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Purpose There is growing enthusiasm for robotic-assisted laparoscopic operations across many surgical specialities, including colorectal surgery, often not supported by robust clinical or cost-effectiveness data. A proper assessment of this new technology is required, prior to widespread recommendation or implementation. Methods/design The ROLARR trial is a pan-world, prospective, randomised, controlled, unblinded, superiority trial of robotic-assisted versus standard laparoscopic surgery for the curative treatment of rectal cancer. It will investigate differences in terms of the rate of conversion to open operation, rate of pathological involvement of circumferential resection margin, 3-year local recurrence, disease-free and overall survival rates and also operative morbidity and mortality, quality of life and cost-effectiveness. The primary outcome measure is the rate of conversion to open operation. For 80% power at the 5% (two-sided) significance level, to identify a relative 50% reduction in open conversion rate (25% to 12.5%), 336 patients will be required. The target recruitment is 400 patients overall to allow loss to follow-up. Patients will be followed up at 30 days and 6 months post-operatively and then annually until 3 years after the last patient has been randomised. Discussion In many centres, robotic-assisted surgery is being implemented on the basis of theoretical advantages, which have yet to be confirmed in practice. Robotic surgery is an expensive health care provision and merits robust evaluation. The ROLARR trial is a pragmatic trial aiming to provide a comprehensive evaluation of both robotic-assisted and standard laparoscopic surgery for the curative resection of rectal cancer.

Understanding how Zika virus (Flaviviridae; ZIKV) affects neural cells is paramount in comprehending pathologies associated with infection. Whilst the effects of ZIKV in neural development are well documented, impact on the adult nervous system remains obscure. Here, we investigated the effects of ZIKV infection in established mature myelinated central nervous system (CNS) cultures. Infection incurred damage to myelinated fibers, with ZIKV-positive cells appearing when myelin damage was first detected as well as axonal pathology, suggesting the latter was a consequence of oligodendroglia infection. Transcriptome analysis revealed host factors that were upregulated during ZIKV infection. One such factor, CCL5, was validated in vitro as inhibiting myelination. Transferred UV-inactivated media from infected cultures did not damage myelin and axons, suggesting that viral replication is necessary to induce the observed effects. These data show that ZIKV infection affects CNS cells even after myelination—which is critical for saltatory conduction and neuronal function—has taken place. Understanding the targets of this virus across developmental stages including the mature CNS, and the subsequent effects of infection of cell types, is necessary to understand effective time frames for therapeutic intervention.

The recent global outbreak of Zika virus (ZIKV) infection has been linked to severe neurological disorders affecting the peripheral and central nervous systems (PNS and CNS, respectively). The pathobiology underlying these diverse clinical phenotypes are the subject of intense research; however, even the principal neural cell types vulnerable to productive Zika infection remain poorly characterised. Here we used CNS and PNS myelinating cultures from wild type and Ifnar1 knockout mice to examine neuronal and glial tropism and short-term consequences of direct infection with a Brazilian variant of ZIKV. Cell cultures were infected pre- or post-myelination for various intervals, then stained with cell-type and ZIKV-specific antibodies. In bypassing systemic immunity using ex vivo culture, and the type I interferon response in Ifnar1 deficient cells, we were able to evaluate the intrinsic infectivity of neural cells. Through systematic quantification of ZIKV infected cells in myelinating cultures, we found that ZIKV infection is enhanced in the absence of the type I interferon responses and that CNS cells are considerably more susceptible to infection than PNS cells. In particular, we demonstrate that CNS axons and myelinating oligodendrocytes are especially vulnerable to injury. These results have implications for understanding the pathobiology of neurological symptoms associated with ZIKV infection. Furthermore, we provide a quantifiable ex vivo infection model that can be used for fundamental and therapeutic studies on viral neuroinvasion and its consequences.

Crohn Disease (CD) is a complex genetic disorder for which more than 140 genes have been identified using genome wide association studies (GWAS). However, the genetic architecture of the trait remains largely unknown. The recent development of machine learning (ML) approaches incited us to apply them to classify healthy and diseased people according to their genomic information. The Immunochip dataset containing 18,227 CD patients and 34,050 healthy controls enrolled and genotyped by the international Inflammatory Bowel Disease genetic consortium (IIBDGC) has been re-analyzed using a set of ML methods: penalized logistic regression (LR), gradient boosted trees (GBT) and artificial neural networks (NN). The main score used to compare the methods was the Area Under the ROC Curve (AUC) statistics. The impact of quality control (QC), imputing and coding methods on LR results showed that QC methods and imputation of missing genotypes may artificially increase the scores. At the opposite, neither the patient/control ratio nor marker preselection or coding strategies significantly affected the results. LR methods, including Lasso, Ridge and ElasticNet provided similar results with a maximum AUC of 0.80. GBT methods like XGBoost, LightGBM and CatBoost, together with dense NN with one or more hidden layers, provided similar AUC values, suggesting limited epistatic effects in the genetic architecture of the trait. ML methods detected near all the genetic variants previously identified by GWAS among the best predictors plus additional predictors with lower effects. The robustness and complementarity of the different methods are also studied. Compared to LR, non-linear models such as GBT or NN may provide robust complementary approaches to identify and classify genetic markers.

The interior of western Canada, up to and including the Arctic, has experienced rapid change in its climate, hydrology, cryosphere, and ecosystems, and this is expected to continue. Although there is general consensus that warming will occur in the future, many critical issues remain. In this first of two articles, attention is placed on atmospheric-related issues that range from large scales down to individual precipitation events. Each of these is considered in terms of expected change organized by season and utilizing mainly “business-as-usual” climate scenario information. Large-scale atmospheric circulations affecting this region are projected to shift differently in each season, with conditions that are conducive to the development of hydroclimate extremes in the domain becoming substantially more intense and frequent after the mid-century. When coupled with warming temperatures, changes in the large-scale atmospheric drivers lead to enhancements of numerous water-related and temperature-related extremes. These include winter snowstorms, freezing rain, drought, forest fires, as well as atmospheric forcing of spring floods, although not necessarily summer convection. Collective insights of these atmospheric findings are summarized in a consistent, connected physical framework.

Most emergency medicine (EM) residency programs provide an orientation program for their incoming interns, with the lecture being the most common education activity during this period. Our orientation program is designed to bridge the gap between undergraduate and graduate medical education by ensuring that all learners demonstrate competency on Level 1 Milestones, including medical knowledge (MK). To teach interns core medical knowledge in EM, we reformulated orientation using the flipped-classroom model by replacing lectures with small group, case-based discussions. Interns demonstrated improvement in medical knowledge through higher scores on a posttest. Evaluation survey results were also favorable for the flipped-classroom teaching format.

BackgroundDespite a high prevalence of problematic substance use among people living with HIV in South Africa, there remains limited access to substance use services within the HIV care system. To address this gap, our team previously developed and adapted a six-session, peer-delivered problem-solving and behavioral activation-based intervention (Khanya) to improve HIV medication adherence and reduce substance use in Cape Town. This study evaluated patient and provider perspectives on the intervention to inform implementation and future adaptation.MethodsFollowing intervention completion, we conducted semi-structured individual interviews with patients (n = 23) and providers (n = 9) to understand perspectives on the feasibility, acceptability, and appropriateness of Khanya and its implementation by a peer. Patients also quantitatively ranked the usefulness of individual intervention components (problem solving for medication adherence ‘Life-Steps’, behavioral activation, mindfulness training, and relapse prevention) at post-treatment and six months follow-up, which we triangulated with qualitative feedback to examine convergence and divergence across methods.ResultsPatients and providers reported high overall acceptability, feasibility, and appropriateness of Khanya, although there were several feasibility challenges. Mindfulness and Life-Steps were identified as particularly acceptable, feasible, and appropriate components by patients across methods, whereas relapse prevention strategies were less salient. Behavioral activation results were less consistent across methods.ConclusionsFindings underscore the importance of examining patients’ perspectives on specific intervention components within intervention packages. While mindfulness training and peer delivery models were positively perceived by consumers, they are rarely used within task-shared behavioral interventions in low- and middle-income countries.

Political responses to the COVID-19 pandemic led to changes in city soundscapes around the globe. From March to October 2020, a consortium of 261 contributors from 35 countries brought together by the Silent Cities project built a unique soundscape recordings collection to report on local acoustic changes in urban areas. We present this collection here, along with metadata including observational descriptions of the local areas from the contributors, open-source environmental data, open-source confinement levels and calculation of acoustic descriptors. We performed a technical validation of the dataset using statistical models run on a subset of manually annotated soundscapes. Results confirmed the large-scale usability of ecoacoustic indices and automatic sound event recognition in the Silent Cities soundscape collection. We expect this dataset to be useful for research in the multidisciplinary field of environmental sciences.

Aldehyde dehydrogenases (ALDHs) catalyze the conversion of various aliphatic and aromatic aldehydes into corresponding carboxylic acids. Traditionally considered as housekeeping enzymes, new biochemical roles are being identified for members of ALDH family. Recent work showed that AldA from the plant pathogen Pseudomonas syringae strain PtoDC3000 (PtoDC3000) functions as an indole-3-acetaldehyde dehydrogenase for the synthesis of indole-3-acetic acid (IAA). IAA produced by AldA allows the pathogen to suppress salicylic acid-mediated defenses in the model plant Arabidopsis thaliana. Here we present a biochemical and structural analysis of the AldA indole-3-acetaldehyde dehydrogenase from PtoDC3000. Site-directed mutants targeting the catalytic residues Cys302 and Glu267 resulted in a loss of enzymatic activity. The X-ray crystal structure of the catalytically inactive AldA C302A mutant in complex with IAA and NAD+ showed the cofactor adopting a conformation that differs from the previously reported structure of AldA. These structures suggest that NAD+ undergoes a conformational change during the AldA reaction mechanism similar to that reported for human ALDH. Site-directed mutagenesis of the IAA binding site indicates that changes in the active site surface reduces AldA activity; however, substitution of Phe169 with a tryptophan altered the substrate selectivity of the mutant to prefer octanal. The present study highlights the inherent biochemical versatility of members of the ALDH enzyme superfamily in P. syringae.

Diet-related sources of ill health, including Fe-deficiency anaemia, are prevalent in the local South Asian population. This population also has a high prevalence of low-birth-weight babies. A need for preventative measures that take a holistic view to dietary change was identified in a South Asian community in Southampton, UK. A peer-led approach was used, training and developing a local workforce to become community food assistants. This workforce, drawn from local black and minority ethnic communities, ran practical ‘hands-on’ culturally-appropriate food-related activities within their communities that were successful in achieving long-term change in the diets of local women and their families. This model has the potential for achieving sustained behaviour change and is able to engage key target groups that can often be difficult to reach through more traditional routes.