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Purpose This study aimed to identify optimal management decisions for surgeons preforming pancreatic head resection on patients with altered anatomy due to a previous Roux-en-Y gastric bypass (RYGB). Methods A multi-national (4), multi-center (28) collaborative of 55 pancreatic surgeons who have performed pancreatoduodenectomy or total pancreatectomy following RYGB for obesity (2005–2018) was created. Demographics, operative details, and perioperative outcomes from this cohort were analyzed and compared in a propensity-score matched analysis with a multi-center cohort of 5533 pancreatoduodenectomies without prior RYGB. Results Ninety-six patients with a previous RYGB undergoing pancreatic head resection were assembled. Pathologic indications between the RYGB and normal anatomy cohorts did not differ. Propensity score matching of RYGB vs. patients with unaltered anatomy demonstrated no differences in major postoperative outcomes. In total 20 distinct reconstructions were employed (of 37 potential options); the three most frequent reconstructions accounted for 52.1%, and none demonstrated superior outcomes. There were no differences in outcomes observed between original biliopancreatic limb use (66.7%) and those where a secondary Roux limb was created for biliopancreatic reconstruction. Remnant stomachs were removed in 54.7% of cases, with no outcome differences between resected and retained stomachs. Venting gastrostomy tubes were used in 36.2% of retained stomachs without obvious outcome benefits. Jejunostomy tubes were used infrequently (11.7%). Conclusions Pancreatic head resection after RYGB is an infrequently encountered, unique and challenging scenario for any given surgeon. These patients do not appear to suffer higher morbidity than those with unaltered anatomy. Various technical reconstructive options do not appear to confer distinct benefits.

Objective To examine the teratogenic potential of statins.Design Cohort study.Setting United States.Participants A cohort of 886 996 completed pregnancies linked to liveborn infants of women enrolled in Medicaid from 2000 to 2007.Methods We examined the risk of major congenital malformations and organ specific malformations in offspring associated with maternal use of a statin in the first trimester. Propensity score based methods were used to control for potential confounders, including maternal demographic characteristics, obstetric and medical conditions, and use of other drugs.Results 1152 (0.13%) women used a statin during the first trimester. In unadjusted analyses, the prevalence of malformations in the offspring of these women was 6.34% compared with 3.55% in those of women who did not use a statin in the first trimester (relative risk 1.79, 95% confidence interval 1.43 to 2.23). Controlling for confounders, particularly pre-existing diabetes, accounted for this increase in risk (1.07, 0.85 to 1.37). There were also no statistically significant increases in any of the organ specific malformations assessed after accounting for confounders. Results were similar across a range of sensitivity analyses.Conclusions Our analysis did not find a significant teratogenic effect from maternal use of statins in the first trimester. However, these findings need to be replicated in other large studies, and the long term effects of in utero exposure to statins needs to be assessed, before use of statins in pregnancy can be considered safe.

Recurrence-free survival has been used as a surrogate endpoint for overall survival in trials involving patients with resected colorectal liver metastases. We aimed to assess the correlation between recurrence-free survival and overall survival after resection of colorectal liver metastases to determine the adequacy of this surrogate endpoint. In this retrospective study and meta-analysis, we compiled an institutional cohort of consecutive patients who had complete resection of colorectal liver metastases from the Memorial Sloan Kettering Cancer Center (New York, NY, USA) prospective database. Patients were eligible for inclusion if they were aged 18 years or older, and underwent hepatectomy, with or without operative ablation, between Jan 1, 1991, and April 30, 2019. We estimated overall survival and recurrence-free survival probabilities at various timepoints using the Kaplan-Meier method, and we assessed pairwise associations between these endpoints using Spearman's rank correlation. We also did a meta-analysis of adjuvant phase 3 clinical trials for colorectal liver metastases to assess the correlation between hazard ratios (HRs) for recurrence-free survival and overall survival. We searched MEDLINE for articles of phase 3 randomised controlled trials analysing adjuvant treatment strategies for resected colorectal metastases from database inception to Jan 1, 2022. The titles and abstracts of identified studies were screened before full-text screening and summary data were either recalculated or extracted manually from the published Kaplan-Meier curves (depending on data availability). Data were available for 3299 patients in the institutional database, of whom 2983 were eligible for inclusion in our cohort. Median follow-up was 8·4 years (95% CI 7·9–9·1) , during which time there were 1995 (67%) disease recurrences and 1684 (56%) deaths. Median recurrence-free survival was 1·3 years (95% CI 1·3–1·4) and median overall survival was 5·2 years (95% CI 5·0–5·5). 1428 (85%) of 1684 deaths were preceded by recurrence, and median time from recurrence to death was 2·0 years (IQR 1·0–3·4). Pairwise correlations between recurrence-free survival and overall survival were low to moderate, with a correlation estimate ranging from 0·30 (SD 0·17) to 0·56 (0·13). In the meta-analysis of adjuvant clinical trials, the Spearman's correlation coefficient between recurrence-free survival HR and overall survival HR was r=0·20 (p=0·71). We found a minimal correlation between recurrence-free survival and overall survival after resection of colorectal liver metastases. Recurrence-free survival is an inadequate surrogate endpoint for overall survival in this disease setting. US National Cancer Institute.

BackgroundIncreasingly, women are serving in the military and seeking care at the Veterans Health Administration (VHA). Women veterans face unique challenges and barriers in seeking mental health (MH) care within VHA. VA Video Connect (VVC), which facilitates video-based teleconferencing between patients and providers, can reduce barriers while maintaining clinical effectiveness.ObjectivePrimary aims were to examine gender differences in VVC use, describe changes in VVC use over time (including pre-COVID and 6 months following the beginning of COVID), and determine whether changes over time differed by gender.DesignA retrospective cohort investigation of video-to-home telehealth for MH care utilization among veterans having at least 1 MH visit from October 2019 to September 2020.ParticipantsVeterans (236,268 women; 1,318,024 men).Interventions (if applicable)VVC involves face-to-face, synchronous, video-based teleconferencing between patients and providers, enabling care at home or another private location.Main MeasuresPercentage of MH encounters delivered via VA Video Connect.Key ResultsWomen veterans were more likely than men to have at least 1 VVC encounter and had a greater percentage of MH care delivered via VVC in FY20. There was an increase in the percentage of MH encounters that were VVC over FY20, and this increase was greater for women than men. Women veterans who were younger than 55 (compared to those 55 and older), lived in urban areas (compared to those in rural areas), or were Asian (compared to other races) had a greater percentage of MH encounters that were VVC since the start of the pandemic, controlling for the mean percentage of VVC MH encounters in the 6 months pre-pandemic.ConclusionsVVC use for MH care is greater in women veterans compared to male veterans and may reduce gender-specific access barriers. Future research and VVC implementation efforts should emphasize maximizing patient choice and satisfaction.

DNA methylation at gene promoters in a CG context is associated with transcriptional repression, including at genes silenced on the inactive X chromosome in females. Non-CG methylation (mCH) is a distinct feature of the neuronal epigenome that is differentially distributed between males and females on the X chromosome. However, little is known about differences in mCH on the active (Xa) and inactive (Xi) X chromosomes because stochastic X-chromosome inactivation (XCI) confounds allele-specific epigenomic profiling. We used whole-genome bisulfite sequencing in a mouse model with nonrandom XCI to examine allele-specific DNA methylation in frontal cortex. Xi was largely devoid of mCH, whereas Xa contained abundant mCH similar to the male X chromosome and the autosomes. In contrast to the repressive association of DNA methylation at CG dinucleotides (mCG), mCH accumulates on Xi in domains with transcriptional activity, including the bodies of most genes that escape XCI and at the X-inactivation center, validating this epigenetic mark as a signature of transcriptional activity. Escape genes showing CH hypermethylation were the only genes with CG-hypomethylated promoters on Xi, a well-known mark of active transcription. Finally, we found extensive allele-specific mCH and mCG at autosomal imprinted regions, some with a negative correlation between methylation in the two contexts, further supporting their distinct functions. Our findings show that neuronal mCH functions independently of mCG and is a highly dynamic epigenomic correlate of allelespecific gene regulation.

Methods for profiling DNA methylation differ in the physical principles used to detect modified cytosines. Harris et al . compare the performances of four sequencing-based technologies for genome-wide analysis of DNA methylation and combine two methods to enable detection of allelic differences in epigenetic marks. Analysis of DNA methylation patterns relies increasingly on sequencing-based profiling methods. The four most frequently used sequencing-based technologies are the bisulfite-based methods MethylC-seq and reduced representation bisulfite sequencing (RRBS), and the enrichment-based techniques methylated DNA immunoprecipitation sequencing (MeDIP-seq) and methylated DNA binding domain sequencing (MBD-seq). We applied all four methods to biological replicates of human embryonic stem cells to assess their genome-wide CpG coverage, resolution, cost, concordance and the influence of CpG density and genomic context. The methylation levels assessed by the two bisulfite methods were concordant (their difference did not exceed a given threshold) for 82% for CpGs and 99% of the non-CpG cytosines. Using binary methylation calls, the two enrichment methods were 99% concordant and regions assessed by all four methods were 97% concordant. We combined MeDIP-seq with methylation-sensitive restriction enzyme (MRE-seq) sequencing for comprehensive methylome coverage at lower cost. This, along with RNA-seq and ChIP-seq of the ES cells enabled us to detect regions with allele-specific epigenetic states, identifying most known imprinted regions and new loci with monoallelic epigenetic marks and monoallelic expression.

The phytochrome (phy) family of sensory photoreceptors transduce informational light signals to selected nuclear genes, inducing plant growth and developmental responses appropriate to the environment. Existing data suggest that one signaling pathway by which this occurs involves direct, intranuclear interaction of the photoactivated phy molecule with PIF3, a basic helix-loop-helix transcription factor. Here, we provide evidence from recently identified pif3 mutant alleles that PIF3 is necessary for early chloroplast greening and rapid phy-induced expression of nuclear genes encoding chloroplast components upon first exposure of seedlings to light. Therefore, these data indicate that PIF3 functions to transduce phy signals to genes involved in a critical facet of the early seedling deetiolation process, the generation of a functional photosynthetic apparatus. When transgenically expressed GUS:PIF3 fusion protein constructs were used, we found that PIF3 protein levels are rapidly and reversibly modulated by the photoreceptor over diurnal cycles in Arabidopsis seedlings. The PIF3 protein declines rapidly to a basal steady-state level upon initial light exposure, but reaccumulates to preirradiation levels in darkness during the subsequent night period. These data suggest that PIF3 may function in early phy signaling at the dark-to-light transition, not only during initial seedling deetiolation, but daily at dawn under diurnal light-dark cycles.

Class II terpene cyclases, such as oxidosqualene and squalene-hopene cyclases, catalyse some of the most complex polycyclization reactions. They minimally exhibit a β,γ-didomain architecture that has been evolutionarily repurposed in a wide range of terpene-processing enzymes and likely resulted from a fusion of unidentified monodomain proteins. Although single domain class I terpene cyclases have already been identified, the corresponding class II counterparts have not been previously reported. Here we present high-resolution X-ray structures of a monodomain class II cyclase, merosterolic acid synthase (MstE). With a minimalistic β-domain architecture, this cyanobacterial enzyme is able to construct four rings in cytotoxic meroterpenoids with a sterol-like topology. The structures with bound substrate, product, and inhibitor provide detailed snapshots of a cyclization mechanism largely governed by residues located in a noncanonical enzyme region. Our results complement the few known class II cyclase crystal structures, while also indicating that archaic monodomain cyclases might have already catalyzed complex reaction cascades.Class II terpene cyclases convert simple linear substrates into complex polycyclic compounds, which typically requires multiple protein domains. Now, a single-domain class II cyclase, a cyanobacterial merosterolic acid synthase, has been identified and characterized. High-resolution X-ray crystal structures provide detailed insights into how a minimalistic enzyme accomplishes this complex cyclization process.

Images document scientific discoveries and are prevalent in modern biomedical research. Microscopy imaging in particular is currently undergoing rapid technological advancements. However, for scientists wishing to publish obtained images and image-analysis results, there are currently no unified guidelines for best practices. Consequently, microscopy images and image data in publications may be unclear or difficult to interpret. Here, we present community-developed checklists for preparing light microscopy images and describing image analyses for publications. These checklists offer authors, readers and publishers key recommendations for image formatting and annotation, color selection, data availability and reporting image-analysis workflows. The goal of our guidelines is to increase the clarity and reproducibility of image figures and thereby to heighten the quality and explanatory power of microscopy data. Community-developed checklists offer best-practice guidance for biologists preparing light microscopy images and describing image analyses for publications.

Epidemic respiratory infections are responsible for extensive morbidity and mortality within both military and civilian populations. We describe a high-throughput method to simultaneously identify and genotype species of bacteria from complex mixtures in respiratory samples. The process uses electrospray ionization mass spectrometry and base composition analysis of PCR amplification products from highly conserved genomic regions to identify and determine the relative quantity of pathogenic bacteria present in the sample. High-resolution genotyping of specific species is achieved by using additional primers targeted to highly variable regions of specific bacterial genomes. This method was used to examine samples taken from military recruits during respiratory disease outbreaks and for follow up surveillance at several military training facilities. Analysis of respiratory samples revealed high concentrations of pathogenic respiratory species, including Haemophilus influenzae, Neisseria meningitidis, and Streptococcus pyogenes. When S. pyogenes was identified in samples from the epidemic site, the identical genotype was found in almost all recruits. This analysis method will provide information fundamental to understanding the polymicrobial nature of explosive epidemics of respiratory disease.