Sex Hormone Therapy and Tenofovir Diphosphate Concentration in Dried Blood Spots: Primary Results of the Interactions Between Antiretrovirals And Transgender Hormones Study.

BACKGROUND: Sex hormone and preexposure prophylaxis (PrEP) drug interactions among transgender women (TGW), transgender men (TGM), and cisgender men (CGM) are not fully understood. METHODS: TGM and TGW on at least 6 months of stable sex hormone therapy containing testosterone or estradiol (respectively) were enrolled in a 4-week study of directly observed dosing of daily oral coformulated emtricitabine and tenofovir disoproxil fumarate (FTC/TDF). TFV-DP in dried blood spots and sex hormones in serum were measured at weekly intervals. TFV-DP was compared with 2- and 4-week samples from Directly Observed Therapy Dried Blood Spots (DOT-DBS) Study (NCT02022657). RESULTS: From May 2017 to June 2018, 24 TGM and 24 TGW were enrolled. Testosterone (total and free) and estradiol concentrations were comparable before and after 4 weeks of PrEP use in TGM and TGW, respectively. Historical controls included 17 cisgender women (CGW) and 15 CGM. TFV-DP concentrations at week 4 were comparable between TGW and TGM (mean difference, -6%; 95% confidence interval [CI], -21% to 12%; P = .47), comparable between TGW and CGM (mean difference, -12%; 95% CI, -27% to 7%; P = .21) and were lower among TGM compared with CGW (mean difference, -23%; 95% CI, -36% to -7%; P = .007). All persons in all groups were projected to reach the TFV-DP threshold that has been associated with high protection from human immunodeficiency virus. CONCLUSIONS: CGM, TGM, and TGW had comparable TFV-DP concentrations in dried blood spots after 4 weeks of directly observed daily FTC/TDF PrEP use. Serum hormone concentrations were not affected by FTC/TDF PrEP use. CLINICAL TRIALS REGISTRATION: NCT04050371.

Large reduction in opioid prescribing by a multipronged behavioral intervention after major urologic surgery.

BACKGROUND: Surgeons play a pivotal role in combating the opioid crisis that currently grips the United States. Changing surgeon behavior is difficult, and the degree to which behavioral science can steer surgeons toward decreased opioid prescribing is unclear. METHODS: This was a single-institution, single-arm, pre- and postintervention study examining the prescribing of opioids by urologists for adult patients undergoing prostatectomy or nephrectomy. The primary outcome was the quantity of opioids prescribed in oral morphine equivalents (OMEs) after hospital discharge. The primary exposure was a multipronged behavioral intervention designed to decrease opioid prescribing. The intervention had 3 components: 1) formal education, 2) individual audit feedback, and 3) peer comparison performance feedback. There were 3 phases to the study: a pre-intervention phase, an intervention phase, and a washout phase. RESULTS: Three hundred eighty-two patients underwent prostatectomy, and 306 patients underwent nephrectomy. The median OMEs decreased from 195 to 19 in the prostatectomy patients and from 200 to 0 in the nephrectomy patients (P < .05 for both). The median OMEs prescribed did not increase during the washout phase. Prostatectomy patients discharged with opioids had higher levels of anxiety than patients discharged without opioids (P < .05). Otherwise, prostatectomy and nephrectomy patients discharged with and without opioids did not differ in their perception of postoperative pain management, activity levels, psychiatric symptoms, or somatic symptoms (P > .05 for all). CONCLUSIONS: Implementing a multipronged behavioral intervention significantly reduced opioid prescribing for patients undergoing prostatectomy or nephrectomy without compromising patient-reported outcomes.

Drugs to Be Used With a Filter for Preparation and/or Administration-2019.

This chart is an update to the 2012 article published in Hospital Pharmacy on injectable drugs to be used with a filter. To update the chart, drugs approved from December 2011 to April 2019 were reviewed to determine if they require filtration and drugs included in the 2012 table were reviewed for accuracy. Readers are urged to review national standards of practice for information about clinical situations that warrant the use of a filter for medication preparation or administration, independent of the drug being given, and the reader should consult the Food and Drug Administration (FDA)-approved prescribing information for the most up-to-date information.

De novo mutations in Caudal Type Homeo Box transcription Factor 2 (CDX2) in patients with persistent cloaca.

The cloaca is an embryonic cavity that is divided into the urogenital sinus and rectum upon differentiation of the cloacal epithelium triggered by tissue-specific transcription factors including CDX2. Defective differentiation leads to persistent cloaca in humans (PC), a phenotype recapitulated in Cdx2 mutant mice. PC is linked to hypo/hyper-vitaminosis A. Although no gene has ever been identified, there is a strong evidence for a genetic contribution to PC. We applied whole-exome sequencing and copy-number-variants analyses to 21 PC patients and their unaffected parents. The damaging p.Cys132* and p.Arg237His de novo CDX2 variants were identified in two patients. These variants altered the expression of CYP26A1, a direct CDX2 target encoding the major retinoic acid (RA)-degrading enzyme. Other RA genes, including the RA-receptor alpha, were also mutated. Genes governing the development of cloaca-derived structures were recurrently mutated and over-represented in the basement-membrane components set (q-value < 1.65 × 10-6). Joint analysis of the patients' profile highlighted the extracellular matrix-receptor interaction pathway (MsigDBID: M7098, FDR: q-value < 7.16 × 10-9). This is the first evidence that PC is genetic, with genes involved in the RA metabolism at the lead. Given the CDX2 de novo variants and the role of RA, our observations could potentiate preventive measures. For the first time, a gene recapitulating PC in mouse models is found mutated in humans.

Beta-amyloid deposition around hepatic bile ducts is a novel pathobiological and diagnostic feature of biliary atresia.

BACKGROUND AND AIMS: Biliary atresia (BA) is a poorly understood and devastating obstructive bile duct disease of newborns. It is often diagnosed late, is incurable and frequently requires liver transplantation. In this study, we aimed to investigate the underlying pathogenesis and molecular signatures associated with BA. METHODS: We combined organoid and transcriptomic analysis to gain new insights into BA pathobiology using patient samples and a mouse model of BA. RESULTS: Liver organoids derived from patients with BA and a rhesus rotavirus A-infected mouse model of BA, exhibited aberrant morphology and disturbed apical-basal organization. Transcriptomic analysis of BA organoids revealed a shift from cholangiocyte to hepatocyte transcriptional signatures and altered beta-amyloid-related gene expression. Beta-amyloid accumulation was observed around the bile ducts in BA livers and exposure to beta-amyloid induced the aberrant morphology in control organoids. CONCLUSION: The novel observation that beta-amyloid accumulates around bile ducts in the livers of patients with BA has important pathobiological implications, as well as diagnostic potential. LAY SUMMARY: Biliary atresia is a poorly understood and devastating obstructive bile duct disease of newborns. It is often diagnosed late, is incurable and frequently requires liver transplantation. Using human and mouse 'liver mini-organs in the dish', we unexpectedly identified beta-amyloid deposition - the main pathological feature of Alzheimer's disease and cerebral amyloid angiopathy - around bile ducts in livers from patients with biliary atresia. This finding reveals a novel pathogenic mechanism that could have important diagnostic and therapeutic implications.

Modulating Pathogenesis with Mobile-CRISPRi.

Conditionally essential (CE) genes are required by pathogenic bacteria to establish and maintain infections. CE genes encode virulence factors, such as secretion systems and effector proteins, as well as biosynthetic enzymes that produce metabolites not found in the host environment. Due to their outsized importance in pathogenesis, CE gene products are attractive targets for the next generation of antimicrobials. However, the precise manipulation of CE gene expression in the context of infection is technically challenging, limiting our ability to understand the roles of CE genes in pathogenesis and accordingly design effective inhibitors. We previously developed a suite of CRISPR interference-based gene knockdown tools that are transferred by conjugation and stably integrate into bacterial genomes that we call Mobile-CRISPRi. Here, we show the efficacy of Mobile-CRISPRi in controlling CE gene expression in an animal infection model. We optimize Mobile-CRISPRi in Pseudomonas aeruginosa for use in a murine model of pneumonia by tuning the expression of CRISPRi components to avoid nonspecific toxicity. As a proof of principle, we demonstrate that knock down of a CE gene encoding the type III secretion system (T3SS) activator ExsA blocks effector protein secretion in culture and attenuates virulence in mice. We anticipate that Mobile-CRISPRi will be a valuable tool to probe the function of CE genes across many bacterial species and pathogenesis models.IMPORTANCE Antibiotic resistance is a growing threat to global health. To optimize the use of our existing antibiotics and identify new targets for future inhibitors, understanding the fundamental drivers of bacterial growth in the context of the host immune response is paramount. Historically, these genetic drivers have been difficult to manipulate precisely, as they are requisite for pathogen survival. Here, we provide the first application of Mobile-CRISPRi to study conditionally essential virulence genes in mouse models of lung infection through partial gene perturbation. We envision the use of Mobile-CRISPRi in future pathogenesis models and antibiotic target discovery efforts.

Identification of Genes Associated With Hirschsprung Disease, Based on Whole-Genome Sequence Analysis, and Potential Effects on Enteric Nervous System Development.

BACKGROUND & AIMS: Hirschsprung disease, or congenital aganglionosis, is believed to be oligogenic-that is, caused by multiple genetic factors. We performed whole-genome sequence analyses of patients with Hirschsprung disease to identify genetic factors that contribute to disease development and analyzed the functional effects of these variants. METHODS: We performed whole-genome sequence analyses of 443 patients with short-segment disease, recruited from hospitals in China and Vietnam, and 493 ethnically matched individuals without Hirschsprung disease (controls). We performed genome-wide association analyses and gene-based rare-variant burden tests to identify rare and common disease-associated variants and study their interactions. We obtained induced pluripotent stem cell (iPSC) lines from 4 patients with Hirschsprung disease and 2 control individuals, and we used these to generate enteric neural crest cells for transcriptomic analyses. We assessed the neuronal lineage differentiation capability of iPSC-derived enteric neural crest cells using an in vitro differentiation assay. RESULTS: We identified 4 susceptibility loci, including 1 in the phospholipase D1 gene (PLD1) (P = 7.4 × 10-7). The patients had a significant excess of rare protein-altering variants in genes previously associated with Hirschsprung disease and in the ß-secretase 2 gene (BACE2) (P = 2.9 × 10-6). The epistatic effects of common and rare variants across these loci provided a sensitized background that increased risk for the disease. In studies of the iPSCs, we observed common and distinct pathways associated with variants in RET that affect risk. In functional assays, we found variants in BACE2 to protect enteric neurons from apoptosis. We propose that alterations in BACE1 signaling via amyloid ß precursor protein and BACE2 contribute to pathogenesis of Hirschsprung disease. CONCLUSIONS: In whole-genome sequence analyses of patients with Hirschsprung disease, we identified rare and common variants associated with disease risk. Using iPSC cells, we discovered some functional effects of these variants.

Association of Endothelin-1 With Accelerated Cardiac Allograft Vasculopathy and Late Mortality Following Heart Transplantation.

BACKGROUND: Endothelin-1 (ET-1) has been implicated in the development of post-heart transplantation (HT) cardiac allograft vasculopathy (CAV), but has not been well studied in humans. METHODS AND RESULTS: In 90 HT patients, plasma ET-1 was measured within 8 weeks after HT (baseline) via a competitive enzyme-linked immunosorbent assay. Three-dimensional volumetric intravascular ultrasound of the left anterior descending artery was performed at baseline and at 1 year. Accelerated CAV (lumen volume loss) was defined with the 75th percentile as a cutoff. Patients were followed beyond the first year after HT for late death or retransplantation. A receiver operating characteristic (ROC) curve demonstrated that a baseline ET-1 concentration of 1.75 pg/mL provided the best accuracy for diagnosis of accelerated CAV at 1 year (area under the ROC curve 0.69, 95% confidence interval [CI] 0.57-0.82; P = .007). In multivariate logistic regression, a higher baseline ET-1 concentration was independently associated with accelerated CAV (odds ratio [OR] 2.13, 95% CI 1.15-3.94; P = .01); this relationship persisted when ET-1 was dichotomized at 1.75 pg/mL (OR 4.88, 95% CI 1.69-14.10; P = .003). Eighteen deaths occurred during a median follow-up period of 3.99 (interquartile range 2.51-9.95) years. Treated as a continuous variable, baseline ET-1 was not associated with late mortality in multivariate Cox regression (hazard ratio [HR] 1.22, 95% CI 0.72-2.05; P = .44). However, ET-1 >1.75 pg/mL conferred a significantly lower cumulative event-free survival on Kaplan-Meier analysis (P = .047) and was independently associated with late mortality (HR 2.94, 95% CI 1.12-7.72; P = .02). CONCLUSIONS: Elevated ET-1 early after HT is an independent predictor of accelerated CAV and late mortality, suggesting that ET-1 has durable prognostic value in the HT arena.

Risk factors for the development of post-operative enterocolitis in short segment Hirschsprung's disease.

AIM OF THE STUDY: The objective of this study is to identify risk factors associated with the development of post-operative enterocolitis (HAEC), in short segment Hirschsprung's disease (HSCR-S). METHODS: A retrospective study was carried out for post-operative patients with HSCR-S from 1997 to 2017. HSCR-S was defined as the most proximal extension of aganglionosis limited to the sigmoid colon. An episode of HAEC was defined as the presence of (1) vomiting or explosive diarrhea; (2) abdominal distension; (3) fever and (4) leukocytosis. Risk factors for the development of HACE were determined using multivariate logistic regression. MAIN RESULTS: The medical records of 96 patients were reviewed. The overall incidence of HAEC was 20.8% (n = 20) and 65.0% (n = 13) of HAEC occurred within the first year of operation. After a univariate logistic regression analysis, three risk factors for HAEC were identified: (1) presence of other major anomalies [OR: 1.43 (1.12-2.32), p = 0.041]; (2) creation of pre-operative defunctioning stoma [OR: 2.28 (1.47-3.23), p = 0.035]; (3) extension of aganglionosis to the sigmoid colon [OR: 1.89 (1.05-3.19), p = 0.049]. After multivariate logistic regression analysis, a significant association was demonstrated for creation of pre-operative defunctioning stoma [OR: 1.81 (1.08-3.22), p = 0.045] and extension of aganglionosis to the sigmoid colon [OR: 1.91 (1.37-2.98), p = 0.038]. CONCLUSIONS: The requirement of pre-operative defunctioning stoma and a more proximal extension of aganglionosis are risk factors for the development of post-operative HAEC in HSCR-S. Patients with these risk factors should be closely followed up especially during the first year after the operation.

3 Steps to a Strong Pricing Strategy.

The need for a strong pricing strategy is a foregone conclusion. Hospitals and health systems have a window of opportunity now to craft a thoughtful approach to pricing that avoids common pitfalls and ultimately creates a competitive advantage in the market.

Through-Space Intervalence Charge Transfer as a Mechanism for Charge Delocalization in Metal-Organic Frameworks.

Understanding the nature of charge transfer mechanisms in 3-dimensional metal-organic frameworks (MOFs) is an important goal owing to the possibility of harnessing this knowledge to design electroactive and conductive frameworks. These materials have been proposed as the basis for the next generation of technological devices for applications in energy storage and conversion, including electrochromic devices, electrocatalysts, and battery materials. After nearly two decades of intense research into MOFs, the mechanisms of charge transfer remain relatively poorly understood, and new strategies to achieve charge mobility remain elusive and challenging to experimentally explore, validate, and model. We now demonstrate that aromatic stacking interactions in Zn(II) frameworks containing cofacial thiazolo[5,4- d]thiazole (TzTz) units lead to a mixed-valence state upon electrochemical or chemical reduction. This through-space intervalence charge transfer (IVCT) phenomenon represents a new mechanism for charge transfer in MOFs. Computational modeling of the optical data combined with application of Marcus-Hush theory to the IVCT bands for the mixed-valence framework has enabled quantification of the degree of charge transfer using both in situ and ex situ electro- and spectro-electrochemical methods. A distance dependence for the through-space electron transfer has also been identified on the basis of experimental studies and computational calculations. This work provides a new window into electron transfer phenomena in 3-dimensional coordination space, of relevance to electroactive MOFs where new mechanisms for charge transfer are highly sought after, and to understanding biological light-harvesting systems where through-space mixed-valence interactions are operative.

Sacral neuromodulation blocks pudendal inhibition of reflex bladder activity in cats: insight into the efficacy of sacral neuromodulation in Fowler's syndrome.

This study tested the hypothesis that sacral neuromodulation, i.e., electrical stimulation of afferent axons in sacral spinal root, can block pudendal afferent inhibition of the micturition reflex. In α-chloralose-anesthetized cats, pudendal nerve stimulation (PNS) at 3-5 Hz was used to inhibit bladder reflex activity while the sacral S1 or S2 dorsal root was stimulated at 15-30 Hz to mimic sacral neuromodulation and to block the bladder inhibition induced by PNS. The intensity threshold (T) for PNS or S1/S2 dorsal root stimulation (DRS) to induce muscle twitch of anal sphincter or toe was determined. PNS at 1.5-2T intensity inhibited the micturition reflex by significantly ( P < 0.01) increasing bladder capacity to 150-170% of control capacity. S1 DRS alone at 1-1.5T intensity did not inhibit bladder activity but completely blocked PNS inhibition and restored bladder capacity to control level. At higher intensity (1.5-2T), S1 DRS alone inhibited the micturition reflex and significantly increased bladder capacity to 135.8 ± 6.6% of control capacity. However, the same higher intensity S1 DRS applied simultaneously with PNS, suppressed PNS inhibition and significantly ( P < 0.01) reduced bladder capacity to 126.8 ± 9.7% of control capacity. S2 DRS at both low (1T) and high (1.5-2T) intensity failed to significantly reduce PNS inhibition. PNS and S1 DRS did not change the amplitude and duration of micturition reflex contractions, but S2 DRS at 1.5-2T intensity doubled the duration of the contractions and increased bladder capacity. These results are important for understanding the mechanisms underlying sacral neuromodulation of nonobstructive urinary retention in Fowler's syndrome.

Risk factors associated with hypertensive disorders of pregnancy within an urban indigenous population in south western Sydney.

BACKGROUND: The prevalence of hypertensive disorders of pregnancy (HDP) in Australia's urban indigenous women is unknown. AIM: To explore the risk factors associated with HDP for a cohort of urban indigenous women in South-Western Sydney, Australia. METHODS: This study was conducted in partnership with the Tharawal Aboriginal Medical Service. Women (18-45 years) were recruited at the clinic and community events. The quantitative questionnaire included obstetric history, personal and family history of hypertension. Anthropometric measurements and blood pressure were conducted. Rates were compared with Australian Bureau of Statistics (ABS) national rates. RESULTS: Eighty-three participants completed the questionnaire. The rate of ever having HDP in a pregnancy was 36.1%. The overall ABS rate was 9.8% and for indigenous women, 14%. The mean maternal age at first pregnancy was 20.8 years (SD 3.7 years). The mean body mass index (BMI) of the sample population (n = 81) was 32.2 kg/m2 (SD 9.5 kg/m2 ) and BMI was not related to HDP (P = 0.197). Of those questioned, 25.3% had an individual history and 63.9% had a family history of hypertension. The effect of family history of hypertension (P = 0.020) (odds ratio (OR) 4.29; 95% confidence interval (CI); 1.42-12.93) and individual history of hypertension (P < 0.001) (OR 15.69; 95% CI; 4.50-54.76) were associated with HDP. CONCLUSION: There was a higher rate of HDP in urban indigenous women compared to the national indigenous prevalence. The family history, or individual history of hypertension was the most significant risk factors and BMI was not identified as a risk factor for HDP in this population.

An excitatory reflex from the superficial peroneal nerve to the bladder in cats.

This study in α-chloralose-anesthetized cats discovered an excitatory peroneal nerve-to-bladder reflex. A urethral catheter was used to infuse the bladder with saline and record bladder pressure changes. Electrical stimulation was applied to the superficial peroneal nerve to trigger reflex bladder activity. With the bladder distended at a volume ~90% of bladder capacity, superficial peroneal nerve stimulation (PNS) at 1-3 Hz and threshold (T) intensity for inducing muscle twitching on the posterior thigh induced large-amplitude (40-150 cmH2O) bladder contractions. PNS (1-3 Hz, 1-2T) applied during cystometrograms (CMGs) when the bladder was slowly (1-3 ml/min) infused with saline significantly (P < 0.01) reduced bladder capacity to ~80% of the control capacity and significantly (P < 0.05) enhanced reflex bladder contractions. To determine the impact of PNS on tibial nerve stimulation (TNS)-induced changes in bladder function, PNS was delivered following TNS. TNS of 30-min duration produced long-lasting poststimulation inhibition and significantly (P < 0.01) increased bladder capacity to 140.5 ± 7.6% of the control capacity. During the post-TNS inhibition period, PNS (1-3 Hz, 1-4T) applied during CMGs completely restored bladder capacity to the control level and significantly (P < 0.05) increased the duration of reflex bladder contractions to ~200% of control. The excitatory peroneal nerve-to-bladder reflex could also be activated by transcutaneous PNS using skin surface electrodes attached to the dorsal surface of the foot. These results raise the possibility of developing novel neuromodulation therapies to treat underactive bladder and nonobstructive urinary retention.

Role of cannabinoid receptor type 1 in tibial and pudendal neuromodulation of bladder overactivity in cats.

The role of cannabinoid type 1 (CB1) receptors in tibial and pudendal neuromodulation of bladder overactivity induced by intravesical infusion of 0.5% acetic acid (AA) was determined in α-chloralose anesthetized cats. AA irritation significantly (P < 0.01) reduced bladder capacity to 36.6 ± 4.8% of saline control capacity. Tibial nerve stimulation (TNS) at two or four times threshold (2T or 4T) intensity for inducing toe movement inhibited bladder overactivity and significantly (P < 0.01) increased bladder capacity to 69.2 ± 9.7 and 79.5 ± 7.2% of saline control, respectively. AM 251 (a CB1 receptor antagonist) administered intravenously at 0.03 or 0.1 mg/kg significantly (P < 0.05) reduced the inhibition induced by 2T or 4T TNS, respectively, without changing the prestimulation bladder capacity. However, intrathecal administration of AM 251 (0.03 mg) to L7 spinal segment had no effect on TNS inhibition. Pudendal nerve stimulation (PNS) also inhibited bladder overactivity induced by AA irritation, but AM 251 at 0.01-1 mg/kg iv had no effect on PNS inhibition or the prestimulation bladder capacity. These results indicate that CB1 receptors play an important role in tibial but not pudendal neuromodulation of bladder overactivity and the site of action is not within the lumbar L7 spinal cord. Identification of neurotransmitters involved in TNS or PNS inhibition of bladder overactivity is important for understanding the mechanisms of action underlying clinical application of neuromodulation therapies for bladder disorders.

Glutamatergic Mechanisms Involved in Bladder Overactivity and Pudendal Neuromodulation in Cats.

The involvement of ionotropic glutamate receptors in bladder overactivity and pudendal neuromodulation was determined in α-chloralose anesthetized cats by intravenously administering MK801 (a NMDA receptor antagonist) or CP465022 (an AMPA receptor antagonist). Infusion of 0.5% acetic acid (AA) into the bladder produced bladder overactivity. In the first group of 5 cats, bladder capacity was significantly (P < 0.05) reduced to 55.3±10.0% of saline control by AA irritation. Pudendal nerve stimulation (PNS) significantly (P < 0.05) increased bladder capacity to 106.8 ± 15.0% and 106.7 ± 13.3% of saline control at 2T and 4T intensity, respectively. T is threshold intensity for inducing anal twitching. MK801 at 0.3 mg/kg prevented the increase in capacity by 2T or 4T PNS. In the second group of 5 cats, bladder capacity was significantly (P < 0.05) reduced to 49.0 ± 7.5% of saline control by AA irritation. It was then significantly (P < 0.05) increased to 80.8±13.5% and 79.0±14.0% of saline control by 2T and 4T PNS, respectively. CP465022 at 0.03-1 mg/kg prevented the increase in capacity by 2T PNS and at 0.3-1 mg/kg prevented the increase in capacity by 4T PNS. In both groups, MK801 at 0.3 mg/kg and CP465022 at 1 mg/kg significantly (P < 0.05) increased the prestimulation bladder capacity (about 80% and 20%, respectively) and reduced the amplitude of bladder contractions (about 30 and 20 cmH2O, respectively). These results indicate that NMDA and AMPA glutamate receptors are important for PNS to inhibit bladder overactivity and that tonic activation of these receptors also contributes to the bladder overactivity induced by AA irritation.

HCV screening in a cohort of HIV infected and uninfected homeless and marginally housed women in San Francisco, California.

BACKGROUND: Hepatitis C virus (HCV) screening has taken on new importance as a result of updated guidelines and new curative therapies. Relatively few studies have assessed HCV infection in homeless populations, and a minority include women. We assessed prevalence and correlates of HCV exposure in a cohort of homeless and unstably housed women in San Francisco, and estimated the proportion undiagnosed. METHODS: A probability sample of 246 women were recruited at free meal programs, homeless shelters, and low-cost single room occupancy hotels in San Francisco; women with HIV were oversampled. At baseline, anti-HCV status was assessed using an enzyme immunoassay, and results compared in both HIV-positive and negative women. Exposures were assessed by self-report. Logistic regression was used to assess factors independently associated th HCV exposure. RESULTS: Among 246 women 45.9% were anti-HCV positive, of whom 61.1% were HIV coinfected; 27.4% of positives reported no prior screening. Most (72%) women were in the 'baby-boomer' birth cohort; 19% reported recent injection drug use (IDU). Factors independently associated with anti-HCV positivity were: being born in 1965 or earlier (AOR) 3.94; 95%CI: 1.88, 8.26), IDU history (AOR 4.0; 95%CI: 1.68, 9.55), and number of psychiatric diagnoses (AOR 1.16; 95%CI: 1.08, 1.25). CONCLUSIONS: Results fill an important gap in information regarding HCV among homeless women, and confirm the need for enhanced screening in this population where a high proportion are baby-boomers and have a history of drug use and psychiatric problems. Due to their age and risk profile, there is a high probability that women in this study have been infected for decades, and thus have significant liver disease. The association with mental illness and HCV suggests that in addition increased screening, augmenting mental health care and support may enhance treatment success.

Follicular helper T cells promote liver pathology in mice during Schistosoma japonicum infection.

Following Schistosoma japonicum (S. japonicum) infection, granulomatous responses are induced by parasite eggs trapped in host organs, particular in the liver, during the acute stage of disease. While excessive liver granulomatous responses can lead to more severe fibrosis and circulatory impairment in chronically infected host. However, the exact mechanism of hepatic granuloma formation has remained obscure. In this study, we for the first time showed that follicular helper T (Tfh) cells are recruited to the liver to upregulate hepatic granuloma formation and liver injury in S. japonicum-infected mice, and identified a novel function of macrophages in Tfh cell induction. In addition, our results showed that the generation of Tfh cells driven by macrophages is dependent on cell-cell contact and the level of inducible costimulator ligand (ICOSL) on macrophages which is regulated by CD40-CD40L signaling. Our findings uncovered a previously unappreciated role for Tfh cells in liver pathology caused by S. japonicum infection in mice.

Single center outcomes after reconstructive surgical correction of adult acquired buried penis: measurements of erectile function, depression, and quality of life.

INTRODUCTION: Management of adult acquired buried penis is a troublesome situation for both patient and surgeon. The buried penis has been associated with significant erectile and voiding dysfunction, depression, and overall poor quality of life (QOL). AIM: To identify outcomes following reconstructive surgery with release of buried penis, escutcheonectomy, and circumcision with or without skin grafting. METHODS: We retrospectively identified 11 patients treated by a single surgeon between 2007 and 2011, patient ages were 44-69; complete data review was available on all 11. OUTCOME MEASURES: Validated European Organisation for Research and Treatment of Cancer 15 QOL, Center for Epidemiologic Studies Depression Scale (CES-D), and International Index of Erectile Function (IIEF) surveys assessed patient QOL, depression, and erectile function pre- and postoperatively. RESULTS: Mean body mass index (BMI) was 48.8 (42.4-64.6). Mean operative time was 191 minutes (139-272). Mean length of stay was 2.1 days. Ten of 11 patients required phallic skin grafting. There was one perioperative complication resulting in respiratory failure and overnight stay in the intensive care unit. Wound complications were seen in 2/11 patients, and 1 needed surgical debridement for superficial wound infection. Skin graft take was seen in 100% of the patients. Ninety-one percent of patients noted significant improvement in voiding postoperatively. Ninety-one percent of patients reported significant erectile dysfunction preoperatively. Subsequently, IIEF scores improved post surgery by an average of 7.7 points. Clinical depression was noted to be present in 7/11 patients preoperatively and 2/11 postoperatively based on CES-D surveys. QOL improved significantly in 10/11 compared with preoperative baseline; however, many patients noted significant difficulties based on their weight and other comorbidities. CONCLUSIONS: Management of adult acquired buried penis is a challenging, yet correctable problem. In our series it appears that by using established surgical techniques we were able to achieve significant improvements in erectile function, QOL, and measures of depression.