Transcriptionally Active Human Papillomavirus Infection in a Minority of Esophageal Squamous Cell Carcinomas in North America.

The role of Human papillomavirus (HPV) infection in esophageal squamous cell carcinoma (ESCC) is a topic of ongoing debate. This study used two screening approaches to look for evidence of HPV infection in esophageal squamous cell carcinoma. We initially checked for HPV infection in a randomly selected group of 53 ESCC cases. We did not detect any tumors positive for high-risk HPV. However, during clinical practice, we identified an HPV-positive ESCC in the distal esophagus, which tested positive for HPV16. This index case was TP53 wild-type, as determined by next-generation DNA sequencing (NGS). Since TP53 mutations are rare in other HPV-driven cancers, we improved our screening method by limiting our screen to a subset of ESCC cases without TP53 mutations. A second screen of 95 ESCCs (from 93 patients) sequenced by NGS revealed an additional 7 ESCCs with TP53 wild-type status (7.3% of the total). Of the 7 cases, 2 cases were found to be high-risk HPV positive. Both patients also tested positive for circulating cell-free HPV DNA and had a complete response to neoadjuvant chemoradiation. The index patient had microscopic residual tumor following neoadjuvant therapy. The patient underwent adjuvant immunotherapy and remained disease free after 22 months of surveillance. This study affirms the transcriptionally active status of high-risk HPV in a minority of ESCC patients in North America.

Cluster wild bootstrapping to handle dependent effect sizes in meta-analysis with a small number of studies.

The most common and well-known meta-regression models work under the assumption that there is only one effect size estimate per study and that the estimates are independent. However, meta-analytic reviews of social science research often include multiple effect size estimates per primary study, leading to dependence in the estimates. Some meta-analyses also include multiple studies conducted by the same lab or investigator, creating another potential source of dependence. An increasingly popular method to handle dependence is robust variance estimation (RVE), but this method can result in inflated Type I error rates when the number of studies is small. Small-sample correction methods for RVE have been shown to control Type I error rates adequately but may be overly conservative, especially for tests of multiple-contrast hypotheses. We evaluated an alternative method for handling dependence, cluster wild bootstrapping, which has been examined in the econometrics literature but not in the context of meta-analysis. Results from two simulation studies indicate that cluster wild bootstrapping maintains adequate Type I error rates and provides more power than extant small-sample correction methods, particularly for multiple-contrast hypothesis tests. We recommend using cluster wild bootstrapping to conduct hypothesis tests for meta-analyses with a small number of studies. We have also created an R package that implements such tests.

Psychosocial and Behavioral Effects of the COVID-19 Pandemic in the Indian Population: Protocol for a Cross-sectional Study.

BACKGROUND: During the year 2020, the COVID-19 pandemic spread from China to the rest of the world, which prompted the world to implement a widespread mandated quarantine or social isolation. The impending uncertainty of the pandemic must have resulted in a variety of widespread mental health maladies. There has been documentation in the literature about a lot of these in small populations of the world but limited studies have been conducted in India, leading to limited evidence in the literature. OBJECTIVE: The main objective of our study is to investigate the mental health effects that the COVID-19 pandemic has had on the general population in India both quantitatively and qualitatively. These results will help contribute to reducing the knowledge gap that is recognized in the literature, which is the result of the unprecedented and novel nature of the pandemic. METHODS: We designed and validated our own questionnaire and used the method of circulating the questionnaire via WhatsApp (Facebook Inc). WhatsApp is a social media app that is very popularly used in India; hence, it turned out to be an effective medium for gathering pilot data. We analyzed the pilot data and used them to validate the questionnaire. This was done with the expertise of our mentor, Nilima Shah, MD (psychiatry). We gathered pilot data on 545 subjects and used the results to determine the changes that were needed for the questionnaire while simultaneously validating the questionnaire. RESULTS: The study protocol was approved in September 2020 by the institutional review board at Vadilal Sarabhai General Hospital, Ahmedabad, Gujarat, India. CONCLUSIONS: The following preliminary assumptions can be made about the study based on the pilot data: the majority of the survey respondents were male (289/545, 53%), most of them were educated and employed as health care workers (199/545, 36.5%). The majority of the responders were self-employed (185/545, 33.9%), single (297/545, 54.5%), and stayed with their families (427/541, 79%) for the lockdown, which helped them psychologically. Findings that are specific to mental health have been elaborated upon in the manuscript. It is evident from the data collected in previous literature that the pandemic has had significant detrimental effects on the mental health of a vast proportion of the Indian population. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/29896.

Global Epidemiology of End-Stage Kidney Disease and Disparities in Kidney Replacement Therapy.

BACKGROUND: The global epidemiology of end-stage kidney disease (ESKD) reflects each nation's unique genetic, environmental, lifestyle, and sociodemographic characteristics. The response to ESKD, particularly regarding kidney replacement therapy (KRT), depends on local disease burden, culture, and socioeconomics. Here, we explore geographic variation and global trends in ESKD incidence and prevalence and examine variations in KRT modality, practice patterns, and mortality. We conclude with a discussion on disparities in access to KRT and strategies to reduce ESKD global burden and to improve access to treatment in low- and middle-income countries (LMICs). SUMMARY: From 2003 to 2016, incidence rates of treated ESKD were relatively stable in many higher income countries but rose substantially predominantly in East and Southeast Asia. The prevalence of treated ESKD has increased worldwide, likely due to improving ESKD survival, population demographic shifts, higher prevalence of ESKD risk factors, and increasing KRT access in countries with growing economies. Unadjusted 5-year survival of ESKD patients on KRT was 41% in the USA, 48% in Europe, and 60% in Japan. Dialysis is the predominant KRT in most countries, with hemodialysis being the most common modality. Variations in dialysis practice patterns account for some of the differences in survival outcomes globally. Worldwide, there is a greater prevalence of KRT at higher income levels, and the number of people who die prematurely because of lack of KRT access is estimated at up to 3 times higher than the number who receive treatment. Key Messages: Many people worldwide in need of KRT as a life-sustaining treatment do not receive it, mostly in LMICs where health care resources are severely limited. This large treatment gap demands a focus on population-based prevention strategies and development of affordable and cost-effective KRT. Achieving global equity in KRT access will require concerted efforts in advocating effective public policy, health care delivery, workforce capacity, education, research, and support from the government, private sector, nongovernmental, and professional organizations.

The Performance of Multivariate Methods for Two-Group Comparisons with Small Samples and Incomplete Data.

In intervention studies having multiple outcomes, researchers often use a series of univariate tests (e.g., ANOVAs) to assess group mean differences. Previous research found that this approach properly controls Type I error and generally provides greater power compared to MANOVA, especially under realistic effect size and correlation combinations. However, when group differences are assessed for a specific outcome, these procedures are strictly univariate and do not consider the outcome correlations, which may be problematic with missing outcome data. Linear mixed or multivariate multilevel models (MVMMs), implemented with maximum likelihood estimation, present an alternative analysis option where outcome correlations are taken into account when specific group mean differences are estimated. In this study, we use simulation methods to compare the performance of separate independent samples t tests estimated with ordinary least squares and analogous t tests from MVMMs to assess two-group mean differences with multiple outcomes under small sample and missingness conditions. Study results indicated that a MVMM implemented with restricted maximum likelihood estimation combined with the Kenward-Roger correction had the best performance. Therefore, for intervention studies with small N and normally distributed multivariate outcomes, the Kenward-Roger procedure is recommended over traditional methods and conventional MVMM analyses, particularly with incomplete data.

Detection of PLA2R Autoantibodies before the Diagnosis of Membranous Nephropathy.

BACKGROUND: Circulating serum autoantibodies against the M-type phospholipase A2 receptor (PLA2R-AB) are a key biomarker in the diagnosis and monitoring of primary membranous nephropathy (MN). However, little is known about the appearance and trajectory of PLA2R-AB before the clinical diagnosis of MN. METHODS: Using the Department of Defense Serum Repository, we analyzed PLA2R-AB in multiple, 1054 longitudinal serum samples collected before diagnosis of MN from 134 individuals with primary MN, 35 individuals with secondary MN, and 134 healthy volunteers. We evaluated the presence and timing of non-nephrotic range proteinuria (NNRP) and serum albumin measurements in relation to PLA2R-AB status. RESULTS: Analysis of PLA2R-AB in longitudinal serum samples revealed seropositivity in 44% (59 out of 134) of primary MN cases, 3% (one out of 35) of secondary MN cases, and in 0% of healthy controls. Among patients with MN, PLA2R-AB were detectable at a median of 274 days before renal biopsy diagnosis (interquartile range, 71-821 days). Approximately one third of the participants became seropositive within 3 months of MN diagnosis. Of the 21 individuals with documented prediagnostic NNRP, 43% (nine out of 21) were seropositive before NNRP was first documented and 28.5% (six out of 21) were seropositive at the same time as NNRP; 66% (39 out of 59) of those seropositive for PLA2R-AB had hypoalbuminemia present at the time antibody was initially detected. Twelve participants (20%) were seropositive before hypoalbuminemia became apparent, and eight participants (14%) were seropositive after hypoalbuminemia became apparent. CONCLUSIONS: Circulating PLA2R-AB are detectable months to years before documented NNRP and biopsy-proven diagnosis in patients with MN.

Direct Ties to a Faculty Mentor Related to Positive Outcomes for Undergraduate Researchers.

Mentored research is critical for integrating undergraduates into the scientific community. Undergraduate researchers experience a variety of mentoring structures, including dyads (i.e., direct mentorship by faculty) and triads (i.e., mentorship by graduate or postdoctoral researchers [postgraduates] and faculty). Social capital theory suggests that these structures may offer different resources that differentially benefit undergraduates. To test this, we collected data from a national sample of more than 1,000 undergraduate life science researchers and used structural equation modeling to identify relationships between mentoring structures and indicators of integration into the scientific community. Undergraduates in dyads and triads with direct faculty interactions reported similar levels of science self-efficacy, scientific identity, and scholarly productivity, and higher levels of these outcomes than students in triads lacking faculty interactions. Undergraduates' career intentions were unrelated to their mentoring structure, and their gains in thinking and working like scientists were higher if they interacted with both postgraduates and faculty.

Effects of Process Improvement on Guideline-Concordant Cardiac Enzyme Testing.

Easily implemented ordering practices in the electronic health record increased the rate of guideline-concordant testing, decreased cost, and furthered the goal of high-value medical care.

Logistical, cultural, and structural barriers to immediate neonatal care and neonatal resuscitation in Bihar, India.

BACKGROUND: In India, the neonatal mortality rate is nearly double the Sustainable Development Goal target with more than half of neonatal deaths occurring in only four states, one of which is Bihar. Evaluations of immediate neonatal care and neonatal resuscitation skills in Bihar have demonstrated a need for significant improvement. However, barriers to evidence based practices in clinical care remain incompletely characterized. METHODS: To better understand such barriers, semi-structured interviews were conducted with 18 nurses who participated as mentors in the AMANAT maternal and child health quality improvement project, implemented by CARE India and the Government of Bihar. Nurse-mentors worked in primary health centers throughout Bihar facilitating PRONTO International emergency obstetric and neonatal simulations for nurse-mentees in addition to providing direct supervision of clinical care. Interviews focused on mentors' perceptions of barriers to evidence based practices in immediate neonatal care and neonatal resuscitation faced by mentees employed at Bihar's rural primary health centers. Data was analyzed using the thematic content approach. RESULTS: Mentors identified numerous interacting logistical, cultural, and structural barriers to care. Logistical barriers included poor facility layout, supply issues, human resource shortages, and problems with the local referral system. Cultural barriers included norms such as male infant preference, traditional clinical practices, hierarchy in the labor room, and interpersonal relations amongst staff as well as with patients' relatives. Poverty was described as an overarching structural barrier. CONCLUSION: Interacting logistical, cultural and structural barriers affect all aspects of immediate neonatal care and resuscitation in Bihar. These barriers must be addressed in any intervention focused on improving providers' clinical skills. Strategic local partnerships are vital to addressing such barriers and to contextualizing skills-based trainings developed in Western contexts to achieve the desired impact of reducing neonatal mortality.

Development and In Vitro Evaluation of Vitamin E-Enriched Nanoemulsion Vehicles Loaded with Genistein for Chemoprevention Against UVB-Induced Skin Damage.

There is a great need for effective protection against cutaneous pathologies arising from chronic exposure to harmful solar UVB radiations. A promising pharmaceutical strategy to improve the efficacy of chemotherapeutic/preventative natural compounds (e.g., soy isoflavone Genistein, Gen) is to enhance their dermal delivery using nanoemulsion (NE) formulations. This report investigates the development of nanoemulsified tocotrienol(T3)-rich fraction of red palm oil (Tocomin®), to yield an optimal NE delivery system for dermal photoprotection (z-average size <150 nm, ζ-potential ≈ -30 mV, polydispersity index < 0.25). Physicochemical characterization and photostability studies indicate NE formulations utilizing surfactant mixture (Smix) of Solutol® HS-15 (SHS15) blended with vitamin E TPGS (TPGS) as cosurfactant was significantly superior to formulations that utilized Lutrol® F68 (LF68) as the cosurfactant. A ratio of 60:40 of SHS15-TPGS-NE was further identified as lead Tocomin® NE topical platform using in vitro pharmaceutical skin reactivity studies that assess cutaneous irritancy and cytotoxicity. Prototype Tocomin® NE loaded with the antiphotocarcinogenic molecule Gen (Gen-Tocomin® NE) showed slow-release profile in both liquid and cream forms. Gen-Tocomin® NE also showed excellent biocompatibility, and provided substantial UVB protection to cultured subcutaneous L929 fibroblasts, indicating the great potential of our Tocomin® NE warranting further prototype development as topical pharmaceutical platform for skin photoprotection applications.

Dual therapy of vildagliptin and telmisartan on diabetic nephropathy in experimentally induced type 2 diabetes mellitus rats.

INTRODUCTION: The objective of this article is to investigate the combination of telmisartan with vildagliptin therapy versus monotherapy of vildagliptin and telmisartan on diabetic nephropathy in type 2 diabetes mellitus rats. MATERIALS AND METHODS: In adult rats streptozotocin (65 mg/kg) and nicotinamide (110 mg/kg) were injected intraperitoneally to produce diabetic nephropathy. Rats of either sex allotted to the following groups: (i) triple therapy: metformin (120 mg/kg, o.d.) + pioglitazone (1.25 mg/kg, o.d.) + glimepiride (0.7 mg/kg, o.d.); (ii) dual therapy: vildagliptin (8.76 mg/kg, o.d.) + telmisartan (6.48 mg/kg, o.d.); (iii) vildagliptin (8.76 mg/kg, o.d.); and (iv) telmisartan (6.48 mg/kg, o.d.); therapy was carried out for 35 days orally. Weekly at days 7, 14, 21, 28 and 35, blood pressure, blood glucose level, body weight, blood serum creatinine level, protein albumin level in urine, and blood urea nitrogen (BUN) were estimated. Renal structural changes were observed. RESULTS: Blood pressure, blood glucose level, blood serum creatinine level, protein albumin level in urine, BUN and renal deterioration increased significantly in diabetic rats compared with normal control rats. The vildagliptin + telmisartan treatment group showed no weight gain and controlled blood pressure, renovascular structural and biochemical parameters in diabetic neuropathy rats. CONCLUSIONS: The addition of telmisartan to vildagliptin demonstrated the best control over blood pressure, glycemia and diabetic nephropathy markers, renal structural changes and improvement of renal function as opposed to monotherapy with either drug, possibly because of the dual inhibitory effect on the renin-angiotensin system.

Base-mediated chemo- and stereoselective addition of 5-aminoindole/tryptamine and histamines onto alkynes.

Transition-metal-free chemo- and stereoselective addition of 5-aminoindole (1a), tryptamine (1b), and histamine (1c) to alkynes 2a-s to synthesize the indolyl/imidazolyl enamines 3a-p, 5a-o, and 6a-e using superbasic solutions of alkali-metal hydroxides in DMSO is described. The addition of N-heterocycles onto alkynes takes places chemoselectively without affecting the 1° amino groups (aromatic and aliphatic) of 5-aminoindole, tryptamine, and histamine. The stereochemistry of the products was found to be dependent upon reaction time; an increase in reaction time leads to the formation of a mixture of E/Z isomers and the thermodynamically stable E addition product. The chemoselective addition of N-heterocycle 1a onto alkyne over thiophenol 7 and phenol 8 is supported by control experiments. Competitive experiments showed that 5-aminoindole was more reactive than tryptamine, and histamine was found to be the least reactive. The present methodology provides an efficient chemoselective method to synthesize a variety of (Z)-enamines of 5-aminoindole, tryptamine, and histamine without affecting the 1° amino group. The presence of the free amino group in enamines could be further used for synthetic elaboration, which proved to be highly advantageous for structural and biological activity assessments.

Pathologist workforce in the United States: I. Development of a predictive model to examine factors influencing supply.

CONTEXT: Results of prior pathology workforce surveys have varied between a state of equilibrium and predictions of shortage. OBJECTIVE: To assess the current and future supply of pathologists, and apply a dynamic modeling tool for assessing the effects of changing market forces and emerging technologies on the supply of pathologists' services through 2030. DESIGN: Data came from various sources, including the literature, College of American Pathologists' internal data, and primary research through custom-developed surveys for the membership and for pathology practice managers RESULTS: Through 2010, there were approximately 18 000 actively practicing pathologists in the United States (5.7 per 100 000 population), approximately 93% of whom were board certified. Our model projects that the absolute and per capita numbers of practicing pathologists will decrease to approximately 14 000 full-time equivalent (FTE) pathologists or 3.7 per 100 000 in the coming 2 decades. This projection reflects that beginning in 2015, the numbers of pathologists retiring will increase precipitously, and is anticipated to peak by 2021. Including all types of separation, the net pathologist strength will begin falling by year 2015. Unless workforce entry or exit rates change, this trend will continue at least through 2030. These changes reflect the closure of many training programs 2 to 4 decades ago and the substantially decreased number of graduating residents. CONCLUSIONS: This comprehensive analysis predicts that pathologist numbers will decline steadily beginning in 2015. Anticipated population growth in general and increases in disease incidence owing to the aging population, to be presented in a companion article on demand, will lead to a net deficit in excess of more than 5700 FTE pathologists. To reach the projected need in pathologist numbers of nearly 20 000 FTE by 2030 will require an increase from today of approximately 8.1% more residency positions. We believe a pathologist shortage will negatively impact both patient access to laboratory services and health care providers' abilities to deliver more effective health care to their patient populations.

Base-mediated selective synthesis of diversely substituted N-heterocyclic enamines and enaminones by the hydroamination of alkynes.

Regio- and stereoselective alkynylation of various N-heterocycles 1a-l using potassium and cesium salts in DMSO is described. Terminal alkynes 2a-k and internal alkynes 4a-f provided the kinetically stable Z-enamines 3a-l and 5a-i in good to excellent yields using KOH at 120 °C. Addition of heterocyclic amines to 1,3- and 1,4-diethynylbenzene 6a-b provided the mixture of E/Z isomers with KOH; however, with Cs(2)CO(3) selectively Z-isomers 7ab-db were obtained by the hydroamination at one triple bond. This developed methodology also provides an easy and novel access for the synthesis of enaminones 10a-c. The detailed work also supports the formation of cis-isomer by preferential addition of o-haloarylalkynes followed by intramolecular C2 arylation in the copper-catalyzed tandem synthesis of indolo and pyrrolo[2,1-a]isoquinolines.

Regioselective preferential nucleophilic addition of N-heterocycles onto haloarylalkynes over N-arylation of aryl halides.

The study of preferential addition of heterocyclic amines onto halo-substituted arylalkynes over N-arylation under various catalytic conditions is described. The present work supports and confirms the mechanistic pathway of our recent work on the tandem synthesis of indolo- and pyrrolo-[2,1-a]isoquinolines via hydroamination followed by oxidative addition and not vice versa.