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Haiti is the poorest country in the Western Hemisphere and faces numerous challenges, including inadequate medication access for its residents. The objective of this study was to determine the availability, prices, and affordability of essential medicines

Background/objective: The genetic architecture of extreme non-syndromic obesity in adults remains to be elucidated. A range of genes are known to cause monogenic obesity, but even when pathogenic mutations are present, there may be variable penetrance., Methods: Whole-exome sequencing (WES) was carried out on a 15-year-old male proband of Pakistani ancestry who had severe obesity. This was followed by family segregation analysis, using Sanger sequencing. We also undertook re-analysis of WES data from 91 unrelated adults with severe obesity (86% white European ancestry) from the Personalised Medicine for Morbid Obesity (PMMO) cohort, recruited from the UK National Health Service., Results: We identified an oligogenic mode of inheritance of obesity in the proband's family-this provided the impetus to reanalyze existing sequence data in a separate dataset. Analysis of PMMO participant data revealed two further patients who carried more than one rare, predicted-deleterious mutation in a known monogenic obesity gene. In all three cases, the genes involved had known autosomal dominant inheritance, with incomplete penetrance., Conclusion: Oligogenic inheritance may explain some of the variable penetrance in Mendelian forms of obesity. We caution clinicians and researchers to avoid confining sequence analysis to individual genes and, in particular, not to stop looking when the first potentially-causative mutation is found., (© 2024. The Author(s).)

Background: Overactive bladder (OAB) is a common condition in elderly men with coexisting benign prostatic enlargement (BPE), and it significantly impairs their quality of life (QoL)., Aim: This study aimed to assess the safety and efficacy of adding beta-3 adrenergic receptor agonist (mirabegron 50 mg) to tamsulosin 0.4 mg for symptomatic men with BPE and OAB symptoms (OABS)., Materials and Methods: It was an open-labeled randomized controlled trial. Ninety men with BPE and International Prostate Symptom Score (IPSS) of more than seven with predominant OABS were enrolled for the study. A detailed history, uroflowmetry, and baseline scores, including IPSS, OABS score (OABSS), and QoL assessment, were done for each patient. After written informed consent, patients were randomized into two groups of 45 each. Group-1 received tamsulosin 0.4 mg and placebo, and Group-2 received a combination of tamsulosin 0.4 mg plus mirabegron 50 mg once daily at bedtime. Follow-up of patients was done at 2 nd , 4 th , and 8 th weeks. Efficacy at 8 weeks was assessed using repeat history for symptoms, uroflowmetry, IPSS, OABSS, and QoL score., Results: After 8 weeks of therapy, collected data were compared to baseline parameters in both groups. Significant improvement with respect to OABSS ( P = 0.046), IPSS ( P = 0.006), and QoL ( P = 0.038) was observed with combination therapy versus tamsulosin alone. There were mild adverse effects, which were self-limiting., Conclusions: A combination of tamsulosin with mirabegron is effective and safe in improving the OABSS, IPSS, and QoL in men with BPE who have predominant OABS., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 International Journal of Applied and Basic Medical Research.)

Background: Renal transplantation is the treatment of choice in patients with end-stage renal disease. However, allograft recipients are at a higher risk of infection due to immunosuppressive therapies. This study aimed to analyze the utility of fine needle aspiration cytology (FNAC) lung in the etiological diagnosis of pulmonary infections in renal allograft recipients with respiratory failure., Materials and Methods: This is a retrospective study done in post-renal transplant patients presenting with pulmonary infections and respiratory failure in the past 7 years, in whom image-guided lung FNAC was done for diagnosis., Results: A total of 35 renal allograft recipients presenting with respiratory failure and having focal or diffuse pulmonary opacities (lesions) on radiological imaging were subjected to lung FNAC. The mean age of the patients was 41.1 ± 11.8 years (range 19-72), with the majority being males ( n = 28, 80%); six (17.1%) of them were on invasive ventilation. The diagnostic yield of FNAC in our cohort was 77.1% (27 out of 35). Microorganisms were isolated in 21 cases (60%), with Nocardia being the most common (nine cases, 25.7%), Mycobacterial tuberculosis identified in six patients (17.1%), Aspergillus in three (8.6%), and one (2.9%) each had atypical Mycobacterium , zygomycetes, and Cryptococcus . FNAC suggested viral cytopathic effect in five patients, and cytomegalovirus (CMV) quantitative polymerase chain reaction test was found positive in four of these. One case was diagnosed as adenocarcinoma lung., Conclusion: Lung FNAC is a useful for establishing the etiological diagnosis of pulmonary lesions in renal transplant patients with respiratory failure., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 Indian Journal of Nephrology.)

Competing Interests: Conflict of InterestThe authors declare no competing interests.

Importance: The US Food and Drug Administration (FDA) has 4 programs that can be used alone or in combination to expedite drug availability: Accelerated Approval, Breakthrough Therapy, Fast Track, and Priority Review. Drugs using these programs can include novel drugs, which do not contain a previously FDA-approved active moiety, and orphan drugs, intended for diseases or conditions affecting fewer than 200 000 people; to date, no comprehensive evaluation of how these programs have been used in combination has been published., Objective: To assess how often and in what combinations expedited programs are used in the development and review of approved novel biologics and small-molecule drugs, stratified by orphan drug status and indication., Design, Setting, and Participants: This cross-sectional study evaluated all novel drugs that were FDA approved between January 1, 2008, and December 31, 2021., Main Outcomes and Measures: The main outcome was the frequency with which expedited programs were used and in what combinations, stratified by orphan drug status and drug type (small molecule vs therapeutic biologic). The unit of analysis was the novel drug-indication pair because a drug can be approved for multiple indications, each of which may use a different expedited program or differ in orphan drug status., Results: The study included 581 novel drug-indication pairs approved during the 14-year study period; 252 (43.4%) were orphan drugs, 139 (23.9%) were therapeutic biologics, and 442 (76.1%) were small-molecule drugs. Use of at least 1 expedited program increased from 11 of 26 drug-indication pairs (42.3%) in 2008 to 41 of 55 (74.5%) in 2021. Of the 363 approved drug-indication pairs using at least 1 expedited program, 225 (62.0%) were orphan drugs; at least 1 expedited program was used by 97 of the 139 approved biologic drugs (69.8%) and by 266 of the 442 approved small-molecule drugs (60.2%). Eighty-two of the 581 novel drug-indication pairs (14.1%) used the Accelerated Approval Program; of those, 65 (79.3%) were oncology drugs and 70 (85.4%) had an orphan designation., Conclusions and Relevance: The study showed that use of the FDA's expedited programs to bring novel drugs to market in the US increased from 2008 to 2021. The findings suggest that this trend is likely to continue.

Background: Complicated urinary tract infection (cUTI) is the one which is associated with structural and functional abnormalities of the urinary tract, thus increasing the risk of infection and failure of therapy., Aim: This study aims to determine the risk factors, changing trends in etiology, current treatment options, and outcomes in cUTI., Materials and Methods: This prospective observational study was done on patients presenting with cUTI. Hematological, biochemical workup, urine routine, urine culture, blood culture, ultrasonography, and wherever necessary computerized tomography of the genitourinary tract was done. The medical/surgical interventions and outcomes in these patients were recorded., Results: A total of 100 patients were enrolled in the study. Diabetes mellitus was the most common risk factor present in 53%. The most common organism isolated in urine culture was Escherichia coli (48%) followed by Klebsiella pneumoniae (19%) and similar trend but lesser positive yield was there in blood culture ( Escherichia coli - 26% followed by Klebsiella pneumoniae - 3%). The organisms were most susceptible to colistin/polymyxin (100%) followed by carbapenems (88%), and later were the most commonly used empirical antibiotics in our study, yielding 95% survival rate. Surgical interventions (percutaneous/endourological) were required in 28%, renal replacement therapy in 14%, intensive care in 40% and mechanical ventilation in 10%, with 4% overall mortality at the end of 1-month follow-up. The mean duration of hospital stay was 9.1 ± 2.7 days., Conclusion: Escherichia coli was the most common organism causing cUTI, with diabetes being the most common risk factor. Most of the patients were treated with carbapenems with excellent survival outcomes., Competing Interests: There are no conflicts of interest., (Copyright: © 2022 International Journal of Applied and Basic Medical Research.)

Bilateral Tessier type 4 craniofacial clefts are extremely rare and disfiguring malformations with vision-threatening ramifications. To date, there is no consensus in the literature with respect to the ideal surgical technique and management of these patients. Emergent eyelid reconstruction and additional procedures may be required to protect the cornea and avoid further ophthalmic and surgical complications. We present our experience and challenges of managing a case of bilateral Tessier type 4 clefting with an emphasis on oculoplastic considerations.

Background: In the era of widespread antibiotic (AB) resistance, the role of prophylaxis in diagnostic cystoscopy is controversial., Aim: This study aimed to compare the incidence of postcystoscopy positive urinary culture (PC-PUC) and urinary tract infection (UTI) in patients undergoing diagnostic rigid cystoscopy with and without prophylaxis with preprocedural single-dose intravenous AB., Materials and Methods: This prospective study was done in patients with preprocedural sterile urine undergoing elective diagnostic rigid cystoscopy. Patients were randomized into two groups, with one group receiving preprocedure single dose of intravenous cefuroxime sodium as prophylaxis half to 1 h before the procedure (Group AB prophylaxis) and the other group receiving no antibiotic prophylaxis (Group NAB). All patients were followed up till 1-month postprocedure, for any symptoms of urinary infection, mandatory urine microscopy and culture at 24-48 h, 1 week and 4 weeks post procedure, and addition sample in case of any urinary symptoms or fever., Results: A total of 225 patients were studied, with 110 in AB prophylaxis and 115 in NAB groups. The use of prophylaxis did not decrease the incidence of PC-PUC (8.7%-3.6%; P = 0.167) or UTI (6.1%-1.8%; P = 0.102). Females and diabetics had significantly higher risk of PC-PUC, on univariate and multivariate analysis, not affected by prophylaxis., Conclusion: Preprocedural AB prophylaxis does not decrease the incidence of postcystoscopy bacteriuria significantly. Females and diabetics have significantly increased risk, but prophylaxis has no role in them either., Competing Interests: There are no conflicts of interest., (Copyright: © 2021 International Journal of Applied and Basic Medical Research.)

Importance: Before reviewing drug applications, the US Food and Drug Administration (FDA) conducts "filing reviews" to assess whether they are complete enough for full review. If the applications are incomplete, the FDA issues refuse-to-file (RTF) letters identifying deficiencies. The FDA does not make these RTF letters public at the time of issuance. Why the FDA issues RTF letters and how often the letters and their contents are made publicly available are unknown., Objectives: To quantitatively analyze the FDA's reasons for issuing RTF letters and assess the public transparency of RTF letters and their contents., Design and Setting: This cross-sectional study analyzes RTF letters issued in response to new drug applications and efficacy supplements (applications for new indications or patient populations for already approved drugs) submitted to the FDA between January 1, 2008, and December 31, 2017. Statistical analysis was conducted in July 2019., Main Outcomes and Measures: Two types of information were extracted and cataloged from RTF letters: (1) the reasons why the FDA refused to file applications and (2) the FDA comments that, while not a basis for RTF letters, conveyed important information to applicants. The extent to which applicants publicly disclosed the FDA's refusal reasons were also assessed., Results: The study included 103 RTF letters containing a total of 644 identified FDA refusal reasons. Among the 2475 applications that the FDA received during the study time frame, 98 (4.0%) received RTF letters. Overall, 84.5% (544 of 644) of the refusal reasons were for scientific deficiencies; most reasons were related to drug efficacy and safety (196 [30.4%]) and drug quality (125 [19.4%]). The remaining 15.5% of refusal reasons (100 of 644) were for application organization deficiencies or legal issues. A total of 26.2% of the RTF letters (27 of 103) identified presubmission advice from the FDA that applicants did not follow; the most frequently ignored advice was related to clinical trial design (33.3% [9 of 27]), followed by product chemistry and manufacturing (25.9% [7 of 27]). Applicants publicly disclosed the existence of 16 of 103 RTF letters (15.5%); however, only 5.4% of applicant-disclosed reasons (35 of 644) matched the refusal reasons that the FDA had provided in the RTF letters., Conclusions and Relevance: This cross-sectional study found that the FDA refused to file applications for substantive reasons related to quality, safety, and efficacy, and applicants' disclosure of those reasons was incomplete. This work sheds light on the FDA's regulatory decision-making processes and the RTF reasons that could delay availability of therapies to patients.

Pregnancy-related acute kidney injury (PRAKI) and urological complications can significantly increase the maternal morbidity and mortality, and morbidly adherent placenta (MAP) has been found to increase the risk of both. This is a four-year prospective study, conducted on patients with MAP. Baseline parameters (demographic/antenatal/perinatal), operative details (obstetric/urological/hemostatic), peri-operative complications (AKI/urological), and maternal/fetal outcomes were studied till six weeks after delivery. Statistical analysis was done using IBM SPSS Statistics version 21.0, and P <0.05 was considered statistically significant. Out of the 5475 deliveries conducted in the study period, 64 had adherent placentation. AKI occurred in 39.1% of patients, with severe AKI (AKIN-2, 3) in 10.9%, and significantly higher incidence in placenta percreta (P = 0.021, relative risk [RR] - 2.34), urological injuries (P = 0.001, RR - 2.86), and high blood loss (P = 0.001) on univariate analysis, but placenta percreta was the most statistically significant factor P = 0.049) on multivariate analysis. Urological involvement/injuries requiring intervention were encountered in 22 patients, with statistically significantly high incidence in placenta previa (P = 0.023, RR - 1.62), placenta percreta (P = 0.000, RR - 17.18), and patients undergoing hysterectomy (P = 0.000, RR - 2.01) on univariate analysis, but placenta percreta was most statistically significantly implicated on multivariate analysis (P = 0.017). AKI and urological injuries significantly increased the need for intensive care and days of hospitalization. On six-week follow-up, all AKI patients recovered completely; no urinary leak or vesico-vaginal fistula was seen in urologically intervened patients and no maternal mortality occurred. There is an alarmingly high incidence of PRAKI and urological complications in MAP, posing a great threat to their worldwide improving statistics. Awareness of this condition among renal fraternity can significantly improve the maternal renal and overall prognosis.

Background: Obesity surgery has pronounced effects on metabolic profile of patients with type 2 diabetes mellitus (T2DM); however, reports on long-term remission rates based on the standardised and holistic criteria by the International Diabetes Federation (IDF) and effects on T2DM microvascular complications are scarce in the literature. In this retrospective clinical trial, our objectives were to assess these variables 5 years after surgery., Methods: Clinical data and direct measurements of renal and retinal damage were collected prospectively and analysed retrospectively for 82 patients with T2DM who underwent obesity surgery and were followed up for 5 years., Results: The cohort of 82 patients with T2DM that were followed up 5 years after obesity surgery was predominantly female (71%) with a median age of 51 years, weight of 133.5 kg, BMI of 46.8 kg/m 2 and pre-operative duration of T2DM of 8 years; 6% of patients had diet-controlled T2DM, 57% were on non-insulin treatment and 37% were on insulin treatment pre-operatively. Of the total 82 patients, 59 patients underwent Roux-en-Y gastric bypass, 15 sleeve gastrectomy and 8 patients underwent gastric band operations. At 5 years, 5% and 15% patients achieved optimisation and improvement of the metabolic state based on the IDF criteria respectively. Surgery was associated with almost halving of the albumin-creatinine ratio in 22 patients with pre-existing albuminuria (follow-up data available for 64 patients) and an overall stabilisation of retinopathy in 24 patients with retinal images available at 5 years., Conclusion: Whilst the findings on microvascular complications are encouraging, the rates of metabolic remission were lower than expected and raise the need for validated protocols to assist clinicians in managing these patients more aggressively post-operatively to achieve optimum cardio-metabolic risk factor control and hopefully further reduction in microvascular and macrovascular complications.

Background: Roughly, a fourth of all placental abruption cases have an acute aetiologic underpinning, but the causes of acute abruption are poorly understood. Studies indicate that symptoms of stress, depression, and anxiety during pregnancy may be associated with a higher risk of abruption., Objective: We examined the rate of abruption in the 2 hours immediately following outbursts of anger., Methods: In a multicentre case-crossover study, we interviewed 663 women diagnosed with placental abruption admitted to one of the seven Peruvian hospitals between January 2013 and August 2015. We asked women about outbursts of anger before symptom onset and compared this with their usual frequency of anger during the week before abruption., Results: The rate of abruption was 2.83-fold (95% confidence interval [CI] 1.85, 4.33) higher in the 2 hours following an outburst of anger compared with other times. The rate ratio (RR) was lower for women who completed technical school or university (RR 1.38, 95% CI 0.52, 3.69) compared to women with secondary school education or less (RR 3.73, 95% CI 2.32, 5.99, P-homogeneity = .07). There was no evidence that the association between anger episodes and abruption varied by hypertensive disorders of pregnancy (ie preeclampsia/ eclampsia) or antepartum depressive symptoms., Conclusion: There was a higher rate of abruption in the 2 hours following outbursts of anger compared with other times, providing potential clues to the aetiologic mechanisms of abruption of acute onset., (© 2019 John Wiley & Sons Ltd.)

Importance: The US Food and Drug Administration (FDA) program to review antiretroviral drugs for use in low-resource settings via the US President's Emergency Plan for AIDS Relief (PEPFAR) now supports treatment of more than 14 million patients with HIV. However, an in-depth evaluation of the program has not been undertaken., Objective: To conduct a quantitative analysis of the FDA-reviewed antiretroviral drug applications in order to assess the contributions of PEPFAR and to identify areas for improvement., Design, Setting, and Participants: A cross-sectional study was conducted of all PEPFAR applications submitted to the FDA from December 1, 2004, to May 31, 2018. The analyses were conducted between October 2018 and February 2019., Main Outcomes and Measures: Numbers and types of applications reviewed, how long it took for applications to obtain approval or tentative approval (time to registration), how often the FDA issued a complete response letter (CRL) identifying deficiencies precluding application approval or tentative approval and their reasons, and the association between CRLs and time to registration., Results: Overall, 260 PEPFAR applications for 327 antiretroviral therapies were reviewed by FDA, of which 216 applications (83%) for 272 drugs were authorized for use. Of the 216 authorized applications, 184 applications for 231 drugs remain in active status and, thus, are available for use. Twenty-six percent (56 of 216) of the applications were for pediatric-specific formulations or strengths; the remainder were for adults. For all 216 applications, the median (interquartile range) time to registration was 10.0 (7.0-17.5) months. Thirty-seven percent (95 of 260) of the applications received 1 or more CRLs, resulting in a total of 172 CRLs; most applications received 1 CRL, whereas some were issued up to 6 CRLs. Among all CRLs, 264 deficiency reasons were identified; the most common deficiencies were associated with manufacturing processes (155 [44%]), followed by product labeling (62 [23%]), and failing facility inspections (54 [20%]). Complete response letters were associated with an increased time to registration. Applications without CRLs had a median (interquartile range) time to registration of 9.0 (5.5-12.0) months, whereas those with at least 1 CRL took a median (interquartile range) of 22.0 (14.0-38.0) months (P < .001)., Conclusions and Relevance: The FDA's PEPFAR program has made many antiretroviral drugs available for global use. However, FDA and the pharmaceutical companies could take steps to improve the quality of applications submitted to prevent avoidable deficiencies in manufacturing processes and labeling. Further efforts to develop better, easier to use pediatric-specific therapies are needed.

Background: Occupational exertion is associated with a higher risk of preterm delivery, although studies of leisure time activities generally document reduced risks. Less is known about the risk of preterm delivery immediately following episodes of moderate or heavy physical exertion., Methods: We conducted a case-crossover study of 722 women interviewed during their hospital stay for early preterm delivery, defined by a gestational age before 34 weeks, and after 20 weeks. Interviews occurred between March 2013 and December 2015 in seven hospitals in Lima, Peru., Results: The incidence rate ratio (RR) of early preterm delivery was 5.82-fold higher (95% confidence interval [CI] = 4.29, 7.36) in the hour following moderate or heavy physical exertion compared with other times and returned to baseline in the hours thereafter. The RR of early preterm delivery within an hour of physical exertion was lower for exertion at moderate intensity (RR = 2.43; 95% CI = 1.50, 3.96) than at heavy intensity (RR = 23.62; 95% CI = 15.54, 35.91; P-homogeneity < 0.001). The RR of early preterm delivery was lower in the hour following moderate physical exertion among women who habitually engaged in physical exertion >3 times per week in the year before pregnancy (RR = 1.56; 95% CI = 0.81, 3.00) compared with more sedentary women (RR = 6.91; 95% CI = 3.20, 14.92; P-homogeneity = 0.003)., Conclusions: Our study showed a heightened risk of early preterm delivery in the hour following moderate or heavy physical exertion.

Background: Physical exertion and caffeine consumption are associated with acute myocardial infarction (MI). However, physical exertion and caffeine consumption have not been examined as immediate triggers of MI in low and middle-income countries., Objective: Using a self-matched case-crossover design, we examined the acute risk of MI in the hour following episodes of physical exertion, caffeinated coffee, and tea consumption among MI survivors in Thailand., Methods: A total of 506 Thai participants (women = 191, men = 315) were interviewed between 2014 and 2017 after sustaining an acute MI. We compared each subject's exposure to physical exertion and consumption of caffeine- containing beverages in the hour preceding the onset of MI with the subject's expected usual frequency in the prior year to calculate relative risks (RRs) and 95% confidence intervals (95%CIs)., Results: Of the 506 participants, 47 (9.3%) engaged in moderate or heavy physical exertion, 6 (1.2%) consumed tea, and 21 (4.2%) consumed coffee within the hour before MI. The relative risk of MI after moderate or heavy physical exertion was 3.0 (95% CI 2.2-4.2) compared to periods of no exertion, with a higher risk among more sedentary participants compared to active participants. Compared to times with no caffeinated beverage consumption, there was a higher risk of MI in the hour following consumption of caffeinated tea (RR = 3.7; 95%CI: 1.5-9.3) and coffee (RR = 2.3; 95%CI: 1.4-3.6)., Conclusion: Physical exertion, coffee and tea consumption were associated with a higher risk of MI in the subsequent hour compared to times when the participants were sedentary or did not consume caffeinated beverages. Our study identifies high-risk populations for targeted screening and intervention to prevent acute MI., Competing Interests: The authors have declared that no competing interests exist.

Background: Two million individuals with chronic hepatitis B (CHB) in the United States are at risk for premature death due to liver cancer and cirrhosis. CHB can be prevented by vaccination and controlled with treatment., Methods: We created a lifetime Markov model to estimate the cost-effectiveness of strategies to prevent or treat CHB in 6 high-risk populations: foreign-born Asian/Pacific Islanders (API), Africa-born blacks (AbB), incarcerated, refugees, persons who inject drugs (PWID), and men who have sex with men (MSM). We studied 3 strategies: (a) screen for HBV infection and treat infected ("treatment only"), (b) screen for HBV susceptibility and vaccinate susceptible ("vaccination only"), and (c) screen for both and follow-up appropriately ("inclusive"). Outcomes were expressed in incremental cost-effectiveness ratios (ICERs), clinical outcomes, and new infections., Results: Vaccination-only and treatment-only strategies had ICERs of $6000-$21 000 per quality-adjusted life-year (QALY) gained, respectively. The inclusive strategy added minimal cost with substantial clinical benefit, with the following costs per QALY gained vs no intervention: incarcerated $3203, PWID $8514, MSM $10 954, AbB $17 089, refugees $17 432, and API $18 009. Clinical complications dropped in the short/intermediate (1%-25%) and long (0.4%-16%) term. Findings were sensitive to age, discount rate, health state utility in immune or susceptible stages, progression rate to cirrhosis or inactive disease, and tenofovir cost. The probability of an inclusive program costing <$50 000 per QALY gained varied between 61% and 97% by population., Conclusions: An inclusive strategy to screen and treat or vaccinate is cost-effective in reducing the burden of hepatitis B virus among all 6 high-risk, high-prevalence populations.

While there is consistent evidence that episodes of physical exertion are associated with an immediately higher risk of acute ischemic vascular events, the risk of placental abruption immediately following episodes of physical exertion has not been studied. In a multicenter case-crossover study, we interviewed 663 women with placental abruption at 7 Peruvian hospitals between January 2013 and August 2015. We asked women about physical exertion in the hour before symptom onset and compared this with their frequency of physical exertion over the prior week. Compared with times with light or no exertion, the risk of placental abruption was 7.8 (95% confidence interval (CI): 5.5, 11.0) times greater in the hour following moderate or heavy physical exertion. The instantaneous incidence rate ratio of placental abruption within an hour of moderate or heavy physical exertion was lower for women who habitually engaged in moderate or heavy physical activity more than 3 times per week in the year before pregnancy (rate ratio (RR) = 3.0, 95% CI: 1.6, 5.9) compared with more sedentary women (RR = 17.3, 95% CI: 11.3, 26.7; P for homogeneity < 0.001), and the rate ratio was higher among women with preeclampsia/eclampsia (RR = 13.6, 95% CI: 7.0, 26.2) than among women without (RR = 6.7, 95% CI: 4.4, 10.0; P for homogeneity = 0.07).

Background: Since 2004, the US Food and Drug Administration's (USFDA) dedicated drug review process in support of President's Emergency Plan for AIDS Relief (PEPFAR) has made safe, effective and quality antiretrovirals (ARVs) available for millions of patients. Furthermore, the WHO and Global Fund to Fight AIDS, Tuberculosis and Malaria (Global Fund) can add the USFDA-reviewed products to their respective formularies, through a novel process of 'one-way reliance'. We assessed the number of ARVs made available through WHO and Global Fund based on the USFDA review., Methods: We conducted a cross-sectional study of all the USFDA-reviewed PEPFAR drugs between 1 December 2014 and 20 March 2017 to determine 1) the percentage that are included on the WHO and Global Fund formularies; 2) the number of the USFDA ARVs supporting the WHO HIV treatment guidelines, and their uptake by WHO and Global Fund and 3) time between the USFDA review and WHO review of the same ARVs., Findings: Overall, 91% (204/224) of the USFDA products appeared on either the WHO/Prequalification of Medicines Programme (PQP) or the Global Fund ARV lists. Forty-five per cent (100/224) and 83% (184/224) appear on WHO/PQP and Global Fund formularies through one-way reliance, respectively. Forty-one per cent (91/224) of the USFDA products support the WHO-preferred first-line HIV treatment options. Of these 91 products, 38% and 85% of products were adopted by WHO/PQP and Global Fund through one-way reliance, respectively. Sixty-six products that were fully reviewed and registered by WHO (vs one-way reliance) had also undergone the USFDA review; 46 of these were registered by WHO after the USFDA review was complete (median delay of 559 days (IQR 233-798 days))., Conclusions: The USFDA's PEPFAR process is making safe and effective ARVs available worldwide, in part because the major global ARV procurement organisations rely on the USFDA registration as proof of quality. There is room for improved information sharing and collaboration to reduce duplication of effort, save resources and further expedite access to ARVs., Competing Interests: Competing interests: None declared.

Purpose: To describe the role and efficacy of scleral contact lenses (SCLs) in the treatment of progressive keratopathy in patients who have undergone periocular surgical procedures, to investigate the financial impact of these surgical interventions, and to demonstrate the role of oculoplastic surgery in improving scleral contact lens fit., Methods: A retrospective medical record review was performed to identify patients who both received SCLs and were examined by the oculoplastics service at the University of Iowa between January 1990 and December 2015. Inclusion criteria also required a minimum of 12 months of patient follow up after being fit with a SCL. The indication for SCL use, as well as clinical outcomes and cumulative relative value units (RVUs) of prior oculoplastic treatments and SCL therapy were recorded for each patient., Results: Six hundred and fifty-nine patients were fitted with SCLs at the authors' institution during the 25-year study period, 43 of whom were examined by the oculoplastics service for reasons related to their SCL. Patients who were fitted for SCLs before (27 patients) or after (16 patients) evaluation in the oculoplastics clinic presented with a variety of corneal and periocular pathology. Corneal indications for SCLs in patients seen secondarily in the oculoplastics clinic included decreased corneal sensation (from CN V palsy or neurotrophic keratopathy), decreased corneal healing from limbal stem cell deficiency, exposure keratopathy, and keratoconjunctivitis sicca secondary to Sjogren's syndrome or orbital radiation. Indications for oculoplastic clinic evaluation in current scleral lens patients included lagophthalmos, trichiasis, epiphora, cicatricial changes in the eyelids or fornices, and eyelid or eyebrow malposition affecting SCL centration. In all 27 patients, surgical intervention resulted in improved SCL centration. Sixteen patients (5 with CN VII palsy, 4 with CN V and CN VII palsy, 4 with neurotrophic keratitis, and 3 with cicatricial entropion) had progressive corneal decompensation despite primary oculoplastics procedures to protect the cornea and ultimately benefitted from SCL treatment secondarily. Fourteen of these 16 patients demonstrated an improved visual acuity of 1 line or more using SCLs. Procedures performed before referral for SCLs included tarsorrhaphies, gold weights, ectropion repair with lateral tarsal strip, retraction repair with spacer grafts, full-thickness skin grafts, cheek lifts, and punctal occlusion. The total RVUs of these procedures performed per patient were tabulated. The RVU range was 10.47-33.96 with an average of 19.5 RVUs (standard deviation = 9.4 RVUs) per patient., Conclusions: Scleral contact lenses may offer a useful alternative to stabilize the ocular surface, improve vision, and minimize the financial impact and morbidity of multiple periocular procedures in select patients with progressive keratopathy of varying etiologies. The therapeutic indications and utilization of SCLs are likely to increase in oculoplastic practices with optometric support, particularly in academic settings. Surgical correction of eyelid and eyebrow malposition, as well as epiphora, may also be useful adjunctive procedures to optimize SCL fit.

Introduction: Germline aryl hydrocarbon receptor-interacting protein ( AIP ) mutations are responsible for 15-30% of familial isolated pituitary adenomas (FIPAs). We report a FIPA kindred with a heterozygous deletion in AIP , aiming to highlight the indications and benefits of genetic screening, variability in clinical presentations, and management challenges in this setting., Patients: An 18-year-old male was diagnosed with a clinically nonfunctioning pituitary adenoma (NFPA). Two years later, his brother was diagnosed with a somatolactotrophinoma, and a small Rathke's cleft cyst and a microadenoma were detected on screening in their 17-year-old sister. Following amenorrhoea, their maternal cousin was diagnosed with hyperprolactinaemia and two distinct pituitary microadenomas. A 12-year-old niece developed headache and her MRI showed a microadenoma, not seen on a pituitary MRI scan 3 years earlier., Discussion: Out of the 14 members harbouring germline AIP mutations in this kindred, 5 have pituitary adenoma. Affected members had different features and courses of disease. Bulky pituitary and not fully suppressed GH on OGTT can be challenging in the evaluation of females in teenage years. Multiple pituitary adenomas with different secretory profiles may arise in the pituitary of these patients. Small, stable NFPAs can be present in mutation carriers, similar to incidentalomas in the general population. Genetic screening and baseline review, with follow-up of younger subjects, are recommended in AIP mutation-positive families.

Isolated neurofibromas in the absence of systemic neurofibromatosis are known as solitary or localized neurofibromas. When present in the orbit, these lesions may appear clinically and radiographically similar to other tumors, complicating diagnosis and management. Key radiographic signs may guide clinicians to the correct diagnosis when the presentation and patient demographic data obfuscate the disease entity. We present a case of a large multi-lobulated neurofibroma misdiagnosed as a lymphangioma. A brief review of these tumors emphasizing key radiographic features is also included.

Introduction: In 2004, the US government began to utilize the Food and Drug Administration's (USFDA) tentative approval process (tFDA) as a basis to determine which HIV drugs are appropriate to be purchased and used in resource-constrained settings. This process permits products that are not approved for marketing in the US, including medicines with active patents or marketing restrictions in the US, to be purchased and distributed in resource-constrained settings. Although the tFDA was originally intended to support the United States' President's Emergency Plan for AIDS Relief (PEPFAR), the USFDA list has become a cornerstone of international HIV programmes that support procurement of ARVs, such as the World Health Organization and the Global Fund to Fight AIDS, Tuberculosis, and Malaria. Our objective in this article is to help the global HIV policy makers and implementers of HIV programmes better understand the benefits and limitations of the tFDA by providing an in-depth review of the relevant legal and regulatory processes., Discussion: USFDA's dedicated tFDA process for ARVs used by the PEPFAR programme has a wide impact globally; however, the implementation and the regulatory processes governing the programme have not been thoroughly described in the medical literature. This paper seeks to help stakeholders better understand the legal and regulatory aspects associated with review of ARVs under the tFDA by describing the following: (1) the tFDA and its importance to global ARV procurement; (2) the regulatory pathways for applications under tFDA for the PEPFAR programme, including modifications to applications, review timelines and costs; (3) the role of US patents, US marketing exclusivity rights, and the Medicines Patents Pool in tFDA; and (4) an overview of how applications for PEPFAR programme are processed through the USFDA. We also provide a case study of a new ARV, tenofovir alafenamide fumarate (TAF), not yet reviewed by USFDA for PEPFAR use., Conclusions: In this paper, we describe the importance and implementation of USFDA's tentative approval process to review ARVs for resource-constrained settings. We also highlight the impact of patents and exclusivities on review of HIV drugs under tFDA and illustrate the concepts using a new HIV drug as an example., (© 2017 The Authors. Journal of the International AIDS Society published by John Wiley & sons Ltd on behalf of the International AIDS Society.)

DNA repair plays a critical role in protecting the genome from ultraviolet radiation and maintaining the genomic integrity of cells. Genetic variants in DNA repair-related genes can influence an individual's DNA repair capacity, which may be related to the risk of developing basal cell carcinoma (BCC). We comprehensively assessed the associations of 2,965 independent single-nucleotide polymorphisms (SNPs) across 165 DNA repair pathway genes with BCC risk in a genome-wide association meta-analysis totaling 17,187 BCC cases and 287,054 controls from two data sets. After multiple testing corrections, we identified three SNPs (rs2805831 upstream of XPA: OR = 0.93, P = 1.35 × 10 -6 ; rs659857 in exon of MUS81: OR = 1.06, P = 3.09 × 10 -6 and rs57343616 in 3' UTR of NABP2: OR = 1.11, P = 6.47 × 10 -6 ) as significantly associated with BCC risk in meta-analysis, and all of them were nominally significant in both data sets. Furthermore, rs659857 [T] was significantly associated with decreased expression of MUS81 mRNA in the expression quantitative trait locus (eQTL) analysis. Our findings suggest that the inherited common variation in three DNA repair genes-XPA, MUS81 and NABP2-may be involved in the development of BCC. To our knowledge, our study is the first report thoroughly examining the effects of SNPs across DNA repair pathway genes on BCC risk based on a genome-wide association meta-analysis., (© 2017 UICC.)

Objective: To evaluate the association between chocolate intake and incident clinically apparent atrial fibrillation or flutter (AF)., Methods: The Danish Diet, Cancer, and Health Study is a large population-based prospective cohort study. The present study is based on 55 502 participants (26 400 men and 29 102 women) aged 50-64 years who had provided information on chocolate intake at baseline. Incident cases of AF were ascertained by linkage with nationwide registries., Results: During a median of 13.5 years there were 3346 cases of AF. Compared with chocolate intake less than once per month, the rate of AF was lower for people consuming 1-3 servings/month (hazard ratio (HR) 0.90, 95% confidence interval (CI) 0.82 to 0.98), 1 serving/week (HR 0.83, 95% CI 0.74 to 0.92), 2-6 servings/week (HR 0.80, 95% CI 0.71 to 0.91) and ≥1 servings/day (HR 0.84, 95% CI 0.65 to 1.09; p-linear trend <0.0001), with similar results for men and women., Conclusions: Accumulating evidence indicates that moderate chocolate intake may be inversely associated with AF risk, although residual confounding cannot be ruled out., Competing Interests: Competing interests: None declared., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

An increasing number of studies have reported a protective association between vitamin D and cancer risk. The vitamin D endocrine system regulates transcriptional programs involved in inflammation, cell growth and differentiation through the binding of vitamin D receptor (VDR) to specific VDR elements. However, limited attention has been given to the role of variation within VDR binding sites in the development of basal cell carcinoma (BCC). Across 2,776 previously identified VDR binding sites, we identified 2,540 independent single-nucleotide polymorphisms (SNPs) and examined their associations with BCC risk in a genome-wide association meta-analysis totaling 17,187 BCC cases and 287,054 controls from two data sets. After multiple testing corrections, we identified two SNPs at new loci (rs16917546 at 10q21.1: odds ratio (OR) = 1.06, p = 3.16 × 10 -7 and rs79824801 at 12q13.3: OR = 1.10, p = 1.88 × 10 -5 ) for the first time as independently related to BCC risk in meta-analysis; and both SNPs were nominally significant in two data sets. In addition, the SNP rs3769823 within VDR binding site at a previously reported BCC susceptibility locus (2q33.1, rs13014235) also exhibited a significant association (OR = 1.12, p = 3.99 × 10 -18 ). A mutually adjusted model suggested that rs3769823 explained the signal in this region. Our findings support the hypothesis that inherited common variation in VDR binding sites affects the development of BCC., (© 2017 UICC.)

Mucormycosis is an aggressive fungal infection characterized by rapidly progressive angioinvasion and tissue necrosis. When present in the orbit, mucormycosis can quickly lead to permanent visual loss and potentially fatal cerebral extension. Orbital involvement is almost universally preceded by infection of the paranasal sinuses. Secondary infection of the orbit via direct extension of neighboring cutaneous mucormycosis has not been previously described. The authors present a case of cutaneous mucormycosis with orbital extension in a poorly controlled diabetic patient.

Importance: Patients with basal cell nevus syndrome (BCNS) have a greater risk of developing numerous basal cell carcinomas (BCCs). Risk factors influencing the wide variation in tumor burden are poorly understood., Objective: To describe the burden of BCCs in patients with BCNS in the United States and identify potential risk factors for BCCs., Design, Setting, and Participants: Prospective clinical registry with data collected from September 2014 to March 2016. Participants were recruited from a mailing list of patients with BCNS at Children's Hospital Oakland Research Institute and Basal Cell Carcinoma Nevus Syndrome Life Support Network. Patients of all ages with a diagnosis of BCNS were eligible for enrollment. Participants completed a clinical questionnaire on their disease characteristics and risk factors., Main Outcomes and Measures: Number of BCCs in the past 2 years and over lifetime (disease burden), risk factors for BCCs., Results: A consecutive sample of the first 141 participants was included (34% [100 of 297] response rate from paper survey, 23% [41 of 179] from online survey; 85 [60%] female; mean age at start of study, 53 [range, 8-83] years; 131 [93%] white). In the previous 2 years, participants reported a mean of 25 BCCs (median, 11; range, 0-250). Over their lifetime, participants reported a mean of 257 BCCs (median, 160; range, 0-2200). Univariate analysis identified age (odds ratio [OR], 1.05; 95% CI, 1.03-1.07; P < .001), number of sunburns (OR, 1.05; 95% CI, 1.00-1.10; P = .047), and history of radiation exposure (OR, 2.26; 95% CI, 1.02-5.03; P = .046) as potential risk factors for lifetime BCC severity. On multivariate analysis, only age (OR, 1.04; 95% CI, 1.02-1.07; P < .001) and number of sunburns (OR, 1.06; 95% CI, 1.00-1.11; P = .04) were statistically significant. In our adjusted models, BCC burden increased by 4% per year of age and by 6% per number of sunburns., Conclusions and Relevance: Patients with BCNS have a high burden of BCCs. Age and number of sunburns were significantly associated with the severity of lifetime BCC. Further interventions to prevent and treat BCCs in patients with BCNS are needed.

Basal cell carcinoma (BCC) is the most common cancer worldwide with an annual incidence of 2.8 million cases in the United States alone. Previous studies have demonstrated an association between 21 distinct genetic loci and BCC risk. Here, we report the results of a two-stage genome-wide association study of BCC, totalling 17,187 cases and 287,054 controls. We confirm 17 previously reported loci and identify 14 new susceptibility loci reaching genome-wide significance (P<5 × 10(-8), logistic regression). These newly associated SNPs lie within predicted keratinocyte regulatory elements and in expression quantitative trait loci; furthermore, we identify candidate genes and non-coding RNAs involved in telomere maintenance, immune regulation and tumour progression, providing deeper insight into the pathogenesis of BCC.

Cutaneous squamous cell carcinoma represents the second most common cutaneous malignancy, affecting 7-11% of Caucasians in the United States. The genetic determinants of susceptibility to cutaneous squamous cell carcinoma remain largely unknown. Here we report the results of a two-stage genome-wide association study of cutaneous squamous cell carcinoma, totalling 7,404 cases and 292,076 controls. Eleven loci reached genome-wide significance (P<5 × 10(-8)) including seven previously confirmed pigmentation-related loci: MC1R, ASIP, TYR, SLC45A2, OCA2, IRF4 and BNC2. We identify an additional four susceptibility loci: 11q23.3 CADM1, a metastasis suppressor gene involved in modifying tumour interaction with cell-mediated immunity; 2p22.3; 7p21.1 AHR, the dioxin receptor involved in anti-apoptotic pathways and melanoma progression; and 9q34.3 SEC16A, a putative oncogene with roles in secretion and cellular proliferation. These susceptibility loci provide deeper insight into the pathogenesis of squamous cell carcinoma.

Improving basic capacities for regulation of medicines and health technologies through regulatory systems strengthening is particularly challenging in resource-constrained settings. "Regionalization"-an approach in which countries with common histories, cultural values, languages, and economic conditions work together to establish more efficient systems-may be one answer. This report describes the Caribbean Regulatory System (CRS), a regionalization initiative being implemented in the mostly small countries of the Caribbean Community and Common Market (CARICOM). This initiative is an innovative effort to strengthen regulatory systems in the Caribbean, where capacity is limited compared to other subregions of the Americas. The initiative's concept and design includes a number of features and steps intended to enhance sustainability in resource-constrained contexts. The latter include 1) leveraging existing platforms for centralized cooperation, governance, and infrastructure; 2) strengthening regulatory capacities with the largest potential public health impact; 3) incorporating policies that promote reliance on reference authorities; 4) changing the system to encourage industry to market their products in CARICOM (e.g., using a centralized portal of entry to reduce regulatory burdens); and 5) building human resource capacity. If implemented properly, the CRS will be self-sustaining through user fees. The experience and lessons learned thus far in implementing this initiative, described in this report, can serve as a case study for the development of similar regulatory strengthening initiatives in resource-constrained environments.

Corticotropin-releasing factor (CRF) is a neuropeptide commonly associated with the hypothalamic-pituitary adrenal axis stress response. Upon release, CRF activates two G protein-coupled receptors (GPCRs): CRF receptor 1 (CRFR1) and CRF receptor 2 (CRFR2). Although both receptors contribute to mood regulation, CRFR1 antagonists have demonstrated anxiolytic and antidepressant-like properties that may be exploited in the generation of new pharmacological interventions for mental illnesses. Previous studies have demonstrated CRFR1 capable of heterologously sensitizing serotonin 2A receptor (5-HT2AR) signaling: another GPCR implicated in psychiatric disease. Interestingly, this phenomenon was dependent on Postsynaptic density 95 (PSD-95)/Disc Large/Zona Occludens (PDZ) interactions on the distal carboxyl termini of both receptors. In the current study, we demonstrate that endogenous PSD-95 can be co-immunoprecipitated with CRFR1 from cortical brain homogenate, and this interaction appears to be primarily via the PDZ-binding motif. Additionally, PSD-95 colocalizes with CRFR1 within the dendritic projections of cultured mouse neurons in a PDZ-binding motif-dependent manner. In HEK 293 cells, PSD-95 overexpression inhibited CRFR1 endocytosis, whereas PSD-95 shRNA knockdown enhanced CRFR1 endocytosis. Although PSD-95 does not appear to play a significant role in CRF-mediated cAMP or ERK1/2 signaling, PSD-95 was demonstrated to suppress β-arrestin2 recruitment: providing a potential mechanism for PSD-95's inhibition of endocytosis. In revisiting previously documented heterologous sensitization, PSD-95 shRNA knockdown did not prevent CRFR1-mediated enhancement of 5-HT2AR signaling. In conclusion, we have identified and characterized a novel functional relationship between CRFR1 and PSD-95 that may have implications in the design of new treatment strategies for mental illness., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Medicines Regulatory Authorities (MRAs) are an essential part of national health systems and are charged with protecting and promoting public health through regulation of medicines. However, MRAs in resource-constrained settings often struggle to provide effective oversight of market entry and use of health commodities. This paper proposes a regulatory value chain model (RVCM) that policymakers and regulators can use as a conceptual framework to guide investments aimed at strengthening regulatory systems. The RVCM incorporates nine core functions of MRAs into five modules: (i) clear guidelines and requirements; (ii) control of clinical trials; (iii) market authorization of medical products; (iv) pre-market quality control; and (v) post-market activities. Application of the RVCM allows national stakeholders to identify and prioritize investments according to where they can add the most value to the regulatory process. Depending on the economy, capacity, and needs of a country, some functions can be elevated to a regional or supranational level, while others can be maintained at the national level. In contrast to a "one size fits all" approach to regulation in which each country manages the full regulatory process at the national level, the RVCM encourages leveraging the expertise and capabilities of other MRAs where shared processes strengthen regulation. This value chain approach provides a framework for policymakers to maximize investment impact while striving to reach the goal of safe, affordable, and rapidly accessible medicines for all.