Key clinical point: Teriflunomide is effective and well-tolerated in treatment-naive patients with relapsing-remitting multiple sclerosis (RRMS), with females with mild disease activity and lesser disability most likely to benefit.

Major finding: Overall, 79% of patients achieved No Evidence of Disease Activity 3 (NEDA) at 12 months, with the mean annualized relapse rate reducing significantly (P < .001), the mean Expanded Disability Status Scale (EDSS) score remaining stable (P = .658), and only 8.3% of patients discontinuing treatment because of adverse events. Male sex (hazard ratio [HR] 1.856; P < .017), frequent relapses before treatment (HR 3.056; P < .000), and a baseline EDSS score of ≥4 (HR 2.682; P < .004) were associated with the failure to achieve NEDA 3.

Study details: This was an observational cohort study including 217 treatment-naive patients with RRMS who were treated with teriflunomide.

Disclosures: This study was supported by the National Key Research and Development Program of China, CAMS Innovation Fund for Medical Sciences, and others. The authors declared no conflicts of interests.

Source: Zhang Y et al. Real-world outcomes of teriflunomide in relapsing–remitting multiple sclerosis: A prospective cohort study. J Neurol. 2022 (Apr 11). Doi: 10.1007/s00415-022-11118-7

Key clinical point: Teriflunomide is effective and well-tolerated in treatment-naive patients with relapsing-remitting multiple sclerosis (RRMS), with females with mild disease activity and lesser disability most likely to benefit.

Major finding: Overall, 79% of patients achieved No Evidence of Disease Activity 3 (NEDA) at 12 months, with the mean annualized relapse rate reducing significantly (P < .001), the mean Expanded Disability Status Scale (EDSS) score remaining stable (P = .658), and only 8.3% of patients discontinuing treatment because of adverse events. Male sex (hazard ratio [HR] 1.856; P < .017), frequent relapses before treatment (HR 3.056; P < .000), and a baseline EDSS score of ≥4 (HR 2.682; P < .004) were associated with the failure to achieve NEDA 3.

Study details: This was an observational cohort study including 217 treatment-naive patients with RRMS who were treated with teriflunomide.

Disclosures: This study was supported by the National Key Research and Development Program of China, CAMS Innovation Fund for Medical Sciences, and others. The authors declared no conflicts of interests.

Source: Zhang Y et al. Real-world outcomes of teriflunomide in relapsing–remitting multiple sclerosis: A prospective cohort study. J Neurol. 2022 (Apr 11). Doi: 10.1007/s00415-022-11118-7

Key clinical point: Teriflunomide is effective and well-tolerated in treatment-naive patients with relapsing-remitting multiple sclerosis (RRMS), with females with mild disease activity and lesser disability most likely to benefit.

Major finding: Overall, 79% of patients achieved No Evidence of Disease Activity 3 (NEDA) at 12 months, with the mean annualized relapse rate reducing significantly (P < .001), the mean Expanded Disability Status Scale (EDSS) score remaining stable (P = .658), and only 8.3% of patients discontinuing treatment because of adverse events. Male sex (hazard ratio [HR] 1.856; P < .017), frequent relapses before treatment (HR 3.056; P < .000), and a baseline EDSS score of ≥4 (HR 2.682; P < .004) were associated with the failure to achieve NEDA 3.

Study details: This was an observational cohort study including 217 treatment-naive patients with RRMS who were treated with teriflunomide.

Disclosures: This study was supported by the National Key Research and Development Program of China, CAMS Innovation Fund for Medical Sciences, and others. The authors declared no conflicts of interests.

Source: Zhang Y et al. Real-world outcomes of teriflunomide in relapsing–remitting multiple sclerosis: A prospective cohort study. J Neurol. 2022 (Apr 11). Doi: 10.1007/s00415-022-11118-7

Key clinical point: Women vs men with multiple sclerosis (MS) showed greater inflammatory disease activity up to menopausal age, whereas men vs women with MS showed greater disability accrual.

Major finding: Women vs men had a 16% higher relapse rate and a higher estimated marginal mean of annualized relapse rate (0.32 vs 0.28; P < .001); however, the difference disappeared after the age of 50 years. The deterioration in the Expanded Disability Status Scale (EDSS) points was higher in men vs women (0.065 vs 0.049 EDSS points per year; P = .0017), with men at a higher risk of reaching EDSS 4 (P < .001).

Study details: Findings are from an analysis of 9647 patients (3028 men and 6619 women) with MS from the Danish MS registry (DMSR) who received disease-modifying therapy and were followed-up for at least 1 year and two control visits.

Disclosures: The DMSR was funded by the Danish MS Society. M Magyari declared receiving consulting and speakers’ fees and serving on scientific advisory boards for various sources.

Source: Magyari M et al. Quantitative effect of sex on disease activity and disability accumulation in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2022 (Apr 7). Doi: 10.1136/jnnp-2022-328994

Key clinical point: Women vs men with multiple sclerosis (MS) showed greater inflammatory disease activity up to menopausal age, whereas men vs women with MS showed greater disability accrual.

Major finding: Women vs men had a 16% higher relapse rate and a higher estimated marginal mean of annualized relapse rate (0.32 vs 0.28; P < .001); however, the difference disappeared after the age of 50 years. The deterioration in the Expanded Disability Status Scale (EDSS) points was higher in men vs women (0.065 vs 0.049 EDSS points per year; P = .0017), with men at a higher risk of reaching EDSS 4 (P < .001).

Study details: Findings are from an analysis of 9647 patients (3028 men and 6619 women) with MS from the Danish MS registry (DMSR) who received disease-modifying therapy and were followed-up for at least 1 year and two control visits.

Disclosures: The DMSR was funded by the Danish MS Society. M Magyari declared receiving consulting and speakers’ fees and serving on scientific advisory boards for various sources.

Source: Magyari M et al. Quantitative effect of sex on disease activity and disability accumulation in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2022 (Apr 7). Doi: 10.1136/jnnp-2022-328994

Key clinical point: Women vs men with multiple sclerosis (MS) showed greater inflammatory disease activity up to menopausal age, whereas men vs women with MS showed greater disability accrual.

Major finding: Women vs men had a 16% higher relapse rate and a higher estimated marginal mean of annualized relapse rate (0.32 vs 0.28; P < .001); however, the difference disappeared after the age of 50 years. The deterioration in the Expanded Disability Status Scale (EDSS) points was higher in men vs women (0.065 vs 0.049 EDSS points per year; P = .0017), with men at a higher risk of reaching EDSS 4 (P < .001).

Study details: Findings are from an analysis of 9647 patients (3028 men and 6619 women) with MS from the Danish MS registry (DMSR) who received disease-modifying therapy and were followed-up for at least 1 year and two control visits.

Disclosures: The DMSR was funded by the Danish MS Society. M Magyari declared receiving consulting and speakers’ fees and serving on scientific advisory boards for various sources.

Source: Magyari M et al. Quantitative effect of sex on disease activity and disability accumulation in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2022 (Apr 7). Doi: 10.1136/jnnp-2022-328994

Key clinical point: This real-world analysis of patients with relapsing-remitting multiple sclerosis (RRMS) showed a favorable benefit-risk profile for up to 5 years of fingolimod treatment, with a sustained efficacy and manageable safety profile.

Major finding:  Overall, 69.6% of the patients remained relapse free after 5 years of treatment with fingolimod, with the annualized relapse rate reducing significantly from 0.804 at baseline to 0.185, 0.149, 0.122, 0.091, and 0.097 (P < .001) after 1, 2, 3, 4, and 5 years of fingolimod treatment, respectively. Overall, 65.5% and 12.5% of the patients reported any adverse and serious adverse events, respectively.

Study details: This was a 5-year prospective, cross-sectional, observational study including 570 patients with RRMS who were on fingolimod treatment for at least 1 year.

Disclosures: This study was supported by Novartis Pharma AG, Basel, Switzerland. The authors declared no conflicts of interests.

Source: Biernacki T et al. The safety and efficacy of fingolimod: Real-world data from a long-term, non-interventional study on the treatment of RRMS patients spanning up to 5 years from Hungary. PLoS One. 2022;17(4): e0267346 (Apr 22). Doi: 10.1371/journal.pone.0267346

Key clinical point: This real-world analysis of patients with relapsing-remitting multiple sclerosis (RRMS) showed a favorable benefit-risk profile for up to 5 years of fingolimod treatment, with a sustained efficacy and manageable safety profile.

Major finding:  Overall, 69.6% of the patients remained relapse free after 5 years of treatment with fingolimod, with the annualized relapse rate reducing significantly from 0.804 at baseline to 0.185, 0.149, 0.122, 0.091, and 0.097 (P < .001) after 1, 2, 3, 4, and 5 years of fingolimod treatment, respectively. Overall, 65.5% and 12.5% of the patients reported any adverse and serious adverse events, respectively.

Study details: This was a 5-year prospective, cross-sectional, observational study including 570 patients with RRMS who were on fingolimod treatment for at least 1 year.

Disclosures: This study was supported by Novartis Pharma AG, Basel, Switzerland. The authors declared no conflicts of interests.

Source: Biernacki T et al. The safety and efficacy of fingolimod: Real-world data from a long-term, non-interventional study on the treatment of RRMS patients spanning up to 5 years from Hungary. PLoS One. 2022;17(4): e0267346 (Apr 22). Doi: 10.1371/journal.pone.0267346

Key clinical point: This real-world analysis of patients with relapsing-remitting multiple sclerosis (RRMS) showed a favorable benefit-risk profile for up to 5 years of fingolimod treatment, with a sustained efficacy and manageable safety profile.

Major finding:  Overall, 69.6% of the patients remained relapse free after 5 years of treatment with fingolimod, with the annualized relapse rate reducing significantly from 0.804 at baseline to 0.185, 0.149, 0.122, 0.091, and 0.097 (P < .001) after 1, 2, 3, 4, and 5 years of fingolimod treatment, respectively. Overall, 65.5% and 12.5% of the patients reported any adverse and serious adverse events, respectively.

Study details: This was a 5-year prospective, cross-sectional, observational study including 570 patients with RRMS who were on fingolimod treatment for at least 1 year.

Disclosures: This study was supported by Novartis Pharma AG, Basel, Switzerland. The authors declared no conflicts of interests.

Source: Biernacki T et al. The safety and efficacy of fingolimod: Real-world data from a long-term, non-interventional study on the treatment of RRMS patients spanning up to 5 years from Hungary. PLoS One. 2022;17(4): e0267346 (Apr 22). Doi: 10.1371/journal.pone.0267346

Key clinical point: Early use of anti-SARS-CoV-2 monoclonal antibodies (mAb) was effective and safe in treating acute COVID-19 in patients with multiple sclerosis (MS) treated with fingolimod or ocrelizumab.

Major finding:  Overall, 74% of patients with MS were managed as outpatients (median duration to mAb 4 days), and 48% of patients with MS recovered from COVID-19 infection in <7 days after mAb receipt, with no clinical MS relapses documented during or shortly after COVID-19 infection (median follow-up 18 days). No adverse events or deaths were reported.

Study details: Findings are from an observational study including 23 patients with MS, most of whom had completed the initial COVID-19 vaccine series prior to infection, were either untreated or treated with fingolimod/ocrelizumab, and received anti-SARS-CoV2-mAb (bamlanivimab/etesevimab, casirivimab/imdevimab, sotrovimab, or undocumented formulation) for treatment of active COVID-19 infection.

Disclosures: This study did not receive any funding. Some authors reported receiving consulting fees and research support from various sources.

Source: Manzano GS et al. Anti-SARS-CoV-2 monoclonal antibodies for the treatment of active COVID-19 in multiple sclerosis: An observational study. Mult Scler. 2022 (Apr 27). Doi: 10.1177/13524585221092309

Key clinical point: Early use of anti-SARS-CoV-2 monoclonal antibodies (mAb) was effective and safe in treating acute COVID-19 in patients with multiple sclerosis (MS) treated with fingolimod or ocrelizumab.

Major finding:  Overall, 74% of patients with MS were managed as outpatients (median duration to mAb 4 days), and 48% of patients with MS recovered from COVID-19 infection in <7 days after mAb receipt, with no clinical MS relapses documented during or shortly after COVID-19 infection (median follow-up 18 days). No adverse events or deaths were reported.

Study details: Findings are from an observational study including 23 patients with MS, most of whom had completed the initial COVID-19 vaccine series prior to infection, were either untreated or treated with fingolimod/ocrelizumab, and received anti-SARS-CoV2-mAb (bamlanivimab/etesevimab, casirivimab/imdevimab, sotrovimab, or undocumented formulation) for treatment of active COVID-19 infection.

Disclosures: This study did not receive any funding. Some authors reported receiving consulting fees and research support from various sources.

Source: Manzano GS et al. Anti-SARS-CoV-2 monoclonal antibodies for the treatment of active COVID-19 in multiple sclerosis: An observational study. Mult Scler. 2022 (Apr 27). Doi: 10.1177/13524585221092309

Key clinical point: Early use of anti-SARS-CoV-2 monoclonal antibodies (mAb) was effective and safe in treating acute COVID-19 in patients with multiple sclerosis (MS) treated with fingolimod or ocrelizumab.

Major finding:  Overall, 74% of patients with MS were managed as outpatients (median duration to mAb 4 days), and 48% of patients with MS recovered from COVID-19 infection in <7 days after mAb receipt, with no clinical MS relapses documented during or shortly after COVID-19 infection (median follow-up 18 days). No adverse events or deaths were reported.

Study details: Findings are from an observational study including 23 patients with MS, most of whom had completed the initial COVID-19 vaccine series prior to infection, were either untreated or treated with fingolimod/ocrelizumab, and received anti-SARS-CoV2-mAb (bamlanivimab/etesevimab, casirivimab/imdevimab, sotrovimab, or undocumented formulation) for treatment of active COVID-19 infection.

Disclosures: This study did not receive any funding. Some authors reported receiving consulting fees and research support from various sources.

Source: Manzano GS et al. Anti-SARS-CoV-2 monoclonal antibodies for the treatment of active COVID-19 in multiple sclerosis: An observational study. Mult Scler. 2022 (Apr 27). Doi: 10.1177/13524585221092309

Key clinical point: Serum neurofilament light chain (sNfL) could serve as an effective prognostic biomarker for long-term disability progression in patients with progressive multiple sclerosis (PMS).

Major finding: An sNfL value of >10.2 pg/mL at baseline differentiated long-term progressors and nonprogressors with a sensitivity of 75% and a specificity of 67% (adjusted odds ratio [aOR] 7.8; P = .01), and an increase of >5.1 pg/mL in the sNfL value from baseline to 6 years differentiated long-term progressors and nonprogressors with a sensitivity of 71% and a specificity of 86% (aOR 49.4; P = .008).

Study details: This was a 6-year prospective observational cohort study that included 51 patients with PMS who had participated in a 2-year phase 2, randomized, placebo-controlled trial of interferon-beta.

Disclosures: No external funding was received for this study. The authors declared no conflicts of interests.

Source: Comabella M et al. Serum neurofilament light chain levels predict long-term disability progression in patients with progressive multiple sclerosis. J Neurol Neurosurg Psychiatry. 2022 (Apr 29). Doi: 10.1136/jnnp-2022-329020

Key clinical point: Serum neurofilament light chain (sNfL) could serve as an effective prognostic biomarker for long-term disability progression in patients with progressive multiple sclerosis (PMS).

Major finding: An sNfL value of >10.2 pg/mL at baseline differentiated long-term progressors and nonprogressors with a sensitivity of 75% and a specificity of 67% (adjusted odds ratio [aOR] 7.8; P = .01), and an increase of >5.1 pg/mL in the sNfL value from baseline to 6 years differentiated long-term progressors and nonprogressors with a sensitivity of 71% and a specificity of 86% (aOR 49.4; P = .008).

Study details: This was a 6-year prospective observational cohort study that included 51 patients with PMS who had participated in a 2-year phase 2, randomized, placebo-controlled trial of interferon-beta.

Disclosures: No external funding was received for this study. The authors declared no conflicts of interests.

Source: Comabella M et al. Serum neurofilament light chain levels predict long-term disability progression in patients with progressive multiple sclerosis. J Neurol Neurosurg Psychiatry. 2022 (Apr 29). Doi: 10.1136/jnnp-2022-329020

Key clinical point: Serum neurofilament light chain (sNfL) could serve as an effective prognostic biomarker for long-term disability progression in patients with progressive multiple sclerosis (PMS).

Major finding: An sNfL value of >10.2 pg/mL at baseline differentiated long-term progressors and nonprogressors with a sensitivity of 75% and a specificity of 67% (adjusted odds ratio [aOR] 7.8; P = .01), and an increase of >5.1 pg/mL in the sNfL value from baseline to 6 years differentiated long-term progressors and nonprogressors with a sensitivity of 71% and a specificity of 86% (aOR 49.4; P = .008).

Study details: This was a 6-year prospective observational cohort study that included 51 patients with PMS who had participated in a 2-year phase 2, randomized, placebo-controlled trial of interferon-beta.

Disclosures: No external funding was received for this study. The authors declared no conflicts of interests.

Source: Comabella M et al. Serum neurofilament light chain levels predict long-term disability progression in patients with progressive multiple sclerosis. J Neurol Neurosurg Psychiatry. 2022 (Apr 29). Doi: 10.1136/jnnp-2022-329020

Key clinical point: Switching to once every-6-weeks (QW6) dosing of natalizumab from a stable dosing of once every-4-weeks (QW4) was safe without any clinically meaningful loss of efficacy in most patients with relapsing-remitting multiple sclerosis (RRMS).

Major finding: The mean number of new or newly enlarging T2 hyperintense lesions at 72 weeks was 0.20 (95% CI 0.07-0.63) vs 0.05 (95% CI 0.01-0.22) with natalizumab QW6 vs QW4 dosing regimen, with two patients developing ≥25 lesions contributing to most of the excess lesions in the QW6 dosing regimen. The safety profile was similar for both the regimens.

Study details: Findings are from a phase 3b NOVA trial including 499 patients with RRMS on stable intravenous natalizumab QW4 dosing who were randomly assigned to continue QW4 (n  = 248) or switch to QW6 (n = 251) natalizumab dosing.

Disclosures: This study was funded by Biogen. Five authors reported being current or former employees or holding stocks in Biogen, and some authors reported receiving consulting or speakers’ fees, personal compensation, or serving as a steering committee or advisory board member for various sources.

Source: Foley JF et al. Comparison of switching to 6-week dosing of natalizumab versus continuing with 4-week dosing in patients with relapsing-remitting multiple sclerosis (NOVA): A randomised, controlled, open-label, phase 3b trial. Lancet Neurol. 2022 (Apr 25). Doi: 10.1016/ S1474-4422(22)00143-0

Key clinical point: Switching to once every-6-weeks (QW6) dosing of natalizumab from a stable dosing of once every-4-weeks (QW4) was safe without any clinically meaningful loss of efficacy in most patients with relapsing-remitting multiple sclerosis (RRMS).

Major finding: The mean number of new or newly enlarging T2 hyperintense lesions at 72 weeks was 0.20 (95% CI 0.07-0.63) vs 0.05 (95% CI 0.01-0.22) with natalizumab QW6 vs QW4 dosing regimen, with two patients developing ≥25 lesions contributing to most of the excess lesions in the QW6 dosing regimen. The safety profile was similar for both the regimens.

Study details: Findings are from a phase 3b NOVA trial including 499 patients with RRMS on stable intravenous natalizumab QW4 dosing who were randomly assigned to continue QW4 (n  = 248) or switch to QW6 (n = 251) natalizumab dosing.

Disclosures: This study was funded by Biogen. Five authors reported being current or former employees or holding stocks in Biogen, and some authors reported receiving consulting or speakers’ fees, personal compensation, or serving as a steering committee or advisory board member for various sources.

Source: Foley JF et al. Comparison of switching to 6-week dosing of natalizumab versus continuing with 4-week dosing in patients with relapsing-remitting multiple sclerosis (NOVA): A randomised, controlled, open-label, phase 3b trial. Lancet Neurol. 2022 (Apr 25). Doi: 10.1016/ S1474-4422(22)00143-0

Key clinical point: Switching to once every-6-weeks (QW6) dosing of natalizumab from a stable dosing of once every-4-weeks (QW4) was safe without any clinically meaningful loss of efficacy in most patients with relapsing-remitting multiple sclerosis (RRMS).

Major finding: The mean number of new or newly enlarging T2 hyperintense lesions at 72 weeks was 0.20 (95% CI 0.07-0.63) vs 0.05 (95% CI 0.01-0.22) with natalizumab QW6 vs QW4 dosing regimen, with two patients developing ≥25 lesions contributing to most of the excess lesions in the QW6 dosing regimen. The safety profile was similar for both the regimens.

Study details: Findings are from a phase 3b NOVA trial including 499 patients with RRMS on stable intravenous natalizumab QW4 dosing who were randomly assigned to continue QW4 (n  = 248) or switch to QW6 (n = 251) natalizumab dosing.

Disclosures: This study was funded by Biogen. Five authors reported being current or former employees or holding stocks in Biogen, and some authors reported receiving consulting or speakers’ fees, personal compensation, or serving as a steering committee or advisory board member for various sources.

Source: Foley JF et al. Comparison of switching to 6-week dosing of natalizumab versus continuing with 4-week dosing in patients with relapsing-remitting multiple sclerosis (NOVA): A randomised, controlled, open-label, phase 3b trial. Lancet Neurol. 2022 (Apr 25). Doi: 10.1016/ S1474-4422(22)00143-0

“Here and now is what counts. So, let’s go to work!” –Walter Orthmann, 100 years old
 

How long before you retire? If you know the answer in exact years, months, and days, you aren’t alone. For many good reasons, we doctors are more likely to be counting down the years until we retire rather than counting up the years since we started working. For me, if I’m to break the Guinness World Record, I have 69 more years, 3 months and 6 days left to go. That would surpass the current achievement for the longest career at one company, Mr. Walter Orthmann, who has been sitting at the same desk for 84 years. At 100 years old, Mr. Orthmann still shows up every Monday morning, as bright eyed and bushy tailed as a young squirrel. I’ll be 119 when I break his streak, which would also put me past Anthony Mancinelli, a New York barber who at 107 years of age was still brushing off his chair for the next customer. Unbelievable, I know! I wonder, what’s the one weird trick these guys are doing that keeps them going?

Guinness World Records

Of course, the job itself matters. Some jobs, like being a police officer, aren’t suitable for old people. Or are they? Officer L.C. “Buckshot” Smith was still keeping streets safe from his patrol car at 91 years old. After a bit of searching, I found pretty much any job you can think of has a very long-lasting Energizer Bunny story: A female surgeon who was operating at 90 years old, a 100-year-old rheumatologist who was still teaching at University of California, San Francisco, and a 105-year-old Japanese physician who was still seeing patients. There are plenty of geriatric lawyers, nurses, land surveyors, accountants, judges, you name it. So it seems it’s not the work, but the worker that matters. Why do some older workers recharge daily and carry on while many younger ones say the daily grind is burning them out? What makes the Greatest Generation so great?

We all know colleagues who hung up their white coats early. In my medical group, it’s often financially feasible to retire at 58 and many have chosen that option. Yet, we have loads of Partner Emeritus docs in their 70’s who still log on to EPIC and pitch in everyday.

“So, how do you keep going?” I asked my 105-year-old patient who still walks and manages his affairs. “Just stay healthy,” he advised. A circular argument, yet he’s right. You must both be lucky and also choose to be active mentally and physically. Mr. Mancinelli, who was barbering full time at 107 years old, had no aches and pains and all his teeth. He pruned his own bushes. The data are crystal clear that physical activity adds not only years of life, but also improves cognitive capabilities during those years.

As for beating burnout, it seems the one trick that these ultraworkers do is to focus only on the present. Mr. Orthmann’s pithy advice as quoted by NPR is, “You need to get busy with the present, not the past or the future.” These centenarian employees also frame their work not as stressful but rather as their daily series of problems to be solved.

When I asked my super-geriatric patient how he sleeps so well, he said, “I never worry when I get into bed, I just shut my eyes and sleep. I’ll think about tomorrow when I wake up.” Now if I can do that about 25,000 more times, I’ll have the record.

Dr. Jeff 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]

“Here and now is what counts. So, let’s go to work!” –Walter Orthmann, 100 years old
 

How long before you retire? If you know the answer in exact years, months, and days, you aren’t alone. For many good reasons, we doctors are more likely to be counting down the years until we retire rather than counting up the years since we started working. For me, if I’m to break the Guinness World Record, I have 69 more years, 3 months and 6 days left to go. That would surpass the current achievement for the longest career at one company, Mr. Walter Orthmann, who has been sitting at the same desk for 84 years. At 100 years old, Mr. Orthmann still shows up every Monday morning, as bright eyed and bushy tailed as a young squirrel. I’ll be 119 when I break his streak, which would also put me past Anthony Mancinelli, a New York barber who at 107 years of age was still brushing off his chair for the next customer. Unbelievable, I know! I wonder, what’s the one weird trick these guys are doing that keeps them going?

Guinness World Records

Of course, the job itself matters. Some jobs, like being a police officer, aren’t suitable for old people. Or are they? Officer L.C. “Buckshot” Smith was still keeping streets safe from his patrol car at 91 years old. After a bit of searching, I found pretty much any job you can think of has a very long-lasting Energizer Bunny story: A female surgeon who was operating at 90 years old, a 100-year-old rheumatologist who was still teaching at University of California, San Francisco, and a 105-year-old Japanese physician who was still seeing patients. There are plenty of geriatric lawyers, nurses, land surveyors, accountants, judges, you name it. So it seems it’s not the work, but the worker that matters. Why do some older workers recharge daily and carry on while many younger ones say the daily grind is burning them out? What makes the Greatest Generation so great?

We all know colleagues who hung up their white coats early. In my medical group, it’s often financially feasible to retire at 58 and many have chosen that option. Yet, we have loads of Partner Emeritus docs in their 70’s who still log on to EPIC and pitch in everyday.

“So, how do you keep going?” I asked my 105-year-old patient who still walks and manages his affairs. “Just stay healthy,” he advised. A circular argument, yet he’s right. You must both be lucky and also choose to be active mentally and physically. Mr. Mancinelli, who was barbering full time at 107 years old, had no aches and pains and all his teeth. He pruned his own bushes. The data are crystal clear that physical activity adds not only years of life, but also improves cognitive capabilities during those years.

As for beating burnout, it seems the one trick that these ultraworkers do is to focus only on the present. Mr. Orthmann’s pithy advice as quoted by NPR is, “You need to get busy with the present, not the past or the future.” These centenarian employees also frame their work not as stressful but rather as their daily series of problems to be solved.

When I asked my super-geriatric patient how he sleeps so well, he said, “I never worry when I get into bed, I just shut my eyes and sleep. I’ll think about tomorrow when I wake up.” Now if I can do that about 25,000 more times, I’ll have the record.

Dr. Jeff 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]

“Here and now is what counts. So, let’s go to work!” –Walter Orthmann, 100 years old
 

How long before you retire? If you know the answer in exact years, months, and days, you aren’t alone. For many good reasons, we doctors are more likely to be counting down the years until we retire rather than counting up the years since we started working. For me, if I’m to break the Guinness World Record, I have 69 more years, 3 months and 6 days left to go. That would surpass the current achievement for the longest career at one company, Mr. Walter Orthmann, who has been sitting at the same desk for 84 years. At 100 years old, Mr. Orthmann still shows up every Monday morning, as bright eyed and bushy tailed as a young squirrel. I’ll be 119 when I break his streak, which would also put me past Anthony Mancinelli, a New York barber who at 107 years of age was still brushing off his chair for the next customer. Unbelievable, I know! I wonder, what’s the one weird trick these guys are doing that keeps them going?

Guinness World Records

Of course, the job itself matters. Some jobs, like being a police officer, aren’t suitable for old people. Or are they? Officer L.C. “Buckshot” Smith was still keeping streets safe from his patrol car at 91 years old. After a bit of searching, I found pretty much any job you can think of has a very long-lasting Energizer Bunny story: A female surgeon who was operating at 90 years old, a 100-year-old rheumatologist who was still teaching at University of California, San Francisco, and a 105-year-old Japanese physician who was still seeing patients. There are plenty of geriatric lawyers, nurses, land surveyors, accountants, judges, you name it. So it seems it’s not the work, but the worker that matters. Why do some older workers recharge daily and carry on while many younger ones say the daily grind is burning them out? What makes the Greatest Generation so great?

We all know colleagues who hung up their white coats early. In my medical group, it’s often financially feasible to retire at 58 and many have chosen that option. Yet, we have loads of Partner Emeritus docs in their 70’s who still log on to EPIC and pitch in everyday.

“So, how do you keep going?” I asked my 105-year-old patient who still walks and manages his affairs. “Just stay healthy,” he advised. A circular argument, yet he’s right. You must both be lucky and also choose to be active mentally and physically. Mr. Mancinelli, who was barbering full time at 107 years old, had no aches and pains and all his teeth. He pruned his own bushes. The data are crystal clear that physical activity adds not only years of life, but also improves cognitive capabilities during those years.

As for beating burnout, it seems the one trick that these ultraworkers do is to focus only on the present. Mr. Orthmann’s pithy advice as quoted by NPR is, “You need to get busy with the present, not the past or the future.” These centenarian employees also frame their work not as stressful but rather as their daily series of problems to be solved.

When I asked my super-geriatric patient how he sleeps so well, he said, “I never worry when I get into bed, I just shut my eyes and sleep. I’ll think about tomorrow when I wake up.” Now if I can do that about 25,000 more times, I’ll have the record.

Dr. Jeff 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]

Doctors are advising women who have had bariatric surgery to wait at least 2 years before trying to conceive to reduce the risk of a small-for-gestational-age baby.

In fact, babies conceived less than 2 years post bariatric surgery are 15 times more likely to be small for gestational age as those conceived after this cut-off point, new study findings indicate.

Ana Carreira, MD, Coimbra Hospital and University Centre, Portugal, presented the findings as a poster at the European Congress on Obesity (ECO) 2022.

“The prevalence of small-for-gestational-age babies was similar across the different types of bariatric surgery, and we calculated that the cut-off for the bariatric-surgery-to-conception interval for a lower risk of small for gestational age babies was 24.5 months,” Dr. Carreira reported.

The study also found that for each additional month after the 2-year time point from bariatric surgery to conception, there was a 4.2-g (0.15-oz) increase in birth weight, and there was a 5% lower risk for a small-for-gestational-age neonate. 

“Clinically, this is very significant,” she told this news organization.

“While it may be possible to slightly adjust this on an individual basis, it is important that women who are undergoing bariatric surgery are aware of the risk of early conception and of the benefits of delaying pregnancy,” she added.

Asked to comment, Kari Johansson, PhD, of the Karolinska Institute, Stockholm, who has worked in the field, said: “These increased risks have been hypothesized to potentially be attributed to the inadequate in utero availability of nutrients to the fetus, especially during the first year post bariatric surgery when the rapid and largest weight loss occurs. This is why many clinical guidelines recommend women wait 12-24 months until getting pregnant.”

Indeed, the American College of Obstetricians and Gynecologists recommends women wait 12-24 months post bariatric surgery before trying to conceive.

Dr. Johansson also noted, however, that there were no significant increased risks of adverse outcomes between pregnancies with a surgery-to-conception interval of 12 months or less versus over 12 months in a recent meta-analysis. But those authors also concluded that large cohorts with sufficient power are needed “before any definite conclusions can be made on the optimal surgery-to-conception interval,” she cautioned.
 

All types of bariatric surgery investigated

Bariatric surgery, which is increasingly popular in women of reproductive age, involves rapid weight loss, which can trigger improved fertility, Dr. Carreira explained. Currently, clinics generally advise women to wait at least 1 year before trying for a baby post-surgery.

Dr. Carreira and colleagues conducted the study because “the optimal bariatric-surgery-to-conception interval has yet to be determined,” and they wanted to examine the issue of small-for-gestational-age babies in particular, she noted. They also examined outcomes after a number of different bariatric procedures.

They retrospectively reviewed a cohort of 48 post surgery pregnancies (in 2008-2020) with a minimum follow-up of 30 weeks and determined the proportion of small-for-gestational-age neonates, defined as having a birth weight less than the 10th percentile according to National Center for Health Statistics growth charts.

Mean maternal age was 34.3 years, mean body mass index at conception was 30.9 kg/m², and 70.8% had a bariatric-surgery-to-conception interval of over 24 months, 14.6% of 12-24 months, and 14.6% of less than 12 months.

Bariatric surgeries included adjustable gastric banding (22.9%), sleeve gastrectomy (35.4%), Roux-en-Y gastric bypass (37.5%), and biliopancreatic diversion (4.2%).

Overall, mean birth weight was 2.98 kg (6.6 lb) and the prevalence of small-for-gestational-age babies was 26.3%.

“For an interval of less than 24 months, around 60% of babies were small for gestational age,” Dr. Carreira noted. 

Most babies who were small for gestational age were conceived at 18 months (median), and those who were not were conceived at 59 months (median).

And, after adjustment for maternal comorbidities, the odds ratio for a small-for-gestational-age neonate was 15.1 (95% confidence interval, 2.4-93.1) for a baby conceived less than 24 months after surgery.  

“Some people think the interval can change according to the type of bariatric surgery, but we found no difference in findings according to [surgery] type,” added Dr. Carreira.

She pointed out that after discharge from their endocrinology clinic (after bariatric surgery), the women are cared for by their family doctor, “and we find that when they return to us in pregnancy their nutrient deficiencies have not been properly addressed. They need to be addressed at least 6 months prior to conception.”

“We recommend that women wait at least 2 years after bariatric surgery before trying to conceive, irrespective of the type of surgery,” she reiterated.

Dr. Carreira and Dr. Johansson have reported no relevant financial relationships.

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

Doctors are advising women who have had bariatric surgery to wait at least 2 years before trying to conceive to reduce the risk of a small-for-gestational-age baby.

In fact, babies conceived less than 2 years post bariatric surgery are 15 times more likely to be small for gestational age as those conceived after this cut-off point, new study findings indicate.

Ana Carreira, MD, Coimbra Hospital and University Centre, Portugal, presented the findings as a poster at the European Congress on Obesity (ECO) 2022.

“The prevalence of small-for-gestational-age babies was similar across the different types of bariatric surgery, and we calculated that the cut-off for the bariatric-surgery-to-conception interval for a lower risk of small for gestational age babies was 24.5 months,” Dr. Carreira reported.

The study also found that for each additional month after the 2-year time point from bariatric surgery to conception, there was a 4.2-g (0.15-oz) increase in birth weight, and there was a 5% lower risk for a small-for-gestational-age neonate. 

“Clinically, this is very significant,” she told this news organization.

“While it may be possible to slightly adjust this on an individual basis, it is important that women who are undergoing bariatric surgery are aware of the risk of early conception and of the benefits of delaying pregnancy,” she added.

Asked to comment, Kari Johansson, PhD, of the Karolinska Institute, Stockholm, who has worked in the field, said: “These increased risks have been hypothesized to potentially be attributed to the inadequate in utero availability of nutrients to the fetus, especially during the first year post bariatric surgery when the rapid and largest weight loss occurs. This is why many clinical guidelines recommend women wait 12-24 months until getting pregnant.”

Indeed, the American College of Obstetricians and Gynecologists recommends women wait 12-24 months post bariatric surgery before trying to conceive.

Dr. Johansson also noted, however, that there were no significant increased risks of adverse outcomes between pregnancies with a surgery-to-conception interval of 12 months or less versus over 12 months in a recent meta-analysis. But those authors also concluded that large cohorts with sufficient power are needed “before any definite conclusions can be made on the optimal surgery-to-conception interval,” she cautioned.
 

All types of bariatric surgery investigated

Bariatric surgery, which is increasingly popular in women of reproductive age, involves rapid weight loss, which can trigger improved fertility, Dr. Carreira explained. Currently, clinics generally advise women to wait at least 1 year before trying for a baby post-surgery.

Dr. Carreira and colleagues conducted the study because “the optimal bariatric-surgery-to-conception interval has yet to be determined,” and they wanted to examine the issue of small-for-gestational-age babies in particular, she noted. They also examined outcomes after a number of different bariatric procedures.

They retrospectively reviewed a cohort of 48 post surgery pregnancies (in 2008-2020) with a minimum follow-up of 30 weeks and determined the proportion of small-for-gestational-age neonates, defined as having a birth weight less than the 10th percentile according to National Center for Health Statistics growth charts.

Mean maternal age was 34.3 years, mean body mass index at conception was 30.9 kg/m², and 70.8% had a bariatric-surgery-to-conception interval of over 24 months, 14.6% of 12-24 months, and 14.6% of less than 12 months.

Bariatric surgeries included adjustable gastric banding (22.9%), sleeve gastrectomy (35.4%), Roux-en-Y gastric bypass (37.5%), and biliopancreatic diversion (4.2%).

Overall, mean birth weight was 2.98 kg (6.6 lb) and the prevalence of small-for-gestational-age babies was 26.3%.

“For an interval of less than 24 months, around 60% of babies were small for gestational age,” Dr. Carreira noted. 

Most babies who were small for gestational age were conceived at 18 months (median), and those who were not were conceived at 59 months (median).

And, after adjustment for maternal comorbidities, the odds ratio for a small-for-gestational-age neonate was 15.1 (95% confidence interval, 2.4-93.1) for a baby conceived less than 24 months after surgery.  

“Some people think the interval can change according to the type of bariatric surgery, but we found no difference in findings according to [surgery] type,” added Dr. Carreira.

She pointed out that after discharge from their endocrinology clinic (after bariatric surgery), the women are cared for by their family doctor, “and we find that when they return to us in pregnancy their nutrient deficiencies have not been properly addressed. They need to be addressed at least 6 months prior to conception.”

“We recommend that women wait at least 2 years after bariatric surgery before trying to conceive, irrespective of the type of surgery,” she reiterated.

Dr. Carreira and Dr. Johansson have reported no relevant financial relationships.

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

Doctors are advising women who have had bariatric surgery to wait at least 2 years before trying to conceive to reduce the risk of a small-for-gestational-age baby.

In fact, babies conceived less than 2 years post bariatric surgery are 15 times more likely to be small for gestational age as those conceived after this cut-off point, new study findings indicate.

Ana Carreira, MD, Coimbra Hospital and University Centre, Portugal, presented the findings as a poster at the European Congress on Obesity (ECO) 2022.

“The prevalence of small-for-gestational-age babies was similar across the different types of bariatric surgery, and we calculated that the cut-off for the bariatric-surgery-to-conception interval for a lower risk of small for gestational age babies was 24.5 months,” Dr. Carreira reported.

The study also found that for each additional month after the 2-year time point from bariatric surgery to conception, there was a 4.2-g (0.15-oz) increase in birth weight, and there was a 5% lower risk for a small-for-gestational-age neonate. 

“Clinically, this is very significant,” she told this news organization.

“While it may be possible to slightly adjust this on an individual basis, it is important that women who are undergoing bariatric surgery are aware of the risk of early conception and of the benefits of delaying pregnancy,” she added.

Asked to comment, Kari Johansson, PhD, of the Karolinska Institute, Stockholm, who has worked in the field, said: “These increased risks have been hypothesized to potentially be attributed to the inadequate in utero availability of nutrients to the fetus, especially during the first year post bariatric surgery when the rapid and largest weight loss occurs. This is why many clinical guidelines recommend women wait 12-24 months until getting pregnant.”

Indeed, the American College of Obstetricians and Gynecologists recommends women wait 12-24 months post bariatric surgery before trying to conceive.

Dr. Johansson also noted, however, that there were no significant increased risks of adverse outcomes between pregnancies with a surgery-to-conception interval of 12 months or less versus over 12 months in a recent meta-analysis. But those authors also concluded that large cohorts with sufficient power are needed “before any definite conclusions can be made on the optimal surgery-to-conception interval,” she cautioned.
 

All types of bariatric surgery investigated

Bariatric surgery, which is increasingly popular in women of reproductive age, involves rapid weight loss, which can trigger improved fertility, Dr. Carreira explained. Currently, clinics generally advise women to wait at least 1 year before trying for a baby post-surgery.

Dr. Carreira and colleagues conducted the study because “the optimal bariatric-surgery-to-conception interval has yet to be determined,” and they wanted to examine the issue of small-for-gestational-age babies in particular, she noted. They also examined outcomes after a number of different bariatric procedures.

They retrospectively reviewed a cohort of 48 post surgery pregnancies (in 2008-2020) with a minimum follow-up of 30 weeks and determined the proportion of small-for-gestational-age neonates, defined as having a birth weight less than the 10th percentile according to National Center for Health Statistics growth charts.

Mean maternal age was 34.3 years, mean body mass index at conception was 30.9 kg/m², and 70.8% had a bariatric-surgery-to-conception interval of over 24 months, 14.6% of 12-24 months, and 14.6% of less than 12 months.

Bariatric surgeries included adjustable gastric banding (22.9%), sleeve gastrectomy (35.4%), Roux-en-Y gastric bypass (37.5%), and biliopancreatic diversion (4.2%).

Overall, mean birth weight was 2.98 kg (6.6 lb) and the prevalence of small-for-gestational-age babies was 26.3%.

“For an interval of less than 24 months, around 60% of babies were small for gestational age,” Dr. Carreira noted. 

Most babies who were small for gestational age were conceived at 18 months (median), and those who were not were conceived at 59 months (median).

And, after adjustment for maternal comorbidities, the odds ratio for a small-for-gestational-age neonate was 15.1 (95% confidence interval, 2.4-93.1) for a baby conceived less than 24 months after surgery.  

“Some people think the interval can change according to the type of bariatric surgery, but we found no difference in findings according to [surgery] type,” added Dr. Carreira.

She pointed out that after discharge from their endocrinology clinic (after bariatric surgery), the women are cared for by their family doctor, “and we find that when they return to us in pregnancy their nutrient deficiencies have not been properly addressed. They need to be addressed at least 6 months prior to conception.”

“We recommend that women wait at least 2 years after bariatric surgery before trying to conceive, irrespective of the type of surgery,” she reiterated.

Dr. Carreira and Dr. Johansson have reported no relevant financial relationships.

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

Advanced maternal age and maternal hypertension are a one-two punch that boosts the risk of cesarean births, a new study reports.

While the findings presented at the 2022 annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists aren’t surprising, the insight they provide can be helpful in counseling women at risk about delivery options, lead author and Loma Linda (Calif.) University maternal-fetal medicine physician Sarah D. Smithson, DO, said in an interview.

The prospect of a cesarean birth “can be introduced early and often, which can be important in managing expectations,” she said, especially since women can feel depression and a sense of failure if it turns out they can’t give birth vaginally as they anticipated.

As Dr. Smithson noted, there’s a continuum of maternal hypertension conditions from less severe to more severe. The physicians need to hurry delivery along in the most severe cases. “The clock is clicking when you have preeclampsia, and you do not have time for an induction that could take 2-3 days if you’re having a hard time controlling blood pressure. You may consider cesarean to expedite delivery,” she said.

For the new study, Dr. Smithson and colleagues sought to understand how a combination of maternal hypertension and advanced maternal age affected cesarean delivery rates. They retrospectively tracked 1,625 women with maternal hypertension (chronic hypertension, gestational hypertension, preeclampsia without severe features, and preeclampsia with severe features) who were treated in the Oregon Health & Science University system from 2013 to 2018.

Of the women, 450 were older than 35, and they were more likely than younger women to have cesarean deliveries (46% vs. 34%; P < .001; adjusted OR, 1.7; 95% CI, 1.0-2.7; P = .03).

“We aim to get our cesarean section rates below 20%,” Dr. Smithson said. “These are high rates, and the fact that they’re significantly higher in the advanced maternal age group is compelling.”

The cesarean rates were higher at a statistically significant rate in patients with gestational hypertension (37% in older women vs. 26% in younger women; P = .021) and in those with preeclampsia with severe features (57% vs. 44%, respectively; P = .02). However, the differences were not statistically significant in the groups with chronic hypertension and preeclampsia without severe features.

In an interview, maternal-fetal medicine specialist Alex C. Vidaeff, MD, MPH, of Baylor College of Medicine, Houston, questioned the usefulness of the subgroup analysis, which he thinks may be statistically misleading. “How would one otherwise explain that the rate difference between advanced maternal-age and non–advanced maternal-age subjects is statistically significant for gestational hypertension but not for preeclampsia without severe features?”

He added: “With the very limited information provided by this study, important questions remained unanswered. What is causing the increased rate of cesarean delivery? Provider’s bias or preferences? It would have been useful to know if the cesarean deliveries were elective, without labor, or cesarean deliveries performed during labor or even emergency cesarean deliveries.”

No study funding or disclosures are reported.

Advanced maternal age and maternal hypertension are a one-two punch that boosts the risk of cesarean births, a new study reports.

While the findings presented at the 2022 annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists aren’t surprising, the insight they provide can be helpful in counseling women at risk about delivery options, lead author and Loma Linda (Calif.) University maternal-fetal medicine physician Sarah D. Smithson, DO, said in an interview.

The prospect of a cesarean birth “can be introduced early and often, which can be important in managing expectations,” she said, especially since women can feel depression and a sense of failure if it turns out they can’t give birth vaginally as they anticipated.

As Dr. Smithson noted, there’s a continuum of maternal hypertension conditions from less severe to more severe. The physicians need to hurry delivery along in the most severe cases. “The clock is clicking when you have preeclampsia, and you do not have time for an induction that could take 2-3 days if you’re having a hard time controlling blood pressure. You may consider cesarean to expedite delivery,” she said.

For the new study, Dr. Smithson and colleagues sought to understand how a combination of maternal hypertension and advanced maternal age affected cesarean delivery rates. They retrospectively tracked 1,625 women with maternal hypertension (chronic hypertension, gestational hypertension, preeclampsia without severe features, and preeclampsia with severe features) who were treated in the Oregon Health & Science University system from 2013 to 2018.

Of the women, 450 were older than 35, and they were more likely than younger women to have cesarean deliveries (46% vs. 34%; P < .001; adjusted OR, 1.7; 95% CI, 1.0-2.7; P = .03).

“We aim to get our cesarean section rates below 20%,” Dr. Smithson said. “These are high rates, and the fact that they’re significantly higher in the advanced maternal age group is compelling.”

The cesarean rates were higher at a statistically significant rate in patients with gestational hypertension (37% in older women vs. 26% in younger women; P = .021) and in those with preeclampsia with severe features (57% vs. 44%, respectively; P = .02). However, the differences were not statistically significant in the groups with chronic hypertension and preeclampsia without severe features.

In an interview, maternal-fetal medicine specialist Alex C. Vidaeff, MD, MPH, of Baylor College of Medicine, Houston, questioned the usefulness of the subgroup analysis, which he thinks may be statistically misleading. “How would one otherwise explain that the rate difference between advanced maternal-age and non–advanced maternal-age subjects is statistically significant for gestational hypertension but not for preeclampsia without severe features?”

He added: “With the very limited information provided by this study, important questions remained unanswered. What is causing the increased rate of cesarean delivery? Provider’s bias or preferences? It would have been useful to know if the cesarean deliveries were elective, without labor, or cesarean deliveries performed during labor or even emergency cesarean deliveries.”

No study funding or disclosures are reported.

Advanced maternal age and maternal hypertension are a one-two punch that boosts the risk of cesarean births, a new study reports.

While the findings presented at the 2022 annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists aren’t surprising, the insight they provide can be helpful in counseling women at risk about delivery options, lead author and Loma Linda (Calif.) University maternal-fetal medicine physician Sarah D. Smithson, DO, said in an interview.

The prospect of a cesarean birth “can be introduced early and often, which can be important in managing expectations,” she said, especially since women can feel depression and a sense of failure if it turns out they can’t give birth vaginally as they anticipated.

As Dr. Smithson noted, there’s a continuum of maternal hypertension conditions from less severe to more severe. The physicians need to hurry delivery along in the most severe cases. “The clock is clicking when you have preeclampsia, and you do not have time for an induction that could take 2-3 days if you’re having a hard time controlling blood pressure. You may consider cesarean to expedite delivery,” she said.

For the new study, Dr. Smithson and colleagues sought to understand how a combination of maternal hypertension and advanced maternal age affected cesarean delivery rates. They retrospectively tracked 1,625 women with maternal hypertension (chronic hypertension, gestational hypertension, preeclampsia without severe features, and preeclampsia with severe features) who were treated in the Oregon Health & Science University system from 2013 to 2018.

Of the women, 450 were older than 35, and they were more likely than younger women to have cesarean deliveries (46% vs. 34%; P < .001; adjusted OR, 1.7; 95% CI, 1.0-2.7; P = .03).

“We aim to get our cesarean section rates below 20%,” Dr. Smithson said. “These are high rates, and the fact that they’re significantly higher in the advanced maternal age group is compelling.”

The cesarean rates were higher at a statistically significant rate in patients with gestational hypertension (37% in older women vs. 26% in younger women; P = .021) and in those with preeclampsia with severe features (57% vs. 44%, respectively; P = .02). However, the differences were not statistically significant in the groups with chronic hypertension and preeclampsia without severe features.

In an interview, maternal-fetal medicine specialist Alex C. Vidaeff, MD, MPH, of Baylor College of Medicine, Houston, questioned the usefulness of the subgroup analysis, which he thinks may be statistically misleading. “How would one otherwise explain that the rate difference between advanced maternal-age and non–advanced maternal-age subjects is statistically significant for gestational hypertension but not for preeclampsia without severe features?”

He added: “With the very limited information provided by this study, important questions remained unanswered. What is causing the increased rate of cesarean delivery? Provider’s bias or preferences? It would have been useful to know if the cesarean deliveries were elective, without labor, or cesarean deliveries performed during labor or even emergency cesarean deliveries.”

No study funding or disclosures are reported.

Benzophenones are a family of compounds that include dixoxybenzone, sulisobenzone, and benzophenone-3, or oxybenzone. These benzophenones are found in various skin care and personal care products, including body washes, exfoliants, fragrances, liquid hand soaps, lip balms, lipsticks, moisturizers, styling gels/creams, and sunscreens, as well as conditioners, hair sprays, and shampoos. Benzophenones (BPs) act as penetration enhancers, as they modify the structure of the skin and facilitate the absorption of other chemical ingredients into the body. The best known uses of these compounds are as perfume fixatives and sunscreen agents.

Sunscreens and benzophenones

BP-2, -3 and -4 are used as sunscreens but have many downsides. They are well known photoallergens, are toxic to aquatic animals (especially BP-3), and are found in urine. BP-2 has weak estrogenic effects, and some studies suggest that it decreases fertility in men. BP-4 can increase absorption of pesticides. BP-3 is banned in Hawaii because of the risk to coral and is the most worrisome.

mark wragg/iStockphoto.com

In particular, BP-3 is known to protect skin and hair from UV radiation-induced harm.¹ Unfortunately, BPs are also associated with photocontact allergies, hypersensitivity, hives, contact urticaria, anaphylaxis, hormone disruption, and DNA damage.^2,3 BP-3 has also been implicated as an environmental contaminant. This column will focus on recent studies pertaining to effects on humans, primarily, and on the role of BPs in sunscreen agents.
 

Effects of BPs in animals

A recent study on the cytotoxicity of BP-3 against thymocytes in rats revealed that cell mortality increased significantly after 3 hours of exposure to 300 μM BP-3, but the membrane potential of thymocytes was unchanged by BP-3 exposure. In a concentration-dependent fashion, intracellular Zn2+ levels increased significantly after administration of at least 30 μM BP-3. The investigators concluded that the cytotoxicity engendered by BP-3 could be the result of oxidative stress linked to elevated intracellular Zn2+ levels.¹

Effects of BPs in humans and systemic absorption

In multiple studies, exposure to BP-3, as well as to octinoxate, has been linked to endocrine and hormonal disruptions in humans and animals.^4,5 Motivated by several notable observations (global increase in the use of sunscreens with UV filters; rapid rise in malignant melanoma, against which sunscreens should protect; increase in reported experimental findings of UV filters acting as endocrine disruptors), Krause et al. in 2012 reviewed animal and human data on the UV filters BP-3, 3-benzylidene camphor (3-BC), 3-(4-methyl-benzylidene) camphor (4-MBC), 2-ethylhexyl 4-methoxy cinnamate (OMC), homosalate (HMS), 2-ethylhexyl 4-dimethylaminobenzoate, and 4-aminobenzoic acid (PABA). Importantly, BP-3 was present in 96% of human urine samples in the United States, and various filters were found in 85% of the human breast milk samples in Switzerland.⁶

A 2019 analysis by Wang and Ganley reported that systemic absorption of the active sunscreen ingredient BP-3 can be substantial, justifying the assessment and understanding of systemic exposure to characterize the risks of long-term usage.⁷

Between January and February 2019, Matta et al. conducted a randomized clinical trial with 48 healthy participants to evaluate the systemic absorption and pharmacokinetics of six active ingredients in four sunscreen formulations, including avobenzone and BP-3. The researchers found that all ingredients were systemically absorbed, with plasma concentrations exceeding the Food and Drug Administration threshold for considering the waiving of further safety studies. They concluded that these results did not warrant discontinuing the use of the tested sunscreen ingredients.⁸ Yeager and Lim add that, while BP-3 has been incorporated into sunscreen formulations for sale in the United States since 1978, there have been no reports of adverse systemic reactions in human beings.³

However, topical reactions have elicited a different assessment. That is, in 2014, the American Contact Dermatitis Society labeled BPs the Contact Allergen of the Year, as they were identified as the most common source of photoallergic and contact allergic reactions of all UV filters.^3,9

Risks of BPs in sunscreens and other skincare products

In 2015, Amar et al. investigated the photogenotoxicity and apoptotic effects in human keratinocytes (HaCaT cells) of BP-1, which is used as a UV blocker in sunscreens. They found that BP-1, when exposed to UV radiation, photosensitized cells and yielded intracellular reactive oxygen species. Significant reductions in cell viability were also seen with exposure to sunlight, UVA, and UVB. The researchers also confirmed genotoxic activity, with BP-1 augmenting lipid peroxidation and upregulating apoptotic proteins. They concluded that sunscreen users should be advised to avoid products that contain BP-1.¹⁰

In 2019, Amar et al. evaluated the effects of BPs on the differential expression of proteins in HaCaT cells exposed to UVA. Their findings indicated the expression of novel proteins that helped to initiate or promote apoptosis. They concluded that, because of the predilection to render such effects in human skin keratinocytes, consumers should avoid the use of sunscreens that contain BPs as UV blocking ingredients.¹¹

Still widely used as an effective filter against UVA2 and UVB, BP-3 was believed to be present in two thirds of nonmineral sunscreens in the United States in 2018.^3,12

Notably, BP-1 and BP-3 were found in small proportions (3.7% and 4.9%, respectively) among a total of 283 products culled from various stores in Lecce, Italy, in a survey of the potentially dangerous chemicals found in rinse-off, leave-on, and makeup products in 2019.¹³ The authors added that the International Agency for Research on Cancer, in 2010, classified BP as potentially carcinogenic to humans (2B group).^13,14

Promising use of nanocapsules

The widespread concern about the phototoxicity of BP has prompted some interesting research into workarounds. Specifically, in 2019, Barbosa et al. reported on the creation of a new sunscreen formulation using polymeric nanocapsules loading BP-3. The nanocapsules are made of poly(ε-caprolactone) carrot oil and Pluronic F68 (nonionic surfactant used in suspension cultures), and the BP-3–loaded capsules were found to be noncytotoxic in L929 fibroblast cell lines with a sun protection factor of 8.64. The researchers concluded that this promising nanocapsule may be an effective and safe way to use lipophilic sunscreen ingredients such as BP-3.¹⁵

Conclusion

The body of evidence is weighted against the use of BPs. Luckily, we have safe sunscreen choices that allow us to protect our skin without using these compounds.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann has written two textbooks and a New York Times Best Sellers book for consumers. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Revance, Evolus, and Burt’s Bees. She is the CEO of Skin Type Solutions Inc., a company that independently tests skin care products and makes recommendations to physicians on which skin care technologies are best. Write to her at [email protected].

References

1. Utsunomiya H et al. Chem Biol Interact. 2019 Jan 25;298:52-6.

2. Schneider SL and Lim HW. J Am Acad Dermatol. 2019 Jan;80(1):266-71.

3. Yeager DG and Lim HW. Dermatol Clin. 2019 Apr;37(2):149-57.

4. Ramos S et al. Sci Total Environ. 2015 Sep 1;526:278-311.

5. Siller A et al. Plast Surg Nur. 2019 Oct/Dec;39(4):157-60.

6. Krause M et al. Int J Androl. 2012 Jun;35(3):424-36.

7. Wang J and Ganley CJ. Clin Pharmacol Ther. 2019 Jan;105(1):161-7.

8. Matta MK et al. JAMA. 2020 Jan 21;323(3):256-67.

9. Warshaw EM et al. Dermatitis. 2013 Jul-Aug;24(4):176-82.

10. Amar SK et al. Toxicol Lett. 2015 Dec 15;239(3):182-93.

11. Amar SK et al. Toxicol Ind Health. 2019 Jul;35(7):457-65.

12. EWG. The trouble with ingredients in sunscreens. Accessed on 4 April 2020.

13. Panico A et al. J Prev Med Hyg. 2019 Mar 29;60(1):E50-7.

14. International Agency for Research on Cancer (IARC). Benzophenone. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. WHO, IARC Press, Lyon, France. 2010;101:285-304.

15. Barbosa TC et al. Toxics. 2019 Sep 22;7(4):51.

Benzophenones are a family of compounds that include dixoxybenzone, sulisobenzone, and benzophenone-3, or oxybenzone. These benzophenones are found in various skin care and personal care products, including body washes, exfoliants, fragrances, liquid hand soaps, lip balms, lipsticks, moisturizers, styling gels/creams, and sunscreens, as well as conditioners, hair sprays, and shampoos. Benzophenones (BPs) act as penetration enhancers, as they modify the structure of the skin and facilitate the absorption of other chemical ingredients into the body. The best known uses of these compounds are as perfume fixatives and sunscreen agents.

Sunscreens and benzophenones

BP-2, -3 and -4 are used as sunscreens but have many downsides. They are well known photoallergens, are toxic to aquatic animals (especially BP-3), and are found in urine. BP-2 has weak estrogenic effects, and some studies suggest that it decreases fertility in men. BP-4 can increase absorption of pesticides. BP-3 is banned in Hawaii because of the risk to coral and is the most worrisome.

mark wragg/iStockphoto.com

In particular, BP-3 is known to protect skin and hair from UV radiation-induced harm.¹ Unfortunately, BPs are also associated with photocontact allergies, hypersensitivity, hives, contact urticaria, anaphylaxis, hormone disruption, and DNA damage.^2,3 BP-3 has also been implicated as an environmental contaminant. This column will focus on recent studies pertaining to effects on humans, primarily, and on the role of BPs in sunscreen agents.
 

Effects of BPs in animals

A recent study on the cytotoxicity of BP-3 against thymocytes in rats revealed that cell mortality increased significantly after 3 hours of exposure to 300 μM BP-3, but the membrane potential of thymocytes was unchanged by BP-3 exposure. In a concentration-dependent fashion, intracellular Zn2+ levels increased significantly after administration of at least 30 μM BP-3. The investigators concluded that the cytotoxicity engendered by BP-3 could be the result of oxidative stress linked to elevated intracellular Zn2+ levels.¹

Effects of BPs in humans and systemic absorption

In multiple studies, exposure to BP-3, as well as to octinoxate, has been linked to endocrine and hormonal disruptions in humans and animals.^4,5 Motivated by several notable observations (global increase in the use of sunscreens with UV filters; rapid rise in malignant melanoma, against which sunscreens should protect; increase in reported experimental findings of UV filters acting as endocrine disruptors), Krause et al. in 2012 reviewed animal and human data on the UV filters BP-3, 3-benzylidene camphor (3-BC), 3-(4-methyl-benzylidene) camphor (4-MBC), 2-ethylhexyl 4-methoxy cinnamate (OMC), homosalate (HMS), 2-ethylhexyl 4-dimethylaminobenzoate, and 4-aminobenzoic acid (PABA). Importantly, BP-3 was present in 96% of human urine samples in the United States, and various filters were found in 85% of the human breast milk samples in Switzerland.⁶

A 2019 analysis by Wang and Ganley reported that systemic absorption of the active sunscreen ingredient BP-3 can be substantial, justifying the assessment and understanding of systemic exposure to characterize the risks of long-term usage.⁷

Between January and February 2019, Matta et al. conducted a randomized clinical trial with 48 healthy participants to evaluate the systemic absorption and pharmacokinetics of six active ingredients in four sunscreen formulations, including avobenzone and BP-3. The researchers found that all ingredients were systemically absorbed, with plasma concentrations exceeding the Food and Drug Administration threshold for considering the waiving of further safety studies. They concluded that these results did not warrant discontinuing the use of the tested sunscreen ingredients.⁸ Yeager and Lim add that, while BP-3 has been incorporated into sunscreen formulations for sale in the United States since 1978, there have been no reports of adverse systemic reactions in human beings.³

However, topical reactions have elicited a different assessment. That is, in 2014, the American Contact Dermatitis Society labeled BPs the Contact Allergen of the Year, as they were identified as the most common source of photoallergic and contact allergic reactions of all UV filters.^3,9

Risks of BPs in sunscreens and other skincare products

In 2015, Amar et al. investigated the photogenotoxicity and apoptotic effects in human keratinocytes (HaCaT cells) of BP-1, which is used as a UV blocker in sunscreens. They found that BP-1, when exposed to UV radiation, photosensitized cells and yielded intracellular reactive oxygen species. Significant reductions in cell viability were also seen with exposure to sunlight, UVA, and UVB. The researchers also confirmed genotoxic activity, with BP-1 augmenting lipid peroxidation and upregulating apoptotic proteins. They concluded that sunscreen users should be advised to avoid products that contain BP-1.¹⁰

In 2019, Amar et al. evaluated the effects of BPs on the differential expression of proteins in HaCaT cells exposed to UVA. Their findings indicated the expression of novel proteins that helped to initiate or promote apoptosis. They concluded that, because of the predilection to render such effects in human skin keratinocytes, consumers should avoid the use of sunscreens that contain BPs as UV blocking ingredients.¹¹

Still widely used as an effective filter against UVA2 and UVB, BP-3 was believed to be present in two thirds of nonmineral sunscreens in the United States in 2018.^3,12

Notably, BP-1 and BP-3 were found in small proportions (3.7% and 4.9%, respectively) among a total of 283 products culled from various stores in Lecce, Italy, in a survey of the potentially dangerous chemicals found in rinse-off, leave-on, and makeup products in 2019.¹³ The authors added that the International Agency for Research on Cancer, in 2010, classified BP as potentially carcinogenic to humans (2B group).^13,14

Promising use of nanocapsules

The widespread concern about the phototoxicity of BP has prompted some interesting research into workarounds. Specifically, in 2019, Barbosa et al. reported on the creation of a new sunscreen formulation using polymeric nanocapsules loading BP-3. The nanocapsules are made of poly(ε-caprolactone) carrot oil and Pluronic F68 (nonionic surfactant used in suspension cultures), and the BP-3–loaded capsules were found to be noncytotoxic in L929 fibroblast cell lines with a sun protection factor of 8.64. The researchers concluded that this promising nanocapsule may be an effective and safe way to use lipophilic sunscreen ingredients such as BP-3.¹⁵

Conclusion

The body of evidence is weighted against the use of BPs. Luckily, we have safe sunscreen choices that allow us to protect our skin without using these compounds.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann has written two textbooks and a New York Times Best Sellers book for consumers. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Revance, Evolus, and Burt’s Bees. She is the CEO of Skin Type Solutions Inc., a company that independently tests skin care products and makes recommendations to physicians on which skin care technologies are best. Write to her at [email protected].

References

1. Utsunomiya H et al. Chem Biol Interact. 2019 Jan 25;298:52-6.

2. Schneider SL and Lim HW. J Am Acad Dermatol. 2019 Jan;80(1):266-71.

3. Yeager DG and Lim HW. Dermatol Clin. 2019 Apr;37(2):149-57.

4. Ramos S et al. Sci Total Environ. 2015 Sep 1;526:278-311.

5. Siller A et al. Plast Surg Nur. 2019 Oct/Dec;39(4):157-60.

6. Krause M et al. Int J Androl. 2012 Jun;35(3):424-36.

7. Wang J and Ganley CJ. Clin Pharmacol Ther. 2019 Jan;105(1):161-7.

8. Matta MK et al. JAMA. 2020 Jan 21;323(3):256-67.

9. Warshaw EM et al. Dermatitis. 2013 Jul-Aug;24(4):176-82.

10. Amar SK et al. Toxicol Lett. 2015 Dec 15;239(3):182-93.

11. Amar SK et al. Toxicol Ind Health. 2019 Jul;35(7):457-65.

12. EWG. The trouble with ingredients in sunscreens. Accessed on 4 April 2020.

13. Panico A et al. J Prev Med Hyg. 2019 Mar 29;60(1):E50-7.

14. International Agency for Research on Cancer (IARC). Benzophenone. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. WHO, IARC Press, Lyon, France. 2010;101:285-304.

15. Barbosa TC et al. Toxics. 2019 Sep 22;7(4):51.

Benzophenones are a family of compounds that include dixoxybenzone, sulisobenzone, and benzophenone-3, or oxybenzone. These benzophenones are found in various skin care and personal care products, including body washes, exfoliants, fragrances, liquid hand soaps, lip balms, lipsticks, moisturizers, styling gels/creams, and sunscreens, as well as conditioners, hair sprays, and shampoos. Benzophenones (BPs) act as penetration enhancers, as they modify the structure of the skin and facilitate the absorption of other chemical ingredients into the body. The best known uses of these compounds are as perfume fixatives and sunscreen agents.

Sunscreens and benzophenones

BP-2, -3 and -4 are used as sunscreens but have many downsides. They are well known photoallergens, are toxic to aquatic animals (especially BP-3), and are found in urine. BP-2 has weak estrogenic effects, and some studies suggest that it decreases fertility in men. BP-4 can increase absorption of pesticides. BP-3 is banned in Hawaii because of the risk to coral and is the most worrisome.

mark wragg/iStockphoto.com

In particular, BP-3 is known to protect skin and hair from UV radiation-induced harm.¹ Unfortunately, BPs are also associated with photocontact allergies, hypersensitivity, hives, contact urticaria, anaphylaxis, hormone disruption, and DNA damage.^2,3 BP-3 has also been implicated as an environmental contaminant. This column will focus on recent studies pertaining to effects on humans, primarily, and on the role of BPs in sunscreen agents.
 

Effects of BPs in animals

A recent study on the cytotoxicity of BP-3 against thymocytes in rats revealed that cell mortality increased significantly after 3 hours of exposure to 300 μM BP-3, but the membrane potential of thymocytes was unchanged by BP-3 exposure. In a concentration-dependent fashion, intracellular Zn2+ levels increased significantly after administration of at least 30 μM BP-3. The investigators concluded that the cytotoxicity engendered by BP-3 could be the result of oxidative stress linked to elevated intracellular Zn2+ levels.¹

Effects of BPs in humans and systemic absorption

In multiple studies, exposure to BP-3, as well as to octinoxate, has been linked to endocrine and hormonal disruptions in humans and animals.^4,5 Motivated by several notable observations (global increase in the use of sunscreens with UV filters; rapid rise in malignant melanoma, against which sunscreens should protect; increase in reported experimental findings of UV filters acting as endocrine disruptors), Krause et al. in 2012 reviewed animal and human data on the UV filters BP-3, 3-benzylidene camphor (3-BC), 3-(4-methyl-benzylidene) camphor (4-MBC), 2-ethylhexyl 4-methoxy cinnamate (OMC), homosalate (HMS), 2-ethylhexyl 4-dimethylaminobenzoate, and 4-aminobenzoic acid (PABA). Importantly, BP-3 was present in 96% of human urine samples in the United States, and various filters were found in 85% of the human breast milk samples in Switzerland.⁶

A 2019 analysis by Wang and Ganley reported that systemic absorption of the active sunscreen ingredient BP-3 can be substantial, justifying the assessment and understanding of systemic exposure to characterize the risks of long-term usage.⁷

Between January and February 2019, Matta et al. conducted a randomized clinical trial with 48 healthy participants to evaluate the systemic absorption and pharmacokinetics of six active ingredients in four sunscreen formulations, including avobenzone and BP-3. The researchers found that all ingredients were systemically absorbed, with plasma concentrations exceeding the Food and Drug Administration threshold for considering the waiving of further safety studies. They concluded that these results did not warrant discontinuing the use of the tested sunscreen ingredients.⁸ Yeager and Lim add that, while BP-3 has been incorporated into sunscreen formulations for sale in the United States since 1978, there have been no reports of adverse systemic reactions in human beings.³

However, topical reactions have elicited a different assessment. That is, in 2014, the American Contact Dermatitis Society labeled BPs the Contact Allergen of the Year, as they were identified as the most common source of photoallergic and contact allergic reactions of all UV filters.^3,9

Risks of BPs in sunscreens and other skincare products

In 2015, Amar et al. investigated the photogenotoxicity and apoptotic effects in human keratinocytes (HaCaT cells) of BP-1, which is used as a UV blocker in sunscreens. They found that BP-1, when exposed to UV radiation, photosensitized cells and yielded intracellular reactive oxygen species. Significant reductions in cell viability were also seen with exposure to sunlight, UVA, and UVB. The researchers also confirmed genotoxic activity, with BP-1 augmenting lipid peroxidation and upregulating apoptotic proteins. They concluded that sunscreen users should be advised to avoid products that contain BP-1.¹⁰

In 2019, Amar et al. evaluated the effects of BPs on the differential expression of proteins in HaCaT cells exposed to UVA. Their findings indicated the expression of novel proteins that helped to initiate or promote apoptosis. They concluded that, because of the predilection to render such effects in human skin keratinocytes, consumers should avoid the use of sunscreens that contain BPs as UV blocking ingredients.¹¹

Still widely used as an effective filter against UVA2 and UVB, BP-3 was believed to be present in two thirds of nonmineral sunscreens in the United States in 2018.^3,12

Notably, BP-1 and BP-3 were found in small proportions (3.7% and 4.9%, respectively) among a total of 283 products culled from various stores in Lecce, Italy, in a survey of the potentially dangerous chemicals found in rinse-off, leave-on, and makeup products in 2019.¹³ The authors added that the International Agency for Research on Cancer, in 2010, classified BP as potentially carcinogenic to humans (2B group).^13,14

Promising use of nanocapsules

The widespread concern about the phototoxicity of BP has prompted some interesting research into workarounds. Specifically, in 2019, Barbosa et al. reported on the creation of a new sunscreen formulation using polymeric nanocapsules loading BP-3. The nanocapsules are made of poly(ε-caprolactone) carrot oil and Pluronic F68 (nonionic surfactant used in suspension cultures), and the BP-3–loaded capsules were found to be noncytotoxic in L929 fibroblast cell lines with a sun protection factor of 8.64. The researchers concluded that this promising nanocapsule may be an effective and safe way to use lipophilic sunscreen ingredients such as BP-3.¹⁵

Conclusion

The body of evidence is weighted against the use of BPs. Luckily, we have safe sunscreen choices that allow us to protect our skin without using these compounds.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann has written two textbooks and a New York Times Best Sellers book for consumers. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Revance, Evolus, and Burt’s Bees. She is the CEO of Skin Type Solutions Inc., a company that independently tests skin care products and makes recommendations to physicians on which skin care technologies are best. Write to her at [email protected].

References

1. Utsunomiya H et al. Chem Biol Interact. 2019 Jan 25;298:52-6.

2. Schneider SL and Lim HW. J Am Acad Dermatol. 2019 Jan;80(1):266-71.

3. Yeager DG and Lim HW. Dermatol Clin. 2019 Apr;37(2):149-57.

4. Ramos S et al. Sci Total Environ. 2015 Sep 1;526:278-311.

5. Siller A et al. Plast Surg Nur. 2019 Oct/Dec;39(4):157-60.

6. Krause M et al. Int J Androl. 2012 Jun;35(3):424-36.

7. Wang J and Ganley CJ. Clin Pharmacol Ther. 2019 Jan;105(1):161-7.

8. Matta MK et al. JAMA. 2020 Jan 21;323(3):256-67.

9. Warshaw EM et al. Dermatitis. 2013 Jul-Aug;24(4):176-82.

10. Amar SK et al. Toxicol Lett. 2015 Dec 15;239(3):182-93.

11. Amar SK et al. Toxicol Ind Health. 2019 Jul;35(7):457-65.

12. EWG. The trouble with ingredients in sunscreens. Accessed on 4 April 2020.

13. Panico A et al. J Prev Med Hyg. 2019 Mar 29;60(1):E50-7.

14. International Agency for Research on Cancer (IARC). Benzophenone. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. WHO, IARC Press, Lyon, France. 2010;101:285-304.

15. Barbosa TC et al. Toxics. 2019 Sep 22;7(4):51.