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Chemical and psychological stressors can exert long lasting changes in brain function and behaviour. Changes in DNA methylation have been shown to be an important mechanism mediating long lasting changes in neural function and behaviour, especially for anxiety-like or stress responses. In the present study, we examined the effects of either a social or chemical stressor on DNA methyltransferase (DNMT) gene expression in the amygdala, an important brain region modulating stress responses and anxiety. In adult California mice (Peromyscus californicus) that were naïve to social defeat, females had higher levels of Dnmt1 expression in punch samples of the central amygdala (CeA) than males. In addition, mice that underwent social defeat stress showed reduced Dnmt1 and Dnmt3a expression in the CeA of females but not males. A second study using more anatomically specific punch samples replicated these effects for Dnmt1. Perinatal exposure (spanning from periconception through lactation) to bisphenol A or ethinyl oestradiol (oestrogens in birth control pills) also abolished sex differences in Dnmt1 expression in the CeA but not the basolateral amygdala. These findings identify a robust sex difference in Dnmt1 expression in the CeA that is sensitive to both psychological and chemical stressors. Future studies should aim to examine the impact of psychological and chemical stressors on DNA methylation in the CeA and also investigate whether Dnmt1 may have an underappreciated role in plasticity in behaviour.

Background: Routine laboratory reporting of estimated glomerular filtration rate (eGFR) may help clinicians detect kidney disease. The current national prevalence of eGFR reporting in clinical laboratories is unknown; thus, the extent of the situation of laboratories not routinely reporting eGFR with serum creatinine results is not quantified.Design: Observational analysis.Setting: National Kidney Disease Education Program survey of clinical laboratories conducted in 2006 to 2007 by mail, web, and telephone follow-up.Participants: A national random sample, 6,350 clinical laboratories, drawn from the Federal Clinical Laboratory Improvement Amendments database and stratified by 6 major laboratory types/groupings.Predictors: Laboratory reports serum creatinine results.Outcomes: Reporting eGFR values with serum creatinine results.Measurements: Percentage of laboratories reporting eGFR along with reporting serum creatinine values, reporting protocol, eGFR formula used, and style of reporting cutoff values.Results: Of laboratories reporting serum creatinine values, 38.4% report eGFR (physician offices, 25.8%; hospitals, 43.6%; independents, 38.9%; community clinics, 47.2%; health fair/insurance/public health, 45.5%; and others, 43.2%). Physician office laboratories have a reporting prevalence lower than other laboratory types (P < 0.001). Of laboratories reporting eGFR, 66.7% do so routinely with all adult serum creatinine determinations; 71.6% use the 4-variable Modification of Diet in Renal Disease Study equation; and 45.3% use the ">60 mL/min/1.73 m(2)" reporting convention. Independent laboratories are least likely to routinely report eGFR (50.6%; P < 0.05) and most likely to report only when specifically requested (45.4%; P < 0.05). High-volume laboratories across all strata are more likely to report eGFR (P < 0.001).Limitations: Self-reporting by laboratories, federal database did not have names of laboratory directors/managers (intended respondents), assumed accuracy of federal database for sample purposes.Conclusions: Routine eGFR reporting with serum creatinine values is not yet universal, and laboratories vary in their reporting practices. [ABSTRACT FROM AUTHOR]

Discusses the problem of non-compliance in patients. Definition and measurement of compliance; Doctors' prejudices; Patients' perceptions on drug compliance; Educating doctors on the art of prescribing; Counseling patients; Simplification of treatment regimens.

The hypocretin (Hcrt) system modulates arousal and anxiety-related behaviors and has been considered as a novel treatment target for stress-related affective disorders. We examined the effects of Hcrt acting in the nucleus accumbens shell (NAcSh) and anterodorsal bed nucleus of the stria terminalis (adBNST) on social behavior in male and female California mice (Peromyscus californicus). In female but not male California mice, infusion of Hcrt1 into NAcSh decreased social approach. Weak effects of Hcrt1 on social vigilance were observed in both females and males. No behavioral effects of Hcrt1 infused into the adBNST were observed. Analyses of sequencing data from California mice and Mus musculus NAc showed that Hcrtr2 was more abundant than Hcrtr1, so we infused the selective Hcrt receptor 2 antagonist into the NAcSh, which increased social approach in females previously exposed to social defeat. A calcium imaging study in the NAcSh of females before and after stress exposure showed that neural activity increased immediately following the expression of social avoidance but not during freezing behavior. This observation is consistent with previous studies that identified populations of neurons in the NAc that drive avoidance. Intriguingly, calcium transients were not affected by stress. These data suggest that hypocretin acting in the NAcSh plays a key role in modulating stress-induced social avoidance., (© 2024. The Author(s).)

Psychiatric research encompasses diverse methodologies to understand the complex interplay between neurochemistry and behavior in mental health disorders. Despite significant advancements in pharmacological interventions, there remains a critical gap in understanding the precise functional changes underlying psychiatric conditions and the mechanisms of action of therapeutic agents. Genetically encoded sensors have emerged as powerful tools to address these challenges by enabling real-time monitoring of neurochemical dynamics in specific neuronal populations. This prospective explores the utility of neurotransmitter binding genetically encoded sensors in uncovering the nature of neuronal dysregulation underpinning mental illness, assessing the impact of pharmaceutical interventions, and facilitating the discovery of novel treatments., (© 2024. The Author(s).)

Context: Tumor volume doubling time (TVDT) is emerging as a useful tool in predicting oncologic outcomes. There is limited data on the prognostic role of TVDT in metastatic medullary thyroid cancer (MTC)., Purpose: The goal of this study was to assess the value of TVDT in predicting disease-specific survival (DSS) in patients with hereditary and sporadic MTC., Methods: This was an Institutional Review Board-approved cohort study including patients with metastatic MTC having at least 3 consecutive imaging studies. TVDT of up to the five largest lesions per organ was calculated using a standardized formula. The association between TVDT and DSS was analyzed using Kaplan-Meier survival curves. Cox proportional regression model was used to account for confounding factors., Results: The study sample consisted of 51 patients presenting with 286 metastatic lesions measured with 457 scans during the follow-up of 51 (IQR 25-102) months. Median age was 19 years (IQR 15-41), 53% female patients. Cumulative volumes of all metastatic lesions and proportion of patients with TVDT of <1 year were higher in patients with sporadic as compared with hereditary MTC (p<0.01). Factors independently associated with shorter DSS were TVDT of <1 year based on 3 initial and 3 last scans as well as lung, brain and prostate as the organs with the fastest growing tumor. TVDT based on 2-dimentional and 3-dimentional measurements showed strong correlation (r=0.94, p<0.05)., Conclusions: Three baseline and three most recent scans preceding follow-up visit enable calculation of TVDT and can be used as predictors of mortality from MTC., (Published by Oxford University Press on behalf of the Endocrine Society 2024.)

Introduction: Splenic stiffness (SS) measurement (SSM) is an evolving noninvasive assessment to evaluate portal hypertension. Studies with respect to SSM in patients with alcohol use disorder are limited., Methods: We studied patients seeking treatment for alcohol use disorder in an inpatient treatment protocol at the National Institutes of Health and parsed SSM into 3 groups based on degree of change., Results: The improved SS group had statistically higher initial SSM and a nonstatistically increased liver stiffness measurement compared with others., Discussion: SS is dynamic in a subset of patients immediately after alcohol cessation, and improved SS is associated with a normalization of platelet count., (Copyright © 2024 Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a “work of the United States Government” for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government.)

Background: Long-term management of intermediate- and high-risk differentiated thyroid cancer (DTC) involves thyrotropin (TSH) suppression with thyroid hormone to prevent potential stimulation of TSH receptors on DTC cells, leading to tumor growth. However, the current guidelines recommending TSH suppression are based on low- to moderate-quality evidence. Methods: We performed a systematic review and meta-analysis of studies evaluating the role of TSH suppression in intermediate- and high-risk DTC patients (≥18 years) treated as per regional guideline-based therapy with a follow-up duration of 5 years (PROSPERO #252396). TSH suppression was defined as "below normal reference range" or, when known, <0.5 mIU/L. Primary outcome measures included (i) composite of progression-free survival (PFS), disease-free survival (DFS), and relapse-free survival (RLFS), and (ii) composite of disease-specific survival (DSS), and overall survival (OS). Secondary outcome included a composite of cardiac or skeletal adverse events. All outcomes and comparisons were represented as TSH suppression versus TSH nonsuppression. Randomized controlled trials, cohort studies, and case-control studies were included for analysis. Pooled hazard ratio (HR) and 95% confidence interval (CI) were calculated using random-effects model. Results: Abstract screening was performed on 6,369 studies. After the exclusion of irrelevant studies and full-text screening, nine studies were selected for the final meta-analysis. Based on seven studies (3,591 patients), the composite outcome of PFS, DFS, and RLFS was not significantly different between TSH suppression and nonsuppression groups (HR: 0.75; 95% CI: 0.48-1.17; I 2 = 76%). Similarly, a DSS and OS composite outcome assessment based on four studies (3,616 patients) did not favor TSH suppression (HR: 0.69; 95% CI: 0.31-1.52; I 2 = 88%). Even after excluding studies of lower quality, the primary outcomes were not significantly different between the TSH suppression and nonsuppression cohorts. The secondary outcome, obtained from two studies (1,294 patients), was significantly higher in the TSH-suppressed groups (HR: 1.82; 95% CI: 1.30-2.55; I 2 = 0%). Significant study heterogeneity was noted for primary outcomes. Conclusion: TSH suppression in intermediate- and high-risk DTC may not improve survival outcomes but may increase the risk of secondary complications. However, the limited evidence and study heterogeneity warrant cautious interpretation of our findings. Registration: PROSPERO #252396.

Introduction: Nitric oxide (NO) is a vasodilator gas that plays a critical role in mitochondrial respiration and skeletal muscle function. NO is endogenously generated by NO synthases: neuronal NO synthase (nNOS), endothelial NO synthase (eNOS), or inducible NO synthase (iNOS). NO in skeletal muscle is partly generated by nNOS, and nNOS deficiency can contribute to muscular dystrophic diseases. However, we and others discovered an alternative nitrate/nitrite reductive pathway for NO generation: nitrate to nitrite to NO. We hypothesized that nitrate supplementation would increase nitrate accumulation in skeletal muscle and promote a nitrate/nitrite reductive pathway for NO production to compensate for the loss of nNOS in skeletal muscle., Methods: Wild-type (WT) and genetic nNOS knockout (nNOS-/-) mice were fed normal chow (386.9 nmol/g nitrate) and subjected to three treatments: high-nitrate water (1 g/L sodium nitrate for 7 days), low-nitrate diet (46.8 nmol/g nitrate for 7 days), and low-nitrate diet followed by high-nitrate water for 7 days each., Results: High-nitrate water supplementation exhibited a greater and more significant increase in nitrate levels in skeletal muscle and blood in nNOS-/- mice than in WT mice. A low-nitrate diet decreased blood nitrate and nitrite levels in both WT and nNOS-/- mice. WT and nNOS-/- mice, treated with low-nitrate diet, followed by high-nitrate water supplementation, showed a significant increase in nitrate levels in skeletal muscle and blood, analogous to the increases observed in nNOS-/- mice supplemented with high-nitrate water. In skeletal muscle of nNOS-/- mice on high-nitrate water supplementation, on low-nitrate diet, and in low-high nitrate treatment, the loss of nNOS resulted in a corresponding increase in the expression of nitrate/nitrite reductive pathway-associated nitrate transporters [sialin and chloride channel 1 (CLC1)] and nitrate/nitrite reductase [xanthine oxidoreductase (XOR)] but did not show a compensatory increase in iNOS or eNOS protein and eNOS activation activity [p-eNOS (Ser1177)]., Discussion: These findings suggest that a greater increase in nitrate levels in skeletal muscle of nNOS-/- mice on nitrate supplementation results from reductive processes to increase NO production with the loss of nNOS in skeletal muscle., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Upanan, Lee, Tunau-Spencer, Rajvanshi, Wright, Noguchi and Schechter.)

Background and Aims: The Fontan palliation is the final stage of surgery for many children born with univentricular physiology. Almost all Fontan patients develop liver fibrosis which may eventually lead to cirrhosis and hepatocellular carcinoma (HCC). These are important causes of morbidity and mortality in these patients. We performed a systematic review and meta-analysis to assess the incidence of cirrhosis and HCC in Fontan patients and stratify it based on time since surgery., Methods: A literature search of seven databases identified 1158 records. Studies reporting the number of cirrhosis and HCC cases in Fontan patients and time since Fontan surgery were included. In the cirrhosis cohort, we included only those studies where all patients underwent liver biopsy., Results: A total of 23 studies were included: 12 and 13 studies in the cirrhosis and HCC cohorts, respectively, with two studies included in both cohorts. The incidence of cirrhosis was 0.97 per 100 patient-years (95% CI 0.57-1.63), with the incidence and cumulative incidence ≥20 years post Fontan surgery being 1.61 per 100 patient-years (95% CI 1.24-2.08) and 32.2% (95% CI 25.8%-39.4%), respectively. The incidence of HCC was 0.12 per 100 patient-years (95% CI 0.07-0.21), with the incidence and cumulative incidence ≥20 years post Fontan surgery being 0.20 per 100 patient-years (95% CI 0.12-0.35) and 3.9% (95% CI 2.2%-6.8%), respectively. Only about 70% of patients with HCC (20/28) had underlying cirrhosis., Conclusion: The incidence of cirrhosis and HCC increases over time, especially at ≥20 years post Fontan surgery. Studies are needed to further identify at-risk patients in order to streamline surveillance for these highly morbid conditions., (© 2024 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Background: Alcohol cessation is the only intervention that both prevents and halts the progressions of alcohol-associated liver disease. The aim of this study was to assess the relationship between a return to alcohol use and consultation with hepatology in treatment-seeking patients with alcohol use disorder (AUD)., Methods: Two hundred forty-two patients with AUD were enrolled in an inpatient treatment program, with hepatology consultation provided for 143 (59%) patients at the request of the primary team. Patients not seen by hepatology served as controls. The primary outcome was any alcohol use after discharge assessed using AUDIT-C at 26 weeks after discharge., Results: For the primary endpoint, AUDIT at week 26, 61% of the hepatology group and 28% of the controls completed the questionnaire (p=0.07). For the secondary endpoint at week 52, these numbers were 22% and 11% (p = 0.6). At week 26, 39 (45%) patients in the hepatology group versus 31 (70%) controls (p = 0.006) returned to alcohol use. Patients evaluated by hepatology had decreased rates of hazardous alcohol use compared to controls, with 36 (41%) versus 29 (66%) (p = 0.008) of the patients, respectively, reporting hazardous use. There were no significant differences in baseline characteristics between groups and no difference in rates of prescribing AUD therapy. There was no difference in outcomes at 52 weeks., Conclusions: Patients evaluated by hepatology had significantly lower rates of return to alcohol use and lower rates of hazardous drinking at 26 weeks but not at 52 weeks. These findings suggest that hepatology evaluation during inpatient treatment of AUD may lead to decreased rates of early return to alcohol use., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Objective: Web-based prolonged exposure therapy (Web-PE) has potential to increase the reach of effective posttraumatic stress disorder (PTSD) treatment. While there is initial support for the efficacy of Web-PE, no studies have examined the perceptions and experiences of participants receiving PE in this novel, Web based format., Method: We used a mixed-methods convergent design to examine and integrate quantitative and qualitative data of participant perceptions and experiences of Web-PE. Treatment-seeking active duty military personnel or veterans ( N = 29) who received Web-PE completed posttreatment surveys about perceptions of Web-PE and a brief qualitative interview. Thematic coding was used to identify qualitative themes, which were integrated with quantitative data in a joint display., Results: Although many were initially skeptical of experiencing benefit, participants reported that Web-PE was helpful. They appreciated the flexibility of online therapy and reported that self-motivation was important for engagement. Web-PE therapists were well-regarded, although additional therapist support and technical improvements to the Web-PE program were suggested. Scores on the perceptions of Web-PE survey, PTSD survey, and other quantitative data corroborated the qualitative themes., Conclusion: Perceptions and experience of Web-PE are favorable and help to highlight the strengths (e.g., flexibility) and challenges (e.g., requiring self-motivation) associated with Web-treatment for PTSD. The results of this study may inform further development of Web-PE or other Web-based treatment programs. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Purpose: Introducing healthy and sustainable diets early in life can promote lifelong healthy dietary patterns with a low environmental impact. Therefore, we aimed to estimate the environmental and nutritional consequences of a dietary change for 2-year-old children in Norway towards healthier dietary patterns., Methods: Environmental impacts of the current habitual diet among 2-year-olds (n = 1413) were estimated for six impact categories and compared with scenario diets based on the Norwegian food-based dietary guidelines (FBDG) and the EAT-Lancet Commission reference diet. Last, we evaluated the nutritional adequacy of the diets against the Norwegian nutrition recommendations for children aged 2-5 years. The current diet was assessed by an FFQ., Results: Environmental impacts of the current habitual diet were up to two times higher than those of the scenario diets. Compared with the current diet, impacts from the FBDG scenario diet were reduced by 35% for water use and 18% for terrestrial acidification, whereas impacts from the EAT-Lancet scenario diet were reduced by 51% for water use, 57% for terrestrial acidification, 36% for global warming potential and 27% for freshwater eutrophication. Milk and dairy products were the main contributors to environmental impacts in both the current diet and the FBDG scenario diet. The scenario diets were nutritionally adequate and improved the dietary quality among Norwegian 2-year-olds., Conclusion: Compared to current diets among young children, more plant-based dietary patterns in line with national FBDG or the EAT-Lancet Commission reference diet can improve the nutritional adequacy of diets and simultaneously reduce environmental impacts., (© 2023. The Author(s).)

Anxiety disorders are a major public health concern and current treatments are inadequate for many individuals. Anxiety is more common in women than men and this difference arises during puberty. Sex differences in physiological stress responses may contribute to this variability. During puberty, gonadal hormones shape brain structure and function, but the extent to which these changes affect stress sensitivity is unknown. We examined how pubertal androgens shape behavioral and neural responses to social stress in California mice ( Peromyscus californicus ), a model species for studying sex differences in stress responses. In adults, social defeat reduces social approach and increases social vigilance in females but not males. We show this sex difference is absent in juveniles, and that prepubertal castration sensitizes adult males to social defeat. Adult gonadectomy does not alter behavioral responses to defeat, indicating that gonadal hormones act during puberty to program behavioral responses to stress in adulthood. Calcium imaging in the medioventral bed nucleus of the stria terminalis (BNST) showed that social threats increased neural activity and that prepubertal castration generalized these responses to less threatening social contexts. These results support recent hypotheses that the BNST responds to immediate threats. Prepubertal treatment with the nonaromatizable androgen dihydrotestosterone acts in males and females to reduce the effects of defeat on social approach and vigilance in adults. These data indicate that activation of androgen receptors during puberty is critical for programming behavioral responses to stress in adulthood.

In a hepatitis C virus (HCV)-controlled human infection model (CHIM), healthy volunteers are inoculated with HCV and then treated. Residual hepatocellular carcinoma (HCC) risk after viral clearance is an important consideration when evaluating the CHIM. We estimate HCC risk in spontaneously cleared HCV and in noncirrhosis after sustained virological response (SVR) to HCV treatment in a systematic review and using data from 3 cohorts: German anti-D, Taiwan, and US Veterans Affairs (VA). For noncirrhosis SVR, the overall HCC rate is 0.33 per 100 patient-years in meta-analysis. HCC rates for the German, Taiwan, and US Veterans Affairs cohorts are 0, 0.14, and 0.02 per 100 patient-years, respectively. Past hepatitis B virus exposure was not accounted for in the Taiwan cohort, while VA patients were likely tested based on liver disease/risk factors, which may confound HCC outcomes. The German cohort with no HCC after 44 years is most comparable to the CHIM participants. Although it is difficult to precisely estimate HCC risk from an HCV CHIM, the data suggest the risk to be very low or negligible., Competing Interests: Potential conflicts of interest. M. W. received study materials with no payment for research. J. F. reports research funding from AbbVie, Gilead, and the Canadian Institutes for Health Research Planning and Dissemination Grant and holding an unpaid position as the president of the Canadian Association for the Study of the Liver. D. E. K. reports grants or contracts from Gilead Sciences, Inc, AstraZeneca, Glycotest, Inc, Genentech, and Exact Sciences. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2023.)

Background & Aims: Results of randomized clinical trials are often first presented as conference abstracts, but these abstracts may be difficult to find, and trial results included in the abstract may not be followed by subsequent journal publications. In a review of abstracts submitted to eight major medical and surgical conferences in 2017, we identified 237 abstracts reporting primary results of randomized clinical trials accepted for presentation at three major gastroenterology and hepatology conferences. The aims of this new analysis were to determine the publication rate for these abstracts and the proportion of publications that included trial registration numbers in the publication abstract., Methods: Clinical trial registries, PubMed, Europe PMC, and Google Scholar were searched through November 1, 2021, for publications reporting trial results for the selected abstracts. Publications were reviewed to determine if they included a trial registration number and if the registration number was in the abstract., Results: Publications were found for 157 abstracts (66%) within four years of the conference. Publications were found more frequently for the 194 abstracts reporting results of registered trials (144, 74%) than for the 43 abstracts reporting unregistered trials (13, 30%), but only 67% of these 144 publications included the registration number in the publication abstract. Ten unpublished trials had summary results posted on ClinicalTrials.gov., Conclusions: Clinical trial results could be more accessible if all trials were registered, authors included registration numbers in both conference and journal abstracts, and journal editors required the inclusion of registration numbers in publication abstracts for registered clinical trials., Competing Interests: Conflicts of Interest: The authors disclose no conflicts.

Hepatic chronic graft-versus-host disease (cGVHD) causes morbidity and current diagnostic criteria are nonspecific. An accurate diagnosis is imperative because overdiagnosis can lead to unnecessary treatment with immunosuppressive agents and raising the risk of opportunistic infections. We aim to characterize different patterns of liver injury and cytokine profiles associated with hepatic dysfunction in cGVHD, to evaluate the accuracy of the NIH Consensus Criteria (NCC) for hepatic cGVHD and to explore predictors for hepatic cGHVD. Patients were evaluated in this prospective cross-sectional study of patients with cGVHD recruited under a natural history protocol. Laboratory tests and cytokines were measured. The cGVHD were diagnosed and scored based on NCC. Clinically indicated liver biopsy specimens or autopsies were reviewed by an expert hepatopathologist (D.E.K.). Comparisons were made between groups, and univariable and multivariable logistic regression were calculated. Of the 302 patients enrolled, 151 fulfilled hepatic cGVHD based on NCC; however, 69% had at least 1 abnormal liver test result. Abnormal alanine aminotransferase (ALT) and aspartate aminotransferase were associated with lower platelets, higher total bilirubin (TB), total cholesterol, serum amyloid A, and IL 15. Abnormal ALP and gamma-glutamyl transpeptidase were associated with higher cholesterol, and IL7. Lower platelet count was associated with higher ALT, TB, and triglycerides and lower albumin. Of the 27 with liver tissue, 16 had histologic features of GVHD, only eight met clinical criteria for hepatic GVHD. Sensitivity and specificity of NCC in identifying hepatic GVHD were 50% and 27% (Kappa = -0.23). Only 6 had only hepatic GVHD, whereas 10 had hepatic GVHD with either iron overload, nodular regenerative hyperplasia, or steatosis. Multivariable logistic regression showed that ALP and total cholesterol were associated with hepatic GVHD and total cholesterol >220 mg/dL increased the sensitivity for histologic hepatic GVHD. In conclusion, abnormal liver enzymes in cGVHD are nonspecific and have poor correlation with histologic evidence for hepatic GVHD, highlighting the importance of histology. Cytokines provide insight into the pathogenesis of hepatic cGVHD. Decreased platelet count was associated with factors associated with liver disease including portal vein diameter, which may suggest progression of liver disease. This highlights the need of incorporating these factors in natural history study and using liver biopsy to understand the development of liver dysfunction in hematopoietic stem cell transplantation and to develop better instruments to decreased hepatic cGVHD related morbidity and mortality. The study was registered with a ClinicalTrials.gov identifier NCT00092235., (Published by Elsevier Inc.)

Hepatic graft-versus-host disease (HGVHD) contributes significantly to morbidity and mortality after hematopoietic stem cell transplantation (HSCT). Clinical findings and liver biomarkers are neither sensitive nor specific. The relationship between clinical and histologic diagnoses of HGVHD was assessed premortem and at autopsy. Medical records from patients who underwent HSCT at the National Institutes of Health (NIH) Clinical Center between 2000 and 2012 and expired with autopsy were reviewed, and laboratory tests within 45 days of death were divided into 15-day periods. Clinical diagnosis of HGVHD was based on Keystone Criteria or NIH Consensus Criteria, histologic diagnosis based on bile duct injury without significant inflammation, and exclusion of other potential etiologies. We included 37 patients, 17 of whom had a cholestatic pattern of liver injury and two had a mixed pattern. Fifteen were clinically diagnosed with HGVHD, two showed HGVHD on autopsy, and 13 had histologic evidence of other processes but no HGVHD. Biopsy or clinical diagnosis of GVHD of other organs during life did not correlate with HGVHD on autopsy. The diagnostic accuracy of the current criteria was poor (κ = -0.20). A logistic regression model accounting for dynamic changes included peak bilirubin 15 days before death, and an increase from period -30 (days 30 to 16 before death) to period -15 (15 days before death) showed an area under the receiver operating characteristic curve of 0.77. Infection was the immediate cause of death in 68% of patients. In conclusion, liver biomarkers at baseline and GVHD elsewhere are poor predictors of HGVHD on autopsy, and current clinical diagnostic criteria have unsatisfactory performance. Peak bilirubin and cholestatic injury predicted HGVHD on autopsy. A predictive model was developed accounting for changes over time. Further validation is needed., (Published 2022. This article is a U.S. Government work and is in the public domain in the USA. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Recent advances in fluorescence imaging permit large-scale recording of neural activity and dynamics of neurochemical release with unprecedented resolution in behaving animals. Calcium imaging with highly optimized genetically encoded indicators provides a mesoscopic view of neural activity from genetically defined populations at cellular and subcellular resolutions. Rigorously improved voltage sensors and microscopy allow for robust spike imaging of populational neurons in various brain regions. In addition, recent protein engineering efforts in the past few years have led to the development of sensors for neurotransmitters and neuromodulators. Here, we discuss the development and applications of these genetically encoded fluorescent indicators in reporting neural activity in response to various behaviors in different biological systems as well as in drug discovery. We also report a simple model to guide sensor selection and optimization.

Reports an error in "The effects of web-prolonged exposure among military personnel and veterans with posttraumatic stress disorder" by Carmen P. McLean, Edna B. Foa, Katherine A. Dondanville, Christopher K. Haddock, Madeleine L. Miller, Sheila A. M. Rauch, Jeffery S. Yarvis, Edward C. Wright, Brittany N. Hall-Clark, Brooke A. Fina, Brett T. Litz, Jim Mintz, Stacey Young-McCaughan and Alan L. Peterson ( Psychological Trauma: Theory, Research, Practice, and Policy , 2021[Sep], Vol 13[6], 621-631). In the original article, "for the STRONG STAR Consortium" was missing from the end of the author line. In addition, the numbering and text of the affiliations for Edward C. Wright, Brittany N. Hall-Clark, Brooke A. Fina, Brett T. Litz, Jim Mintz, Stacey Young-McCaughan, and Alan L. Peterson were incorrect because of duplicated affiliation details and associated typographical errors. Finally, in the References, "for the STRONG STAR Consortium" and "on behalf of the STRONG STAR Consortium" were missing from the ends of the author lists for Foa et al. (2018) and Resick et al. (2015), respectively. The online version of this article has been corrected. (The following abstract of the original article appeared in record 2020-86687-001)., Objective: Web-based treatments address many of the logistical and stigma-related barriers to in-person behavioral health care. Prior studies of web-based treatments for posttraumatic stress disorder (PTSD) did not employ gold-standard treatments and have not compared to in-person therapy., Method: We compared a web version of Prolonged Exposure Therapy, "Web-PE," to in-person Present-Centered Therapy (PCT) in a randomized controlled trial (RCT) with 40 military personnel with PTSD seeking treatment at Fort Hood, Texas. Due to recruitment challenges, we terminated the RCT and subsequently examined the effects of Web-PE in an uncontrolled open trial with 34 service members and veterans recruited nationwide. Both studies assessed PTSD, depressive symptoms, and health functioning at baseline and 1 and 3 months posttreatment; the RCT also included a 6-month assessment., Results: Results of the RCT showed no differential impact for Web-PE and PCT, although more PCT participants achieved clinically significant change at one of the follow-up assessments. Both treatment conditions significantly reduced self-reported and blind independent interviewer-assessed symptoms of PTSD. Results of the open trial showed that Web-PE was associated with significant reductions in self-reported PTSD symptoms, with a much larger effect size than in the RCT., Conclusions: Web-PE significantly reduced PTSD symptoms in both studies, although the reductions in PTSD symptoms were greater among open trial participants, who were specifically seeking a web-based treatment. Future research should evaluate Web-PE relative to another web-based treatment. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Many returning military service members and veterans who were deployed following the September 11, 2001, terrorist attacks (9/11) suffer from posttraumatic stress disorder (PTSD) and insomnia. Although intensive treatment programs for PTSD have shown promise in the treatment of PTSD symptoms, recent research has demonstrated that sleep disturbance shows little improvement following intensive trauma-focused treatment. The aim of the present study was to evaluate changes in self-reported insomnia symptoms among veterans and service members following participation in a 2-week intensive program for PTSD. We further aimed to investigate if residual PTSD symptoms, specifically hyperarousal, were associated with residual insomnia symptoms. Participants (N = 326) completed self-report assessments of insomnia, PTSD symptoms, and depressive symptoms at pre- and posttreatment. At pretreatment, 73.9% of participants (n = 241) met the criteria for moderate or severe insomnia, whereas at posttreatment 67.7% of participants (n = 203) met the criteria. Results of paired t tests demonstrated statistically significant differences between pre- and posttreatment Insomnia Severity Index scores; however, the effect size was small, d = 0.34. Analyses revealed that posttreatment hyperarousal symptoms were associated with posttreatment insomnia. These findings suggest that although an intensive program for service members and veterans with PTSD may significantly reduce insomnia symptoms, clinically meaningful residual insomnia symptoms remain. Further research is warranted to elucidate the association between residual hyperarousal and insomnia symptoms following intensive trauma-focused treatment., (© 2021 International Society for Traumatic Stress Studies.)

Suicide-bereaved military widows can struggle with posttraumatic stress disorder (PTSD) and prolonged grief. Intimate partner violence survivors (IPV) are particularly at risk. We examined whether IPV impacts outcomes in a two-week intensive outpatient program for N = 50 suicide-bereaved military widows. Mixed-model regressions were employed to examine the effects of IPV, time, and their interaction on symptoms. Thirty-four percent experienced IPV perpetrated by their deceased veteran. Symptoms improved at post-treatment ( ps < .001), one-month ( ps < .01), and three-month follow-up ( ps < .001). There was no significant effect of IPV or significant interaction ( p s > .05), indicating that IPV survivors also benefitted from treatment., Competing Interests: The authors have no potential conflicts of interest to report., (© 2022 Society for Military Psychology, Division 19 of the American Psychological Association.)

The unprecedented effects and duration of the COVID-19 crisis are likely to elevate the population's level of anxiety due to psychological stress, economic hardship, and social isolation. This effect may be especially potent for individuals with preexisting mental health conditions, such as posttraumatic stress disorder (PTSD). Prolonged Exposure (PE) therapy is a highly effective treatment for PTSD across trauma-exposed populations, and has been implemented effectively via telehealth. Nevertheless, PE implementation via telehealth may require specific adaptations during the COVID-19 crisis due to public health mandates calling for sheltering in place and physical distancing. This paper discusses strategies for implementing PE for PTSD during the COVID-19 pandemic, which may also be applied to other situations in which physical distancing must be considered., (© 2021 Association for Behavioral and Cognitive Therapies. Published by Elsevier Ltd. All rights reserved.)

The Psychiatric Consultation Service at Massachusetts General Hospital sees medical and surgical inpatients with comorbid psychiatric symptoms and conditions. During their twice-weekly rounds, Dr Stern and other members of the Consultation Service discuss diagnosis and management of hospitalized patients with complex medical or surgical problems who also demonstrate psychiatric symptoms or conditions. These discussions have given rise to rounds reports that will prove useful for clinicians practicing at the interface of medicine and psychiatry., (© Copyright 2021 Physicians Postgraduate Press, Inc.)

[Correction Notice: An Erratum for this article was reported online in Psychological Trauma: Theory, Research, Practice, and Policy on Mar 14 2022 (see record 2022-44650-001). In the original article, "for the STRONG STAR Consortium" was missing from the end of the author line. In addition, the numbering and text of the affiliations for Edward C. Wright, Brittany N. Hall-Clark, Brooke A. Fina, Brett T. Litz, Jim Mintz, Stacey Young-McCaughan, and Alan L. Peterson were incorrect because of duplicated affiliation details and associated typographical errors. Finally, in the References, "for the STRONG STAR Consortium" and "on behalf of the STRONG STAR Consortium" were missing from the ends of the author lists for Foa et al. (2018) and Resick et al. (2015), respectively. The online version of this article has been corrected.] Objective: Web-based treatments address many of the logistical and stigma-related barriers to in-person behavioral health care. Prior studies of web-based treatments for posttraumatic stress disorder (PTSD) did not employ gold-standard treatments and have not compared to in-person therapy., Method: We compared a web version of Prolonged Exposure Therapy, "Web-PE," to in-person Present-Centered Therapy (PCT) in a randomized controlled trial (RCT) with 40 military personnel with PTSD seeking treatment at Fort Hood, Texas. Due to recruitment challenges, we terminated the RCT and subsequently examined the effects of Web-PE in an uncontrolled open trial with 34 service members and veterans recruited nationwide. Both studies assessed PTSD, depressive symptoms, and health functioning at baseline and 1 and 3 months posttreatment; the RCT also included a 6-month assessment., Results: Results of the RCT showed no differential impact for Web-PE and PCT, although more PCT participants achieved clinically significant change at one of the follow-up assessments. Both treatment conditions significantly reduced self-reported and blind independent interviewer-assessed symptoms of PTSD. Results of the open trial showed that Web-PE was associated with significant reductions in self-reported PTSD symptoms, with a much larger effect size than in the RCT., Conclusions: Web-PE significantly reduced PTSD symptoms in both studies, although the reductions in PTSD symptoms were greater among open trial participants, who were specifically seeking a web-based treatment. Future research should evaluate Web-PE relative to another web-based treatment. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Objective: While the comparative efficacy of prolonged exposure (PE) and cognitive processing therapy (CPT) has been examined in outpatient settings, there is a dearth of literature on the relative effectiveness of these interventions when adapted for an intensive treatment format. In an expanded secondary analysis of a previous study, we sought to examine the comparative effectiveness of PE and CPT delivered in the naturalistic setting of an intensive treatment format including maintenance of outcomes through a 6-month follow-up period., Method: A sample of 296 veterans with posttraumatic stress disorder (PTSD) received either PE ( n = 186) or CPT ( n = 90), alongside other trauma-informed interventions, in a 2-week intensive clinical program. Treatment selection was determined collaboratively between patient and therapist. Our primary outcome was self-reported PTSD symptom severity (i.e., PTSD Checklist for DSM-5, PCL-5); secondarily, we examined self-reported depression (i.e., Patient Health Questionnaire) symptom severity outcomes., Results: A mixed-model regression controlling for age and gender revealed a significant effect of time from baseline to endpoint ( p < .001), 3-month ( p < .001), and 6-month follow-up ( p < .001) on PCL-5 scores but no significant effect of treatment or effect of treatment by time interaction (all p s > .05; model: Wald's χ² = 232.38, p < .001). Results were similar for depression outcomes. Attrition at posttreatment was not significantly different between groups: 7.2% for CPT and 6.5% PE ( z score = 0.22)., Conclusions: Both PE and CPT are associated with comparable improvements when delivered as part of a 2-week intensive outpatient program. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Domesticated mice and rats have shown to be powerful model systems for biomedical research, but there are cases in which the biology of species is a poor match for the hypotheses under study. The California mouse ( Peromyscus californicus ) has unique traits that make it an ideal model for studying biological mechanisms underlying human-relevant behaviors such as intra-female aggression, biparental care, and monogamy. Indeed, peer-reviewed scientific publications using California mouse as a model for behavioral research have more than doubled in the past decade. Critically, behavioral outcomes in captive animals can be profoundly affected by housing conditions, but there is very limited knowledge regarding species-specific housing needs in California mice. Currently, California mouse investigators have to rely on guidelines aimed for more common laboratory species that show vastly different physiology, behavior, and/or ecological niche. This not only could be suboptimal for animals' welfare, but also result in lack of standardization that could potentially compromise experimental reproducibility and replicability across laboratories. With the aim of assessing how different housing systems can affect California mouse behavior both in the home cage as well as the open field and social interaction tests before and after social defeat stress, here we tested three different caging systems: 1. Standard mouse cage, 2. Large cage, and 3. Large cage + environmental enrichment (EE), which focused on increasing vertical complexity based on observations that California mice are semiarboreal in the wild. We found that the effects of housing were largely sex specific: compared to standard cages, in females large + EE reduced home cage stereotypic-like backflipping and rearing behaviors, while large cage increased social interactions. In males, the large+EE cage reduced rearing and digging but did not significantly affect backflipping behavior. Interestingly, while there were no significant differences in the open field and social interaction pre-stress behaviors, large and large+EE housing increased the sensitivity of these tests to detect stress induced phenotypes in females. Together, these results suggest that increasing social and environmental complexity affects home cage behaviors in male and female California mice without interfering with, but rather increasing the magnitude of, the effects of defeat stress on the open field and social interaction tests.

Ictal bradycardia and asystole are rare, but potentially serious complications of epileptic seizures. We present a case series of three such patients diagnosed through our syncope service. For two patients, treatment with anticonvulsant therapy alone achieved symptom control. The third patient was initially managed with permanent pacemaker insertion due to detection of a significant ventricular pause. He subsequently developed more pronounced symptoms suggestive of seizure.Ictal asystole can cause significant diagnostic challenge and management strategies remain controversial due to the overlap in presentation to cardiology and neurology services. The number of patients affected is low, impeding the formulation of an evidence base for treatment. We propose multidisciplinary working facilitated by a specialist syncope service as a means of recognising and treating this condition more effectively., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Erythropoietin (EPO) is the primary regulator of bone marrow erythropoiesis. Mouse models have provided evidence that EPO also promotes bone remodeling and that EPO-stimulated erythropoiesis is accompanied by bone loss independent of increased red blood cell production. EPO has been used clinically for three decades to treat anemia in end-stage renal disease, and notably, although the incidence of hip fractures decreased in the United States generally after 1990, it rose among hemodialysis patients coincident with the introduction and subsequent dose escalation of EPO treatment. Given this clinical paradox and findings from studies in mice that elevated EPO affects bone health, we examined EPO treatment as a risk factor for fractures in hemodialysis patients. Relationships between EPO treatment and hip fractures were analyzed using United States Renal Data System (USRDS) datasets from 1997 to 2013 and Consolidated Renal Operations in a Web-enabled Network (CROWNWeb) datasets for 2013. Fracture risks for patients treated with <50 units of EPO/kg/week were compared to those receiving higher doses by multivariable Cox regression. Hip fracture rates for 747,832 patients in USRDS datasets (1997-2013) increased from 12.0 per 1000 patient years in 1997 to 18.9 in 2004, then decreased to 13.1 by 2013. Concomitantly, average EPO doses increased from 11,900 units/week in 1997 to 18,300 in 2004, then decreased to 8,800 by 2013. During this time, adjusted hazard ratios for hip fractures with EPO doses of 50-149, 150-299, and ≥ 300 units/kg/week compared to <50 units/kg/week were 1.08 (95% confidence interval [CI], 1.01-1.15), 1.22 (95% CI, 1.14-1.31), and 1.41 (95% CI, 1.31-1.52), respectively. Multivariable analyses of 128,941 patients in CROWNWeb datasets (2013) replicated these findings. This study implicates EPO treatment as an independent risk factor for hip fractures in hemodialysis patients and supports the conclusion that EPO treatment may have contributed to changing trends in fracture incidence for these patients during recent decades. Published 2021. This article is a U.S. Government work and is in the public domain in the USA. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)., (Published 2021. This article is a U.S. Government work and is in the public domain in the USA. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).)

Social vigilance is a behavioral strategy commonly used in adverse or changing social environments. In animals, a combination of avoidance and vigilance allows an individual to evade potentially dangerous confrontations while monitoring the social environment to identify favorable changes. However, prolonged use of this behavioral strategy in humans is associated with increased risk of anxiety disorders, a major burden for human health. Elucidating the mechanisms of social vigilance in animals could provide important clues for new treatment strategies for social anxiety. Importantly, during adolescence the prevalence of social anxiety increases significantly. We hypothesize that many of the actions typically characterized as anxiety behaviors begin to emerge during this time as strategies for navigating more complex social structures. Here, we consider how the social environment and the pubertal transition shape neural circuits that modulate social vigilance, focusing on the bed nucleus of the stria terminalis and prefrontal cortex. The emergence of gonadal hormone secretion during adolescence has important effects on the function and structure of these circuits, and may play a role in the emergence of a notable sex difference in anxiety rates across adolescence. However, the significance of these changes in the context of anxiety is still uncertain, as not enough studies are sufficiently powered to evaluate sex as a biological variable. We conclude that greater integration between human and animal models will aid the development of more effective strategies for treating social anxiety., (© 2019 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Objectives: Given that veterans are significantly more likely to suffer from post-traumatic stress disorder (PTSD), traumatic brain injury (TBI), depression, and anxiety than civilians, yet current gold-standard treatments for PTSD are not effective for all patients, the present study sought to examine the feasibility and acceptability of a collaborative songwriting intervention (CSI) while exploring its potential effectiveness in improving physical and mental health outcomes for veterans with PTSD. Design: Ten veterans took part in the CSI. A variety of pre- and postintervention measures were administered, including the Measurement of Current Status (MOCS), the Coping Expectancies Scale (CES), the Post-traumatic Stress Disorder Checklist-Military (PCL-M), and the Patient Health Questionnaire-9 (PHQ-9). Participants also wore a Fitbit to track average heart rate, sleep, and step count. Intervention: The CSI consisted of each veteran meeting with a professional songwriter, trained specifically for co-writing original material with the veteran population. There were three phases of songwriting that took about an hour and 15 min total. Veterans were instructed to listen to their song daily for 5 weeks. Results: Participants reported that the intervention was helpful and relevant to them, and most participants (95%) would refer others to this treatment. We found that the CSI reduced participant's PTSD symptoms ( d  = 0.869), specifically the Numbing ( d  = 0.853) and Hyperarousal ( d  = 1.077) subscales. Depressive symptoms ( d  = 0.72) and stress reactivity ( d  = 0.785) also marginally decreased. There was no significant change in physiological data (i.e., sleep, no. of steps) from pre- to postintervention. Conclusion: These data suggest that a CSI is an acceptable intervention for veterans with PTSD that may also improve their PTSD symptoms.

Objective: Equine-assisted activities and therapies (EAATs) have been a growing adjunctive integrative health modality, as they allow participants to practice mindfulness, emotional regulation, and self-mastery or self-esteem building skills. Preliminary evidence suggests that these programs may be helpful in reducing posttraumatic stress disorder (PTSD), anxiety, and depressive symptoms. The current study examines the acceptability of integrating an EAAT program as part of a two-week, intensive clinical program for veterans with PTSD and/or traumatic brain injury (TBI)., Methods: A family member or support person could accompany veterans and participate in the program. One hundred and six participants (veteran n = 62, family n = 44) left the urban environment in an intensive outpatient program (IOP) to attend a two-day, weekend EAAT in rural New Hampshire. Satisfaction surveys were conducted on the last day of the program and examined using thematic analysis., Results: The following themes were reported in the surveys: ability of horses to catalyze emotional rehabilitation, effectiveness of immersion in equine-assisted activities, program's ability to foster interpersonal relationships and necessity of education about PTSD for staff. Participants also reported enjoying the program as highlighted by qualitative feedback, a mean score of 9.76 (standard deviation [SD] = 0.61) as reported by veterans and a mean score of 9.91 (SD = 0.29) as reported by family members on a 10-point visual analog scale with higher scores indicating a greater overall experience., Conclusion: These data offer preliminary evidence that an adjunct EAAT program is acceptable for veterans with PTSD and/or TBI participating in an IOP., (Copyright © 2020 Shanghai Changhai Hospital. Published by Elsevier B.V. All rights reserved.)

A potential indicator of female lifetime productivity in swine is age of puberty, when a gilt achieves her first behavioral estrus. Follicular activity, as determined by tertiary follicle development, in prepubertal gilts begins during postnatal day (PND) 75 to 115. The central hypothesis of this study is that gilts demonstrating tertiary follicle development earlier in life, assessed using vulva size as a proxy, achieve puberty earlier in life compared with counterparts of a similar age and weight that lack tertiary follicle development. The objectives of this project were to identify a developmental time point when variation in ovarian development exists and to determine whether a relationship between the age prepubertal ovarian development and the age at onset of puberty exists. To accomplish this, 155 gilts of similar age (± 2 d) were weighed and vulva size measured on PND 75, 85, 95, 105, and 115. Vulva measures, including vulva width (VW), vulva length (VL), and vulva area (VA), were utilized as developmental proxies for follicular activity. At each time point, gilts ( n = 10) were sacrificed and ovarian follicular activity recorded. In a subset of gilts ( n = 105), estrus detection was conducted daily on PND days 126 to 200. Mean VA on PND 75, 85, 95, 105, and 115 was 596 ± 206, 683 ± 190, 864 ± 212, 1014 ± 228, and 1265 ± 252 mm 2 , respectively. Of the gilts demonstrating behavioral estrus, 28 were within PND 140 to 160, 36 between PND 161 to 180, 15 between PND 181 to 200, and 26 did not demonstrate estrus behavior within 200 d of age. All gilts euthanized at PND 75 lacked follicular activity as defined by having a minimum of 2 antral follicles per ovary, whereas 60%, 80%, 90%, and 100% demonstrated follicular activity on PND 85, 95, 105, and 115, respectively. Body weight at PND 75 and VW at PND 115 were correlated to age at first estrus ( P < 0.05). Of the gilts whose VA was less than 1 SD from the mean on PND 95 (i.e., <652 mm 2 ), 31% and 50% demonstrated their first behavioral estrus by PND 180 and 200, respectively. However, of gilts whose VA was within or greater than 1 SD of the mean (i.e., ≥652 mm 2 ), 66% and 79% exhibited estrus prior to PND 180 and 200, respectively. These data support utilization of VA changes between 95 and 115 d of age as a useful tool to identify replacement gilts prior to puberty for inclusion into the sow herd., (© The Author(s) 2019. Published by Oxford University Press on behalf of the American Society of Animal Science.)

Background: Fibrosis regression has been associated with nucleoside analogue (NA) treatment in chronic hepatitis B (CHB) patients. Although non-invasive fibrosis markers have been evaluated in CHB, their utility for monitoring on-treatment histologic regression has not been evaluated., Aims: To characterize improvements in disease severity and the utility of non-invasive biomarkers in CHB NA treated patients., Methods: Histology, labs, AST-to-platelet ratio index, and Fibrosis-4 (Fib-4) from treatment-naïve CHB patients were evaluated at baseline and longitudinally. Relative change from baseline to various time points during treatment were evaluated. Correlative analysis of APRI and Fib-4 with histology was performed longitudinally., Results: 80 CHB patients (84% male, median age 45 (IQR 32, 54)) with histology up to 17 years (median 6(IQR 3.9, 8.0)) years were studied. Median baseline Ishak fibrosis was 3 (IQR 2, 4), histologic activity index (HAI) inflammation was 9 (IQR 7, 11), and AUROC of fibrosis markers for detecting cirrhosis (Ishak ≥ 5) was >0.64. HAI improved at a rate of 54% during year 1 and 37% in year 2, both greater than in the remaining follow-up periods. Within the first year, fibrosis improved by 35%, greater than all other time periods. Non-invasive biomarkers began to correlate with histology beyond 4 years (APRI: 4-6 years: r = 0.33, p = 0.03; ≥6 years: r = 0.41, p = 0.009; Fib-4: ≥6 years: r = 0.35, p = 0.03)., Conclusion: Early dynamic changes in histology occur in CHB patients on NA followed by linear improvements. Non-invasive fibrosis biomarkers do not capture these dynamic changes and may demonstrate clinical utility beyond 4 years of treatment., (Published by Elsevier B.V.)

Common bean (Phaseolus vulgaris L.) is an important grain legume domesticated independently in Mexico and Andean South America approximately 8000 years ago. Wild forms are obligate short-day plants, and relaxation of photoperiod sensitivity was important for expansion to higher latitudes and subsequent global spread. To better understand the nature and origin of this key adaptation, we examined its genetic control in progeny of a wide cross between a wild accession and a photoperiod-insensitive cultivar. We found that photoperiod sensitivity is under oligogenic control, and confirm a major effect of the Ppd locus on chromosome 1. The red/far-red photoreceptor gene PHYTOCHROME A3 (PHYA3) was identified as a strong positional candidate for Ppd, and sequencing revealed distinct deleterious PHYA3 mutations in photoperiod-insensitive Andean and Mesoamerican accessions. These results reveal the independent origins of photoperiod insensitivity within the two major common bean gene pools and demonstrate the conserved importance of PHYA genes in photoperiod adaptation of short-day legume species., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Hepatitis C virus (HCV) infection induces interferon (IFN)-stimulated genes (ISGs) and downstream innate immune responses. This study investigated whether baseline and on-treatment differences in these responses predict response versus virological breakthrough during therapy with direct-acting antivirals (DAAs). Thirteen HCV genotype 1b-infected patients who had previously failed a course of pegylated IFN/ribavirin were retreated with asunaprevir/daclatasvir for 24 weeks. After pretreatment biopsy, patients were randomized to undergo a second biopsy at week 2 or 4 on therapy. Microarray and NanoString analyses were performed on paired liver biopsies and analyzed using linear mixed models. As biomarkers for peripheral IFN responses, peripheral blood natural killer cells were assessed for phosphorylated signal transducer and activator of transcription 1 (pSTAT1) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expression and degranulation. Nine of 13 (69%) patients achieved sustained virological response at 12 weeks off therapy (SVR12), and 4 experienced virological breakthroughs between weeks 4 and 12. Patients who achieved SVR12 displayed higher ISG expression levels in baseline liver biopsies and a higher frequency of pSTAT1 and TRAIL-expressing, degranulating natural killer cells in baseline blood samples than those who experienced virological breakthrough. Comparing gene expression levels from baseline and on-therapy biopsies, 408 genes (±1.2-fold, P < 0.01) were differentially expressed. Genes down-regulated on treatment were predominantly ISGs. Down-regulation of ISGs was rapid and correlated with HCV RNA suppression. Conclusion: An enhanced IFN signature is observed at baseline in liver and blood of patients who achieve SVR12 compared to those who experience a virological breakthrough; the findings suggest that innate immunity may contribute to clearance of HCV during DAA therapy by preventing the emergence of resistance-associated substitutions that lead to viral breakthrough during DAA therapy., (Published 2018. This article is a U.S. Government work and is in the public domain in the USA.)

Kappa opioid receptor activation has been linked to stress and anxiety behavior, thus leading to kappa antagonists being popularized in research as potential anxiolytics. However, while these findings may hold true in standard models, the neuromodulatory effects of social defeat may change the behavioral outcome of kappa opioid receptor activation. Previous research has shown that social defeat can lead to hyperactivity of serotonergic neurons in the dorsal raphe nucleus, and that inhibition of this increase blocks the social deficits caused by defeat. Kappa opioid receptor activation in the dorsal raphe nucleus works to decrease serotonergic activity. We injected the kappa opioid receptor U50,488 directly into the dorsal raphe nucleus of male and female, defeat and control adult California mice. Here we show evidence that U50,488 induces anxiety behavior in control male California mice, but helps relieve it in defeated males. Consistent with previous literature, we find little effect in females adding evidence that there are marked and important sex differences in the kappa opioid system., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The pubertal transition of gonadotropin secretion in pigs is metabolically gated. Kisspeptin (KISS1) and neurokinin B (NKB) are coexpressed in neurons within the arcuate nucleus of the hypothalamus (ARC) and are thought to play an important role in the integration of nutrition and metabolic state with the reproductive neuroendocrine axis. The hypothesis that circulating concentrations of luteinizing hormone (LH) and expression of KISS1 and tachykinin 3(TAC3, encodes NKB) in the ARC of female pigs are reduced with negative energy balance was tested using ovariectomized, prepubertal gilts fed to either gain or lose body weight. Restricted feeding of ovariectomized gilts caused a rapid and sustained metabolic response characterized by reduced concentrations of plasma urea nitrogen, insulin, leptin, and insulin-like growth factor-1 and elevated concentrations of free fatty acids. The secretory pattern of LH shifted from one of low amplitude to one of high amplitude, which caused overall circulating concentrations of LH to be greater in restricted gilts. Nutrient-restricted gilts had greater expression of follicle-stimulating hormone and gonadotropin-releasing hormone receptor, but not LH in the anterior pituitary gland. Expression of KISS1 in the ARC was not affected by dietary treatment, but expression of TAC3 was greater in restricted gilts. These data are consistent with the idea that hypothalamic expression of KISS1 is correlated with the number of LH pulse in pig, and further indicate that amplitude of LH pulses may be regulated by NKB in the gilt.

Background: Sodium glucose cotransporter-2 (SGLT2) inhibitors are the most recently approved class of drugs for type 2 diabetes and provide both glycemic efficacy and cardiovascular risk reduction. A number of safety issues have been identified, including treatment-emergent bone fractures. To understand the overall clinical profile, these safety issues must be balanced against an attractive efficacy profile. Our study was designed to investigate pathophysiological mechanisms mediating treatment-emergent adverse effects on bone health., Methods: We conducted a single-blind randomized crossover study in hospitalized healthy adults (n = 25) receiving either canagliflozin (300 mg/d) or placebo for 5 days. The primary end-point was the drug-induced change in AUC for plasma intact fibroblast growth factor 23 (FGF23) immunoactivity between 24 and 72 hours., Results: Canagliflozin administration increased placebo-subtracted mean levels of serum phosphorus (+16%), plasma FGF23 (+20%), and plasma parathyroid hormone (PTH) (+25%), while decreasing the level of 1,25-dihydroxyvitamin D (-10%). There was substantial interindividual variation in the magnitude of each of these pharmacodynamic responses. The increase in plasma FGF23 was correlated with the increase in serum phosphorus, and the decrease in plasma 1,25-dihydroxyvitamin D was correlated with the increase in plasma FGF23., Conclusions: Canagliflozin induced a prompt increase in serum phosphorus, which triggers downstream changes in FGF23, 1,25-dihydroxyvitamin D, and PTH, with potential to exert adverse effects on bone health. These pharmacodynamic data provide a foundation for future research to elucidate pathophysiological mechanisms of adverse effects on bone health, with the objective of devising therapeutic strategies to mitigate the drug-associated fracture risk., Trial Registration: ClinicalTrial.gov (NCT02404870)., Funding: Supported by the Intramural Program of NIDDK.

Importance: Effective and efficient treatment is needed for posttraumatic stress disorder (PTSD) in active duty military personnel., Objective: To examine the effects of massed prolonged exposure therapy (massed therapy), spaced prolonged exposure therapy (spaced therapy), present-centered therapy (PCT), and a minimal-contact control (MCC) on PTSD severity., Design, Setting, and Participants: Randomized clinical trial conducted at Fort Hood, Texas, from January 2011 through July 2016 and enrolling 370 military personnel with PTSD who had returned from Iraq, Afghanistan, or both. Final follow-up was July 11, 2016., Interventions: Prolonged exposure therapy, cognitive behavioral therapy involving exposure to trauma memories/reminders, administered as massed therapy (n = 110; 10 sessions over 2 weeks) or spaced therapy (n = 109; 10 sessions over 8 weeks); PCT, a non-trauma-focused therapy involving identifying/discussing daily stressors (n = 107; 10 sessions over 8 weeks); or MCC, telephone calls from therapists (n = 40; once weekly for 4 weeks)., Main Outcomes and Measures: Outcomes were assessed before and after treatment and at 2-week, 12-week, and 6-month follow-up. Primary outcome was interviewer-assessed PTSD symptom severity, measured by the PTSD Symptom Scale-Interview (PSS-I; range, 0-51; higher scores indicate greater PTSD severity; MCID, 3.18), used to assess efficacy of massed therapy at 2 weeks posttreatment vs MCC at week 4; noninferiority of massed therapy vs spaced therapy at 2 weeks and 12 weeks posttreatment (noninferiority margin, 50% [2.3 points on PSS-I, with 1-sided α = .05]); and efficacy of spaced therapy vs PCT at posttreatment., Results: Among 370 randomized participants, data were analyzed for 366 (mean age, 32.7 [SD, 7.3] years; 44 women [12.0%]; mean baseline PSS-I score, 25.49 [6.36]), and 216 (59.0%) completed the study. At 2 weeks posttreatment, mean PSS-I score was 17.62 (mean decrease from baseline, 7.13) for massed therapy and 21.41 (mean decrease, 3.43) for MCC (difference in decrease, 3.70 [95% CI,0.72 to 6.68]; P = .02). At 2 weeks posttreatment, mean PSS-I score was 18.03 for spaced therapy (decrease, 7.29; difference in means vs massed therapy, 0.79 [1-sided 95% CI, -∞ to 2.29; P = .049 for noninferiority]) and at 12 weeks posttreatment was 18.88 for massed therapy (decrease, 6.32) and 18.34 for spaced therapy (decrease, 6.97; difference, 0.55 [1-sided 95% CI, -∞ to 2.05; P = .03 for noninferiority]). At posttreatment, PSS-I scores for PCT were 18.65 (decrease, 7.31; difference in decrease vs spaced therapy, 0.10 [95% CI, -2.48 to 2.27]; P = .93)., Conclusions and Relevance: Among active duty military personnel with PTSD, massed therapy (10 sessions over 2 weeks) reduced PTSD symptom severity more than MCC at 2-week follow-up and was noninferior to spaced therapy (10 sessions over 8 weeks), and there was no significant difference between spaced therapy and PCT. The reductions in PTSD symptom severity with all treatments were relatively modest, suggesting that further research is needed to determine the clinical importance of these findings., Trial Registration: clinicaltrials.gov Identifier: NCT01049516.

It is now widely recognized that social bonds are critical to human health and well-being. One of the most important social bonds is the attachment relationship between two adults, known as the pair bond . The pair bond involves many characteristics that are inextricably linked to quality of health, including providing a secure psychological base and acting as a social buffer against stress. The majority of our knowledge about the neurobiology of pair bonding comes from studies of a socially monogamous rodent, the prairie vole ( Microtus ochrogaster ), and from human imaging studies, which inherently lack control. Here, we first review what is known of the neurobiology of pair bonding from humans and prairie voles. We then present a summary of the studies we have conducted in titi monkeys ( Callicebus cupreus )-a species of socially monogamous New World primates. Finally, we construct a neural model based on the location of neuropeptide receptors in the titi monkey brain, as well as the location of neural changes in our imaging studies, with some basic assumptions based on the prairie vole model. In this model, we emphasize the role of visual mating stimuli as well as contributions of the dopaminergic reward system and a strong role for the lateral septum. This model represents an important step in understanding the neurobiology of social bonds in non-human primates, which will in turn facilitate a better understanding of these mechanisms in humans.