Iridium Catalyzed Enantioselective Intermolecular Indole C2-Allylation

The enantioselective intermolecular C2-allylation of 3-substituted indoles is reported for the first time. This directing group-free approach relies on a chiral Ir-(P, olefin) complex and Mg(ClO4)2 Lewis acid catalyst system to promote allylic substitution, providing the C2-allylated products in typically high yields (40-99%) and enantioselectivities (83-99% ee) with excellent regiocontrol. Experimental studies and DFT calculations suggest that the reaction proceeds via direct C2-allylation, rather than C3-allylation followed by in situ migration. Steric congestion at the indole-C3 position and improved π-π stacking interactions have been identified as major contributors to the C2-selectivity

A molecular barcode to inform the geographical origin and transmission dynamics of Plasmodium vivax malaria.

Although Plasmodium vivax parasites are the predominant cause of malaria outside of sub-Saharan Africa, they not always prioritised by elimination programmes. P. vivax is resilient and poses challenges through its ability to re-emerge from dormancy in the human liver. With observed growing drug-resistance and the increasing reports of life-threatening infections, new tools to inform elimination efforts are needed. In order to halt transmission, we need to better understand the dynamics of transmission, the movement of parasites, and the reservoirs of infection in order to design targeted interventions. The use of molecular genetics and epidemiology for tracking and studying malaria parasite populations has been applied successfully in P. falciparum species and here we sought to develop a molecular genetic tool for P. vivax. By assembling the largest set of P. vivax whole genome sequences (n = 433) spanning 17 countries, and applying a machine learning approach, we created a 71 SNP barcode with high predictive ability to identify geographic origin (91.4%). Further, due to the inclusion of markers for within population variability, the barcode may also distinguish local transmission networks. By using P. vivax data from a low-transmission setting in Malaysia, we demonstrate the potential ability to infer outbreak events. By characterising the barcoding SNP genotypes in P. vivax DNA sourced from UK travellers (n = 132) to ten malaria endemic countries predominantly not used in the barcode construction, we correctly predicted the geographic region of infection origin. Overall, the 71 SNP barcode outperforms previously published genotyping methods and when rolled-out within new portable platforms, is likely to be an invaluable tool for informing targeted interventions towards elimination of this resilient human malaria

A Simple Method for Combining Genetic Mapping Data from Multiple Crosses and Experimental Designs

Over the past decade many linkage studies have defined chromosomal intervals containing polymorphisms that modulate a variety of traits. Many phenotypes are now associated with enough mapping data that meta-analysis could help refine locations of known QTLs and detect many novel QTLs.We describe a simple approach to combining QTL mapping results for multiple studies and demonstrate its utility using two hippocampus weight loci. Using data taken from two populations, a recombinant inbred strain set and an advanced intercross population we demonstrate considerable improvements in significance and resolution for both loci. 1-LOD support intervals were improved 51% for Hipp1a and 37% for Hipp9a. We first generate locus-wise permuted P-values for association with the phenotype from multiple maps, which can be done using a permutation method appropriate to each population. These results are then assigned to defined physical positions by interpolation between markers with known physical and genetic positions. We then use Fisher's combination test to combine position-by-position probabilities among experiments. Finally, we calculate genome-wide combined P-values by generating locus-specific P-values for each permuted map for each experiment. These permuted maps are then sampled with replacement and combined. The distribution of best locus-specific P-values for each combined map is the null distribution of genome-wide adjusted P-values.Our approach is applicable to a wide variety of segregating and non-segregating mapping populations, facilitates rapid refinement of physical QTL position, is complementary to other QTL fine mapping methods, and provides an appropriate genome-wide criterion of significance for combined mapping results

Modeling timing and size of juvenile Chinook salmon out-migrants at three Elwha River rotary screw traps: a window into early life history post dam removal

Chinook salmon (Oncorhynchus tshawytscha) populations express diverse early life history pathways that increase habitat utilization and demographic resiliency. Extensive anthropogenic alterations to freshwater habitats along with hatchery and harvest impacts have led to marked reductions in early life history diversity across much of the species’ range. The recent removal of two Elwha River dams between 2011 and 2014 restored access to over 90% of the available habitat that had been inaccessible to Chinook salmon since the early 1900s. This provided an opportunity to investigate how renewed access to this habitat might affect life history diversity. As exotherms, egg-to-fry development, juvenile growth, and movement are influenced by water temperatures. We used spatially and temporally explicit Elwha River water temperature and Chinook salmon spawning location data, in conjunction with spawn timing, emergence, growth, and movement models, to predict observed timing and sizes of juvenile Chinook salmon captured in three rotary screw traps in the mainstem and two tributaries during four trap years. This effort allowed us to test hypotheses regarding Elwha River Chinook salmon early life history, identify potential problems with the data, and predict how emergence and growth would change with increased spawning in the upper watershed. Predicted Chinook salmon emergence timing and predicted dates that juveniles reached 65 mm differed by as much as 2 months for different river locations due to large differences in thermal regimes longitudinally in the mainstem and between tributaries. For 10 out of the 12 trap–year combinations, the model was able to replicate important characteristics of the out-migrant timing and length data collected at the three traps. However, in most cases, there were many plausible parameter combinations that performed well, and in some cases, the model predictions and observations differed. Potential problems with the data and model assumptions were identified as partial explanations for differences and provide avenues for future work. We show that juvenile out-migrant data combined with mechanistic models can improve our understanding of how differences in temperature, spawning extent, and spawn timing affect the emergence, growth, and movement of juvenile fish across diverse riverine habitats

One-year outcomes of the ARTISAN-SNM study with the Axonics System for the treatment of urinary urgency incontinence

Aims: Sacral neuromodulation (SNM) is a guideline-recommended treatment for voiding dysfunction including urgency, urge incontinence, and nonobstructive retention as well

A multiple timepoint pre-post evaluation of a ‘sexual respect’ dvd to improve competence in discussing sex with patients with disability

Sexual problems are common after chronic illnesses and disability, yet research indicates that this is a neglected area in healthcare services. Evaluation studies provide evidence of the effectiveness of education in enhancing professionals’ knowledge, skills, and comfort in addressing patients’ sexual concerns. However, there are limited evaluations aimed at improving ability to discuss sexuality when working with people with disabilities. The overall aim of this study was to evaluate a ‘Sexual Respect’ DVD as an intervention to improve competence in addressing ‘sexuality and disability’. A mixed methods design was used with both quantitative and qualitative components. Nursing students’ self-report ratings of knowledge, confidence, comfort and willingness (to discuss sexuality) levels were collected across four time points: baseline, pre-intervention, post-intervention, and follow-up. Data were analysed using one-way repeated measures ANOVAs with post hoc comparisons. Open-ended qualitative comments relating to the barriers and facilitators to discussing sexuality were analysed using content analysis and subsequent frequency analysis. Reported barriers included lack of knowledge about sex¬uality and disability issues, the patient’s level of disability, and waiting for the patient to raise sexuality issues first. Facilitators included education/training, written information, and if the patient raised it first. Overall, the DVD intervention had a significant and positive impact on nursing students’ self-reported knowledge, confidence, comfort and willingness levels. The findings are discussed in relation to the PLISSIT model, which emphasises the importance of a proactive approach to addressing sexuality issues

Resting-State Quantitative Electroencephalography Reveals Increased Neurophysiologic Connectivity in Depression

Symptoms of Major Depressive Disorder (MDD) are hypothesized to arise from dysfunction in brain networks linking the limbic system and cortical regions. Alterations in brain functional cortical connectivity in resting-state networks have been detected with functional imaging techniques, but neurophysiologic connectivity measures have not been systematically examined. We used weighted network analysis to examine resting state functional connectivity as measured by quantitative electroencephalographic (qEEG) coherence in 121 unmedicated subjects with MDD and 37 healthy controls. Subjects with MDD had significantly higher overall coherence as compared to controls in the delta (0.5–4 Hz), theta (4–8 Hz), alpha (8–12 Hz), and beta (12–20 Hz) frequency bands. The frontopolar region contained the greatest number of “hub nodes” (surface recording locations) with high connectivity. MDD subjects expressed higher theta and alpha coherence primarily in longer distance connections between frontopolar and temporal or parietooccipital regions, and higher beta coherence primarily in connections within and between electrodes overlying the dorsolateral prefrontal cortical (DLPFC) or temporal regions. Nearest centroid analysis indicated that MDD subjects were best characterized by six alpha band connections primarily involving the prefrontal region. The present findings indicate a loss of selectivity in resting functional connectivity in MDD. The overall greater coherence observed in depressed subjects establishes a new context for the interpretation of previous studies showing differences in frontal alpha power and synchrony between subjects with MDD and normal controls. These results can inform the development of qEEG state and trait biomarkers for MDD

Characterizing Long COVID in Children and Adolescents

ImportanceMost research to understand postacute sequelae of SARS-CoV-2 infection (PASC), or long COVID, has focused on adults, with less known about this complex condition in children. Research is needed to characterize pediatric PASC to enable studies of underlying mechanisms that will guide future treatment.ObjectiveTo identify the most common prolonged symptoms experienced by children (aged 6 to 17 years) after SARS-CoV-2 infection, how these symptoms differ by age (school-age [6-11 years] vs adolescents [12-17 years]), how they cluster into distinct phenotypes, and what symptoms in combination could be used as an empirically derived index to assist researchers to study the likely presence of PASC.Design, setting, and participantsMulticenter longitudinal observational cohort study with participants recruited from more than 60 US health care and community settings between March 2022 and December 2023, including school-age children and adolescents with and without SARS-CoV-2 infection history.ExposureSARS-CoV-2 infection.Main outcomes and measuresPASC and 89 prolonged symptoms across 9 symptom domains.ResultsA total of 898 school-age children (751 with previous SARS-CoV-2 infection [referred to as infected] and 147 without [referred to as uninfected]; mean age, 8.6 years; 49% female; 11% were Black or African American, 34% were Hispanic, Latino, or Spanish, and 60% were White) and 4469 adolescents (3109 infected and 1360 uninfected; mean age, 14.8 years; 48% female; 13% were Black or African American, 21% were Hispanic, Latino, or Spanish, and 73% were White) were included. Median time between first infection and symptom survey was 506 days for school-age children and 556 days for adolescents. In models adjusted for sex and race and ethnicity, 14 symptoms in both school-age children and adolescents were more common in those with SARS-CoV-2 infection history compared with those without infection history, with 4 additional symptoms in school-age children only and 3 in adolescents only. These symptoms affected almost every organ system. Combinations of symptoms most associated with infection history were identified to form a PASC research index for each age group; these indices correlated with poorer overall health and quality of life. The index emphasizes neurocognitive, pain, and gastrointestinal symptoms in school-age children but change or loss in smell or taste, pain, and fatigue/malaise-related symptoms in adolescents. Clustering analyses identified 4 PASC symptom phenotypes in school-age children and 3 in adolescents.Conclusions and relevanceThis study developed research indices for characterizing PASC in children and adolescents. Symptom patterns were similar but distinguishable between the 2 groups, highlighting the importance of characterizing PASC separately for these age ranges