A Multicentre Retrospective Analysis of Toxicity in 6-weekly Versus 3-weekly Pembrolizumab.

Pembrolizumab is an anti-programmed cell death protein 1 immune checkpoint inhibitor with a dosing schedule of 200 mg 3 weekly (q3w). Dose of 400 mg 6 weekly (q6w) was approved based on simulation of dose/exposure relationships and predicted no difference in toxicity. We present real-world comparative toxicity data. Patients receiving pembrolizumab for any indication between March and December 2019 were included across 3 regional centers. Toxicity data were collected retrospectively using Common Terminology Criteria for Adverse Events, v5.0. Clinically significant immune-related adverse events (CSirAE) were defined as immune-related events and grade ≥3 rash. Data were analyzed using incidence (Poisson distribution) and incidence ratio. Overall, 63 patients started on q6w and 110 patients received q3w. There were 3 (q6w) and 8 (q3w) grade 3-5 CSirAE and 13 (q6w) and 31 (q3w) grade 1-2 CSirAE. The incidence of grade 3-5 CSirAE was 0.77 (95% confidence interval: 0.16-2.24) per 100 patient-months in q6w and 0.68 (95% confidence interval: 0.29-1.34) per 100 patient-months in q3w (incidence ratio of 1.13; 95% confidence interval: 0.19-4.70). Low-grade toxicity was common (fatigue, pruritus, rash; q6w 46%, q3w 42%). Incidence of CSirAEs was low but low-grade toxicity was common. Despite a limited number of events, there is the suggestion that the q6w schedule has a similar toxicity profile to q3w and therefore consideration should be given to the reduced burden to patients and health services when deciding treatment.

Brief Report: Modeling the Impact of Voluntary Medical Male Circumcision on Cervical Cancer in Uganda.

BACKGROUND: In addition to providing millions of men with lifelong lower risk for HIV infection, voluntary medical male circumcision (VMMC) also provides female partners with health benefits including decreased risk for human papillomavirus (HPV) and resultant cervical cancer (CC). SETTING: We modeled potential impacts of VMMC on CC incidence and mortality in Uganda as an additional benefit beyond HIV prevention. METHODS: HPV and CC outcomes were modeled using the CC model from the Spectrum policy tool suite, calibrated for Uganda, to estimate HPV infection incidence and progression to CC, using a 50-year (2018-2067) time horizon. 2016 Demographic Health Survey data provided baseline VMMC coverage. The baseline (no VMMC scale-up beyond current coverage, minimal HPV vaccination coverage) was compared with multiple scenarios to assess the varying impact of VMMC according to different implementations of HPV vaccination and HPV screening programs. RESULTS: Without further intervention, annual CC incidence was projected to rise from 16.9 to 31.2 per 100,000 women in 2067. VMMC scale-up alone decreased 2067 annual CC incidence to 25.3, averting 13,000 deaths between 2018 and 2067. With rapidly-achieved 90% HPV9 vaccination coverage for adolescent girls and young women, 2067 incidence dropped below 10 per 100,000 with or without a VMMC program. With 45% vaccine coverage, the addition of VMMC scaleup decreased incidence by 2.9 per 100,000 and averted 8000 additional deaths. Similarly, with HPV screen-and-treat without vaccination, the addition of VMMC scaleup decreased incidence by 5.1 per 100,000 and averted 10,000 additional deaths. CONCLUSIONS: Planned VMMC scale-up to 90% coverage from current levels could prevent a substantial number of CC cases and deaths in the absence of rapid scale-up of HPV vaccination to 90% coverage.

Impact of male circumcision on risk of HIV infection in men in a changing epidemic context - systematic review and meta-analysis.

INTRODUCTION: WHO/UNAIDS recommended Voluntary Medical Male Circumcision in 2007 based on systematic review of observational studies prior to 1999 and three randomized controlled trials (RCTs). To inform updated WHO guidance, we conducted a systematic review and meta-analysis of impact of circumcision on the risk of HIV infection among heterosexual men. METHODS: Studies in PubMed of HIV incidence and changes in prevalence in heterosexual men by circumcision status were identified. Pooled incidence rate ratios were computed using fixed- and random-effects meta-analysis and risk of bias was assessed using the ROBINS-I tool. RESULTS AND DISCUSSION: In three RCTs, the pooled incidence ratio was 0.41 (95% CI 0.30 to 0.56), with risk difference 10 (8 to 12) fewer infections per 1000 person-years (py). Pooled incidence ratios were 0.34 (0.24 to 0.49) in two post-RCT follow-up studies, 0.29 (0.19 to 0.43) in men at high HIV risk (five cohorts), 0.48 (0.33 to 0.70) in four community-based cohorts before circumcision scale-up, and 0.56 (0.49 to 0.64) (7 [6 to 8] fewer per 1000 py) in six community-based cohorts during circumcision and antiretroviral treatment scale-up. Heterogeneity between studies was low except in men at high HIV risk. We estimated 520,000 (425,000 to 605,000) fewer infections occurred in men by end of 2018 from 22.7 million circumcisions performed since 2008 and increasing by 155,000 (125,000 to 180,000) annually if epidemic conditions remain similar. After exclusion of studies with high risk of bias and those conducted outside Africa, pooled incidence ratios were similar. There was no evidence of confounding nor changes in risk behaviour following circumcision. In post-hoc exploratory analyses we observed a trend of decreasing effectiveness of circumcision in cohorts with lower HIV incidence. CONCLUSIONS: Efficacy of medical male circumcision on HIV incidence from randomized controlled trials was supported by effectiveness from observational studies in populations with diverse HIV risk and changing epidemic contexts. Voluntary Medical Male Circumcision remains an important evidence-based intervention for control of generalized HIV epidemics.

Correction: Assessing Progress, Impact, and Next Steps in Rolling Out Voluntary Medical Male Circumcision for HIV Prevention in 14 Priority Countries in Eastern and Southern Africa through 2014.

[This corrects the article DOI: 10.1371/journal.pone.0158767.].

Re-analysing tobacco industry funded research on the effect of plain packaging on minors in Australia: Same data but different results.

INTRODUCTION: Our objective was to re-analyse the data used in an industry-funded working paper to study the effect of plain packaging on youth smoking prevalence in Australia, allowing for other tobacco control measures introduced over the period 2001-2013, and using a more appropriate method of analysis. METHODS: Monthly smoking prevalence and sample sizes from repeat cross-sectional surveys were reconstructed from the working paper by reverse engineering of the industry-presented data, and analysed as a time series using logistic regression. Power analysis presented in the industry-funded working paper was re-calculated. RESULTS: Smoking prevalence among minors in Australia declined from 11.6% to 5.6% over the 13-year period examined; an overall 52% relative reduction or an average annual reduction of 5.5% (95% confidence interval 4.6% to 6.4%). There was a 12.1% (-4.8% to 26.2%) relative reduction in smoking prevalence when plain packaging was introduced, though the reduction was not statistically significant. Re-calculated power values were much lower than those reported in the industry-funded paper, confirming the inconclusiveness of its findings, as pointed out in previous critiques. CONCLUSIONS: Our findings suggest a decline of smoking prevalence in minors following the introduction of plain packaging in Australia. They differ substantially from those presented in an industry-funded study on the effects of plain packaging on smoking prevalence in minors in Australia, which used the same data.

Correction: Assessing Progress, Impact, and Next Steps in Rolling Out Voluntary Medical Male Circumcision for HIV Prevention in 14 Priority Countries in Eastern and Southern Africa through 2014.

[This corrects the article DOI: 10.1371/journal.pone.0158767.].

Assessing Progress, Impact, and Next Steps in Rolling Out Voluntary Medical Male Circumcision for HIV Prevention in 14 Priority Countries in Eastern and Southern Africa through 2014.

BACKGROUND: In 2007, the World Health Organization and the Joint United Nations Programme on HIV/AIDS (UNAIDS) identified 14 priority countries across eastern and southern Africa for scaling up voluntary medical male circumcision (VMMC) services. Several years into this effort, we reflect on progress. METHODS: Using the Decision Makers' Program Planning Tool (DMPPT) 2.1, we assessed age-specific impact, cost-effectiveness, and coverage attributable to circumcisions performed through 2014. We also compared impact of actual progress to that of achieving 80% coverage among men ages 15-49 in 12 VMMC priority countries and Nyanza Province, Kenya. We populated the models with age-disaggregated VMMC service statistics and with population, mortality, and HIV incidence and prevalence projections exported from country-specific Spectrum/Goals files. We assumed each country achieved UNAIDS' 90-90-90 treatment targets. RESULTS: More than 9 million VMMCs were conducted through 2014: 43% of the estimated 20.9 million VMMCs required to reach 80% coverage by the end of 2015. The model assumed each country reaches the UNAIDS targets, and projected that VMMCs conducted through 2014 will avert 240,000 infections by the end of 2025, compared to 1.1 million if each country had reached 80% coverage by the end of 2015. The median estimated cost per HIV infection averted was $4,400. Nyanza Province in Kenya, the 11 priority regions in Tanzania, and Uganda have reached or are approaching MC coverage targets among males ages 15-24, while coverage in other age groups is lower. Across all countries modeled, more than half of the projected HIV infections averted were attributable to circumcising 10- to 19-year-olds. CONCLUSIONS: The priority countries have made considerable progress in VMMC scale-up, and VMMC remains a cost-effective strategy for epidemic impact, even assuming near-universal HIV diagnosis, treatment coverage, and viral suppression. Examining circumcision coverage by five-year age groups will inform countries' decisions about next steps.

Hand Blisters in Major League Baseball Pitchers: Current Concepts and Management.

Friction blisters are a common sequela of many athletic activities. Their significance can range from minor annoyance to major performance disruptions. The latter is particularly true in baseball pitchers, who sustain repeated trauma between the baseball seams and the fingers of the pitching hand, predominately at the tips of the index and long fingers. Since 2010, 6 Major League Baseball (MLB) players accounted for 7 stints on the disabled list (DL) due to blisters. These injuries resulted in a total of 151 days spent on the DL. Since 2012, 8 minor league players spent time on the DL due to blisters. Moreover, there have been several documented and publicized instances of professional baseball pitchers suffering blisters that did not require placement on the DL but did result in injury time and missed starts. The purpose of this article is to review the etiology and pathophysiology of friction blisters with particular reference to baseball pitchers; provide an overview of past and current prevention methods; and discuss our experience in treating friction blisters in MLB pitchers.

Maternal anaemia and duration of zidovudine in antiretroviral regimens for preventing mother-to-child transmission: a randomized trial in three African countries.

BACKGROUND: Although substantiated by little evidence, concerns about zidovudine-related anaemia in pregnancy have influenced antiretroviral (ARV) regimen choice for preventing mother-to-child transmission of HIV-1, especially in settings where anaemia is common. METHODS: Eligible HIV-infected pregnant women in Burkina Faso, Kenya and South Africa were followed from 28 weeks of pregnancy until 12-24 months after delivery (n = 1070). Women with a CD4 count of 200-500 cells/mm(3) and gestational age 28-36 weeks were randomly assigned to zidovudine-containing triple-ARV prophylaxis continued during breastfeeding up to 6-months, or to zidovudine during pregnancy plus single-dose nevirapine (sd-NVP) at labour. Additionally, two cohorts were established, women with CD4 counts: <200 cells/mm(3) initiated antiretroviral therapy, and >500 cells/mm(3) received zidovudine during pregnancy plus sd-NVP at labour. Mild (haemoglobin 8.0-10.9 g/dl) and severe anaemia (haemoglobin < 8.0 g/dl) occurrence were assessed across study arms, using Kaplan-Meier and multivariable Cox proportional hazards models. RESULTS: At enrolment (corresponded to a median 32 weeks gestation), median haemoglobin was 10.3 g/dl (IQR = 9.2-11.1). Severe anaemia occurred subsequently in 194 (18.1%) women, mostly in those with low baseline haemoglobin, lowest socio-economic category, advanced HIV disease, prolonged breastfeeding (≥ 6 months) and shorter ARV exposure. Severe anaemia incidence was similar in the randomized arms (equivalence P-value = 0.32). After 1-2 months of ARV's, severe anaemia was significantly reduced in all groups, though remained highest in the low CD4 cohort. CONCLUSIONS: Severe anaemia occurs at a similar rate in women receiving longer triple zidovudine-containing regimens or shorter prophylaxis. Pregnant women with pre-existing anaemia and advanced HIV disease require close monitoring. TRIAL REGISTRATION NUMBER: ISRCTN71468401.

Postoperative shoulder magnetic resonance imaging.

Magnetic resonance imaging (MRI) and MR arthrography have proven invaluable for managing the postoperative shoulder, particularly in relation to the rotator cuff and labrum. MRI has proven to be an accurate imaging technique for differentiating expected findings versus complications in the postoperative setting. The transition from metallic hardware to bioabsorbable suture anchors used in orthopedic surgery has rendered less metallic susceptibility artifact over the years, allowing more accurate interpretation of MR images. This article gives a pictorial review of various expected postoperative findings in the shoulder and complications related to repair of the rotator cuff and labrum.

Voluntary medical male circumcision: modeling the impact and cost of expanding male circumcision for HIV prevention in eastern and southern Africa.

BACKGROUND: There is strong evidence showing that voluntary medical male circumcision (VMMC) reduces HIV incidence in men. To inform the VMMC policies and goals of 13 priority countries in eastern and southern Africa, we estimate the impact and cost of scaling up adult VMMC using updated, country-specific data. METHODS AND FINDINGS: We use the Decision Makers' Program Planning Tool (DMPPT) to model the impact and cost of scaling up adult VMMC in Botswana, Lesotho, Malawi, Mozambique, Namibia, Rwanda, South Africa, Swaziland, Tanzania, Uganda, Zambia, Zimbabwe, and Nyanza Province in Kenya. We use epidemiologic and demographic data from recent household surveys for each country. The cost of VMMC ranges from US$65.85 to US$95.15 per VMMC performed, based on a cost assessment of VMMC services aligned with the World Health Organization's considerations of models for optimizing volume and efficiencies. Results from the DMPPT models suggest that scaling up adult VMMC to reach 80% coverage in the 13 countries by 2015 would entail performing 20.34 million circumcisions between 2011 and 2015 and an additional 8.42 million between 2016 and 2025 (to maintain the 80% coverage). Such a scale-up would result in averting 3.36 million new HIV infections through 2025. In addition, while the model shows that this scale-up would cost a total of US$2 billion between 2011 and 2025, it would result in net savings (due to averted treatment and care costs) amounting to US$16.51 billion. CONCLUSIONS: This study suggests that rapid scale-up of VMMC in eastern and southern Africa is warranted based on the likely impact on the region's HIV epidemics and net savings. Scaling up of safe VMMC in eastern and southern Africa will lead to a substantial reduction in HIV infections in the countries and lower health system costs through averted HIV care costs.

Sino-implant (II)--a levonorgestrel-releasing two-rod implant: systematic review of the randomized controlled trials.

BACKGROUND: Sino-implant (II) is a subdermal contraceptive implant manufactured in China. This two-rod levonorgestrel-releasing implant has the same amount of active ingredient (150 mg levonorgestrel) and mechanism of action as the widely available contraceptive implant Jadelle. We examined randomized controlled trials of Sino-implant (II) for effectiveness and side effects. STUDY DESIGN: We searched electronic databases for studies of Sino-implant (II) and then restricted our review to randomized controlled trials. The primary outcome of this review was pregnancy. RESULTS: Four randomized trials with a total of 15,943 women assigned to Sino-implant (II) had first-year probabilities of pregnancy ranging from 0.0% to 0.1%. Cumulative probabilities of pregnancy during the 4 years of the product's approved duration of use were 0.9% and 1.06% in the two trials that presented date for 4-year use. Five-year cumulative probabilities of pregnancy ranged from 0.7% to 2.1%. In one trial, the cumulative probability of pregnancy more than doubled during the fifth year (from 0.9% to 2.1%), which may be why the implant is approved for 4 years of use in China. Five-year cumulative probabilities of discontinuation due to menstrual problems ranged from 12.5% to 15.5% for Sino-implant (II). CONCLUSIONS: Sino-implant (II) is one of the most effective contraceptives available today. These available clinical data, combined with independent laboratory testing, and the knowledge that 7 million women have used this method since 1994, support the safety and effectiveness of Sino-implant (II). The lower cost of Sino-implant (II) compared with other subdermal implants could improve access to implants in resource-constrained settings.

Prospective study of weight change in new adolescent users of DMPA, NET-EN, COCs, nonusers and discontinuers of hormonal contraception.

BACKGROUND: Weight gain is commonly reported as a side effect of hormonal contraception and can lead to method discontinuation or reluctance to initiate the method. The purpose of this study was to investigate weight change in adolescent (aged 15-19 years) users of depot-medroxyprogesterone acetate (DMPA), norethisterone enanthate (NET-EN), combined oral contraceptives (COCs) and discontinuers of these methods as compared to nonusers of hormonal contraception. STUDY DESIGN: This longitudinal study recruited initiators of DMPA (n=115), NET-EN (n=115), COCs (n=116) and nonusers of contraception (n=144). Participants were followed up for 4-5 years, and details of current contraceptive method, including switching, discontinuing and/or starting hormonal methods were documented at each 6-monthly visit. Women were classified according to their contraceptive histories on completion of the study, and injectable users were combined into one group for analysis. Height, weight and self-reported dieting were recorded at each visit. RESULTS: There was no difference in mean age or weight between the groups at baseline. Women using DMPA or NET-EN throughout, or switching between the two, had gained an average of 6.2 kg compared to average increases of 2.3 kg in the COC group, 2.8 kg in nonusers and 2.8 kg among discontinued users of any method (p=.02). There was no evidence of a difference in weight gain between women classified as nonobese or classified as overweight/obese in any of the four study groups at baseline. CONCLUSION: There is fairly strong evidence that adolescent contraceptive hormonal injectable users appear to gain more weight than COC users, discontinuers and nonusers of contraception.

Bone mineral density in young women aged 19-24 after 4-5 years of exclusive and mixed use of hormonal contraception.

BACKGROUND: Use of depot-medroxyprogesterone acetate (DMPA), norethisterone enanthate (NET-EN) and low-dose combined oral contraceptives (COCs) has been associated with loss of bone mineral density (BMD) in adolescents. However, the effect of using a combination of these methods over time in this age group is limited. The aim of this cross-sectional study was to investigate BMD in young women (aged 19-24 years) with a history of mixed hormonal contraceptive use. STUDY DESIGN: BMD was measured at the spine, hip and femoral neck using dual X-ray absorptiometry. Women were classified into three groups: (1) injectable users (DMPA, NET-EN or both) (n=40), (2) mixed COC and injectable users (n=13) and (3) non-user control (n=41). RESULTS: Women in the injectables-only user group were found to have lower BMDs compared to the non-user group at all three sites, and there was evidence of a difference in BMD between these two groups at the spine after adjusting for body mass index (p=.042), hip (p=.025) and femoral neck (p=.023). The mixed COC/injectable user group BMD values were lower than those for controls; however, there was no evidence of a significant difference between this group and the non-user group at any of the three sites. CONCLUSION: This study suggests that BMD is lower in long-term injectable users but not when women have mixed injectable and COC use.

Bone mineral density in a cohort of adolescents during use of norethisterone enanthate, depot-medroxyprogesterone acetate or combined oral contraceptives and after discontinuation of norethisterone enanthate.

BACKGROUND: Depot medroxyprogesterone acetate (DMPA), norethisterone enanthate (NET-EN) and combined oral contraceptives (COCs) have been shown to have a negative effect on bone mineral density (BMD) in adolescents. The aim of this study was to investigate BMD in 15- to 19-year-old new users of DMPA, NET-EN and COCs. STUDY DESIGN: This 5-year longitudinal study followed up new users of DMPA (n=115), NET-EN (n=115) and COCs (n=116) and 144 nonuser controls. BMD was measured at the distal radius using dual-energy X-ray absorptiometry. RESULTS: BMD increased in all groups (annual percent increase: nonusers, 1.49%; DMPA, 1.39%; NET-EN, 1.03%; COCs, 0.84%) during follow-up (p<.001). There was evidence for lower BMD increases per annum in NET-EN (p=.050) and COC (p=.010) users compared to nonusers but no difference between DMPA and nonusers (p=.76). In 14 NET-EN discontinuers, an overall reduction of 0.61% per year BMD was followed upon cessation by an increase of 0.69% per year (p=.066). CONCLUSION: This study suggests that BMD increases in adolescents may be less in NET-EN and COC users; however, recovery of BMD in NET-EN users was found in the small sample of adolescents followed post-discontinuation.

Prostate cancer and vasectomy: a hospital-based case-control study in China, Nepal and the Republic of Korea.

BACKGROUND: The study of a possible relationship between vasectomy and prostate cancer has yielded mixed results. Data from developing countries are limited. STUDY DESIGN: We conducted a hospital-based case-control study in China, Nepal and the Republic of Korea to evaluate the risk of prostate cancer after vasectomy. RESULTS: Prostate cancer in 294 cases (confirmed by independent pathologists) and 879 matched controls were included. The odds ratio of prostate cancer in men with a history of vasectomy was 1.21 [95% confidence interval (95% CI)=0.79, 1.87]. No significant trend was observed in risk by time since vasectomy or age at vasectomy. The odds ratio for localized disease was 1.02 (95% CI=0.53, 1.95); the odds ratio for later stages was 1.41 (95% CI=0.78, 2.53). No confounding factor was identified. The study illustrated differential misclassification of disease by vasectomy status; reference pathologists determined that 28% of men with a history of vasectomy, compared with 17% of men without a history of vasectomy, were misdiagnosed with prostate cancer by local pathologists. CONCLUSION: Vasectomy is not associated with an increased risk of prostate cancer in developing countries where the rate of the disease is low.

Prevention of human immunodeficiency virus-1 transmission to the infant through breastfeeding: new developments.

Breastfeeding accounts for up to half of all infant human immunodeficiency virus (HIV) infections worldwide and carries an estimated transmission risk of about 15% when continued into the second year of life. Because replacement feeding is not safely available, culturally acceptable, or affordable in many parts of the world and because breastfeeding provides protection against other causes of infant mortality, approaches that reduce breastfeeding mother-to child transmission of HIV are being explored. These include exclusive breastfeeding for the infant's first few months of life followed by rapid weaning, treatments of expressed milk to inactivate the virus, and antiretroviral prophylaxis taken by the infant or mother during breastfeeding, which are strategies currently being tested in clinical trials. Passive (antibodies) and active (vaccine) immunoprophylaxis will also soon begin to be tested. This paper focuses on current and planned research on strategies to prevent breastfeeding transmission of HIV.

Bone mineral density in adolescents using norethisterone enanthate, depot-medroxyprogesterone acetate or combined oral contraceptives for contraception.

PURPOSE: Most studies have shown a negative effect of depot-medroxyprogesterone acetate (DMPA) on the bone mineral density (BMD) of adolescents. There is no information available on the effect of norethisterone enanthate (NET-EN) on BMD in adolescents and the effect of combined oral contraceptives (COCs) on adolescent BMD is inconclusive. The aim of this longitudinal study was to investigate BMD in adolescent (aged 15-19 years) new users of hormonal contraception (DMPA, NET-EN and COCs). METHOD: New users of DMPA (n=115), NET-EN (n=115), COCs (n=116) and 144 nonuser controls were recruited. BMD was measured at the distal radius and midshaft of the ulna using dual X-ray absorptiometry. RESULTS: In total, 275 women were included in this interim analysis and total follow-up time was 553 person-years. There was no significant difference in radius BMD between users of different contraceptive methods at baseline (p=.40). Overall, an increase in radius BMD of 0.00522 per person-year was observed. This result was similar when adjusting for BMI in the random effects regression model (p=.88). The regression model showed that BMI was significantly associated with radius BMD, with each unit increase in BMI corresponding to an increase of 0.0029 g/cm2 in BMD (95% CI 0.0023 to 0.0036, p<.001). Interaction between contraceptive method and follow-up time adjusted for BMI was not significant (p=.07). The increase in BMD for NET-EN users of 0.0013 g/cm2 per person-year (95% CI -0.0017 to 0.0043) was significantly lower than that of nonusers (p=.017). For DMPA and COC users, the increase in BMD was not significantly different compared to the nonusers. This study suggests that NET-EN users had lower increase in BMD over time compared to the other user groups.