studies should seek to establish the bioavailability and optimal dosing of oral antibiotics in young infants and assess if there are particular subpopulations of infants with bacteremic UTI who may benefit from longer courses of parenteral antibiotic therapy,” Dr. Desai and associates concluded.
In a related editorial, Natalia V. Leva, MD, and Hillary L. Copp, MD, of the University of California, San Francisco, noted that the study represents a “critical piece of a complicated puzzle that not only includes minimum duration of parenteral antibiotic treatment but also involves bioavailability of antimicrobial agents in infants and total treatment duration, which includes parenteral and oral antibiotic therapy.”
The question that remains is how long a duration of parenteral antibiotic is necessary, Dr. Leva and Dr. Copp wrote. “Desai et al. used a relatively arbitrary cutoff of 7 days on the basis of the distribution of antibiotic course among their patient population; however, this is likely more a reflection of clinical practice than it is evidence based.” They concluded that this study provided evidence that a “short course of parenteral antibiotics in infants [aged 60 days or younger] with bacteremic UTI is safe and effective. Although the current study does not address total duration of antibiotics [parenteral and oral], it does shine a light on where we should focus future research endeavors.”
The study authors reported that they had no conflicts of interest. The study was supported in part by a National Center for Advancing Translational Sciences grant and an Agency for Healthcare Research and Quality grant. The editorialists had no relevant conflicts of interest and received no external funding.
SOURCEs: Desai S et al. Pediatrics. 2019 Aug 20. doi: 10.1542/peds.2018-3844; Leva et al. 2019 Aug 20. doi: 10.1542/peds.2019-1611.
according to a study.
While previous studies have shown short-term parenteral antibiotic therapy to be safe and equally effective in uncomplicated urinary tract infections (UTIs), short-term therapy safety in bacteremic UTI had not been established, Sanyukta Desai, MD, of the University of Cincinnati and Cincinnati Children’s Hospital and associates wrote in Pediatrics.
“As a result, infants with bacteremic UTI often receive prolonged courses of parenteral antibiotics, which can lead to long hospitalizations and increased costs,” they said.
In a multicenter, retrospective cohort study, Dr. Desai and associates analyzed a group of 115 infants aged 60 days or younger who were admitted to a group of 11 participating EDs between July 1, 2011, and June 30, 2016, if they had a UTI caused by a bacterial pathogen. Half of the infants were administered parenteral antibiotics for 7 days or less before being switched to oral antibiotics, and the rest were given parenteral antibiotics for more than 7 days before switching to oral. Infants were more likely to receive long-term parenteral treatment if they were ill appearing and had growth of a non–Escherichia coli organism.
Six infants (two in the short-term group, four in the long-term group) had a recurrent UTI, each one diagnosed between 15 and 30 days after discharge; the adjusted risk difference between the two groups was 3% (95% confidence interval, –5.8 to 12.7). Two of the infants in the long-term group with a recurrent UTI had a different organism than during the index infection. When comparing only the infants with growth of the same pathogen that caused the index UTI, the adjusted risk difference between the two groups was 0.2% (95% CI, –7.8 to 8.3).
A total of 15 infants (6 in the short-term group, 9 in the long-term group) had 30-day all-cause reutilization, with no significant difference between groups (adjusted risk difference, 3%; 95% CI, –14.6 to 20.4).
Mean length of stay was significantly longer in the long-term treatment group, compared with the short-term group (11 days vs. 5 days; adjusted mean difference, 6 days; 95% CI, 4.0-8.8).
No infants experienced a serious adverse event such as ICU readmission, need for mechanical ventilation or vasopressor use, or signs of neurologic sequelae within 30 days of discharge from the index hospitalization, the investigators noted. Peripherally inserted central catheters were required in 13 infants; of these, 1 infant had to revisit an ED because of a related mechanical complication.
“Researchers in future prospective studies should seek to establish the bioavailability and optimal dosing of oral antibiotics in young infants and assess if there are particular subpopulations of infants with bacteremic UTI who may benefit from longer courses of parenteral antibiotic therapy,” Dr. Desai and associates concluded.
In a related editorial, Natalia V. Leva, MD, and Hillary L. Copp, MD, of the University of California, San Francisco, noted that the study represents a “critical piece of a complicated puzzle that not only includes minimum duration of parenteral antibiotic treatment but also involves bioavailability of antimicrobial agents in infants and total treatment duration, which includes parenteral and oral antibiotic therapy.”
The question that remains is how long a duration of parenteral antibiotic is necessary, Dr. Leva and Dr. Copp wrote. “Desai et al. used a relatively arbitrary cutoff of 7 days on the basis of the distribution of antibiotic course among their patient population; however, this is likely more a reflection of clinical practice than it is evidence based.” They concluded that this study provided evidence that a “short course of parenteral antibiotics in infants [aged 60 days or younger] with bacteremic UTI is safe and effective. Although the current study does not address total duration of antibiotics [parenteral and oral], it does shine a light on where we should focus future research endeavors.”
The study authors reported that they had no conflicts of interest. The study was supported in part by a National Center for Advancing Translational Sciences grant and an Agency for Healthcare Research and Quality grant. The editorialists had no relevant conflicts of interest and received no external funding.
SOURCEs: Desai S et al. Pediatrics. 2019 Aug 20. doi: 10.1542/peds.2018-3844; Leva et al. 2019 Aug 20. doi: 10.1542/peds.2019-1611.
FROM PEDIATRICS
Key clinical point: Urinary tract infection (UTI) recurrence and hospital reutilization was similar in infants with bacteremic UTIs, regardless of parenteral antibiotic treatment duration of 7 days or less or greater than 7 days prior to oral antibiotics.
Major finding: The adjusted risk difference for both infection recurrence and hospital reutilization was 3% and was nonsignificant in both cases.
Study details: A group of 115 infants aged 60 days or younger who were admitted to an ED with a bacteremic UTI.
Disclosures: The study authors reported that they had no conflicts of interest. The funding of the study was supported in part by a National Center for Advancing Translational Sciences grant and an Agency for Healthcare Research and Quality grant.
Source: Desai S et al. Pediatrics. 2019 Aug 20. doi: 10.1542/peds.2018-3844.
Self-reported falls can predict osteoporotic fracture risk
A single, simple question about a patient’s experience of falls in the previous year can help predict their risk of fractures, a study suggests.
In Osteoporosis International, researchers reported the outcomes of a cohort study using Manitoba clinical registry data from 24,943 men and women aged 40 years and older within the province who had undergone a fracture-probability assessment, and had data on self-reported falls for the previous year and fracture outcomes.
William D. Leslie, MD, of the University of Manitoba in Winnipeg, and coauthors wrote that a frequent criticism of the FRAX fracture risk assessment tool was the fact that it didn’t include falls or fall risk in predicting fractures.
“Recent evidence derived from carefully conducted research cohort studies in men found that falls increase fracture risk independent of FRAX probability,” they wrote. “However, data are inconsistent with a paucity of evidence demonstrating usefulness of self-reported fall data as collected in routine clinical practice.”
0.8% experienced a hip fracture, and 4.9% experienced any incident fracture.
The analysis showed an increased risk of fracture with the increasing number of self-reported falls experienced in the previous year. The risk of major osteoporotic fracture was 49% higher among individuals who reported one fall, 74% in those who reported two falls and 2.6-fold higher for those who reported three or more falls in the previous year, compared with those who did not report any falls.
A similar pattern was seen for any incident fracture and hip fracture, with a 3.4-fold higher risk of hip fracture seen in those who reported three or more falls. The study also showed an increase in mortality risk with increasing number of falls.
“We documented that a simple question regarding self-reported falls in the previous year could be easily collected during routine clinical practice and that this information was strongly predictive of short-term fracture risk independent of multiple clinical risk factors including fracture probability using the FRAX tool with BMD [bone mineral density],” the authors wrote.
The analysis did not find an interaction with age or sex and the number of falls.
John A. Kanis, MD, reported grants from Amgen, Lily, and Radius Health. Three other coauthors reported nothing to declare for the context of this article, but reported research grants, speaking honoraria, consultancies from a variety of pharmaceutical companies and organizations. The remaining five coauthors declared no conflicts of interest.
SOURCE: Leslie WD et al. Osteoporos Int. 2019 Aug. 2. doi: 10.1007/s00198-019-05106-3.
Fragility fractures remain a major contributor to morbidity and even mortality of aging populations. Concerted efforts of clinicians, epidemiologists, and researchers have yielded an assortment of diagnostic strategies and prognostic algorithms in efforts to identify individuals at fracture risk. A variety of demographic (age, sex), biological (family history, specific disorders and medications), anatomical (bone mineral density, body mass index), and behavioral (smoking, alcohol consumption) parameters are recognized as predictors of fracture risk, and often are incorporated in predictive algorithms for fracture predisposition. FRAX (Fracture Risk Assessment) is a widely used screening tool that is valid in offering fracture risk quantification across populations (Arch Osteoporos. 2016 Dec;11[1]:25; World Health Organization Assessment of Osteoporosis at the Primary Health Care Level).
Aging and accompanying neurocognitive deterioration, visual impairment, as well as iatrogenic factors are recognized to contribute to predisposition to falls in aging populations. A propensity for falls has long been regarded as a fracture risk (Curr Osteoporos Rep. 2008;6[4]:149-54). However, the evidence to support this logical assumption has been mixed with resulting exclusion of tendency to fall from commonly utilized fracture risk predictive models and tools. A predisposition to and frequency of falls is considered neither a risk modulator nor a mediator in the commonly utilized FRAX-based fracture risk assessments, and it is believed that fracture probability may be underestimated by FRAX in those predisposed to frequent falls (J Clin Densitom. 2011 Jul-Sep;14[3]:194–204).
The landscape of fracture risk assessment and quantification in the aforementioned backdrop has been refreshingly enhanced by a recent contribution by Leslie et al. wherein the authors provide real-life evidence relating self-reported falls to fracture risk. In a robust population sample nearing 25,000 women, increasing number of falls within the past year was associated with an increasing fracture risk, and this relationship persisted after adjusting for covariates that are recognized to predispose to fragility fractures, including age, body mass index, and bone mineral density. Women’s health providers are encouraged to familiarize themselves with the work of Leslie et al.; the authors’ message, that fall history be incorporated into risk quantification measures, is striking in its simplicity and profound in its preventative potential given that fall risk in and of itself may be mitigated in many through targeted interventions.
Lubna Pal, MBBS, MS, is professor and fellowship director of the division of reproductive endocrinology & infertility at Yale University, New Haven, Conn. She also is the director of the Yale reproductive endocrinology & infertility menopause program. She said she had no relevant financial disclosures. Email her at [email protected].
Fragility fractures remain a major contributor to morbidity and even mortality of aging populations. Concerted efforts of clinicians, epidemiologists, and researchers have yielded an assortment of diagnostic strategies and prognostic algorithms in efforts to identify individuals at fracture risk. A variety of demographic (age, sex), biological (family history, specific disorders and medications), anatomical (bone mineral density, body mass index), and behavioral (smoking, alcohol consumption) parameters are recognized as predictors of fracture risk, and often are incorporated in predictive algorithms for fracture predisposition. FRAX (Fracture Risk Assessment) is a widely used screening tool that is valid in offering fracture risk quantification across populations (Arch Osteoporos. 2016 Dec;11[1]:25; World Health Organization Assessment of Osteoporosis at the Primary Health Care Level).
Aging and accompanying neurocognitive deterioration, visual impairment, as well as iatrogenic factors are recognized to contribute to predisposition to falls in aging populations. A propensity for falls has long been regarded as a fracture risk (Curr Osteoporos Rep. 2008;6[4]:149-54). However, the evidence to support this logical assumption has been mixed with resulting exclusion of tendency to fall from commonly utilized fracture risk predictive models and tools. A predisposition to and frequency of falls is considered neither a risk modulator nor a mediator in the commonly utilized FRAX-based fracture risk assessments, and it is believed that fracture probability may be underestimated by FRAX in those predisposed to frequent falls (J Clin Densitom. 2011 Jul-Sep;14[3]:194–204).
The landscape of fracture risk assessment and quantification in the aforementioned backdrop has been refreshingly enhanced by a recent contribution by Leslie et al. wherein the authors provide real-life evidence relating self-reported falls to fracture risk. In a robust population sample nearing 25,000 women, increasing number of falls within the past year was associated with an increasing fracture risk, and this relationship persisted after adjusting for covariates that are recognized to predispose to fragility fractures, including age, body mass index, and bone mineral density. Women’s health providers are encouraged to familiarize themselves with the work of Leslie et al.; the authors’ message, that fall history be incorporated into risk quantification measures, is striking in its simplicity and profound in its preventative potential given that fall risk in and of itself may be mitigated in many through targeted interventions.
Lubna Pal, MBBS, MS, is professor and fellowship director of the division of reproductive endocrinology & infertility at Yale University, New Haven, Conn. She also is the director of the Yale reproductive endocrinology & infertility menopause program. She said she had no relevant financial disclosures. Email her at [email protected].
Fragility fractures remain a major contributor to morbidity and even mortality of aging populations. Concerted efforts of clinicians, epidemiologists, and researchers have yielded an assortment of diagnostic strategies and prognostic algorithms in efforts to identify individuals at fracture risk. A variety of demographic (age, sex), biological (family history, specific disorders and medications), anatomical (bone mineral density, body mass index), and behavioral (smoking, alcohol consumption) parameters are recognized as predictors of fracture risk, and often are incorporated in predictive algorithms for fracture predisposition. FRAX (Fracture Risk Assessment) is a widely used screening tool that is valid in offering fracture risk quantification across populations (Arch Osteoporos. 2016 Dec;11[1]:25; World Health Organization Assessment of Osteoporosis at the Primary Health Care Level).
Aging and accompanying neurocognitive deterioration, visual impairment, as well as iatrogenic factors are recognized to contribute to predisposition to falls in aging populations. A propensity for falls has long been regarded as a fracture risk (Curr Osteoporos Rep. 2008;6[4]:149-54). However, the evidence to support this logical assumption has been mixed with resulting exclusion of tendency to fall from commonly utilized fracture risk predictive models and tools. A predisposition to and frequency of falls is considered neither a risk modulator nor a mediator in the commonly utilized FRAX-based fracture risk assessments, and it is believed that fracture probability may be underestimated by FRAX in those predisposed to frequent falls (J Clin Densitom. 2011 Jul-Sep;14[3]:194–204).
The landscape of fracture risk assessment and quantification in the aforementioned backdrop has been refreshingly enhanced by a recent contribution by Leslie et al. wherein the authors provide real-life evidence relating self-reported falls to fracture risk. In a robust population sample nearing 25,000 women, increasing number of falls within the past year was associated with an increasing fracture risk, and this relationship persisted after adjusting for covariates that are recognized to predispose to fragility fractures, including age, body mass index, and bone mineral density. Women’s health providers are encouraged to familiarize themselves with the work of Leslie et al.; the authors’ message, that fall history be incorporated into risk quantification measures, is striking in its simplicity and profound in its preventative potential given that fall risk in and of itself may be mitigated in many through targeted interventions.
Lubna Pal, MBBS, MS, is professor and fellowship director of the division of reproductive endocrinology & infertility at Yale University, New Haven, Conn. She also is the director of the Yale reproductive endocrinology & infertility menopause program. She said she had no relevant financial disclosures. Email her at [email protected].
A single, simple question about a patient’s experience of falls in the previous year can help predict their risk of fractures, a study suggests.
In Osteoporosis International, researchers reported the outcomes of a cohort study using Manitoba clinical registry data from 24,943 men and women aged 40 years and older within the province who had undergone a fracture-probability assessment, and had data on self-reported falls for the previous year and fracture outcomes.
William D. Leslie, MD, of the University of Manitoba in Winnipeg, and coauthors wrote that a frequent criticism of the FRAX fracture risk assessment tool was the fact that it didn’t include falls or fall risk in predicting fractures.
“Recent evidence derived from carefully conducted research cohort studies in men found that falls increase fracture risk independent of FRAX probability,” they wrote. “However, data are inconsistent with a paucity of evidence demonstrating usefulness of self-reported fall data as collected in routine clinical practice.”
0.8% experienced a hip fracture, and 4.9% experienced any incident fracture.
The analysis showed an increased risk of fracture with the increasing number of self-reported falls experienced in the previous year. The risk of major osteoporotic fracture was 49% higher among individuals who reported one fall, 74% in those who reported two falls and 2.6-fold higher for those who reported three or more falls in the previous year, compared with those who did not report any falls.
A similar pattern was seen for any incident fracture and hip fracture, with a 3.4-fold higher risk of hip fracture seen in those who reported three or more falls. The study also showed an increase in mortality risk with increasing number of falls.
“We documented that a simple question regarding self-reported falls in the previous year could be easily collected during routine clinical practice and that this information was strongly predictive of short-term fracture risk independent of multiple clinical risk factors including fracture probability using the FRAX tool with BMD [bone mineral density],” the authors wrote.
The analysis did not find an interaction with age or sex and the number of falls.
John A. Kanis, MD, reported grants from Amgen, Lily, and Radius Health. Three other coauthors reported nothing to declare for the context of this article, but reported research grants, speaking honoraria, consultancies from a variety of pharmaceutical companies and organizations. The remaining five coauthors declared no conflicts of interest.
SOURCE: Leslie WD et al. Osteoporos Int. 2019 Aug. 2. doi: 10.1007/s00198-019-05106-3.
A single, simple question about a patient’s experience of falls in the previous year can help predict their risk of fractures, a study suggests.
In Osteoporosis International, researchers reported the outcomes of a cohort study using Manitoba clinical registry data from 24,943 men and women aged 40 years and older within the province who had undergone a fracture-probability assessment, and had data on self-reported falls for the previous year and fracture outcomes.
William D. Leslie, MD, of the University of Manitoba in Winnipeg, and coauthors wrote that a frequent criticism of the FRAX fracture risk assessment tool was the fact that it didn’t include falls or fall risk in predicting fractures.
“Recent evidence derived from carefully conducted research cohort studies in men found that falls increase fracture risk independent of FRAX probability,” they wrote. “However, data are inconsistent with a paucity of evidence demonstrating usefulness of self-reported fall data as collected in routine clinical practice.”
0.8% experienced a hip fracture, and 4.9% experienced any incident fracture.
The analysis showed an increased risk of fracture with the increasing number of self-reported falls experienced in the previous year. The risk of major osteoporotic fracture was 49% higher among individuals who reported one fall, 74% in those who reported two falls and 2.6-fold higher for those who reported three or more falls in the previous year, compared with those who did not report any falls.
A similar pattern was seen for any incident fracture and hip fracture, with a 3.4-fold higher risk of hip fracture seen in those who reported three or more falls. The study also showed an increase in mortality risk with increasing number of falls.
“We documented that a simple question regarding self-reported falls in the previous year could be easily collected during routine clinical practice and that this information was strongly predictive of short-term fracture risk independent of multiple clinical risk factors including fracture probability using the FRAX tool with BMD [bone mineral density],” the authors wrote.
The analysis did not find an interaction with age or sex and the number of falls.
John A. Kanis, MD, reported grants from Amgen, Lily, and Radius Health. Three other coauthors reported nothing to declare for the context of this article, but reported research grants, speaking honoraria, consultancies from a variety of pharmaceutical companies and organizations. The remaining five coauthors declared no conflicts of interest.
SOURCE: Leslie WD et al. Osteoporos Int. 2019 Aug. 2. doi: 10.1007/s00198-019-05106-3.
FROM OSTEOPOROSIS INTERNATIONAL
Addressing suicidality among Indigenous women, girls
Historical trauma and current social factors contribute to depression, PTSD, anxiety disorders
The history of abuse and genocide has its precursors in antiquity. A brief sketch of this history will provide some insights into the impact of intergenerational trauma and a rationale for the crisis of missing and murdered Indigenous women and girls in the United States and Canada, or Turtle Island, as the Indigenous People call it.
Such a review also will provide a partial explanation of why the suicide rate among non-Hispanic Native American or Alaska Native women increased by 139%1 during 1999-2017 – a time when more Indigenous women were gaining access to law and medical school, as well as positions of authority in their tribes.
Church-, state-sanctioned transgressions
The psychological impact of our past history haunts us today. Papal bulletins – decrees from the pope – gave permission to Christian explorers to take land, wealth, and slaves from any nonbeliever. This permission was labeled the Doctrine of Discovery. It was incorporated into U.S. law in 1823, and by the Supreme Court case, Johnson v. M’intosh. It also provided rationale for the Indian Removal Act, which was passed on May 28, 1830, and signed into law by U.S. President Andrew Jackson. As a result of that law, Indigenous People were forced onto reservations, often removed from their traditional and sacred homelands. Many died during forced relocation.2
From the time of “discovery” by settlers until well into the 19th century, the U.S. governmental intent was genocide. It was manifest by the outright murder of Indigenous People, displacement from land, and the disruption of families when children were taken, put into boarding schools, and were forbidden to speak their language. Indigenous medicine people were killed or jailed for practicing their traditional ceremonies. Indigenous nations had their laws, languages, and agricultural practices denied them. Even today, they must practice U.S. law, adapt colonizing forms of land ownership, and engage in the economic practices of the dominant culture. The economic system currently in place rewards rape of the land and creates a trickle-up economy that keeps rewarding the rich at the expense of the poor. The economic system even gives corporations legal status as individuals, and, in some cases, is allowed to supersede the rights of Indigenous nations.
Today, the federal government still can appropriate land for minerals, pipelines,3 and even put indigenous land and water sovereignty at risk of contamination and pollution by mines established upstream.4 Most of those practices are repugnant to Indigenous nations. The Doctrine of Discovery established prior to 1492 is still alive and well on Turtle Island.
It is this background that denies the rights of Mother Earth, and this backdrop that, in turn, generalizes the denial of the rights of Indigenous women. There are women today, who, against their will and knowledge, have been sterilized.5 There are cases in which women have been raped and beaten, and their perpetrators were never been brought to justice.6 There are jurisdictional issues in the federal law that keep non-native perpetrators from being punished for their actions on tribal sovereign land.
This history and those current practices affect Indigenous families. Historical trauma produces epigenetic changes7 that create more anxiety and depression. Families in which one or both parents were taken away have a harder time providing a loving, safe, addiction-free environment for their children. Children often have high scores on measurements of adverse childhood experiences and suffer PTSD. As psychiatrists, we have treated PTSD from residential and boarding school survivors, families with family members who were victims of being missing or murdered, and survivors of sexual abuse – both in the United States and Canada. According to the final Canadian report of the inquiry into missing and murdered Indigenous women and girls, the murder rate for Indigenous women was 12 times that of non-Indigenous women.8
We assert that this combination of historical trauma and current social factors contributes to depression, PTSD, and anxiety disorders that currently feed the rise in attempted and completed suicide. Less-than-optimal educational opportunities and unemployment, often above 10% on reservations,9 along with food insecurity, accentuate the settings in which women and girls live.
Women achieving despite challenges
Yet, Indigenous women are making great strides within their cultures and communities. For example, Indigenous women are leading language revitalization, and within their culture, are healers and carriers of knowledge. Many Indigenous women are doctors, lawyers, dentists, teachers, poets, authors, and artists.10 Voters in last year’s midterms elected two Native American women to the U.S. Congress. Often, however, those achievements within the Western culture come at a cost, and some might have difficulty balancing those roles with their traditional cultures.
Current societal pressures feed the rise of suicide. Santa Fe, N.M., is known for its affluence and reputation as a tricultural city of Anglos, Hispanics, and Native Americans, and yet, a recent health impact assessment survey of urban Indigenous families stated that food insecurity was the leading concern for those families. Unemployment on the Navajo Nation is above 50%.11 The Indian Health Service (IHS) in the United States, which provides the majority of mental services to the Indigenous population, has identified mental health issues as the No. 1 health problem. However, only 7% of the IHS budget is allocated for mental health and substance abuse services. This represents an underfudging of services to American Indian and Alaska Native communities. In fact, there were only two psychiatrists per 100,000 people served by the IHS, which is one-seventh the number of psychiatrists available to the general population in the United States.12
Best practices for psychiatrists working with Indigenous women demands that we know the history, know how that history is still being manifest in subtle ways, and understand how such antiquated papal bulletins as the Doctrine of Discovery still operate to justify the taking and misuse of indigenous land. We must realize that the dominant economic systems, laws, and policing strategies are imposed on cultures that are sophisticated in their own right. This will then allow compassionate care with a level of understanding.
13
We can advocate at all levels, considering that the role of the federal government, the state, corporations, tribes, families, and provision of quality care to individuals can continue the positive collective advancement of women, and reduce the morbidity and mortality associated with suicide attempts.
We need to be sensitive to our patients and their risks of suicide. Treat suicidal ideation as the serious threat that it is. Address the depression, anxiety, PTSD, historical trauma, substance abuse, emotional dysregulation, and loss of relationship in persons with attachment disorders as serious and valid life events than can lead to serious consequences – including completed suicide.
Indigenous women are resilient, and the approach should be to also balance knowledge of those potential barriers with validating the feminine, and supporting the traditional roles of women and men that value women and children, and revere the matriarchs. Encouraging and supporting Indigenous resurgence of cultural practices and values is significant for positive outcomes for healing and wellness. Doing so can carry a greater meaning within Indigenous and First Nations society.
References
1. Curtin SC and H Hedegaard. Suicide rates for females and males by race and ethnicity: United States, 1999 and 2017. NCHS Health E-Stat. 2019.
2. Anderson GC. Ethnic cleansing and the Indian: The crime that should haunt America. Norman, Okla.: University of Oklahoma Press, 2014.
3. Rausch N. “Standing Rock, Morton County work to mend relationships post-DAPL protests.” Billingsgazette.com. Aug 10, 2019.
4. Roy A. “5 ways the government keeps Native Americans in poverty.” Forbes.com. Mar 13, 2014.
5. Blakemore E. “The little-known history of forced sterilization of Native American women.” JSTOR.org. Aug 25, 2016.
6. Bleir G and A Zoledziowski. “Murdered and missing Native American women challenge police and courts.” Publicintegrity.org. Aug 27, 2018.
7. Brockie TN et al. A framework to examine the role of epigenetics in health disparities among Native Americans. Nurs Res Prac. 2013;2013:410395.
8. “Reclaiming power and place: The final report of the national inquiry into missing and murdered Indigenous women and girls.” Vancouver: Privy Office. Jun 3, 2019.
9. Hagan S. “Where U.S. unemployment is still sky-high: Indian reservations.” Bloomberg.com. Apr 5, 2018.
10. Morin B. “Meet 10 Indigenous women who are making the world a better place.” Indian Country Today. Jul 1, 2019.
11. Fact sheet. Discovernavajo.com.
12. Sarche M and P Spicer. Poverty and health disparities for American Indian and Alaska Native children: Current knowledge and future prospects. Ann NY Acad Sci. 2008 Jul 25;1136:126-36.
13. Lewis-Fernández R et al. Culture and psychiatric evaluation: Operationalizing cultural formulation for DSM-5. Psychiatry. 2014 Summer;77(2):130-54.
Dr. Roessel is a Navajo board-certified psychiatrist practicing in Santa Fe, N.M., working with the local Indigenous population. She has special expertise in cultural psychiatry; her childhood was spent growing up in the Navajo nation with her grandfather, who was a Navajo medicine man. Her psychiatric practice focuses on integrating Indigenous knowledge and principles. Dr. Roessel is a distinguished fellow of the American Psychiatric Association.
Dr. Neidhardt is a board-certified psychiatrist who lives in Santa Fe and has an integrative, holistic psychiatric practice that also specializes in trauma-focused therapy. He has provided care for Indigenous People in the Southwest United States and in Canada, and has worked with Navajo medicine people to develop training for mental health professionals with his wife, Dr. Mary Hasbah Roessel. Dr. Reinhardt is a life fellow of the APA.
Historical trauma and current social factors contribute to depression, PTSD, anxiety disorders
Historical trauma and current social factors contribute to depression, PTSD, anxiety disorders
The history of abuse and genocide has its precursors in antiquity. A brief sketch of this history will provide some insights into the impact of intergenerational trauma and a rationale for the crisis of missing and murdered Indigenous women and girls in the United States and Canada, or Turtle Island, as the Indigenous People call it.
Such a review also will provide a partial explanation of why the suicide rate among non-Hispanic Native American or Alaska Native women increased by 139%1 during 1999-2017 – a time when more Indigenous women were gaining access to law and medical school, as well as positions of authority in their tribes.
Church-, state-sanctioned transgressions
The psychological impact of our past history haunts us today. Papal bulletins – decrees from the pope – gave permission to Christian explorers to take land, wealth, and slaves from any nonbeliever. This permission was labeled the Doctrine of Discovery. It was incorporated into U.S. law in 1823, and by the Supreme Court case, Johnson v. M’intosh. It also provided rationale for the Indian Removal Act, which was passed on May 28, 1830, and signed into law by U.S. President Andrew Jackson. As a result of that law, Indigenous People were forced onto reservations, often removed from their traditional and sacred homelands. Many died during forced relocation.2
From the time of “discovery” by settlers until well into the 19th century, the U.S. governmental intent was genocide. It was manifest by the outright murder of Indigenous People, displacement from land, and the disruption of families when children were taken, put into boarding schools, and were forbidden to speak their language. Indigenous medicine people were killed or jailed for practicing their traditional ceremonies. Indigenous nations had their laws, languages, and agricultural practices denied them. Even today, they must practice U.S. law, adapt colonizing forms of land ownership, and engage in the economic practices of the dominant culture. The economic system currently in place rewards rape of the land and creates a trickle-up economy that keeps rewarding the rich at the expense of the poor. The economic system even gives corporations legal status as individuals, and, in some cases, is allowed to supersede the rights of Indigenous nations.
Today, the federal government still can appropriate land for minerals, pipelines,3 and even put indigenous land and water sovereignty at risk of contamination and pollution by mines established upstream.4 Most of those practices are repugnant to Indigenous nations. The Doctrine of Discovery established prior to 1492 is still alive and well on Turtle Island.
It is this background that denies the rights of Mother Earth, and this backdrop that, in turn, generalizes the denial of the rights of Indigenous women. There are women today, who, against their will and knowledge, have been sterilized.5 There are cases in which women have been raped and beaten, and their perpetrators were never been brought to justice.6 There are jurisdictional issues in the federal law that keep non-native perpetrators from being punished for their actions on tribal sovereign land.
This history and those current practices affect Indigenous families. Historical trauma produces epigenetic changes7 that create more anxiety and depression. Families in which one or both parents were taken away have a harder time providing a loving, safe, addiction-free environment for their children. Children often have high scores on measurements of adverse childhood experiences and suffer PTSD. As psychiatrists, we have treated PTSD from residential and boarding school survivors, families with family members who were victims of being missing or murdered, and survivors of sexual abuse – both in the United States and Canada. According to the final Canadian report of the inquiry into missing and murdered Indigenous women and girls, the murder rate for Indigenous women was 12 times that of non-Indigenous women.8
We assert that this combination of historical trauma and current social factors contributes to depression, PTSD, and anxiety disorders that currently feed the rise in attempted and completed suicide. Less-than-optimal educational opportunities and unemployment, often above 10% on reservations,9 along with food insecurity, accentuate the settings in which women and girls live.
Women achieving despite challenges
Yet, Indigenous women are making great strides within their cultures and communities. For example, Indigenous women are leading language revitalization, and within their culture, are healers and carriers of knowledge. Many Indigenous women are doctors, lawyers, dentists, teachers, poets, authors, and artists.10 Voters in last year’s midterms elected two Native American women to the U.S. Congress. Often, however, those achievements within the Western culture come at a cost, and some might have difficulty balancing those roles with their traditional cultures.
Current societal pressures feed the rise of suicide. Santa Fe, N.M., is known for its affluence and reputation as a tricultural city of Anglos, Hispanics, and Native Americans, and yet, a recent health impact assessment survey of urban Indigenous families stated that food insecurity was the leading concern for those families. Unemployment on the Navajo Nation is above 50%.11 The Indian Health Service (IHS) in the United States, which provides the majority of mental services to the Indigenous population, has identified mental health issues as the No. 1 health problem. However, only 7% of the IHS budget is allocated for mental health and substance abuse services. This represents an underfudging of services to American Indian and Alaska Native communities. In fact, there were only two psychiatrists per 100,000 people served by the IHS, which is one-seventh the number of psychiatrists available to the general population in the United States.12
Best practices for psychiatrists working with Indigenous women demands that we know the history, know how that history is still being manifest in subtle ways, and understand how such antiquated papal bulletins as the Doctrine of Discovery still operate to justify the taking and misuse of indigenous land. We must realize that the dominant economic systems, laws, and policing strategies are imposed on cultures that are sophisticated in their own right. This will then allow compassionate care with a level of understanding.
13
We can advocate at all levels, considering that the role of the federal government, the state, corporations, tribes, families, and provision of quality care to individuals can continue the positive collective advancement of women, and reduce the morbidity and mortality associated with suicide attempts.
We need to be sensitive to our patients and their risks of suicide. Treat suicidal ideation as the serious threat that it is. Address the depression, anxiety, PTSD, historical trauma, substance abuse, emotional dysregulation, and loss of relationship in persons with attachment disorders as serious and valid life events than can lead to serious consequences – including completed suicide.
Indigenous women are resilient, and the approach should be to also balance knowledge of those potential barriers with validating the feminine, and supporting the traditional roles of women and men that value women and children, and revere the matriarchs. Encouraging and supporting Indigenous resurgence of cultural practices and values is significant for positive outcomes for healing and wellness. Doing so can carry a greater meaning within Indigenous and First Nations society.
References
1. Curtin SC and H Hedegaard. Suicide rates for females and males by race and ethnicity: United States, 1999 and 2017. NCHS Health E-Stat. 2019.
2. Anderson GC. Ethnic cleansing and the Indian: The crime that should haunt America. Norman, Okla.: University of Oklahoma Press, 2014.
3. Rausch N. “Standing Rock, Morton County work to mend relationships post-DAPL protests.” Billingsgazette.com. Aug 10, 2019.
4. Roy A. “5 ways the government keeps Native Americans in poverty.” Forbes.com. Mar 13, 2014.
5. Blakemore E. “The little-known history of forced sterilization of Native American women.” JSTOR.org. Aug 25, 2016.
6. Bleir G and A Zoledziowski. “Murdered and missing Native American women challenge police and courts.” Publicintegrity.org. Aug 27, 2018.
7. Brockie TN et al. A framework to examine the role of epigenetics in health disparities among Native Americans. Nurs Res Prac. 2013;2013:410395.
8. “Reclaiming power and place: The final report of the national inquiry into missing and murdered Indigenous women and girls.” Vancouver: Privy Office. Jun 3, 2019.
9. Hagan S. “Where U.S. unemployment is still sky-high: Indian reservations.” Bloomberg.com. Apr 5, 2018.
10. Morin B. “Meet 10 Indigenous women who are making the world a better place.” Indian Country Today. Jul 1, 2019.
11. Fact sheet. Discovernavajo.com.
12. Sarche M and P Spicer. Poverty and health disparities for American Indian and Alaska Native children: Current knowledge and future prospects. Ann NY Acad Sci. 2008 Jul 25;1136:126-36.
13. Lewis-Fernández R et al. Culture and psychiatric evaluation: Operationalizing cultural formulation for DSM-5. Psychiatry. 2014 Summer;77(2):130-54.
Dr. Roessel is a Navajo board-certified psychiatrist practicing in Santa Fe, N.M., working with the local Indigenous population. She has special expertise in cultural psychiatry; her childhood was spent growing up in the Navajo nation with her grandfather, who was a Navajo medicine man. Her psychiatric practice focuses on integrating Indigenous knowledge and principles. Dr. Roessel is a distinguished fellow of the American Psychiatric Association.
Dr. Neidhardt is a board-certified psychiatrist who lives in Santa Fe and has an integrative, holistic psychiatric practice that also specializes in trauma-focused therapy. He has provided care for Indigenous People in the Southwest United States and in Canada, and has worked with Navajo medicine people to develop training for mental health professionals with his wife, Dr. Mary Hasbah Roessel. Dr. Reinhardt is a life fellow of the APA.
The history of abuse and genocide has its precursors in antiquity. A brief sketch of this history will provide some insights into the impact of intergenerational trauma and a rationale for the crisis of missing and murdered Indigenous women and girls in the United States and Canada, or Turtle Island, as the Indigenous People call it.
Such a review also will provide a partial explanation of why the suicide rate among non-Hispanic Native American or Alaska Native women increased by 139%1 during 1999-2017 – a time when more Indigenous women were gaining access to law and medical school, as well as positions of authority in their tribes.
Church-, state-sanctioned transgressions
The psychological impact of our past history haunts us today. Papal bulletins – decrees from the pope – gave permission to Christian explorers to take land, wealth, and slaves from any nonbeliever. This permission was labeled the Doctrine of Discovery. It was incorporated into U.S. law in 1823, and by the Supreme Court case, Johnson v. M’intosh. It also provided rationale for the Indian Removal Act, which was passed on May 28, 1830, and signed into law by U.S. President Andrew Jackson. As a result of that law, Indigenous People were forced onto reservations, often removed from their traditional and sacred homelands. Many died during forced relocation.2
From the time of “discovery” by settlers until well into the 19th century, the U.S. governmental intent was genocide. It was manifest by the outright murder of Indigenous People, displacement from land, and the disruption of families when children were taken, put into boarding schools, and were forbidden to speak their language. Indigenous medicine people were killed or jailed for practicing their traditional ceremonies. Indigenous nations had their laws, languages, and agricultural practices denied them. Even today, they must practice U.S. law, adapt colonizing forms of land ownership, and engage in the economic practices of the dominant culture. The economic system currently in place rewards rape of the land and creates a trickle-up economy that keeps rewarding the rich at the expense of the poor. The economic system even gives corporations legal status as individuals, and, in some cases, is allowed to supersede the rights of Indigenous nations.
Today, the federal government still can appropriate land for minerals, pipelines,3 and even put indigenous land and water sovereignty at risk of contamination and pollution by mines established upstream.4 Most of those practices are repugnant to Indigenous nations. The Doctrine of Discovery established prior to 1492 is still alive and well on Turtle Island.
It is this background that denies the rights of Mother Earth, and this backdrop that, in turn, generalizes the denial of the rights of Indigenous women. There are women today, who, against their will and knowledge, have been sterilized.5 There are cases in which women have been raped and beaten, and their perpetrators were never been brought to justice.6 There are jurisdictional issues in the federal law that keep non-native perpetrators from being punished for their actions on tribal sovereign land.
This history and those current practices affect Indigenous families. Historical trauma produces epigenetic changes7 that create more anxiety and depression. Families in which one or both parents were taken away have a harder time providing a loving, safe, addiction-free environment for their children. Children often have high scores on measurements of adverse childhood experiences and suffer PTSD. As psychiatrists, we have treated PTSD from residential and boarding school survivors, families with family members who were victims of being missing or murdered, and survivors of sexual abuse – both in the United States and Canada. According to the final Canadian report of the inquiry into missing and murdered Indigenous women and girls, the murder rate for Indigenous women was 12 times that of non-Indigenous women.8
We assert that this combination of historical trauma and current social factors contributes to depression, PTSD, and anxiety disorders that currently feed the rise in attempted and completed suicide. Less-than-optimal educational opportunities and unemployment, often above 10% on reservations,9 along with food insecurity, accentuate the settings in which women and girls live.
Women achieving despite challenges
Yet, Indigenous women are making great strides within their cultures and communities. For example, Indigenous women are leading language revitalization, and within their culture, are healers and carriers of knowledge. Many Indigenous women are doctors, lawyers, dentists, teachers, poets, authors, and artists.10 Voters in last year’s midterms elected two Native American women to the U.S. Congress. Often, however, those achievements within the Western culture come at a cost, and some might have difficulty balancing those roles with their traditional cultures.
Current societal pressures feed the rise of suicide. Santa Fe, N.M., is known for its affluence and reputation as a tricultural city of Anglos, Hispanics, and Native Americans, and yet, a recent health impact assessment survey of urban Indigenous families stated that food insecurity was the leading concern for those families. Unemployment on the Navajo Nation is above 50%.11 The Indian Health Service (IHS) in the United States, which provides the majority of mental services to the Indigenous population, has identified mental health issues as the No. 1 health problem. However, only 7% of the IHS budget is allocated for mental health and substance abuse services. This represents an underfudging of services to American Indian and Alaska Native communities. In fact, there were only two psychiatrists per 100,000 people served by the IHS, which is one-seventh the number of psychiatrists available to the general population in the United States.12
Best practices for psychiatrists working with Indigenous women demands that we know the history, know how that history is still being manifest in subtle ways, and understand how such antiquated papal bulletins as the Doctrine of Discovery still operate to justify the taking and misuse of indigenous land. We must realize that the dominant economic systems, laws, and policing strategies are imposed on cultures that are sophisticated in their own right. This will then allow compassionate care with a level of understanding.
13
We can advocate at all levels, considering that the role of the federal government, the state, corporations, tribes, families, and provision of quality care to individuals can continue the positive collective advancement of women, and reduce the morbidity and mortality associated with suicide attempts.
We need to be sensitive to our patients and their risks of suicide. Treat suicidal ideation as the serious threat that it is. Address the depression, anxiety, PTSD, historical trauma, substance abuse, emotional dysregulation, and loss of relationship in persons with attachment disorders as serious and valid life events than can lead to serious consequences – including completed suicide.
Indigenous women are resilient, and the approach should be to also balance knowledge of those potential barriers with validating the feminine, and supporting the traditional roles of women and men that value women and children, and revere the matriarchs. Encouraging and supporting Indigenous resurgence of cultural practices and values is significant for positive outcomes for healing and wellness. Doing so can carry a greater meaning within Indigenous and First Nations society.
References
1. Curtin SC and H Hedegaard. Suicide rates for females and males by race and ethnicity: United States, 1999 and 2017. NCHS Health E-Stat. 2019.
2. Anderson GC. Ethnic cleansing and the Indian: The crime that should haunt America. Norman, Okla.: University of Oklahoma Press, 2014.
3. Rausch N. “Standing Rock, Morton County work to mend relationships post-DAPL protests.” Billingsgazette.com. Aug 10, 2019.
4. Roy A. “5 ways the government keeps Native Americans in poverty.” Forbes.com. Mar 13, 2014.
5. Blakemore E. “The little-known history of forced sterilization of Native American women.” JSTOR.org. Aug 25, 2016.
6. Bleir G and A Zoledziowski. “Murdered and missing Native American women challenge police and courts.” Publicintegrity.org. Aug 27, 2018.
7. Brockie TN et al. A framework to examine the role of epigenetics in health disparities among Native Americans. Nurs Res Prac. 2013;2013:410395.
8. “Reclaiming power and place: The final report of the national inquiry into missing and murdered Indigenous women and girls.” Vancouver: Privy Office. Jun 3, 2019.
9. Hagan S. “Where U.S. unemployment is still sky-high: Indian reservations.” Bloomberg.com. Apr 5, 2018.
10. Morin B. “Meet 10 Indigenous women who are making the world a better place.” Indian Country Today. Jul 1, 2019.
11. Fact sheet. Discovernavajo.com.
12. Sarche M and P Spicer. Poverty and health disparities for American Indian and Alaska Native children: Current knowledge and future prospects. Ann NY Acad Sci. 2008 Jul 25;1136:126-36.
13. Lewis-Fernández R et al. Culture and psychiatric evaluation: Operationalizing cultural formulation for DSM-5. Psychiatry. 2014 Summer;77(2):130-54.
Dr. Roessel is a Navajo board-certified psychiatrist practicing in Santa Fe, N.M., working with the local Indigenous population. She has special expertise in cultural psychiatry; her childhood was spent growing up in the Navajo nation with her grandfather, who was a Navajo medicine man. Her psychiatric practice focuses on integrating Indigenous knowledge and principles. Dr. Roessel is a distinguished fellow of the American Psychiatric Association.
Dr. Neidhardt is a board-certified psychiatrist who lives in Santa Fe and has an integrative, holistic psychiatric practice that also specializes in trauma-focused therapy. He has provided care for Indigenous People in the Southwest United States and in Canada, and has worked with Navajo medicine people to develop training for mental health professionals with his wife, Dr. Mary Hasbah Roessel. Dr. Reinhardt is a life fellow of the APA.
Planned Parenthood withdraws from Title X
Planned Parenthood will no longer participate in the federal Title X family planning program in response to a Trump administration rule that prohibits physicians from counseling patients about abortion and referring patients for the procedure.
In an Aug. 19 announcement, Alexis McGill Johnson, Planned Parenthood Federation of America president and CEO, said the Title X changes, which amount to “an unethical and dangerous gag rule,” has forced the organization out of Title X after being part of the program for 50 years. Planned Parenthood health centers are the largest Title X provider, serving 40% of patients who receive care through the program.
“We believe that the Trump administration is doing this as an attack on reproductive health care and to keep providers like Planned Parenthood from serving our patients,” Ms. McGill said in a statement. “Health care shouldn’t come down to how much you earn, where you live, or who you are. Congress must act now. It’s time for the U.S. Senate to act to pass a spending bill that will reverse the harmful rule and restore access to birth control, STD testing, and other critical services to people with low incomes.”
In an Aug. 19 statement, Mia Palmieri Heck, director of external affairs for the U.S. Department of Health & Human Services said every current Title X grantee has the choice to accept their grant and comply with the changes, or reject their funding by refusing to comply.
“The new Title X regulations were final at the time the current grant awards were announced,” Ms. Heck said a statement. “Some grantees are now blaming the government for their own actions – having chosen to accept the grant while failing to comply with the regulations that accompany it – and they are abandoning their obligations to serve their patients under the program. HHS is grateful for the many grantees who continue to serve their patients under the Title X program, and we will work to ensure all patients continue to be served.”
The announcement by Planned Parenthood comes about a month after HHS gave family planning clinics more time to comply with the new rule if they are making good faith efforts to comply with the new rules. The changes to the Title X program make health clinics ineligible for funding if they offer, promote, or support abortion as a method of family planning.
So far, more than 20 states and several abortion rights organizations, including Planned Parenthood, have sued over the rules in four separate states. District judges in Oregon, Washington, and California temporarily blocked the rules from taking effect. In a June 20 decision, the 9th U.S. Circuit Court of Appeals ruled that the federal government may go forward with its plan to restrict Title X funding from clinics that provide abortion counseling or referrals. The decision overturned the lower court injunctions.
Clare Coleman, president and CEO for the National Family Planning & Reproductive Health Association, said she expects further withdrawals from the Title X program to follow Planned Parenthood’s departure.
“The administration’s Title X rule is forcing the program’s 90 grantees and nearly 4,000 service sites to make gut-wrenching choices,” Ms. Coleman said in a statement. “They can stay in the program, despite the rule’s harms and compromises to Title X’s quality of care, for the sake of continuing to offer some Title X care for low-income individuals [or] they can leave the program and forego funding in order to avoid the rule’s limits on pregnancy counseling and other essential care, contrary to HHS’s own professional standards.”
HHS has previously said that the Title X changes ensure that grants and contracts awarded under the program fully comply with the statutory program integrity requirements, “thereby fulfilling the purpose of Title X, so that more women and men can receive services that help them consider and achieve both their short-term and long-term family planning needs.” The agency recently posted guidance on its website on myths vs. facts about the changes.
Ms. Johnson meanwhile, said Planned Parenthood clinics will remain open to serve patients, and that the organization will continue to fight the Title X changes in court.
[email protected]
Planned Parenthood will no longer participate in the federal Title X family planning program in response to a Trump administration rule that prohibits physicians from counseling patients about abortion and referring patients for the procedure.
In an Aug. 19 announcement, Alexis McGill Johnson, Planned Parenthood Federation of America president and CEO, said the Title X changes, which amount to “an unethical and dangerous gag rule,” has forced the organization out of Title X after being part of the program for 50 years. Planned Parenthood health centers are the largest Title X provider, serving 40% of patients who receive care through the program.
“We believe that the Trump administration is doing this as an attack on reproductive health care and to keep providers like Planned Parenthood from serving our patients,” Ms. McGill said in a statement. “Health care shouldn’t come down to how much you earn, where you live, or who you are. Congress must act now. It’s time for the U.S. Senate to act to pass a spending bill that will reverse the harmful rule and restore access to birth control, STD testing, and other critical services to people with low incomes.”
In an Aug. 19 statement, Mia Palmieri Heck, director of external affairs for the U.S. Department of Health & Human Services said every current Title X grantee has the choice to accept their grant and comply with the changes, or reject their funding by refusing to comply.
“The new Title X regulations were final at the time the current grant awards were announced,” Ms. Heck said a statement. “Some grantees are now blaming the government for their own actions – having chosen to accept the grant while failing to comply with the regulations that accompany it – and they are abandoning their obligations to serve their patients under the program. HHS is grateful for the many grantees who continue to serve their patients under the Title X program, and we will work to ensure all patients continue to be served.”
The announcement by Planned Parenthood comes about a month after HHS gave family planning clinics more time to comply with the new rule if they are making good faith efforts to comply with the new rules. The changes to the Title X program make health clinics ineligible for funding if they offer, promote, or support abortion as a method of family planning.
So far, more than 20 states and several abortion rights organizations, including Planned Parenthood, have sued over the rules in four separate states. District judges in Oregon, Washington, and California temporarily blocked the rules from taking effect. In a June 20 decision, the 9th U.S. Circuit Court of Appeals ruled that the federal government may go forward with its plan to restrict Title X funding from clinics that provide abortion counseling or referrals. The decision overturned the lower court injunctions.
Clare Coleman, president and CEO for the National Family Planning & Reproductive Health Association, said she expects further withdrawals from the Title X program to follow Planned Parenthood’s departure.
“The administration’s Title X rule is forcing the program’s 90 grantees and nearly 4,000 service sites to make gut-wrenching choices,” Ms. Coleman said in a statement. “They can stay in the program, despite the rule’s harms and compromises to Title X’s quality of care, for the sake of continuing to offer some Title X care for low-income individuals [or] they can leave the program and forego funding in order to avoid the rule’s limits on pregnancy counseling and other essential care, contrary to HHS’s own professional standards.”
HHS has previously said that the Title X changes ensure that grants and contracts awarded under the program fully comply with the statutory program integrity requirements, “thereby fulfilling the purpose of Title X, so that more women and men can receive services that help them consider and achieve both their short-term and long-term family planning needs.” The agency recently posted guidance on its website on myths vs. facts about the changes.
Ms. Johnson meanwhile, said Planned Parenthood clinics will remain open to serve patients, and that the organization will continue to fight the Title X changes in court.
[email protected]
Planned Parenthood will no longer participate in the federal Title X family planning program in response to a Trump administration rule that prohibits physicians from counseling patients about abortion and referring patients for the procedure.
In an Aug. 19 announcement, Alexis McGill Johnson, Planned Parenthood Federation of America president and CEO, said the Title X changes, which amount to “an unethical and dangerous gag rule,” has forced the organization out of Title X after being part of the program for 50 years. Planned Parenthood health centers are the largest Title X provider, serving 40% of patients who receive care through the program.
“We believe that the Trump administration is doing this as an attack on reproductive health care and to keep providers like Planned Parenthood from serving our patients,” Ms. McGill said in a statement. “Health care shouldn’t come down to how much you earn, where you live, or who you are. Congress must act now. It’s time for the U.S. Senate to act to pass a spending bill that will reverse the harmful rule and restore access to birth control, STD testing, and other critical services to people with low incomes.”
In an Aug. 19 statement, Mia Palmieri Heck, director of external affairs for the U.S. Department of Health & Human Services said every current Title X grantee has the choice to accept their grant and comply with the changes, or reject their funding by refusing to comply.
“The new Title X regulations were final at the time the current grant awards were announced,” Ms. Heck said a statement. “Some grantees are now blaming the government for their own actions – having chosen to accept the grant while failing to comply with the regulations that accompany it – and they are abandoning their obligations to serve their patients under the program. HHS is grateful for the many grantees who continue to serve their patients under the Title X program, and we will work to ensure all patients continue to be served.”
The announcement by Planned Parenthood comes about a month after HHS gave family planning clinics more time to comply with the new rule if they are making good faith efforts to comply with the new rules. The changes to the Title X program make health clinics ineligible for funding if they offer, promote, or support abortion as a method of family planning.
So far, more than 20 states and several abortion rights organizations, including Planned Parenthood, have sued over the rules in four separate states. District judges in Oregon, Washington, and California temporarily blocked the rules from taking effect. In a June 20 decision, the 9th U.S. Circuit Court of Appeals ruled that the federal government may go forward with its plan to restrict Title X funding from clinics that provide abortion counseling or referrals. The decision overturned the lower court injunctions.
Clare Coleman, president and CEO for the National Family Planning & Reproductive Health Association, said she expects further withdrawals from the Title X program to follow Planned Parenthood’s departure.
“The administration’s Title X rule is forcing the program’s 90 grantees and nearly 4,000 service sites to make gut-wrenching choices,” Ms. Coleman said in a statement. “They can stay in the program, despite the rule’s harms and compromises to Title X’s quality of care, for the sake of continuing to offer some Title X care for low-income individuals [or] they can leave the program and forego funding in order to avoid the rule’s limits on pregnancy counseling and other essential care, contrary to HHS’s own professional standards.”
HHS has previously said that the Title X changes ensure that grants and contracts awarded under the program fully comply with the statutory program integrity requirements, “thereby fulfilling the purpose of Title X, so that more women and men can receive services that help them consider and achieve both their short-term and long-term family planning needs.” The agency recently posted guidance on its website on myths vs. facts about the changes.
Ms. Johnson meanwhile, said Planned Parenthood clinics will remain open to serve patients, and that the organization will continue to fight the Title X changes in court.
[email protected]
New measles outbreak reported in western N.Y.
A new measles outbreak in western New York has affected five people within a Mennonite community, according to the New York State Department of Health.

The five cases in Wyoming County, located east of Buffalo, were reported Aug. 8 and no further cases have been confirmed as of Aug. 16, the county health department said on its website.
Those five cases, along with six new cases in Rockland County, N.Y., and 10 more around the country, brought the total for the Centers for Disease Control and Prevention’s latest reporting week to 21 and the total for the year to 1,203, the CDC said Aug. 19.
Along with Wyoming County and Rockland County (296 cases since Sept. 2018), the CDC currently is tracking outbreaks in New York City (653 cases since Sept. 2018), Washington state (85 cases in 2019; 13 in the current outbreak), California (65 cases in 2019; 5 in the current outbreak), and Texas (21 cases in 2019; 6 in the current outbreak).
“More than 75% of the cases this year are linked to outbreaks in New York and New York City,” the CDC said on its website, while also noting that “124 of the people who got measles this year were hospitalized, and 64 reported having complications, including pneumonia and encephalitis.”
A new measles outbreak in western New York has affected five people within a Mennonite community, according to the New York State Department of Health.

The five cases in Wyoming County, located east of Buffalo, were reported Aug. 8 and no further cases have been confirmed as of Aug. 16, the county health department said on its website.
Those five cases, along with six new cases in Rockland County, N.Y., and 10 more around the country, brought the total for the Centers for Disease Control and Prevention’s latest reporting week to 21 and the total for the year to 1,203, the CDC said Aug. 19.
Along with Wyoming County and Rockland County (296 cases since Sept. 2018), the CDC currently is tracking outbreaks in New York City (653 cases since Sept. 2018), Washington state (85 cases in 2019; 13 in the current outbreak), California (65 cases in 2019; 5 in the current outbreak), and Texas (21 cases in 2019; 6 in the current outbreak).
“More than 75% of the cases this year are linked to outbreaks in New York and New York City,” the CDC said on its website, while also noting that “124 of the people who got measles this year were hospitalized, and 64 reported having complications, including pneumonia and encephalitis.”
A new measles outbreak in western New York has affected five people within a Mennonite community, according to the New York State Department of Health.

The five cases in Wyoming County, located east of Buffalo, were reported Aug. 8 and no further cases have been confirmed as of Aug. 16, the county health department said on its website.
Those five cases, along with six new cases in Rockland County, N.Y., and 10 more around the country, brought the total for the Centers for Disease Control and Prevention’s latest reporting week to 21 and the total for the year to 1,203, the CDC said Aug. 19.
Along with Wyoming County and Rockland County (296 cases since Sept. 2018), the CDC currently is tracking outbreaks in New York City (653 cases since Sept. 2018), Washington state (85 cases in 2019; 13 in the current outbreak), California (65 cases in 2019; 5 in the current outbreak), and Texas (21 cases in 2019; 6 in the current outbreak).
“More than 75% of the cases this year are linked to outbreaks in New York and New York City,” the CDC said on its website, while also noting that “124 of the people who got measles this year were hospitalized, and 64 reported having complications, including pneumonia and encephalitis.”







