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The study objective was to assess the potential benefits of using genomic tools in organic plant breeding programs to enhance selection efficiency. A diversity panel of 247 spring naked barley accessions was characterized under Irish organic conditions over 3 years. Genome-wide association studies (GWAS) were performed on 19 traits related to agronomy, phenology, diseases, and grain quality, using the information on 50 K Single Nucleotide Polymorphisms (SNP). Four models (EMMA, G model, BLINK, 3VMrMLM) were applied to 5 types of Best Linear Unbiased Predictors (BLUP): within-year, mean, aggregated within-year). 1653 Marker-Trait-Associations (MTA) were identified, with 259 discovered in at least two analyses. 3VMrMLM was the best-performing model with significant MTA together explaining the largest proportion of the additive variance for most traits and BLUP types (from 1.4 to 50%). This study proposed a methodology to prioritize main effect MTA from different models' outputs, using multi-marker regression analyses with markers fitted as fixed or random factors. 36 QTL, considered major, explained more than 5% of the trait variance on each BLUP type. A candidate gene or known QTL was found for 18 of them, with 13 discovered with 3VMrMLM. Multi-model GWAS was useful for validating additional QTL, including 8 only discovered with BLINK or G model, thus allowing a broader understanding of the traits' genetic architecture. In addition, results highlighted a correlation between the trait value and the number of favorable major QTL exhibited by accessions. We suggest inputting this number in a multi-trait index for a more efficient Marker-Assisted Selection (MAS) of accessions best balancing multiple quantitative traits. [ABSTRACT FROM AUTHOR]

Self-reported and street race have been associated with health in the U.S. Race is a social construction based on phenotypical classifications rooted in colonialism. Yet, perceptions of race are different in the U.S. than in Latin America. We investigated relationships between self-reported race, street race (i.e., socially assigned race), and the health of U.S. Latinx immigrants in a community-engaged study of immigrant health in North Carolina. Latinx immigrants aged 18–44 years (N = 391) completed measures of self-reported race, street race, and health. Many participants reported that they did not know their race (n = 171; 44%), although to be eligible all identified as Hispanic or Latino/a/x. No significant relationships were observed between street race and health. For self-reported race, participants who declined to respond to the race question were more likely to have poorer mental health than participants who reported a biracial race and worse physical health than those of unknown, white, biracial, and other races. In exploratory analyses, participants who declined to answer the self-reported race question had higher immigration stress and language stress, were more likely to be undocumented, as well as were less bicultural and were less acculturated to the U.S. than participants in some of the other racial groups. The relationship between race and health among Latinx immigrants is complex and may not be explained by traditional racial and ethnic classifications in the U.S. Future research should explore how Latinx immigrants perceive and construct racial identity in the U.S., how they are racialized, and its impact on health. [ABSTRACT FROM AUTHOR]

The coronavirus disease 2019 (COVID-19) pandemic has increased public awareness of the influence of epidemiological and economic decision models on public policy decisions. Alongside this is an increased scrutiny on the development, analysis, reporting and utilisation of decision models for public policy making. Therefore, it is important that model developers can clearly explain and justify to all stakeholders what is included and excluded from a model developed to support decision-making, to both improve transparency and trust in decision-making. Our aim is to provide tools for improving communication between modellers and decision-makers, leading to improved transparency in decision-making. To do so, we extend the recently described directed acyclic graphs with omitted objects displayed (DAGWOOD) approach from Haber et al. (Ann Epidemiol 68:64–71, 2022) to decision analytic models, giving the decision analytic models with omitted objects displayed (DAMWOOD) approach. DAMWOOD is a framework for the identification of objects omitted from a decision model, as well as for consideration of the effects of omissions on model outcomes. Objects omitted from a decision model are classed as either an exclusion (known and unknown confounders), misdirection (alternative model pathways) or structure (e.g. model type, methods for estimating relationships between objects). DAMWOOD requires model developers to use explicit statements and provide illustration of included and omitted objects, supporting communication with model users and stakeholders, allowing them to provide input and feedback to modellers about which objects to include or omit in a model. In developing DAMWOOD, we considered two challenges we encountered in modelling for pandemic policy response. First, the scope of the decision problem is not always made sufficiently explicit by decision-makers, requiring modellers to intuit which policy options should be considered, and/or which outcomes should be considered in their evaluation. Second, there is rarely sufficient transparency to ensure stakeholders can see what is included in models and why. This limits stakeholders' ability to advocate to decision-makers for the prioritisation of specific outcomes and challenge the model results. To illustrate the application of DAMWOOD, we apply it to a previously published COVID-19 vaccine allocation optimisation model. The DAMWOOD diagrams illustrate the ways in which it is possible to improve the communication of model assumptions. The diagrams make explicit which outcomes are omitted and provide information on the expected impact of the omissions on model results. We discuss the usefulness of DAMWOOD for framing the decision problem, communicating the model structure and results and engaging with those making and affected by the decisions the model is developed to inform. [ABSTRACT FROM AUTHOR]

Introduction: This post hoc analysis of VOLTAIRE-RA compared patient-reported outcomes, including health-related quality of life (HRQoL), in patients with rheumatoid arthritis (RA) before and after treatment with biosimilar adalimumab-adbm or adalimumab reference product. Methods: HRQoL was assessed by 36-Item Short Form Survey (SF-36) Physical and Mental Component Summary (PCS and MCS, respectively) and domain scores at baseline and weeks 12/24. Results were considered clinically meaningful if improvements were greater than or equal to minimum clinically important differences (MCIDs) of 2.5 for PCS and MCS and 5.0 for domain scores. Comparisons with age- and sex-matched norms and treatment-associated changes in domain scores from baseline were quantified using spydergrams and the health utility SF-6D measure. All comparisons between treatment groups were descriptive in nature. Results: No differences in PCS scores were reported between treatment groups at baseline or weeks 12/24. MCS scores slightly favored the reference product group at baseline, and differences in scores at weeks 12/24 generally reflected those differences. Improvements in PCS scores greater than or equal to MCID at weeks 12/24 were reported by over 65% of patients in both treatment groups, while over 56% experienced improvements in MCS scores greater than or equal to MCID at weeks 12/24. Similar proportions receiving reference product and adalimumab-adbm reported scores greater than or equal to US age- and sex-matched normative values at week 24: 14–39% versus 15–36%, respectively, compared with baseline (1–17%). Conclusion: In patients with moderate to severely active RA, adalimumab-adbm and adalimumab reference product were both associated with clinically meaningful improvements in SF-36 PCS, MCS, and domain scores that were highly similar at weeks 12/24. The high proportion of patients reporting scores greater than or equal to normative values in both treatment groups is notable, as this represents a treatment goal that was difficult to achieve in earlier RA trials. Video abstract available for this article. Trial Registration: VOLTAIRE-RA (ClinicalTrials.gov number, NCT02137226; EudraCT number, 2012-002945-40). DBJHkVR2HZuD6Np7iz6rXW Video abstract (MP4 29755 KB) [ABSTRACT FROM AUTHOR]

Alzheimer’s disease (AD) has recently been associated with diverse cell states1–11, yet when and how these states affect the onset of AD remains unclear. Here we used a data-driven approach to reconstruct the dynamics of the brain’s cellular environment and identified a trajectory leading to AD that is distinct from other ageing-related effects. First, we built a comprehensive cell atlas of the aged prefrontal cortex from 1.65 million single-nucleus RNA-sequencing profiles sampled from 437 older individuals, and identified specific glial and neuronal subpopulations associated with AD-related traits. Causal modelling then prioritized two distinct lipid-associated microglial subpopulations—one drives amyloid-β proteinopathy while the other mediates the effect of amyloid-β on tau proteinopathy—as well as an astrocyte subpopulation that mediates the effect of tau on cognitive decline. To model the dynamics of cellular environments, we devised the BEYOND methodology, which identified two distinct trajectories of brain ageing, each defined by coordinated progressive changes in certain cellular communities that lead to (1) AD dementia or (2) alternative brain ageing. Thus, we provide a cellular foundation for a new perspective on AD pathophysiology that informs personalized therapeutic development, targeting different cellular communities for individuals on the path to AD or to alternative brain ageing.A comprehensive cell atlas of the aged prefrontal cortex identifies two distinct cellular trajectories of ageing driven by specific glial and neuronal subpopulations, some of which are associated with clinicopathologic traits that define Alzheimer’s disease. [ABSTRACT FROM AUTHOR]

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Background: Standardization of procedures for data abstraction by cancer registries is fundamental for cancer surveillance, clinical and policy decision-making, hospital benchmarking, and research efforts. The objective of the current study was to evaluate adherence to the four components (completeness, comparability, timeliness, and validity) defined by Bray and Parkin that determine registries' ability to carry out these activities to the hospital-based National Cancer Database (NCDB). Methods: Tbis study used data from U.S. Cancer Statistics, the official federal cancer statistics and joint effort between the Centers for Disease Control and Prevention (CDC) and the National Cancer Institute (NCI), which includes data from National Program of Cancer Registries (NPCR) and Surveillance, Epidemiology, and End Results (SEER) to evaluate NCDB completeness between 2016 and 2020. The study evaluated comparability of case identification and coding procedures. It used Commission on Cancer (CoC) standards from 2022 to assess timeliness and validity. Results: Completeness was demonstrated with a total of 6,828,507 cases identified within the NCDB, representing 73.7% of all cancer cases nationwide. Comparability was followed using standardized and international guidelines on coding and classification procedures. For timeliness, hospital compliance with timely data submission was 92.7%. Validity criteria for re-abstracting, recording, and reliability procedures across hospitals demonstrated 94.2% compliance. Additionally, data validity was shown by a 99.1% compliance with histologic verification standards, a 93.6% assessment of pathologic synoptic reporting, and a 99.1% internal consistency of staff credentials. Conclusion: The NCDB is characterized by a high level of case completeness and comparability with uniform standards for data collection, and by hospitals with high compliance, timely data submission, and high rates of compliance with validity standards for registry and data quality evaluation. [ABSTRACT FROM AUTHOR]

Introduction: Predicting which patients will get meaningful benefit from total knee arthroplasty remains a challenge. Our aim was to assess if pre-operative quality of life (EuroQol 5-Dimension, 5-Level instrument; EQ-5D-5L) can predict the likelihood of a patient achieving post-operative improvement in patient-reported outcome measures (PROMS) following total knee arthroplasty to a level of minimum clinically-important difference (MCID). Materials and methods: This was a retrospective analysis of a prospective cohort of total knee arthroplasty patients. EQ-5D-5L and Oxford Knee Scores (OKS) were recorded pre-operatively, 6 months and 2 years post-operatively. The primary outcome measure was achievement of MCID in EQ-5D-5L at 2 years. Multivariable analysis through multiple logistic regression was performed to assess for independent predictors of MCID in EQ-5D-5L, OKS and re-operation at 2 years. Results: 400 patients were included, with 57% female and a mean age of 66 years. Pre-operative EQ-5D-5L was the only strong predictor of post-operative EQ-5D-5L MCID (OR: 0.016, CI: 0.004 to 0.06), when adjusted for age, gender, BMI, ASA, smoking status and surgeon grade. The optimal pre-operative EQ-5D-5L threshold was found to be 0.53 by Youden's index, with a sensitivity of 70% and specificity of 73%. Conclusions: Pre-operative quality of life as measured by EQ-5D-5L is a strong independent predictor of reaching MCID in EQ-5D-5L following total knee arthroplasty. Those with worse EQ-5D-5L are more likely to gain meaningful benefit from knee arthroplasty. [ABSTRACT FROM AUTHOR]

The cauda equina syndrome (CES) is a rare but critical disorder, which can result in devastating motor weakness and sensory deficit, alongside often irreversible bladder, bowel and sexual dysfunction. In addition to the clinical burden of disease, this syndrome results in a disproportionately high medicolegal strain due to missed or delayed diagnoses. Despite being an emergency diagnosis, often necessitating urgent surgical decompression to treat, we believe there is a lack of clarity for clinicians in the current literature, with no published Irish guideline concerning screening or detection. The current study aims to identify and analyse appropriate guidelines in relation to CES screening which are available to clinicians in Ireland. The study design included a comprehensive literature review and comparison of existing guidelines. The review identified 13 sources of appropriate guidance for clinicians working in Ireland. These resources included textbooks, websites and guidelines developed in the UK. No Irish guidelines or advice were available on CES screening/treatment at the time of review. This review demonstrated the lack of consensus and guidance for clinicians in Ireland on how to effectively screen for CES, judge who requires further imaging and investigations and how to rule out the condition. A national consensus on thorough screening and prompt investigation for CES is necessary, and the formulation of new CES guidelines would be a welcome addition to what is available to clinicians currently. [ABSTRACT FROM AUTHOR]

Purpose: National studies examining alcohol and other drug use by sexual orientation have been primarily cross-sectional. Understanding changes in sexual orientation over time may further elucidate the mechanisms behind sexual orientation differences in alcohol and other drug use. This national longitudinal study examines changes in sexual orientation across four waves (2013–2019), and the associations with symptomatic alcohol and other drug use. Methods: Data from Waves 1 through 5 of the Population Assessment of Tobacco and Health (PATH) study were used to examine associations of sexual identity change/stability and sexual identity–attraction discordance/concordance from baseline to follow-up with symptomatic substance use at follow-up. We examined four outcomes: any symptomatic substance use, symptomatic alcohol use, symptomatic other drug use, and symptomatic alcohol + other drug use. Mixed effects logistic regression models were used and all analyses were weighted and stratified by sex. Results: In models adjusting for potential confounders, greater likelihood of symptomatic alcohol and other drug use outcomes was found among males and females experiencing a change from a heterosexual to sexual minority identity and among females with new or consistent sexual identity–attraction discordance. Conclusion: These findings highlight important sex differences and suggest that the period of transitioning to a sexual minority identity is a particularly vulnerable period for symptomatic alcohol and other drug use. For females, incongruent sexual identity and attraction is also a risk factor. Interventions that assist individuals during this transitional period and during a time when identity and attraction are incongruent, may reduce symptomatic substance use during this period. [ABSTRACT FROM AUTHOR]

The social media platforms of the twenty-first century have an enormous role in regulating speech in the USA and worldwide1. However, there has been little research on platform-wide interventions on speech2,3. Here we evaluate the effect of the decision by Twitter to suddenly deplatform 70,000 misinformation traffickers in response to the violence at the US Capitol on 6 January 2021 (a series of events commonly known as and referred to here as ‘January 6th’). Using a panel of more than 500,000 active Twitter users4,5 and natural experimental designs6,7, we evaluate the effects of this intervention on the circulation of misinformation on Twitter. We show that the intervention reduced circulation of misinformation by the deplatformed users as well as by those who followed the deplatformed users, though we cannot identify the magnitude of the causal estimates owing to the co-occurrence of the deplatforming intervention with the events surrounding January 6th. We also find that many of the misinformation traffickers who were not deplatformed left Twitter following the intervention. The results inform the historical record surrounding the insurrection, a momentous event in US history, and indicate the capacity of social media platforms to control the circulation of misinformation, and more generally to regulate public discourse.Difference-in-differences analysis indicates that the decision by Twitter to deplatform 70,000 users following the events at the US Capitol on 6 January 2021 had wider effects on the spread of misinformation. [ABSTRACT FROM AUTHOR]

Purpose: To report the margin control process and rate of recurrence of periocular basal cell carcinomas (BCCs) managed by en-face, frozen section margin controlled (FSC), excision by a single surgeon with a 3-year follow-up. Methods: A retrospective analysis of all histopathologically proven cases of periocular BCC who underwent surgical excision with intra-operative, en-face, FSC, excision by a single surgeon from 2015 to 2019 was performed. Patients with less than 3-year follow-up were offered a virtual appointment to determine possible recurrence. Results: A total of 88 BCC excisions from 86 patients were reviewed. Minimum 3-year follow-up data is available for 73 patients. The most common location and histological subtype was the lower eyelid and nodular BCC, respectively (47% and 83% of cases). Primary BCC (pBCC) comprised 98% (86/88) of cases and recurrent BCC (rBCC) comprised 2% (2/88) of cases. Negative frozen section margins were achieved in 93% (82/88) of excisions on the day of surgery. The overall recurrence rate during this time was 1.4% (1/73) at minimum 3 years. Conclusion: Periocular BCC can be managed effectively by en-face, FSC, excision, with a high cure rate and low recurrence rate comparable to alternative excision techniques such as Moh's micrographic surgery. Advantages of en-face excision include same-day excision and reconstruction and reduced theatre time. Primary nodular BCCs with clear margins can be considered for early discharge with advice to self-monitor. [ABSTRACT FROM AUTHOR]

Purpose: To describe the anatomical, visual, and safety results of full-thickness macular hole (FTMH) repair surgery and determine factors influencing outcomes. Patients and methods: A retrospective chart review was performed on all patients who underwent primary FTMH repair surgery by a single surgeon over a 3-year period. For comparisons, Snellen visual acuity (VA) was converted to logMAR equivalent. Anatomical hole closure, visual improvement, and final VA of ≤ 0.30 logMAR were the primary outcome measures. Results: Twenty eyes of 19 patients were included. Mean patient age was 69 years (range 55 to 80 years) and 74% were female. Mean minimum linear diameter (MLD) was 440 μm (range 170 μm to 1200 μm). Mean duration of symptoms before surgery was 16 weeks (range 3 to 39 weeks). 100% of eyes achieved successful anatomical FTMH closure. Mean VA improved from 1.03 ± 0.43 logMAR (Snellen 6/60) preoperatively to 0.35 ± 0.22 logMAR (Snellen 6/15) postoperatively (p = 0.0001). Patients with worse preoperative VA gained more vision than those with better preoperative VA (p = 0.01). Eyes operated on within 4 months of symptom onset were more than twice as likely to achieve a postoperative VA of ≤ 0.30 logMAR (Snellen 6/12 or better) compared to eyes with a longer duration of symptoms (p = 0.03). Conclusion: FTMH repair surgery was safe and effective, with outcomes comparing favourably with published international studies. All patients benefited from surgery regardless of symptom duration, presenting VA or FTMH size. However, surgery performed within 4 months of symptom-onset was particularly beneficial, highlighting the need for prompt referral and surgery. [ABSTRACT FROM AUTHOR]

Background: Early vitrectomy for complete fundus-obscuring vitreous haemorrhage (VH) allows for prompt diagnosis and treatment of the cause. Aims: To analyse the causes of VH of unknown aetiology, whether partially fundus-obscuring or dense, and to determine the outcomes of early vitrectomy. Methods: A retrospective review of patients who underwent early vitrectomy within 10 days of symptom-onset for partially fundus-obscuring or dense VH of unknown origin. Patients with evidence of proliferative diabetic retinopathy in either eye or any other preoperatively diagnosed aetiology of VH were excluded. Results: 19 patients were included. Intraoperative diagnoses were: retinal tears without rhegmatogenous retinal detachment (RRD) (53%); peripheral localised RRD (32%); neovascularisation secondary to retinal vein occlusion (11%) and posterior vitreous detachment without a retinal break (5%). Patients with diffuse VH were as likely to have a retinal tear diagnosed as those with dense VH (88% vs 82%, respectively; p = 0.7). Mean VA improved from 1.26 LogMAR to 0.23 LogMAR postoperatively (p = 0.001). 1 patient (5%) developed a RRD one-year postoperatively. Conclusions: In cases of diffuse or dense VH of unknown aetiology, an occult retinal tear should be suspected. Early vitrectomy should be strongly considered regardless of whether the fundal view is partially or completely obscured, to prevent progression to visually significant RRDs. [ABSTRACT FROM AUTHOR]

Background: Unenhanced low-dose computed tomography of the kidneys, ureter and bladder (CT KUB) is the gold standard diagnostic imaging modality in the assessment of suspected renal colic. As the radiation dose is not negligible, it is important to monitor the diagnostic yield of CT KUBs. The aim of this study is to evaluate the diagnostic yield of CT KUB studies performed for suspected renal colic in patients presenting to the emergency department. Methods: A retrospective review was performed of 500 patients who underwent CT KUB for suspected renal colic over a seven month period from June 2019 to January 2020. Clinical information and imaging was reviewed for each patient. Statistical analysis was performed using GraphPad Prism 8 (GraphPad Software, San Diego, CA, USA). Results: Forty-nine percent of patients in the series were female (248/500) and the mean age was 45. The positivity rate for obstructing ureteral calculus was 34% (169/500). Concerningly, there was a significantly lower positivity rate in females compared to males (19% versus 48%; p < 0.0001) which raises the issue of unnecessary radiation exposure to this cohort. In the 200 female patients who were negative for obstructing urolithiasis, the mean age was 43. Females also had a significantly higher rate of negative CT KUB (62% versus 37%; p < 0.0001) where no underlying alternative pathology was diagnosed. Conclusions: Women are less likely than men to have obstructing urolithiasis on CT KUB for suspected renal colic. This difference is not accounted for by a higher rate of alternative diagnoses among female patients. The findings of this study should prompt clinicians to exercise caution when considering this imaging modality in this patient cohort. [ABSTRACT FROM AUTHOR]

Background: Tumour hypoxia is a recognised cause of radiotherapy treatment resistance in head and neck squamous cell carcinoma (HNSCC). Current positron emission tomography-based hypoxia imaging techniques are not routinely available in many centres. We investigated if an alternative technique called oxygen-enhanced magnetic resonance imaging (OE-MRI) could be performed in HNSCC. Methods: A volumetric OE-MRI protocol for dynamic T1 relaxation time mapping was implemented on 1.5-T clinical scanners. Participants were scanned breathing room air and during high-flow oxygen administration. Oxygen-induced changes in T1 times (ΔT1) and R2* rates (ΔR2*) were measured in malignant tissue and healthy organs. Unequal variance t-test was used. Patients were surveyed on their experience of the OE-MRI protocol. Results: Fifteen patients with HNSCC (median age 59 years, range 38 to 76) and 10 non-HNSCC subjects (median age 46.5 years, range 32 to 62) were scanned; the OE-MRI acquisition took less than 10 min and was well tolerated. Fifteen histologically confirmed primary tumours and 41 malignant nodal masses were identified. Median (range) of ΔT1 times and hypoxic fraction estimates for primary tumours were -3.5% (-7.0 to -0.3%) and 30.7% (6.5 to 78.6%) respectively. Radiotherapy-responsive and radiotherapy-resistant primary tumours had mean estimated hypoxic fractions of 36.8% (95% confidence interval [CI] 17.4 to 56.2%) and 59.0% (95% CI 44.6 to 73.3%), respectively (p = 0.111). Conclusions: We present a well-tolerated implementation of dynamic, volumetric OE-MRI of the head and neck region allowing discernment of differing oxygen responses within biopsy-confirmed HNSCC. Trial registration: ClinicalTrials.gov, NCT04724096. Registered on 26 January 2021. Relevance statement: MRI of tumour hypoxia in head and neck cancer using routine clinical equipment is feasible and well tolerated and allows estimates of tumour hypoxic fractions in less than ten minutes. Key points: • Oxygen-enhanced MRI (OE-MRI) can estimate tumour hypoxic fractions in ten-minute scanning. • OE-MRI may be incorporable into routine clinical tumour imaging. • OE-MRI has the potential to predict outcomes after radiotherapy treatment. [ABSTRACT FROM AUTHOR]

Exposure is an important element of treatment for many evidence-based treatments but can be challenging to implement. Supervision strategies to support exposure delivery may be an important tool to facilitate the use of exposure techniques; however, they must be considered and used in the context of the supervisory alliance. The present study examined relations between supervisory alliance and fidelity to the trauma narrative (TN; i.e., imaginal exposure) component of Trauma-Focused Cognitive Behavioral Therapy. We also examined how supervisory alliance moderated the effect of behavioral rehearsal use in supervision on TN fidelity. We analyzed data from a randomized controlled trial, in which forty-two supervisors and their clinicians (N = 124) from 28 Washington State community-based mental health offices participated. Clinicians were randomized to receive one of two supervision conditions—symptom and fidelity monitoring (SFM) or SFM with behavioral rehearsal (SFM + BR). Supervisory alliance alone did not predict delivery (i.e., occurrence) or extensiveness of delivery of the trauma narrative. Client-focused supervisory alliance moderated the effectiveness of behavioral rehearsal—as client-focused alliance increased, the odds of delivering the TN also increased significantly. Future research should further investigate how to appropriately match supervision techniques with supervisory dyads and explore the interplay of alliance with supervision techniques a supervisor might employ. [ABSTRACT FROM AUTHOR]

Background and Objectives: Ocedurenone (KBP-5074) is a novel nonsteroidal mineralocorticoid receptor antagonist that has demonstrated safety and efficacy in clinical trials in patients with uncontrolled hypertension and stage 3b/4 chronic kidney disease. The aim of this study was to assess the pharmacokinetics, safety, and tolerability of ocedurenone in individuals with moderate hepatic impairment. Methods: This study was an open-label, nonrandomized, multi-center study investigating the pharmacokinetics, safety, and tolerability of a single dose of 0.5 mg ocedurenone administered orally in male and female subjects with moderate hepatic impairment (Child–Pugh B, score 7–9) compared with subjects with normal hepatic function. Serial blood samples were obtained from predose through 264 h postdose for analysis of ocedurenone concentrations using a validated liquid chromatography–tandem mass spectrometry method. Free ocedurenone concentrations in plasma were determined ex vivo using equilibrium dialysis. Results: Following a single oral dose of 0.5 mg ocedurenone administered to subjects with moderate hepatic impairment and subjects with normal hepatic function, ocedurenone was steadily absorbed with median time to peak drug concentration (Tmax) values of 4 and 3 h, respectively. After reaching maximum plasma concentration (Cmax), the disposition of ocedurenone appeared to be biphasic. The geometric mean t1/2 values for the moderate hepatic impairment group and normal hepatic function group were 75.6 and 65.7 h, respectively. Ocedurenone systemic exposure, as assessed by area under the plasma concentration-time curve (AUC) was 23.5–26.6% lower in subjects with moderate hepatic impairment versus subjects with normal hepatic function, whereas Cmax was 41.2% lower. Ocedurenone was determined to be > 99.7% bound to total protein in plasma. Hepatic impairment appeared not to change plasma protein binding or the unbound free fraction. Ocedurenone was safe and well-tolerated in all participants. Conclusions: Considering the long half-life of ocedurenone and previously completed clinical studies using 0.25 mg and 0.5 mg doses demonstrating efficacy and safety, the observed decreases in AUC and Cmax do not warrant a dose adjustment in patients with moderate hepatic impairment. A single 0.5 mg dose of ocedurenone was safe and well-tolerated when administered to subjects with moderate hepatic impairment and subjects with normal hepatic function. Clinical Trial Identifier (www.clinicaltrials.gov) NCT04534699. [ABSTRACT FROM AUTHOR]

Mangrove forests are recognized as one of the most effective ecosystems for storing carbon. In drylands, mangroves operate at the extremes of environmental gradients and, in many instances, offer one of the few opportunities for vegetation-based sequestering of carbon. Developing accurate and reproducible methods to map carbon assimilation in mangroves not only serves to inform efforts related to natural capital accounting, but can help to motivate their protection and preservation. Remote sensing offers a means to retrieve numerous vegetation traits, many of which can be related to plant biophysical or biochemical responses. The leaf area index (LAI) is routinely employed as a biophysical indicator of health and condition. Here, we apply a linear regression model to UAV-derived multispectral data to retrieve LAI across three mangrove sites located along the coastline of the Red Sea, with estimates producing an R2 of 0.72 when compared against ground-sampled LiCOR LAI-2200C LAI data. To explore the potential of monitoring carbon assimilation within these mangrove stands, the UAV-derived LAI estimates were combined with field-measured net photosynthesis rates from a LiCOR 6400/XT, providing a first estimate of carbon assimilation in dryland mangrove systems of approximately 3000 ton C km−2 yr−1. Overall, these results advance our understanding of carbon assimilation in dryland mangroves and provide a mechanism to quantify the carbon mitigation potential of mangrove reforestation efforts. [ABSTRACT FROM AUTHOR]

Patient-reported outcomes (PROs) are an underreported aspect of surgical recovery. The purpose of our study was to track PROs after robotic anatomic lung to determine the timing to recovery of baseline patient baseline quality of life. This was a prospective cohort study at an academic medical center (4/2021–12/2022). Patients who underwent robotic anatomic lung resection were asked to complete PROMIS-29 surveys at the preoperative clinic visit, postoperative clinic visit, 30 days and 90 days postoperatively via in-person and email-based electronic surveys. The PROPr score, a summary of health-related quality of life, and mental and physical health z-scores were estimated for each patient using published methods and compared by postoperative timing. 75 patients completed the preoperative survey and at least one postoperative survey; 56 completed postoperative clinic surveys, 54 completed 30-day postoperative surveys, and 40 completed 90-day postoperative surveys. All three PROMIS scores decreased between the preoperative and first postoperative visit (all p < 0.05). PROPr scores increased over time but remained significantly worse than baseline by 90 days (-0.08 difference between 90 days and preoperative, p = 0.02). While PROMIS summary z-scores for physical health remained − 0.29 lower at 90 days postoperatively, this did not reach statistical significance (p = 0.06). Mental health scores returned to baseline by 90 days postoperatively (p = 0.41). While some PROs returned to baseline by 90 days postoperatively, overall quality-of-life scores remained significantly below preoperative baselines. These findings are important to share with patients during the informed consent process to achieve patient centered care more effectively. [ABSTRACT FROM AUTHOR]

COVID-19 and infectious diseases have been included in strategic development goals (SDG) of United Nations (UN). The CD147 receptor is one of several receptors for the SARS-CoV-2 spike protein that could mediate Covid-19 viral infection of host cells. It has been recently proposed to regulate viral invasion and dissemination among lymphocytes and progenitor/stem cells. A soluble by-product of CD147 (sCD147) exists in plasma and has been previously identified as a marker of diabetes and platelet activation. We examined plasma sCD147 levels in 161 Covid-19 patients at hospital admission. We demonstrated significantly higher plasma sCD147 levels in Covid-19 patients, which correlated with plasma multiorgan dysfunction biomarkers interleukin-6, creatinine and Troponin I. Importantly, sCD147 admission levels were associated with Covid-19 severity and survival, carrying potential value as a biomarker in hospitalized patients with Covid-19 infection. [ABSTRACT FROM AUTHOR]

This randomized experiment tested whether the inclusion of a "something else" response option for a question about sexual identity in a national health survey would significantly moderate estimated differences between sexual identity subgroups in terms of various health outcomes, including substance use and reproductive health. We conducted secondary analyses of data from five consecutive years of the National Survey of Family Growth (NSFG; 2015–2019), where two large national half-samples were randomly assigned to receive one of two different versions of a question about sexual identity (a four-category version that included a "something else" response option or a three-category version omitting this option). We focused on national estimates of differences between subgroups defined by sexual identity. Multivariable models indicated that the estimated subgroup differences changed in a statistically significant fashion when using the four-category version of the sexual identity question for several measures, including 16% of male measures (household size, past-year cigarette use, and past-year illicit drug use) and 15% of female measures (wanting a/another child, ever had a sexually transmitted disease, and past-year marijuana use). The absence of a "something else" response option for questions about sexual identity in national health surveys may cause respondents to select options that do not accurately describe their identities, and this can have a significant effect on national estimates of differences between sexual identity subgroups in terms of selected health outcomes. [ABSTRACT FROM AUTHOR]

Identifying bioactive conformations of small molecules is an essential process for virtual screening applications relying on three-dimensional structure such as molecular docking. For most small molecules, conformer generators retrieve at least one bioactive-like conformation, with an atomic root-mean-square deviation (ARMSD) lower than 1 Å, among the set of low-energy conformers generated. However, there is currently no general method to prioritise these likely target-bound conformations in the ensemble. In this work, we trained atomistic neural networks (AtNNs) on 3D information of generated conformers of a curated subset of PDBbind ligands to predict the ARMSD to their closest bioactive conformation, and evaluated the early enrichment of bioactive-like conformations when ranking conformers by AtNN prediction. AtNN ranking was compared with bioactivity-unaware baselines such as ascending Sage force field energy ranking, and a slower bioactivity-based baseline ranking by ascending Torsion Fingerprint Deviation to the Maximum Common Substructure to the most similar molecule in the training set (TFD2SimRefMCS). On test sets from random ligand splits of PDBbind, ranking conformers using ComENet, the AtNN encoding the most 3D information, leads to early enrichment of bioactive-like conformations with a median BEDROC of 0.29 ± 0.02, outperforming the best bioactivity-unaware Sage energy ranking baseline (median BEDROC of 0.18 ± 0.02), and performing on a par with the bioactivity-based TFD2SimRefMCS baseline (median BEDROC of 0.31 ± 0.02). The improved performance of the AtNN and TFD2SimRefMCS baseline is mostly observed on test set ligands that bind proteins similar to proteins observed in the training set. On a more challenging subset of flexible molecules, the bioactivity-unaware baselines showed median BEDROCs up to 0.02, while AtNNs and TFD2SimRefMCS showed median BEDROCs between 0.09 and 0.13. When performing rigid ligand re-docking of PDBbind ligands with GOLD using the 1% top-ranked conformers, ComENet ranked conformers showed a higher successful docking rate than bioactivity-unaware baselines, with a rate of 0.48 ± 0.02 compared to CSD probability baseline with a rate of 0.39 ± 0.02. Similarly, on a pharmacophore searching experiment, selecting the 20% top-ranked conformers ranked by ComENet showed higher hit rate compared to baselines. Hence, the approach presented here uses AtNNs successfully to focus conformer ensembles towards bioactive-like conformations, representing an opportunity to reduce computational expense in virtual screening applications on known targets that require input conformations. [ABSTRACT FROM AUTHOR]

Use of e-cigarettes have become an important public health concern in the US, particularly among those with health issues like asthma, which has remained high over the last decade. We examined associations between lifetime e-cigarette use and traditional cigarette use, cannabis use, and related health factors among community members with a history of asthma in North Central Florida. Data came from HealthStreet, a University of Florida community engagement program. Adults with a history of asthma (n = 1,475) were interviewed between 2014 and 2021. Bivariate and logistic regression analyses were conducted to examine differences between participants with and without a history of lifetime e-cigarette use. In this sample, lifetime prevalence of e-cigarette use was 19.9%. Over half of the sample reported ever smoking traditional cigarettes (54.4%) or cannabis (55.4%). Compared to those who identified as White, those who identified as Black/African American had lower odds for lifetime e-cigarette use (aOR = 0.30, 95% CI: 0.22, 0.42). Those reporting lifetime traditional cigarette use (aOR = 10.60, 95% CI: 6.93, 16.68) or cannabis use (aOR = 1.81, 95% CI: 1.27, 2.61) had higher odds for reporting lifetime e-cigarette use. Overall, among a community sample of adults with a history of asthma, nearly a fifth reported lifetime e-cigarette use. The use of e-cigarettes was most common among those with lifetime traditional cigarette use and cannabis use. Findings can inform prevention and intervention efforts in this population. [ABSTRACT FROM AUTHOR]

The Neptune's cup sponge is an iconic species found in marine soft sediment habitats in the Indo-West Pacific, with a history of overharvesting and extreme population declines. Access to SCUBA diving surveys has allowed for its rediscovery at Singapore, its type locality; however, with fewer than ten living individuals documented in the twenty-first century, the species is believed to be in need of conservation. Here, we share the results from surveys across the Gulf of Thailand, allowing for a documentation of 29 additional individuals, with information on their ecology and distribution. Of the 29 individuals, extensive damage or mortality caused by marine debris is recorded for six individuals, and one further individual is believed to be lost due to an unknown cause. Documented threats from the Gulf of Thailand differ from those in Singapore; however, low population sizes and poor connectivity remain a significant concern for the survival of the species. [ABSTRACT FROM AUTHOR]

Species occurrence data are foundational for research, conservation, and science communication, but the limited availability and accessibility of reliable data represents a major obstacle, particularly for insects, which face mounting pressures. We present BeeBDC, a new R package, and a global bee occurrence dataset to address this issue. We combined >18.3 million bee occurrence records from multiple public repositories (GBIF, SCAN, iDigBio, USGS, ALA) and smaller datasets, then standardised, flagged, deduplicated, and cleaned the data using the reproducible BeeBDC R-workflow. Specifically, we harmonised species names (following established global taxonomy), country names, and collection dates and, we added record-level flags for a series of potential quality issues. These data are provided in two formats, “cleaned” and “flagged-but-uncleaned”. The BeeBDC package with online documentation provides end users the ability to modify filtering parameters to address their research questions. By publishing reproducible R workflows and globally cleaned datasets, we can increase the accessibility and reliability of downstream analyses. This workflow can be implemented for other taxa to support research and conservation. [ABSTRACT FROM AUTHOR]

Research regarding how people choose their long-term romantic partners is extensive, but the understanding of the psychological processes behind these choices, and predicting who people choose, is elusive. This review attempts to examine potential reasons for this elusive nature by first outlining the current state of the literature and then highlighting issues within the current paradigm. First among these issues is a focus on singular perspectives and little attempt to integrate these perspectives with others. Second, many studies focus on increasingly complex designs to explore the predictive utility of trait preferences, attempts which have had only limited success. Third, novel findings appear to be unintegrated with established findings, leaving the potential combination of these ideas unrealized. Finally, long-term romantic partner selection is a complex psychological phenomenon, but current theory and research methodologies are not sufficiently addressing this complexity. This review concludes with suggestions for future research direction, including a focus on the psychology behind the partner selection process and the potential of qualitative enquiry to reveal novel pathways behind these psychological processes. There is a need for an integrative framework that permits the coexistence of established and novel ideas, and multiple perspectives, from both current and future research paradigms. [ABSTRACT FROM AUTHOR]

Ecological niches are the environmental conditions under which an organism can maintain viable populations. A detailed understanding of an organisms' ecological niche can provide information on its taxonomy and biogeography, and ecological niche modelling allows researchers to investigate how closely-related species are able to coexist. Ecological niche models also enable conservationists to determine species' habitat requirements, map distributions, and assess threats. We used this approach to investigate the conservation biogeography of the dwarf lemurs (genus Cheirogaleus), a group of cryptic, nocturnal primates endemic to Madagascar. Using climatic and vegetation-related variables, we constructed ecological niche models for three species to investigate niche overlap among taxa. We also constructed maps of the availability of forest habitat, and we assessed anthropogenic risk and protection. Our ecological niche models and background tests indicated that each of the three analysed Cheirogaleus species occupies distinct environmental space. The area of suitable habitat (realized niche) varied interspecifically (28,889–41,934 km2). This also was mirrored by variation in the percentage of each species' realized niche within protected areas (20,065–25,266 km2) and near anthropogenic features (5,744–16,999 km2). Our results support the 2020 taxonomy of the dwarf lemurs recognised by the IUCN Red List and provides information on their biogeography. Furthermore, our ecological niche models have highlighted that the habitat of some dwarf lemur species, such as C. crossleyi, are more threatened than other species, such as C. medius and C. major, and these species require urgent conservation attention. [ABSTRACT FROM AUTHOR]

Aim: Many cycling collisions occur due to human error, cycling ability, distraction or infrastructure. One such infrastructural issue for cyclists sharing the road with tram lines is where the wheel of the bicycle gets caught in the rail track itself or in a gap between the rail and the road margin resulting in a sudden stall of the bicycle and potentially significant injury. This study aims to describe the crash characteristics of tram-track cycling collisions and their associated injuries. Methods: A retrospective chart review was conducted over 2 years, looking at cyclists that presented to St James's Emergency Department (ED) following injuries sustained due to a bicycle wheel catching in the on-road tram tracks. Results: Forty-eight patients were identified over a 2-year period. Sixty per cent of cyclists sustained limb fractures with 14% requiring orthopaedic surgery. Fifty per cent of patients were not wearing a helmet at the time of the incident and 54% of the collisions occurred around Dublin city centre during rush hour. Conclusion: Further prospective multi-centre studies are required to properly describe the magnitude cycling accidents around the Luas tracks and inform future public health measures in this area. [ABSTRACT FROM AUTHOR]

Background: Replacement of thyroid hormones (TH) with Levothyroxine (LT4) is the treatment of choice for hypothyroidism, however, there are aspects of treatment where uncertainties exist and practice varies. Factors influencing initiation and choice of TH replacement may impact patient satisfaction, safety, and health care costs. Methods: The aim of the study was to examine the attitudes of Irish endocrinologists regarding the treatment of hypothyroid and euthyroid patients with TH. Members of the Irish Endocrine Society (IES) were invited to participate in an online survey. Results: Forty-eight invitations were sent, and 39 (81.3%) participants responded. All respondents favoured LT4 tablet therapy for treatment of hypothyroidism, but 20.5% prescribed combination therapy (LT4 and liothyronine), and 13% regularly used desiccated thyroid extract. A significant proportion (51%) might prescribe TH in euthyroid patients; 41% for thyroid auto-antibody positive women seeking pregnancy, 18% for goitre and 5% for unexplained fatigue. Many (38%) consider combination therapy in patients with persistent symptoms. Respondents reported seeing LT4 treated patients with persistent symptomatology more frequently and perceive psychosocial factors and comorbidities to be the most common reasons for such symptoms. Conclusion: LT4 tablets are the treatment of choice for hypothyroidism in Ireland. Approximately a third of Irish endocrinologists either regularly use, or would consider, liothyronine for hypothyroid patients. A significant proportion would give TH to euthyroid individuals in specific circumstances. The prescription of TH amongst Irish endocrinologists was generally in keeping with recommended practice, and areas where practice deviated from guidance were typically where evidence was conflicting or insufficient. [ABSTRACT FROM AUTHOR]

Abstract Influenza A virus (IAV)‐induced severe disease is characterized by infected lung epithelia, robust inflammatory responses and acute lung injury. Since type I interferon (IFNαβ) and type III interferon (IFNλ) are potent antiviral cytokines with immunomodulatory potential, we assessed their efficacy as IAV treatments. IFNλ treatment of IAV‐infected Mx1‐positive mice lowered viral load and protected from disease. IFNα treatment also restricted IAV replication but exacerbated disease. IFNα treatment increased pulmonary proinflammatory cytokine secretion, innate cell recruitment and epithelial cell death, unlike IFNλ‐treatment. IFNλ lacked the direct stimulatory activity of IFNα on immune cells. In epithelia, both IFNs induced antiviral genes but no inflammatory cytokines. Similarly, human airway epithelia responded to both IFNα and IFNλ by induction of antiviral genes but not of cytokines, while hPBMCs responded only to IFNα. The restriction of both IFNλ responsiveness and productive IAV replication to pulmonary epithelia allows IFNλ to limit IAV spread through antiviral gene induction in relevant cells without overstimulating the immune system and driving immunopathology. We propose IFNλ as a non‐inflammatory and hence superior treatment option for human IAV infection.

We previously reported initial clinical results of post-transcriptional gene silencing of BCL11A expression (NCT 03282656) reversing the fetal to adult hemoglobin switch. A goal of this approach is to increase fetal hemoglobin (HbF) expression while coordinately reducing sickle hemoglobin (HbS) expression. The resulting combinatorial effect should prove effective in inhibiting HbS polymerization at lower physiologic oxygen values thereby mitigating disease complications. Here we report results of exploratory single-cell analysis of patients in which BCL11A is targeted molecularly and compare results with cells of patients treated with hydroxyurea (HU), the current standard of care. We use single-cell assays to assess HbF, HbS, oxygen saturation, and hemoglobin polymer content in RBCs for nine gene therapy trial subjects (BCLshmiR, median HbF% = 27.9) and compare them to 10 HU-treated subjects demonstrating high and comparable levels of HbF (HU High Responders, median HbF% = 27.0). All BCL11A patients achieved the primary endpoint for NCT 03282656, which was defined by an absolute neutrophil count greater than or equal to 0.5 × 109 cells/L for three consecutive days, achieved within 7 weeks following infusion. Flow cytometric assessment of single-RBC HbF and HbS shows fewer RBCs with high HbS% that would be most susceptible to sickling in BCLshmiR vs. HU High Responders: median 42% of RBCs with HbS%>70% in BCLshmiR vs. 61% in HU High Responders (p = 0.004). BCLshmiR subjects also demonstrate more RBCs resistant to HbS polymerization at lower physiologic oxygen tension: median 32% vs. 25% in HU High Responders (p = 0.006). Gene therapy-induced BCL11A down-regulation reverses the fetal-to-adult hemoglobin switch and induces RBCs with higher HbF%, lower HbS%, and greater resistance to deoxygenation-induced polymerization in clinical trial subjects compared with a cohort of highly responsive hydroxyurea-treated subjects. The authors report in full the primary endpoint data of a pilot clinical trial (NCT 03282656) that used post-transcriptional gene silencing of BCL11A expression to reverse the fetal to adult hemoglobin switch in sickle cell disease. They develop new single-cell flow cytometry and microfluidic techniques to predict the efficacy of HbF induction and show that red blood cells from these patients exhibit greater resistance to deoxygenation-induced polymerization than red blood cells from hydroxyurea-responsive patients. [ABSTRACT FROM AUTHOR]

The El Niño Southern Oscillation (ENSO) in the tropical Pacific Ocean is an important driver of winter precipitation variability over western North America as a whole, but ENSO exhibits a weak and inconsistent relationship with precipitation in several critically important headwaters including the upper Colorado River Basin. We present interactions between North Atlantic sea surface temperatures (SSTs) and ENSO that influence western U.S. precipitation, accounting for substantial variability in areas where ENSO alone yields limited guidance. Specifically, we performed a statistical analysis on hemispheric SSTs and western U.S. winter precipitation in a century of observations and a 10,000-year perpetual current-climate simulation. In both frameworks, the leading coupled pattern is ENSO, and the second pattern links an Atlantic Quadpole Mode (AQM) of SST variability to precipitation anomalies over most of the western U.S., including the transition zone where ENSO provides little predictability. The AQM SST anomalies are expansive in latitude, but its primary mechanism appears to involve a strengthening/shifting of the intertropical convergence zone (ITCZ) over northern South America and the tropical Atlantic. The ENSO pattern accounts for a larger fraction of the total covariance between SSTs and precipitation (65% versus 12% for the AQM pattern), but the percent anomalies of precipitation associated with ENSO and the AQM are comparable in magnitude, meaning 20% or larger over much of the western U.S. The interaction between ENSO and AQM influences precipitation across the western U.S., with cold AQM generally reducing precipitation irrespective of ENSO whereas warm AQM increases the amount of precipitation and the area of influence of ENSO; knowledge of these interactions can increase predictability of western U.S. precipitation. [ABSTRACT FROM AUTHOR]

Biosimilars have been available in the USA for over a decade, and in Europe for almost two decades. In that time, biosimilars have become established in the treatment landscape for a wide range of diseases, facilitating patient access and affordability of healthcare. However, patients can still struggle to access biological therapies in some markets. There is a need to streamline the process of developing biosimilars without compromising their quality, safety, or efficacy. This opinion piece considers the efficiencies that could be achieved within the biosimilar approval process. In clinical trials for biosimilars, clinical efficacy endpoints have been shown to be less sensitive measures of biosimilarity than biochemical, biophysical, and biological functional assays. Additional clinical efficacy studies comparing potential biosimilars and reference products do not add information that is useful for regulatory purposes. Large clinical studies of biosimilars with immunogenicity endpoints are of limited value, given the quality control processes in place for all biologics, including biosimilars. The expectation for multiple-switch studies for US interchangeability designation should be reconsidered immediately, and the category should be eliminated in the future. As biosimilars are typically approved globally based on a single set of clinical trials, and all subsequent manufacturing changes are already carefully monitored by regulatory authorities, comparative pharmacokinetic testing of EU and US reference products is unnecessary. Manufacturers and regulators could take greater advantage of existing real-world evidence. Streamlining biosimilar development would enable biosimilar development of more and a wider variety of biological drugs, accelerating biosimilar development without impacting patient safety or effectiveness. [ABSTRACT FROM AUTHOR]

Understanding the impact of SARS-CoV-2 infection and COVID-19 vaccination in pregnancy on neonatal and maternal outcomes informs clinical decision-making. Here we report a national, population-based, matched cohort study to investigate associations between SARS-CoV-2 infection and, separately, COVID-19 vaccination just before or during pregnancy and the risk of adverse neonatal and maternal outcomes among women in Scotland with a singleton pregnancy ending at ≥20 weeks gestation. Neonatal outcomes are stillbirth, neonatal death, extended perinatal mortality, preterm birth (overall, spontaneous, and provider-initiated), small-for-gestational age, and low Apgar score. Maternal outcomes are admission to critical care or death, venous thromboembolism, hypertensive disorders of pregnancy, and pregnancy-related bleeding. We use conditional logistic regression to derive odds ratios adjusted for socio-demographic and clinical characteristics (aORs). We find that infection is associated with an increased risk of preterm (aOR=1.36, 95% Confidence Interval [CI] = 1.16–1.59) and very preterm birth (aOR = 1.90, 95% CI 1.20–3.02), maternal admission to critical care or death (aOR=1.72, 95% CI = 1.39–2.12), and venous thromboembolism (aOR = 2.53, 95% CI = 1.47–4.35). We find no evidence of increased risk for any of our outcomes following vaccination. These data suggest SARS-CoV-2 infection during pregnancy is associated with adverse neonatal and maternal outcomes, and COVID-19 vaccination remains a safe way for pregnant women to protect themselves and their babies against infection. The impacts of SARS-CoV-2 infection and COVID-19 vaccination in pregnancy are not fully understood. Here, the authors perform a cohort study using data from Scotland and find that infection was associated with increased risk of preterm birth and some adverse maternal outcomes, but there was no evidence of adverse outcomes associated with vaccination. [ABSTRACT FROM AUTHOR]

Structure determination of amorphous materials remains challenging, owing to the disorder inherent to these materials. Nuclear magnetic resonance (NMR) powder crystallography is a powerful method to determine the structure of molecular solids, but disorder leads to a high degree of overlap between measured signals, and prevents the unambiguous identification of a single modeled periodic structure as representative of the whole material. Here, we determine the atomic-level ensemble structure of the amorphous form of the drug AZD4625 by combining solid-state NMR experiments with molecular dynamics (MD) simulations and machine-learned chemical shifts. By considering the combined shifts of all 1H and 13C atomic sites in the molecule, we determine the structure of the amorphous form by identifying an ensemble of local molecular environments that are in agreement with experiment. We then extract and analyze preferred conformations and intermolecular interactions in the amorphous sample in terms of the stabilization of the amorphous form of the drug. The atomic-level ensemble structure of an amorphous form of a drug is determined by combining NMR experiments with molecular dynamics simulations and machine-learned chemical shifts. The structure explains the stabilization of the amorphous form. [ABSTRACT FROM AUTHOR]

Tropical forests are being cleared at an accelerating rate, despite being one of the most important habitats for global biodiversity. Many remaining tropical forest tracts are now highly degraded and fragmented, which presents a major problem for sensitive and threatened forest-dwelling species that depend on this habitat for survival. In this study, we assessed the impacts of forest fragmentation, and its associated edge-effects, on tree species diversity, tree size, and structural diversity within the transitional forests of north west Madagascar. Using data collected from 9,619 trees within 200 vegetation plots, we calculated species diversity indices, a range of dendrometry measurements, and Shannon-Weaver diversity indices of structure, which we compared among core and edge areas of a continuous forest and a fragmented forest. We found that species diversity, tree size, and structural diversity was significantly reduced in fragmented forest, and within forest edge areas in comparison to core, continuous forest. We also observed species diversity and structural diversity to be strongly influenced by the total size, core area size, and shape of forest fragments. Whilst we found fragmentation and edge-effects to individually impact tree species diversity, size and structural diversity, fragmentation and edge-effects are strongly correlated and affect natural forest synergistically. Our results provide evidence that forest fragmentation seriously degrades habitat quality and integrity of transitional forests, which is of great concern for the threatened species that inhabit them. Urgent conservation efforts are needed to halt ongoing forest fragmentation throughout the tropics, and reforestation and restoration efforts are required to reconnect isolated forest patches and to reduce forest edge area. [ABSTRACT FROM AUTHOR]

A novel method aimed at evaluating the active drag profile during front-crawl swimming is proposed. Fourteen full trials were conducted with each trial using a stationary load cell set-up and a commercial resistance trainer to record the tension force in a rope, caused by an athlete swimming. Seven different stroke cycles in each experiment were identified for resampling time dependent data into position dependent data. Active drag was then calculated by subtracting resistance trainer force data away from the stationary load cell force data. Mean active drag values across the stroke cycle were calculated for comparison with existing methods, with mean active drag values calculated between 76 and 140 N depending on the trial. Comparing results with established active drag methods, such as the Velocity Perturbation Method (VPM), shows agreement in the magnitude of the mean active drag forces. Repeatability was investigated using one athlete, repeating the load cell set-up experiment, indicating results collected could range by 88 N depending on stroke cycle position. Variation in results is likely due to inconsistencies in swimmer technique and power output, although further investigation is required. The method outlined is proposed as a representation of the active drag profile over a full stroke cycle. [ABSTRACT FROM AUTHOR]

Subgroups of children with different speech profiles have been described however, little is known about the trajectories of speech development or stability of subgroups over time. This longitudinal study described both speech trajectories and subgroup stability of 22 autistic children, aged 2;0–6;11 years, over 12 months. Independent and relational speech analyses, vocabulary size and nonverbal communication were used in clustering. Results suggest varied speech trajectories, particularly for children with 'low language and low speech' at Time 1. Receptive vocabulary and consonant inventory at Time 1 may predict speech outcomes after 12 months. A small subgroup of children (n = 3) present with low expressive vocabulary and speech but higher receptive vocabulary and use of gestures. This unique profile remained stable. [ABSTRACT FROM AUTHOR]

Purpose: To examine the relationship between deployment-related concussion and long-term health-related quality of life (HRQoL) among injured US military personnel. Methods: The study sample included 810 service members with deployment-related injuries between 2008 and 2012 who responded to a web-based longitudinal health survey. Participants were categorized into three injury groups: concussion with loss of consciousness (LOC; n = 247), concussion without LOC (n = 317), or no concussion (n = 246). HRQoL was measured using the 36-Item Short Form Health Survey physical and mental component summary (PCS and MCS) scores. Current post-traumatic stress disorder (PTSD) and depression symptoms were examined. Multivariable linear regression models assessed the effects of concussion on PCS and MCS scores, while controlling for covariates. Results: A lower PCS score was observed in participants with concussion with LOC (B = − 2.65, p = 0.003) compared with those with no history of concussion. Symptoms of PTSD (PCS: B = − 4.84, p < 0.001; MCS: B = − 10.53, p < 0.001) and depression (PCS: B = − 2.85, p < 0.001; MCS: B = − 10.24, p < 0.001) were the strongest statistically significant predictors of lower HRQoL. Conclusion: Concussion with LOC was significantly associated with lower HRQoL in the physical domain. These findings affirm that concussion management should integrate physical and psychological care to improve long-term HRQoL and warrant a more detailed examination of causal and mediating mechanisms. Future research should continue to incorporate patient-reported outcomes and long-term follow-up of military service members to further define the lifelong impact of deployment-related concussion. [ABSTRACT FROM AUTHOR]

Background and Objectives: Ocedurenone (KBP-5074) is a novel nonsteroidal mineralocorticoid receptor antagonist that has demonstrated safety and efficacy in clinical trials in patients with uncontrolled hypertension and stage 3b/4 chronic kidney disease. This study evaluated the involvement of cytochrome P450 (CYP) isozymes and drug transporters in the biotransformation of ocedurenone, and whether ocedurenone inhibited or induced CYP enzymes and transporters. Clinical pharmacokinetic drug–drug interaction (DDI) of ocedurenone with CYP3A inhibitor and inducer were investigated in healthy volunteers. Methods: In vitro tests were conducted to determine which CYP enzymes were involved in ocedurenone's metabolism and whether ocedurenone inhibited or induced these CYP enzymes; ocedurenone substrate characteristics for efflux and uptake transporters and its inhibitory potential on major drug transporters were also assessed. A clinical DDI study was conducted in healthy volunteers to evaluate the effects of a strong CYP3A inhibitor (itraconazole) and inducer (rifampin) on ocedurenone's pharmacokinetics. Results: The in vitro study showed that ocedurenone was primarily metabolized by CYP3A4 and that it did not inhibit CYP enzymes. Ocedurenone appeared to be a substrate of BCRP and P-gp efflux transporters and inhibited BCRP, BSEP, MDR1, MATE1 and 2-K, OATP1B1/3, and OCT1. The clinical DDI study showed that itraconazole reduced ocedurenone's oral clearance by 51% and increased area under the plasma concentration–time curve extrapolated to infinity (AUC0–inf) by 104%, while rifampin increased its oral clearance by 6.4-fold and decreased plasma AUC0–inf by 84%. Conclusion: Ocedurenone was shown to be a CYP3A substrate, with no inhibition potential on major drug metabolizing CYP enzymes and transporters at clinical efficacious doses. Ocedurenone did not induce CYP1A2 and 3A4 activity in cultured human primary hepatocytes. Clinical DDI study indicated ocedurenone was well tolerated when administered as a single 0.5-mg dose both alone and with itraconazole or rifampin, and while itraconazole had a weak effect on ocedurenone's pharmacokinetics, rifampin had a significant effect reducing systemic exposures. [ABSTRACT FROM AUTHOR]

Worry is a transdiagnostic characteristic across many mental health disorders and given the increased interest and recognized importance of measurement-based care and progress monitoring for mental health treatment, there is a need for psychometrically sound questionnaires that can track weekly progress. The Penn State Worry Questionnaire-Past Week (PSWQ-PW; Stöber & Bittencourt Behaviour Research and Therapy,36(6), 645–656, 1998) was developed to be sensitive to the assessment of short-term changes in worry severity. This study examined the psychometric properties and treatment sensitivity of the PSWQ-PW in a sample of 370 outpatients with anxiety and related disorders. An exploratory factor analysis indicated that the PSWQ-PW has a one-factor structure measuring the unidimensional construct of worry. The PSWQ-PW demonstrated strong reliability and good convergent validity. However, the PSWQ-PW had poor discriminant validity with a measure of depression and stress, which may be explained by the distinct but related nature of these constructs. Additionally, the PSWQ-PW did not have strong diagnostic potential in identifying individuals with Generalized Anxiety Disorder (GAD) from a heterogeneous clinical sample, likely because of the transdiagnostic nature of worry and the state nature of the measure. Finally, the PSWQ-PW demonstrated strong treatment sensitivity (d = 0.85) when measured weekly across a 12-week cognitive behavioural therapy for GAD protocol. These findings suggest that the PSWQ-PW is a reliable and valid way to track changes in worry severity week-to-week to monitor patient progress throughout treatment. However, it should not be used as a diagnostic or screening measure to distinguish patients with GAD from those with other anxiety and related disorders. [ABSTRACT FROM AUTHOR]

Primate encounter rates often vary throughout the year due to seasonal differences in activity, ecology, and behaviour. One notably extreme behaviour is continuous hibernation. Although a rare adaptation in primates, the dwarf lemurs of Madagascar (genus Cheirogaleus) enter obligate hibernation each year during the dry season, after spending the wet season consuming high-energy foods. Whilst seasonal changes in activity in some Cheirogaleus populations are well-known, many species remain little-studied, and there is no specific information on their encounter rates, nor when they enter and emerge from hibernation. This uncertainty critically affects reliable calculation of population density estimates for these highly threatened lemurs. In this study, we assessed how encounter rates of the fat-tailed dwarf lemur (C. medius) vary seasonally in the transitional forests of the Sahamalaza-Iles Radama National Park, northwest Madagascar, during a 4-year period. We established a system of line transects (N = 60) throughout our study area, on which we conducted distance sampling of C. medius. We then used our distance sampling data to calculate encounter rate and population density data. We found encounter rates of C. medius to be significantly higher during the wet season compared with the dry season. Furthermore, encounter rates of C. medius were particularly low from May–August. These results provide some evidence to suggest the time period that C. medius hibernate in Sahamalaza-Iles Radama National Park. These findings underpin the importance of careful study design when surveying threatened species with seasonal differences in activity, such as those that hibernate. This study also demonstrates the importance of species-specific behavioural data for accurate population density assessment, which is required to inform conservation action. [ABSTRACT FROM AUTHOR]

Extinct lineages of Yersinia pestis, the causative agent of the plague, have been identified in several individuals from Eurasia between 5000 and 2500 years before present (BP). One of these, termed the 'LNBA lineage' (Late Neolithic and Bronze Age), has been suggested to have spread into Europe with human groups expanding from the Eurasian steppe. Here, we show that the LNBA plague was spread to Europe's northwestern periphery by sequencing three Yersinia pestis genomes from Britain, all dating to ~4000 cal BP. Two individuals were from an unusual mass burial context in Charterhouse Warren, Somerset, and one individual was from a single burial under a ring cairn monument in Levens, Cumbria. To our knowledge, this represents the earliest evidence of LNBA plague in Britain documented to date. All three British Yersinia pestis genomes belong to a sublineage previously observed in Bronze Age individuals from Central Europe that had lost the putative virulence factor yapC. This sublineage is later found in Eastern Asia ~3200 cal BP. While the severity of the disease is currently unclear, the wide geographic distribution within a few centuries suggests substantial transmissibility. An extinct prehistoric plague lineage of Yersinia pestis has been documented from Central Europe to Asia during the Late Neolithic and Bronze Age. Here, Swali et al. show that this lineage spread to Europe's northwestern periphery by sequencing three ~4000 year-old Yersinia pestis genomes from Britain. [ABSTRACT FROM AUTHOR]