Skeletal Muscle Mass and Fat Mass Relationships With Physical Fitness Test Performance in Law Enforcement Recruits Before Academy.

ABSTRACT: Lockie, RG, Carlock, BN, Ruvalcaba, TJ, Dulla, JM, Orr, RM, Dawes, JJ, and McGuire, MB. Skeletal muscle mass and fat mass relationships with physical fitness test performance in law enforcement recruits before academy. J Strength Cond Res 35(5): 1287-1295, 2021-The purpose of this study was to analyze relationships between skeletal muscle mass percentage (SMM%) and fat mass percentage (FM%) relative to fitness test performance in law enforcement recruits. Retrospective analysis was conducted on 338 recruits (271 men and 67 women) from 4 academy classes. Skeletal muscle mass percentage and FM% were measured using cost-effective and practical bioelectrical impedance analysis (BIA) equipment that used hand and foot placement. The fitness tests included grip strength; vertical jump; 75-yard pursuit run; 2-kg medicine ball throw (MBT); push-ups and sit-ups completed in 60 seconds; and the 20-m multistage fitness test. Partial correlations controlling for sex-derived relationships between SMM%, FM%, and the tests. Recruits were split into quartile groups for SMM% and FM% (group 1 had the lowest SMM% or highest FM% and group 4 the highest SMM% or lowest FM%). A 1-way multivariate analysis of variance (MANOVA), with sex as a covariate and Bonferroni post-hoc, compared between-group results. Skeletal muscle mass percentage correlated with all fitness tests expect for MBT; FM% with all but grip strength and MBT (r = ±0.107-0.293). Greater SMM% or lesser FM% tended to relate to better fitness test performance. The MANOVA data indicated groups 3 and 4 (better SMM% or FM% profiles) exhibited superior fitness than group 1 (poorest SMM% or FM% profile) (p ≤ 0.048). Recruits should ideally increase SMM% and decrease FM% before academy to optimize fitness training and testing performance, although specific guidelines should be agency specific. Staff could use BIA to monitor body composition during academy to indicate how recruits are tolerating training.

Lhx8 regulates primordial follicle activation and postnatal folliculogenesis.

BACKGROUND: The early stages of ovarian follicle formation-beginning with the breakdown of germ cell cysts and continuing with the formation of primordial follicles and transition to primary and secondary follicles-are critical in determining reproductive life span and fertility. Previously, we discovered that global knockouts of germ cell-specific transcriptional co-regulators Sohlh1, Sohlh2, Lhx8, and Nobox, cause rapid oocyte loss and ovarian failure. Also factors such as Nobox and Sohlh1 are associated with human premature ovarian failure. In this study, we developed a conditional knockout of Lhx8 to study oocyte-specific pathways in postnatal folliculogenesis. RESULTS: The conditional deficiency of Lhx8 in the oocytes of primordial follicles leads to massive primordial oocyte activation, in part, by indirectly interacting with the PI3K-AKT pathway, as shown by synergistic effects on FOXO3 nucleocytoplasmic translocation and rpS6 activation. However, LHX8 does not directly regulate members of the PI3K-AKT pathway; instead, we show that LHX8 represses Lin28a expression, a known regulator of mammalian metabolism and of the AKT/mTOR pathway. LHX8 can bind to the Lin28a promoter, and the depletion of Lin28a in Lhx8-deficient oocytes partially suppresses primordial oocyte activation. Moreover, unlike the PI3K-AKT pathway, LHX8 is critical beyond primordial follicle activation, and blocks the primary to secondary follicle transition. CONCLUSIONS: Our results indicate that the LHX8-LIN28A pathway is essential in the earliest stages of primordial follicle activation, and LHX8 is an important oocyte-specific transcription factor in the ovary for regulating postnatal folliculogenesis.

Input-specific regulation of hippocampal circuit maturation by non-muscle myosin IIB.

Myh9 and Myh10, which encode two major isoforms of non-muscle myosin II expressed in the brain, have emerged as risk factors for developmental brain disorders. Myosin II motors regulate neuronal cytoskeletal dynamics leading to optimization of synaptic plasticity and memory formation. However, the role of these motor complexes in brain development remains poorly understood. Here, we disrupted the in vivo expression of Myh9 and/or Myh10 in developing hippocampal neurons to determine how these motors contribute to circuit maturation in this brain area important for cognition. We found that Myh10 ablation in early postnatal, but not mature, CA1 pyramidal neurons reduced excitatory synaptic function in the Schaffer collateral pathway, whereas more distal inputs to CA1 neurons were relatively unaffected. Myh10 ablation in young neurons also selectively impaired the elongation of oblique dendrites that receive Schaffer collateral inputs, whereas the structure of distal dendrites was normal. We observed normal spine density and spontaneous excitatory currents in these neurons, indicating that Myh10 KO impaired proximal pathway synaptic maturation through disruptions to dendritic development rather than post-synaptic strength or spine morphogenesis. To address possible redundancy and/or compensation by other Myosin II motors expressed in neurons, we performed similar experiments in Myh9 null neurons. In contrast to findings in Myh10 mutants, evoked synaptic function in young Myh9 KO hippocampal neurons was normal. Data obtained from double Myh9/Myh10 KO neurons largely resembled the MyH10 KO synaptic phenotype. These data indicate that Myosin IIB is a key molecular factor that guides input-specific circuit maturation in the developing hippocampus. Non-muscle myosin II is an actin binding protein with three isoforms in the brain (IIA, IIB and IIC) encoded by the myh9, myh10, and myh14 genes in mice, respectively. We have studied the structure and the function of hippocampal CA1 neurons missing NMIIB and/or NMIIA proteins at different times during development. We have discovered that NMIIB is the major isoform regulating Schaffer collateral inputs, and that this regulation is restricted to early postnatal development.

SAMBA HIV semiquantitative test, a new point-of-care viral-load-monitoring assay for resource-limited settings.

Routine viral-load (VL) testing of HIV-infected individuals on antiretroviral therapy (ART) is used to monitor treatment efficacy. However, due to logistical challenges, implementation of VL has been difficult in resource-limited settings. The aim of this study was to evaluate the performance of the SAMBA semi-Q (simple amplification-based assay semiquantitative test for HIV-1) in London, Malawi, and Uganda. The SAMBA semi-Q can distinguish between patients with VLs above and below 1,000 copies/ml. The SAMBA semi-Q was validated with diluted clinical samples and blinded plasma samples collected from HIV-1-positive individuals. SAMBA semi-Q results were compared with results from the Roche COBAS AmpliPrep/COBAS TaqMan HIV-1 test, v2.0. Testing of 96 2- to 10-fold dilutions of four samples containing HIV-1 subtype C as well as 488 samples from patients in the United Kingdom, Malawi, and Uganda yielded an overall accuracy for the SAMBA semi-Q of 99% (95% confidence interval [CI], 93.8 to 99.9%) and 96.9% (95% CI 94.9 to 98.3%), respectively, compared to to the Roche test. Analysis of VL data from patients in Malawi and Uganda showed that the SAMBA cutoff of 1,000 copies/ml appropriately distinguished treated from untreated individuals. Furthermore, analysis of the viral loads of 232 patients on ART in Malawi and Uganda revealed similar patterns for virological control, defined as either <1,000 copies/ml (SAMBA cutoff) or <5,000 copies/ml (WHO 2010 criterion; WHO, Antiretroviral Therapy for HIV Infection in Adults and Adolescents: Recommendations for a Public Health Approach, 2010). This study suggests that the SAMBA semi-Q has adequate concurrency with the gold standard measurements for viral load. This test can allow VL monitoring of patients on ART at the point of care in resource-limited settings.

Global VAX: A U.S. contribution to global COVID-19 vaccination efforts, 2021-2023.

In December 2021 the U.S. Government announced a new, whole-of-government $1.8 billion effort, the Initiative for Global Vaccine Access (Global VAX) in response to the global COVID-19 pandemic. Using the foundation of decades of U.S. government investments in global health and working in close partnership with local governments and key global and multilateral organizations, Global VAX enabled the rapid acceleration of the global COVID-19 vaccine rollout in selected countries, contributing to increased COVID-19 vaccine coverage in some of the world's most vulnerable communities. Through Global VAX, the U.S. Government has supported 125 countries to scale up COVID-19 vaccine delivery and administration while strengthening primary health care systems to respond to future health crises. The progress made by Global VAX has paved the way for a stronger global recovery and improved global health security.

Mouse HORMAD1 is a meiosis i checkpoint protein that modulates DNA double- strand break repair during female meiosis.

Oocytes in embryonic ovaries enter meiosis I and arrest in the diplonema stage. Perturbations in meiosis I, such as abnormal double-strand break (DSB) formation and repair, adversely affect oocyte survival. We previously discovered that HORMAD1 is a critical component of the synaptonemal complex but not essential for oocyte survival. No significant differences were observed in the number of primordial, primary, secondary, and developing follicles between wild-type and Hormad1(−/−)newborn, 8-day, and 80-day ovaries. Meiosis I progression in Hormad1(−/−) embryonic ovaries was normal through the zygotene stage and in oocytes arrested in diplonema; however, we did not visualize oocytes with completely synapsed chromosomes. We investigated effects of HORMAD1 deficiency on the kinetics of DNA DSB formation and repair in the mouse ovary. We irradiated Embryonic Day 16.5 wild-type and Hormad1(−/−) ovaries and monitored DSB repair using gammaH2AX, RAD51, and DMC1 immunofluorescence. Our results showed a significant drop in unrepaired DSBs in the irradiated Hormad1(−/−) zygotene oocytes as compared to the wild-type oocytes. Moreover, Hormad1 deficiency rescued Dmc1(−/−) oocytes. These results indicate that Hormad1 deficiency promotes DMC1-independent DSB repairs, which in turn helps asynaptic Hormad1(−/−) oocytes resist perinatal loss.

ShoeCase: A data set of mock crime scene footwear impressions.

This project's main objective is to create an open-source database containing a sizeable number of high-quality images of shoe impressions. The Center for Statistics and Applications in Forensic Evidence (CSAFE) team collected images that represented those found at crime scenes and constructed a database that is publicly available to forensic science and research communities. The database includes images obtained from mixed impression types: full blood impression, partial blood impression, and dust impression. The impressions are made on different flooring (vinyl and tile), and captured via various lift techniques: gel lifts and handiprints (exemplar prints with high definition using graphite powder and clear sticky vinyl, backed by a white sheet), and saved in multiple digital file types (TIF, XMP, CR3, and JPG). Our data were collected to ensure reproducibility, using simple but well-described protocols and easily accessible materials. The complete dataset includes 936 unique shoeprint images saved in 3,275 digital files. Data were collected by trained volunteers making shoe impressions on flooring with the two mediums: spatter blood and graphite powder. To make an impression, volunteers wearing a shoe stepped into the material and then walked on the flooring. A separate "lighter" step was taken to create a partial print for the blood prints. The blood prints were brought to the photography station, where researchers labeled and photographed them. Graphite prints were covered with a gel lifter before being moved to the photography room. There, the researchers removed the lift, labeled, and then photographed them. Our data will be of significant use to researchers, examiners, and anyone who could benefit from using a large dataset like this. Footwear datasets are often difficult to find, especially ones that resemble crime scenes, so our data can help fill that gap.

Benefit of viral load testing for confirmation of immunological failure in HIV patients treated in rural Malawi.

OBJECTIVE: Viral load testing is used in the HIV programme of Chiradzulu, Malawi, to confirm the diagnosis of immunological failure to prevent unnecessary switching to second-line therapy. Our objective was to quantify the benefit of this strategy for management of treatment failure in a large decentralized HIV programme in Africa. METHODS: Retrospective analysis of monitoring data from adults treated with first-line antiretroviral regimens for >1 year and meeting the WHO immunological failure criteria in an HIV programme in rural Malawi. The positive predictive value of using immunological failure criteria to diagnose virological failure (viral load >5000 copies/ml) was estimated. RESULTS: Of the 227 patients with immunological failure (185 confirmed with a repeat CD4 measurement), 155 (68.2%) had confirmatory viral load testing. Forty-four (28.4%) had viral load >5000 copies/ml and 57 (36.8%) >1000 copies/ml. Positive predictive value was 28.4% (95% CI 21.4-36.2%). Repeat CD4 count testing showed that 41% of patients initially diagnosed with immunological failure did no longer meet failure criteria. CONCLUSIONS: Our results support the need for confirming all cases of immunological failure with viral load testing before switching to second-line ART to optimize the use of resources in developing countries.

Vital status of pre-ART and ART patients defaulting from care in rural Malawi.

OBJECTIVES: To ascertain the outcome of pre-Antiretroviral therapy (ART) and ART patients defaulting from care and investigate reasons for defaulting. METHODS: Patients defaulting from HIV care in Chiradzulu between July 2004 and September 2007 were traced at last known home address. Deaths and moves were recorded, and patients found alive were interviewed. Defaulting was defined as missed last appointment by more than 1 month among patients of unknown vital status. RESULTS: A total of 1637 individuals were traced (54%-88% of eligible), 981 pre-ART and 656 ART patients. Of 694 pre-ART patients found, 49% had died (51% of adults and 38% of children), a median of 47 days after defaulting, and 14% had moved away. Of 451 ART patients found, 54% had died (54% of adults and 50% of children), a median of 52 days after defaulting, and 20% had moved away. Overall, 221 patients were interviewed (90% of those found alive), 42% had worked outside the district in the previous year; 49% of pre-ART and 19% of ART patients had not disclosed their HIV status to other household members. Main reasons for defaulting were stigma (43%), care dissatisfaction (34%), improved health (28%) and for ART discontinuation, poor understanding of disease or treatment (56%) and drug side effects (42%). CONCLUSION: This study in a rural African HIV programme reveals the dynamics related to health service access and use, and it provides information to correct programme mortality estimates for adults and children.

We Need You: Influence of Hiring Demand and Modified Applicant Testing on the Physical Fitness of Law Enforcement Recruits.

A challenge for law enforcement agencies is the many positions that need filling. Agencies may modify their applicant test battery (ATB; multilevelled testing including fitness, background checks, psychological evaluations) to increase the hiring pool of potential recruits by augmenting the utility of testing. This study determined fitness differences of law enforcement recruits hired under two different ATB protocols. Retrospective analysis was conducted on seven academy classes (442 males, 84 females) hired under an older ATB, and one class (45 males, 13 females) hired under a newer ATB. Recruits completed the following before academy: 60 s push-ups and sit-ups (muscular endurance); vertical jump (lower-body power); medicine ball throw (upper-body power); 75 yard pursuit run (75PR; change-of-direction speed); and 20 m multistage fitness test (20MSFT; aerobic fitness). Independent sample t-tests (p ≤ 0.001) and effect sizes (d) evaluated between-group fitness differences for recruits hired under the different ATB protocols (combined sexes, males, and females). There were no significant differences between the ATB groups. However, newer ATB female recruits completed 13% fewer 20MSFT shuttles than the older ATB group, which, although not significant (p = 0.007), did have a moderate effect (d = 0.62). Females hired under the newer ATB had lower aerobic fitness, which could impact physical training performance and graduation.

Relationships Between Isometric Strength and the 74.84-kg (165-lb) Body Drag Test in Law Enforcement Recruits.

This study investigated whether: law enforcement recruits could complete a 74.84-kg (165-lb) body drag without specific training; relationships between the body drag and absolute and relative isometric grip and leg/back strength could be established to assist with training recommendations; a strength baseline needed to complete the 74.84-kg body drag could be established. Retrospective analysis on a recruit class (72 males, 21 females) from one agency was conducted. Recruits completed the body drag, and had strength assessed by hand grip and leg/back dynamometers in the week before academy. The body drag required the recruit to lift the dummy to standing and drag it 9.75 m as quickly as possible. Independent samples t-tests calculated between-sex differences in the drag and strength measures. Recruits were ranked according to drag time to describe the strength of recruits that could not perform the task. Pearson's correlations and a stepwise linear regression calculated relationships between the body drag and isometric strength. Male recruits completed the drag faster and were stronger than females (p < 0.001). Only two females could not complete the drag, and they had leg/back strength below 100 kg. Greater absolute (r = -0.599 and -0.677) and relative (r = -0.261 and -0.322) grip (combined score) and leg/back strength, respectively, related to a faster drag. Absolute leg/back strength predicted the body drag (r2 = 0.444). Improving absolute isometric grip and leg/back strength could enhance dragging ability. A minimum isometric leg/back strength score of 100 kg may be needed to perform a 74.84-kg body drag.

Mental health and substance abuse indicators among homeless youth in Denver, Colorado.

We report the results of mental health evaluations from 182 homeless youth residing in a Denver, Colorado, shelter. The literature on homeless youth, although developing, is still somewhat limited as it relates to mental health, substance abuse, and trauma. This study was motivated by clinically observed high rates of mental illness, trauma, dangerousness issues, and drug and alcohol abuse. Using archival data from mental health evaluations conducted over two years, variables including gender, age, ethnicity, primary diagnosis, drug of choice, trauma history, suicidal ideation, homicidal ideation, and legal history were assessed. Results discovered significantly higher than expected diagnoses of mental illness and associations between drug of choice and diagnosis, trauma history and suicidal ideation, and trauma history and diagnosis. Results suggest a strong need for co-occurring treatment, trauma-focused therapy, and attention to both mental illness and substance abuse in homeless youth.

Compositional Characterization of Different Industrial White and Red Grape Pomaces in Virginia and the Potential Valorization of the Major Components.

To better evaluate potential uses for grape pomace (GP) waste, a comprehensive chemical composition analysis of GP in Virginia was conducted. Eight commercial white and red pomace samples (cv. Viognier, Vidal Blanc, Niagara, Petit Manseng, Petit Verdot, Merlot, Cabernet Franc, and Chambourcin) obtained from different wineries in Virginia, USA were used. For extractives, GPs contained 2.89%-4.66% titratable acids, 4.32%-6.60% ash, 4.62%-12.5% lipids with linoleic acid being the predominant (59.0%-70.9%) fatty acid, 10.4-64.8 g total phenolic content (gallic acid equivalents)/kg GP, 2.09-53.3 g glucose/kg GP, 3.79-52.9 g fructose/kg GP, and trace sucrose. As for non-extractives, GPs contained 25.2%-44.5% lignin, 8.04%-12.7% glucan, 4.42%-7.05% xylan, and trace amounts of galactan, arabinan, and mannan (less than 3% in total). Potential usages of these components were further examined to provide information on better valorization of GP. Considering the valuable extractives (e.g., polyphenols and oil) and non-extractives (e.g., lignin), designing a biorefinery process aiming at fully recover and/or utilize these components is of future significance.

Sex workers' accounts of condom use: implications for condom production, promotion and health policy.

OBJECTIVES: To explore sex workers' accounts of condom use and their recommendations about how condoms might be improved. METHODS: In-depth interviews were conducted with 22 female sex workers in sex work premises in London, UK and Amsterdam, The Netherlands. RESULTS: The consistent and effective use of condoms was dependent upon client selection, sex worker control of the condom, communication skills and on condom- and sex-related skills. The design of facilities, the way the encounter was structured and alarm call systems were key to generating an environment in which sex worker control of the interaction was feasible. A wide range of practices used for 'safer sex', including the use of simulated vaginal sex, skills in fitting the condom in a sexually arousing way, checking the condom placement during intercourse and holding onto the condom during withdrawal, were described but awareness of such practices was piecemeal. Several sex workers said that particular care is needed when using condoms in men with a small penis and pointed out to the authors that a smaller condom would be useful. CONCLUSIONS: The sex workers told us about the importance of environmental factors and a range of sex- and condom-related skills in 'safer sex'. Environmental 'safety' features could be addressed through a licensing system for sex work premises. Communication, condom- and sex-related skills should be more broadly disseminated through health promotion initiatives with sex workers. The issue of condom fit deserves further attention.

Evaluation of a Digital Behavioral Counseling Program for Reducing Risk Factors for Chronic Disease in a Workforce.

OBJECTIVE: To evaluate a digitally delivered, intensive behavioral counseling program for a workforce at risk for obesity-related chronic disease. METHODS: Employees were offered a digital health program modeled after the diabetes prevention program (DPP). Annual workforce health assessments were used to examine changes in chronic disease risk factors between participants (n = 634) relative to a matched comparison group (n = 1268). RESULTS: Overall, employees were gaining an average of 3.5 pounds annually before program inception. Program engagement was positive; 83% completed the majority of the curriculum and 31% lost at least 5% of their starting weight. Compared with non-participating peers, participants demonstrated reduced weight, improved fasting blood glucose, and improved nutritional intake after a year. CONCLUSIONS: The digital health program was effective for engaging employees in health behavior change. Digital options facilitate widespread implementation.

Granulocyte colony-stimulating factor with or without stem cell factor extends time to premature ovarian insufficiency in female mice treated with alkylating chemotherapy.

OBJECTIVE: To examine gonadal protective properties of granulocyte colony-stimulating factor (G-CSF) alone or in combination with stem cell factor (SCF) in female mice treated with high-dose alkylating chemotherapy. DESIGN: Experimental laboratory animal study. SETTING: Tertiary care academic hospital and research institute. ANIMAL(S): Six- and 8-week-old C57Bl/6 female mice. INTERVENTION(S): Adult female mice were treated with [1] cyclophosphamide and busulfan (CTx), [2] CTx + G-CSF/SCF, [3] CTx + G-CSF, or [4] normal saline and dimethyl sulfoxide (DMSO; vehicle control). MAIN OUTCOME MEASURE(S): Follicle counts, microvessel density, cellular response to DNA damage, and litter production. RESULT(S): G-CSF ± SCF increased microvessel density and decreased follicle loss in CTx-treated female mice compared with CTx-only treated female mice. Mice administered CTx alone exhibited premature ovarian insufficiency, with only 28% of mice producing two litters. However, 100% of mice receiving CTx with G-CSF + SCF, and 80% of mice receiving CTx + G-CSF alone produced at least three litters and 20% of mice in each group produced five litters. CONCLUSION(S): Treatment of mice with G-CSF decreases chemotherapy-induced ovarian follicle loss and extends time to premature ovarian insufficiency in female mice. Further studies are needed to validate these preclinical results in humans and compare efficacy with the established GnRH analogue treatments.

Task-sharing of HIV care and ART initiation: evaluation of a mixed-care non-physician provider model for ART delivery in rural Malawi.

BACKGROUND: Expanding access to antiretroviral therapy (ART) in sub-Saharan Africa requires implementation of alternative care delivery models to traditional physician-centered approaches. This longitudinal analysis compares outcomes of patients initiated on antiretroviral therapy (ART) by non-physician and physician providers. METHODS: Adults (≥15 years) initiating ART between September 2007 and March 2010, and with >1 follow-up visit were included and classified according to the proportion of clinical visits performed by nurses or by clinical officers (≥ 80% of visits). Multivariable Poisson models were used to compare 2-year program attrition (mortality and lost to follow-up) and mortality by type of provider. In sensitivity analyses only patients with less severe disease were included. RESULTS: A total of 10,112 patients contributed 14,012 person-years to the analysis: 3386 (33.5%) in the clinical officer group, 1901 (18.8%) in the nurse care group and 4825 (47.7%) in the mixed care group. Overall 2-year program retention was 81.8%. Attrition was lower in the mixed care and higher in the clinical officer group, compared to the nurse group (adjusted incidence rate ratio [aIRR]=0.54, 95%CI 0.45-0.65; and aIRR=3.03, 95%CI 2.56-3.59, respectively). While patients initiated on ART by clinical officers in the mixed care group had lower attrition (aIRR=0.36, 95%CI 0.29-0.44) than those in the overall nurse care group; no differences in attrition were found between patients initiated on ART by nurses in the mixed care group and those included in the nurse group (aIRR=1.18, 95%CI 0.95-1.47). Two-year mortality estimates were aIRR=0.72, 95%CI 0.49-1.09 and aIRR=5.04, 95%CI 3.56-7.15, respectively. Slightly higher estimates were observed when analyses were restricted to patients with less severe disease. CONCLUSION: The findings of this study support the use of a mixed care model with well trained and regularly supervised nurses and medical assistants to provide HIV care in countries with high HIV prevalence.

Whole exome sequencing in a random sample of North American women with leiomyomas identifies MED12 mutations in majority of uterine leiomyomas.

Uterine leiomyomas (uterine fibroids) arise from smooth muscle tissue in the majority of women by age 45. It is common for these clonal tumors to develop from multiple locations within the uterus, leading to a variety of symptoms such as pelvic pain, abnormal uterine bleeding, and infertility. We performed whole exome sequencing on genomic DNA from five pairs of leiomyomas and corresponding normal myometrium to determine genetic variations unique to leiomyomas. Whole exome sequencing revealed that the gene encoding transcription factor MED12 (Mediator complex subunit 12) harbored heterozygous missense mutations caused by single nucleotide variants in highly conserved codon 44 of exon 2 in two of five leiomyomas. Sanger re-sequencing of MED12 among these five leiomyomas confirmed the two single nucleotide variants and detected a 42 base-pair deletion within exon 2 of MED12 in a third leiomyoma. MED12 was sequenced in an additional 143 leiomyomas and 73 normal myometrial tissues. Overall, MED12 was mutated in 100/148 (67%) of the genotyped leiomyomas: 79/148 (53%) leiomyomas exhibited heterozygous missense single nucleotide variants, 17/148 (11%) leiomyomas exhibited heterozygous in-frame deletions/insertion-deletions, 2/148 (1%) leiomyomas exhibited intronic heterozygous single nucleotide variants affecting splicing, and 2/148 (1%) leiomyomas exhibited heterozygous deletions/insertion-deletions spanning the intron 1-exon 2 boundary which affected the splice acceptor site. Mutations were not detected in MED12 in normal myometrial tissue. MED12 mutations were equally distributed among karyotypically normal and abnormal uterine leiomyomas and were identified in leiomyomas from both black and white American women. Our studies show an association between MED12 mutations and leiomyomas in ethnically and racially diverse American women.

Response to antiretroviral therapy: improved survival associated with CD4 above 500 cells/µl.

OBJECTIVE: We investigated the association between immune response and mortality in four HIV African programs supported by Médecins Sans Frontières. DESIGN: Multicentric retrospective cohort study. METHODS: All antiretroviral therapy (ART) naive adults (>15 years) who initiated therapy between March 2001 and November 2010 and receiving therapy for 9 months or more were included. We described the evolution of mortality over time. Mixed Poisson models were used to assess the effect of updated CD4 cell counts and other potential risk factors on mortality. FINDINGS: A total of 24 037 patients, of which 68% were women, contributed 69 516.2 person-years of follow-up. At ART initiation, 5718 patients (23.7%) were classified as WHO clinical stage 4, 1587 (6.6%) had a BMI below 16 kg/m and 2568 (10.7%) had CD4 cell count below 50 cells/µl. A total of 568 (2.4%) deaths were recorded during the study period. In the CD4 response categories 500 cells/µl or more, 350-499, 200-349, 50-199 cells/µl and less than 50 cells/µl, unadjusted mortality rates were 0.36; 0.58; 0.88; 1.91 and 7.43 per 100 person-years, respectively. In multivariate analysis, higher mortality was observed in patients with CD4 response levels 350-499 cells/µl [adjusted hazard ratio (aHR) 1.70, 95% confidence interval (CI) 1.26-2.30] and for those between 200-349 (aHR 2.56; 95% CI 1.93-3.38), compared to those with 500 cells/µl or more. INTERPRETATION: The observed higher survival of patients with a CD4 response to ART higher than 500 cells/µl supports the need of further research to evaluate the individual benefit of initiating ART at higher CD4 levels in sub-Saharan Africa.

Gender differences in immune reconstitution: a multicentric cohort analysis in sub-Saharan Africa.

BACKGROUND: In sub-Saharan Africa, men living with HIV often start ART at more advanced stages of disease and have higher early mortality than women. We investigated gender difference in long-term immune reconstitution. METHODS/PRINCIPAL FINDINGS: Antiretroviral-naïve adults who received ART for at least 9 months in four HIV programs in sub-Saharan Africa were included. Multivariate mixed linear models were used to examine gender differences in immune reconstitution on first line ART. A total of 21,708 patients (68% women) contributed to 61,912 person-years of follow-up. At ART start,. Median CD4 at ART were 149 [IQR 85-206] for women and 125 cells/µL [IQR 63-187] for men. After the first year on ART, immune recovery was higher in women than in men, and gender-based differences increased by 20 CD4 cells/µL per year on average (95% CI 16-23; P<0.001). Up to 6 years after ART start, patients with low initial CD4 levels experienced similar gains compared to patients with high initial levels, including those with CD4>250 cells/µL (difference between patients with <50 cells/µL and those with >250 was 284 cells/µL; 95% CI 272-296; LR test for interaction with time p = 0.63). Among patients with initial CD4 count of 150-200 cells/µL, women reached 500 CD4 cells after 2.4 years on ART (95% CI 2.4-2.5) and men after 4.5 years (95% CI 4.1-4.8) of ART use. CONCLUSION: Women achieved better long-term immune response to ART, reaching CD4 level associated with lower risks of AIDS related morbidity and mortality quicker than men.