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Environmental DNA (eDNA) includes a set of rapidly emerging technologies that have the potential to support environmental monitoring and biodiversity conservation through novel, non-invasive, cost-effective and democratic methods and tools. Meanwhile, eDNA researchers are developing international standards for eDNA technologies, methods and data outputs. For eDNA technologies to be accessible, useful and appropriate, we must ensure that any standards developed include a broad conception of users from around the world, a diversity of ecological contexts and locations and, most importantly, a realistic outlook on research capacities and infrastructure. In this article, we assemble perspectives on international standardisation of eDNA from a diverse and global group of users and experts from Africa, South America and the Pacific Islands. The authors of this article collaborated by answering and discussing a set of open-ended questions aimed at eliciting hopes, concerns and experiences regarding eDNA standards. The result is a set of emergent themes and a generative consensus to highlight the need for the creation of adaptable standards, the development of regional capacity, increased sensitising to data sovereignty and the viewing of standardisation as a global capacity-building activity.

OBJECTIVES:. Anemia has been associated with an increased risk of both cardiac arrest and stroke, frequent complications of COVID-19. The effect of hemoglobin level at ICU admission on a composite outcome of cardiac arrest or stroke in an international cohort of COVID-19 patients was investigated. DESIGN:. Retrospective analysis of prospectively collected database. SETTING:. A registry of COVID-19 patients admitted to ICUs at over 370 international sites was reviewed for patients diagnosed with cardiac arrest or stroke up to 30 days after ICU admission. Anemia was defined as: normal (hemoglobin ≥ 12.0 g/dL for women, ≥ 13.5 g/dL for men), mild (hemoglobin 10.0–11.9 g/dL for women, 10.0–13.4 g/dL for men), moderate (hemoglobin ≥ 8.0 and < 10.0 g/dL for women and men), and severe (hemoglobin < 8.0 g/dL for women and men). PATIENTS:. Patients older than 18 years with acute COVID-19 infection in the ICU. INTERVENTIONS:. None. MEASUREMENTS AND MAIN RESULTS:. Of 6926 patients (median age = 59 yr, male = 65%), 760 patients (11.0%) experienced stroke (2.0%) and/or cardiac arrest (9.4%). Cardiac arrest or stroke was more common in patients with low hemoglobin, occurring in 12.8% of patients with normal hemoglobin, 13.3% of patients with mild anemia, and 16.7% of patients with moderate/severe anemia. Time to stroke or cardiac arrest by anemia status was analyzed using Cox proportional hazards regression with death as a competing risk. Covariates selected through clinical knowledge were age, sex, comorbidities (diabetes, hypertension, obesity, and cardiac or neurologic conditions), pandemic era, country income, mechanical ventilation, and extracorporeal membrane oxygenation. Moderate/severe anemia was associated with a higher risk of cardiac arrest or stroke (hazard ratio, 1.32; 95% CI, 1.05–1.67). CONCLUSIONS:. In an international registry of ICU patients with COVID-19, moderate/severe anemia was associated with increased hazard of cardiac arrest or stroke.

Abstract Propylene glycol (PG) is a diol (a double alcohol) that is commonly used as a food additive to preserve shelf life and enhance flavors, texture, and appearance. Although PG makes up only a small percentage of cornstarch, ingestion of large doses can cause lactic acidosis leading to hyperosmolarity, high anion gap metabolic acidosis (HAGMA), and a sepsis‐like syndrome. A 17‐year‐old female presented to our emergency department (ED) with chronic chest pain, dyspnea, nausea, and vomiting. Laboratory testing showed an elevated anion gap of 18 mEq/L with no osmolar gap. Toxicology screening was negative. Twelve hours after ED arrival, she admitted to consuming one box of cornstarch daily for the past 6 months. She was admitted to the intensive care unit (ICU) with multisystem organ failure due to propylene glycol toxicity. After empiric treatment with fomepizole and continuous renal replacement therapy, her clinical status gradually improved. This case highlights the importance of obtaining a thorough dietary history in patients with suspected toxicities, especially when laboratory values demonstrate an unexplained HAGMA and/or lactic acidosis. Prompt recognition and therapeutic intervention with fomepizole, a potent inhibitor of alcohol dehydrogenase, is essential in reducing life‐threatening sequelae following toxic alcohol ingestions.

Abstract We present a wisdom of crowds study where participants are asked to order a small set of images based on the number of dots they contain and then to guess the respective number of dots in each image. We test two input elicitation interfaces—one elicits the two modalities of estimates jointly and the other independently. We show that the latter interface yields higher quality estimates, even though the multimodal estimates tend to be more self-contradictory. The inputs are aggregated via optimization and voting-rule based methods to estimate the true ordering of a larger universal set of images. We demonstrate that the quality of collective estimates from the simpler yet more computationally-efficient voting methods is comparable to that achieved by the more complex optimization model. Lastly, we find that using multiple modalities of estimates from one group yields better collective estimates compared to mixing numerical estimates from one group with the ordinal estimates from a different group.

Virtual Reality (VR) is increasingly used in neuropsychological assessments due to its ability to simulate real-world environments. This study aimed to develop and evaluate the Trail Making Test in VR (TMT-VR) and investigate the effects of different interaction modes and gaming skills on cognitive performance. A total of 71 young female and male adults (aged 18–35) with high and low gaming skills participated in this study. Participants completed the TMT-VR using three interaction modes as follows: eye-tracking, head movement, and controller. Performance metrics included task completion time and accuracy. User experience, usability, and acceptability of TMT-VR were also examined. Results showed that both eye tracking and head movement modes significantly outperformed the controller in terms of task completion time and accuracy. No significant differences were found between eye tracking and head movement modes. Gaming skills did not significantly influence task performance using any interaction mode. The TMT-VR demonstrates high usability, acceptability, and user experience among participants. The findings suggest that VR-based assessments can effectively measure cognitive performance without being influenced by prior gaming skills, indicating potential applicability for diverse populations.

By assuming a type of balance for length ℓ=87\ell =87 and nontrivial subgroups of multiplier groups of Legendre pairs (LPs) for length ℓ=85\ell =85, we find LPs of these lengths. We then study the power spectral density (PSD) values of mm compressions of LPs of length 5m5m. We also formulate a conjecture for LPs of lengths ℓ≡0\ell \equiv 0 (mod 5) and demonstrate how it can be used to decrease the search space and storage requirements for finding such LPs. The newly found LPs decrease the number of integers in the range ≤200\le 200 for which the existence question of LPs remains unsolved from 12 to 10.

Abstract Background Half of child-welfare-involved children and adolescents meet the criteria for at least one mental health diagnosis. This project proposes to improve successful mental health service linkage in child welfare services (CWS) by adapting and testing the after-action review (AAR) team effectiveness intervention to augment the child and family team (CFT) services’ intervention. Despite being both required and a collaborative approach to service planning, CFT meetings are implemented with questionable fidelity and consistency, rarely including the voice of children and families as intended. Methods Using a parallel group trial design, with non-equivalent comparison groups, and qualitative and quantitative methodology, this study will tailor and assess the impact of the AAR on enhancing CFT outcomes. The authors will conduct a qualitative needs assessment targeting the ongoing implementation of the CFT services intervention in a large, publicly funded, CWS system. A qualitative inquiry consisting of interviews and focus groups with key stakeholders will result in the preparation of an action plan to address identified gaps between the current and desired CFT services intervention outcomes. The AAR implementation strategy will be adapted and tailored to address the CFT services’ intervention needs. To test the effectiveness of the AAR on improving outcomes associated with the CFT services intervention, we will utilize blocked randomization of four CWS caseworkers from two CWS system regions to either the intervention condition (CFT + AAR) or standard implementation (CFT as usual). The authors will collect data from the CWS caseworkers and additional CFT members via web-based surveys. Mechanisms of the AAR team effectiveness intervention for CFT implementation will be assessed. Discussion By inclusion of child and family voice, the AAR-enhanced CFT should lead to increased fidelity to the CFT intervention and greater levels of parental satisfaction with the service and shared decision-making, thus resulting in enhanced follow-through with service plans and linkage to mental health treatment services for children. The knowledge gained by this randomized clinical trial has the potential to benefit service delivery and integration for CWS leaders, caseworkers, formal and informal CFT member support persons, parents/caregivers, and children with open cases. Improving intervention effectiveness, both at the system and family levels, is crucial for practice efficiencies and improved child and family outcomes. Trial registration NCT05629013. Approval date: November 28, 2022 (version 1). Trial sponsor University of California, San Diego. Responsible party Danielle Fettes.

Abstract We address the nonperturbative calculation of the inclusive decay rate of semileptonic B (s)-meson decays from lattice QCD. Precise Standard-Model predictions are key ingredients in searches for new physics, and this type of computation may eventually provide new insight into the long-standing tension between the inclusive and exclusive determinations of the Cabibbo-Kobayashi-Maskawa (CKM) matrix elements |V cb | and |V ub |. We present results from a pilot lattice computation for B s → X c lν l , where the initial b quark described by the relativistic-heavy-quark (RHQ) formalism on the lattice and the other valence quarks discretised with domain-wall fermions are simulated approximately at their physical quark masses. We compare two different methods for computing the decay rate from lattice data of Euclidean n-point functions, namely Chebyshev and Backus-Gilbert approaches. We further study how much the ground-state meson dominates the inclusive decay rate and indicate our strategy towards a computation with a more comprehensive systematic error budget.

Abstract Introduction Resection of the mandible and temporomandibular joint (TMJ) without formal reconstruction is a devastating condition that negatively affects all aspects of the patient’s life. We have approached the reconstruction of mandibular defects that include the condyle with simultaneous reconstruction with a vascularized free fibular flap (FFF) using Surgical Design and Simulation (SDS) and alloplastic TMJ prosthesis. The objective of this study is to report the functional and quality of life (QOL) outcomes in a cohort of patients that had undergone our reconstructive protocol. Methods This was a prospective case series of adult patients that underwent mandibular reconstruction with FFF and alloplastic TMJ prosthesis at the our center. Pre-operative and post-operative maximum inter-incisal opening (MIO) measurements were collected, and patients completed a QOL questionnaire (EORTC QLQ—H&N35) during those perioperative visits. Results Six patients were included in the study. The median patient age was 53 years. Heat map analysis of the QOL questionnaire revealed that patients reported a positive clinically significant change in the domains of pain, teeth, mouth opening, dry mouth, sticky saliva, and senses (relative change of 2.0, 3.3, 3.3, 2.0, 2.0, and 1.0 respectively). There were no negative clinically significant changes. There was a median perioperative MIO increase of 15.0 mm, and this was statistically significant (p = 0.027). Conclusions This study highlights the complexities involved in mandibular reconstruction with involvement of the TMJ. Based on our findings, patients can obtain an acceptable QOL and good function following simultaneous reconstruction with FFF employing SDS and an alloplastic TMJ prosthesis. Graphical Abstract

Abstract Hoplodactylus delcourti is a presumably extinct species of diplodactylid gecko known only from a single specimen of unknown provenance. It is by far the largest known gekkotan, approximately 50% longer than the next largest-known species. It has been considered a member of the New Zealand endemic genus Hoplodactylus based on external morphological features including shared toe pad structure. We obtained DNA from a bone sample of the only known specimen to generate high-throughput sequence data suitable for phylogenetic analysis of its evolutionary history. Complementary sequence data were obtained from a broad sample of diplodactylid geckos. Our results indicate that the species is not most closely related to extant Hoplodactylus or any other New Zealand gecko. Instead, it is a member of a clade whose living species are endemic to New Caledonia. Phylogenetic comparative analyses indicate that the New Caledonian diplodactylid clade has evolved significantly more disparate body sizes than either the Australian or New Zealand clades. Toe pad structure has changed repeatedly across diplodactylids, including multiple times in the New Caledonia clade, partially explaining the convergence in form between H. delcourti and New Zealand Hoplodactylus. Based on the phylogenetic results, we place H. delcourti in a new genus.

Die dringende Transformation unseres Energiesystems hin zu einer nachhaltigen Infrastruktur der Daseinsvorsorge scheitert in der regionalen Umsetzung regelmäßig an raumbezogenen und gesellschaftlichen Anforderungen des ländlichen Raums. In diesem Beitrag werden am Beispiel eines transdisziplinären Projektes Dilemmata in der partizipativen Umsetzung der regionalen Energiewende identifiziert und Gelingensbedingungen einer raumsensiblen Energiewende-Governance formuliert. Wie mit dem entwickelten Governance-Ansatz zur „Co-Transformation“ gezeigt wird, können kontextsensitive Partizipationsformen der Co-Regulierung, Co-Allokation und Co-Visionierung zur Verfahrens‑, Verteilungs- sowie Zukunftsgerechtigkeit und damit zur Akzeptabilität der regionalen Energiewende als Daseinsvorsorgeinfrastruktur im ländlichen Raum beitragen. Zentrale Maßnahmenfelder sind dabei ergebnisoffene und regional angepasste Formen der Mitwirkung durch die Co-Regulierung im Planungsprozess, Ansätze zur räumlichen Co-Allokation energiewendebezogener Belastungen und lokaler Mehrwerte sowie die Co-Visionierung regionaler Energiezukünfte und daraus abzuleitender regionaler Energievisionen.

Twitter (recently renamed X) is used by academic anesthesiology departments as a social media platform for various purposes. We hypothesized that Twitter (X) use would be prevalent among academic anesthesiology departments and that the number of tweets would vary by region, physician faculty size, and National Institutes of Health (NIH) research funding rank. We performed a descriptive study of Twitter (X) use by academic anesthesiology departments (i.e. those with a residency program) in 2022. Original tweets were collected using a Twitter (X) analytics tool. Summary statistics were reported for tweet number and content. The median number of tweets was compared after stratifying by region, physician faculty size, and NIH funding rank. Among 166 academic anesthesiology departments, there were 73 (44.0%) that had a Twitter (X) account in 2022. There were 3,578 original tweets during the study period and the median number of tweets per department was 21 (25th-75th = 0, 75) with most tweets (55.8%) announcing general departmental news and a smaller number highlighting social events (12.5%), research (11.1%), recruiting (7.1%), DEI activities (5.2%), and trainee experiences (4.1%). There was no significant difference in the median number of tweets by region (P = 0.81). The median number of tweets differed significantly by physician faculty size (P

Pulmonary artery pseudoaneurysms (PAPs) are rare and life-threatening occurrences. We present a 57-year-old male patient with squamous cell lung cancer, who presented with hemoptysis. Bronchoscopy did not reveal ongoing bleeding. Imaging showed a left lower lobe tumor, a cavitary lesion communicating with the bronchus, and a pulmonary artery pseudoaneurysm. Successful embolization of the originating segmental branch of the pulmonary artery was performed. The pathogenesis of PAPs associated with primary lung malignancies remains poorly understood. We propose a four-step mechanism involving primary tumor expansion, central cavitary necrosis, direct arterial invasion, inflammatory response, vessel wall damage, pseudoaneurysm formation, and subsequent filling of the former cavitary lesion. This case emphasizes the importance of considering PAPs in primary lung malignancies, particularly in male patients with squamous cell pathology. Understanding the proposed pathogenic mechanism could lead to early detection, prompt intervention, and improved outcomes.

Candida albicans is the most prevalent and notorious of the Candida species involved in bloodstream infections, which is characterised by its capacity to form robust biofilms. Biofilm formation is an important clinical entity shown to be highly variable among clinical isolates. There are various environmental and physiological factors, including nutrient availability which influence the phenotype of Candida species. However, mechanisms underpinning adaptive biofilm heterogeneity have not yet been fully explored.Within this study we have profiled previously characterised and phenotypically distinct C. albicans bloodstream isolates. We assessed the dynamic susceptibility of these differing populations to antifungal treatments using population analysis profiling in addition to assessing biofilm formation and morphological changes. High throughput methodologies of RNA-Seq and LC-MS were employed to map and integrate the transcriptional and metabolic reprogramming undertaken by heterogenous C. albicans isolates in response to biofilm and hyphal inducing serum.We found a significant relationship between biofilm heterogeneity and azole resistance (P

Bacterial vaginosis (BV) affects approximately 26% of women of childbearing age globally, presenting with 3–5 times increased risk of miscarriage and two-fold risk of pre-term birth. Antibiotics (metronidazole and clindamycin) are typically employed to treat BV; however the success rate is low due to the formation of recalcitrant polymicrobial biofilms. As a novel therapeutic, promising results have been obtained in vitro using Gardnerella endolysins, although to date their efficacy has only been demonstrated against simple biofilm models.In this study, a four-species biofilm was developed consisting of Gardnerella vaginalis, Fannyhessea vaginae, Prevotella bivia and Mobiluncus curtisii. Biofilms were grown in NYC III broth and treated using antibiotics and an anti-Gardnerella endolysin (CCB7.1) for 24 h. Biofilm composition, viability and structure were assessed using colony counts, live/dead qPCR and scanning electron microscopy.All species colonised biofilms to varying degrees, with G. vaginalis being the most abundant. Biofilm composition remained largely unchanged when challenged with escalated concentrations of conventional antibiotics. A Gardnerella-targeted endolysin candidate (CCB7.1) showed efficacy against several Gardnerella species planktonically, and significantly reduced viable G. vaginalis within polymicrobial biofilms at 1 to 4X pMIC (p

Abstract Machine learning has been applied in recent years to categorize sleep stages (NREM, REM, and wake) using electroencephalogram (EEG) recordings; however, a well-validated sleep scoring automatic pipeline in rodent research is still not publicly available. Here, we present IntelliSleepScorer, a software package with a graphic user interface to score sleep stages automatically in mice. IntelliSleepScorer uses the light gradient boosting machine (LightGBM) to score sleep stages for each epoch of recordings. We developed LightGBM models using a large cohort of data, which consisted of 5776 h of sleep EEG and electromyogram (EMG) signals across 519 unique recordings from 124 mice. The LightGBM model achieved an overall accuracy of 95.2% and a Cohen’s kappa of 0.91, which outperforms the baseline models such as the logistic regression model (accuracy = 93.3%, kappa = 0.88) and the random forest model (accuracy = 94.3%, kappa = 0.89). The overall performance of the LightGBM model as well as the performance across different sleep stages are on par with that of the human experts. Most importantly, we validated the generalizability of the LightGBM models: (1) The LightGBM model performed well on two publicly available, independent datasets (kappa > = 0.80), which have different sampling frequency and epoch lengths; (2) The LightGBM model performed well on data recorded at a lower sampling frequency (kappa = 0.90); (3) The performance of the LightGBM model is not affected by the light/dark cycle; and (4) A modified LightGBM model performed well on data containing only one EEG and one EMG electrode (kappa > = 0.89). Taken together, the LightGBM models offer state-of-the-art performance for automatic sleep stage scoring in mice. Last, we implemented the IntelliSleepScorer software package based on the validated model to provide an out-of-box solution to sleep researchers (available for download at https://sites.broadinstitute.org/pan-lab/resources ).

Background Cascade testing the relatives of people with familial hypercholesterolaemia is an efficient approach to identifying familial hypercholesterolaemia. The cascade-testing protocol starts with identifying an index patient with familial hypercholesterolaemia, followed by one of three approaches to contact other relatives: indirect approach, whereby index patients contact their relatives; direct approach, whereby the specialist contacts the relatives; or a combination of both direct and indirect approaches. However, it is unclear which protocol may be most effective. Objectives The objectives were to determine the yield of cases from different cascade-testing protocols, treatment patterns, and short- and long-term outcomes for people with familial hypercholesterolaemia; to evaluate the cost-effectiveness of alternative protocols for familial hypercholesterolaemia cascade testing; and to qualitatively assess the acceptability of different cascade-testing protocols to individuals and families with familial hypercholesterolaemia, and to health-care providers. Design and methods This study comprised systematic reviews and analysis of three data sets: PASS (PASS Software, Rijswijk, the Netherlands) hospital familial hypercholesterolaemia databases, the Clinical Practice Research Datalink (CPRD)–Hospital Episode Statistics (HES) linked primary–secondary care data set, and a specialist familial hypercholesterolaemia register. Cost-effectiveness modelling, incorporating preceding analyses, was undertaken. Acceptability was examined in interviews with patients, relatives and health-care professionals. Result Systematic review of protocols: based on data from 4 of the 24 studies, the combined approach led to a slightly higher yield of relatives tested [40%, 95% confidence interval (CI) 37% to 42%] than the direct (33%, 95% CI 28% to 39%) or indirect approaches alone (34%, 95% CI 30% to 37%). The PASS databases identified that those contacted directly were more likely to complete cascade testing (p

Abstract Approximately 20 TP53 retrogenes exist in the African and Asian elephant genomes (Loxodonta Africana, Elephas Maximus) in addition to a conserved TP53 gene that encodes a full-length protein. Elephant TP53-RETROGENE 9 (TP53-R9) encodes a p53 protein (p53-R9) that is truncated in the middle of the canonical DNA binding domain. This C-terminally truncated p53 retrogene protein lacks the nuclear localization signals and oligomerization domain of its full-length counterpart. When expressed in human osteosarcoma cells (U2OS), p53-R9 binds to Tid1, the chaperone protein responsible for mitochondrial translocation of human p53 in response to cellular stress. Tid1 expression is required for p53-R9-induced apoptosis. At the mitochondria, p53-R9 binds to the pro-apoptotic BCL-2 family member Bax, which leads to caspase activation, cytochrome c release, and cell death. Our data show, for the first time, that expression of this truncated elephant p53 retrogene protein induces apoptosis in human cancer cells. Understanding the molecular mechanism by which the additional elephant TP53 retrogenes function may provide evolutionary insight that can be utilized for the development of therapeutics to treat human cancers.

ABSTRACTThe FAIR principles of Wilkinson et al. [1] are finding their way from research into application domains, one of which is the precise positioning with global satellite navigation systems (GNSS). Current GNSS users demand that data and services are findable online, accessible via open protocols (by both, machines and humans), interoperable with their legacy systems and reusable in various settings. Comprehensive metadata are essential in seamless communication between GNSS data and service providers and their users, and, for decades, geodetic and geospatial standards are efficiently implemented to support this. However, GNSS user community is transforming from precise positioning by highly specialised use by geodetic professionals to every-day precise positioning by autonomous vehicles or wellness obsessed citizens. Moreover, rapid technological developments allow alternative ways of offering data and services to their users. These transforming circumstances warrant a review whether metadata defined in generic geospatial and geodetic standards in use still support FAIR use of modern GNSS data and services across its novel user spectrum. This paper reports the results of current GNSS users’ requirements in various application sectors on the way data, metadata and services are provided. We engaged with GNSS stakeholders to validate our findings and to gain understanding on their perception of the FAIR principles. Our results confirm that offering FAIR GNSS data and services is fundamental, but for a confident use of these, there is a need to review the way metadata are offered to the community. Defining standard compliant GNSS community metadata profile and providing relevant metadata with data on-demand, the approach outlined in this paper, is a way to manage current GNSS users’ expectations and the way to improve FAIR GNSS data and service delivery for both humans and the machines.

Summary: The management of advanced basal cell carcinoma (BCC) can be challenging and often involves a multi-disciplinary approach with dermatologists, plastic surgeons, and oncologists. Standard therapy for advanced BCCs has historically involved prompt excision and radiation; however, in recent years, management strategies utilizing hedgehog pathway inhibitors as neoadjuvant therapy have gained popularity. While controversy regarding management recommendations still exists, we present a case of advanced BCC with cranial involvement in an immunocompromised patient where the use of neoadjuvant vismodegib led to a favorable outcome and, surprisingly, complete the pathologic clearance of the tumor.

Abstract Background In response to the US opioid epidemic, significant national campaigns have been launched to expand access to `opioid use disorder (MOUD). While adoption has increased in general medical care settings, specialty addiction programs have lagged in both reach and adoption. Elevating the quality of implementation strategy, research requires more precise methods in tailoring strategies rather than a one-size-fits-all-approach, documenting participant engagement and fidelity to the delivery of the strategy, and conducting an economic analysis to inform decision making and policy. Research has yet to incorporate all three of these recommendations to address the challenges of implementing and sustaining MOUD in specialty addiction programs. Methods This project seeks to recruit 72 specialty addiction programs in partnership with the Washington State Health Care Authority and employs a measurement-based stepped implementation-to-target approach within an adaptive trial design. Programs will be exposed to a sequence of implementation strategies of increasing intensity and cost: (1) enhanced monitoring and feedback (EMF), (2) 2-day workshop, and then, if outcome targets are not achieved, randomization to either internal facilitation or external facilitation. The study has three aims: (1) evaluate the sequential impact of implementation strategies on target outcomes, (2) examine contextual moderators and mediators of outcomes in response to the strategies, and (3) document and model costs per implementation strategy. Target outcomes are organized by the RE-AIM framework and the Addiction Care Cascade. Discussion This implementation project includes elements of a sequential multiple assignment randomized trial (SMART) design and a criterion-based design. An innovative and efficient approach, participating programs only receive the implementation strategies they need to achieve target outcomes. Findings have the potential to inform implementation research and provide key decision-makers with evidence on how to address the opioid epidemic at a systems level. Trial registration This trial was registered at ClinicalTrials.gov (NCT05343793) on April 25, 2022.

Summary: Early retirement of coal-fired power is essential for remaining in line with the 2°C target set in the Paris Agreement. Plant age plays the major role in designing retirement pathways, however, this overlooks the economic and health costs associated with coal-fired power. We introduce multi-dimensional retirement schedules that account for age, operating cost, and air pollution hazards. Results show that regional retirement pathways vary substantially with different weighting schemes. Schedules based on age would retire capacity mostly in the US and EU, whereas those based on cost or air pollution would shift the majority of near-term retirements to China and India, respectively. Our approach emphasizes that a “one-size-fits-all” strategy is ineffective in addressing global phase-out pathways. It provides the opportunity for devising region-specific pathways that are sound to the local context. Our results involve emerging economies and highlight incentives for early retirement that surpass climate change mitigation and address regional priorities.

Food production in much of the world relies on groundwater resources. In many regions, groundwater levels are declining due to a combination of anthropogenic extraction, localized meteorological and geological characteristics, and climate change. Groundwater in India is characteristic of this global trend, with an agricultural sector that is highly dependent on groundwater and increasingly threatened by extraction far in excess of recharge. The complexity of inputs makes groundwater depletion highly heterogeneous across space and time. However, modeling this heterogeneity has thus far proven difficult. Using two ensemble tree-based regression models, we predict district level seasonal groundwater dynamics to an accuracy of R ^2 = 0.4–0.6 and Pearson correlations between 0.6 and 0.8. Further using two high-resolution feature importance methods, we demonstrate that atmospheric humidity, groundwater groundwater-based irrigation, and crop cultivation are the most important predictors of seasonal groundwater dynamics at the district level in India. We further demonstrate a shift in the predictors of groundwater depletion over 1998–2014 that is robustly found between the two feature importance methods, namely increasing importance of deep-well irrigation in Central and Eastern India. These areas coincide with districts where groundwater depletion is most severe. Further analysis shows decreases in crop yields per unit of irrigation over those regions, suggesting decreasing marginal returns for largely increasing quantities of groundwater irrigation used. This analysis demonstrates the public policy value of machine learning models for providing high spatiotemporal accuracy in predicting groundwater depletion, while also highlighting how anthropogenic activity impacts groundwater in India, with consequent implications for productivity and well-being.

Abstract POEMS syndrome is a rareparaneoplastic disorder driven by an underlying low level plasma cell dyscrasiaand associated with elevated serum vascular endothelial growth factor (VEGF). Dueto its rarity, there are no internationally agreed standards of care, with verylimited data to guide management in the relapse setting. Agents used in myelomaare rational choices and have been employed. Daratumumab has been reported intwo case studies with lenalidomide‐dexamethasone, one in the upfront and one inthe relapsed setting. We are the first to report here three cases ofdaratumumab‐bortezomib‐dexamethasone (DVd) use in relapsed POEMS postautologous stem cell transplant with good VEGF and clinical responses. Our casesadd to the literature on efficacy of daratumumab and are the first to report onits safe use with bortezomib in relapsed POEMS. It should be considered as aclinical option, in patients not responding to conventional first linetherapies.

Abstract Background ME/CFS is a disorder characterized by recurrent fatigue and intolerance to exertion which manifests as profound post-exertional malaise. Prevalence studies internationally have reported highly variable results due to the 20 + diagnostic criteria. For Australia, the prevalence of ME/CFS based on current case definitions is unknown. Objectives To report prevalence of ME/CFS in patients aged ≥ 13 years attending Australian primary care settings for years 2015–2019, and provide context for patterns of primary care attendance by people living with ME/CFS. Methodology Conducted in partnership with the Patient Advisory Group, this study adopted a mixed methods approach. De-identified primary care data from the national MedicineInsight program were analyzed. The cohort were regularly attending patients, i.e. 3 visits in the preceding 2 years. Crude prevalence rates were calculated for years 2015–2019, by sex, 10-year age groups, remoteness and socioeconomic status. Rates are presented per 100,000population (95% confidence intervals (CI)). Qualitative data was collected through focus groups and in-depth 1:1 interview. Results Qualitative evidence identified barriers to reaching diagnosis, and limited interactions with primary care due to a lack of available treatments/interventions, stigma and disbelief in ME/CFS as a condition. In each year of interest, crude prevalence in the primary care setting ranged between 94.9/100,000 (95% CI: 91.5–98.5) and 103.9/100,000 population (95%CI: 100.3–107.7), equating to between 20,140 and 22,050 people living with ME/CFS in Australia in 2020. Higher rates were observed for age groups 50-59 years and 40-49 years. Rates were substantially higher in females (130.0–141.4/100,000) compared to males (50.9–57.5/100,000). In the context of the qualitative evidence, our prevalence rates likely represent an underestimate of the true prevalence of ME/CFS in the Australian primary care setting. Conclusion ME/CFS affects a substantial number of Australians. Whilst this study provides prevalence estimates for the Australian primary care setting, the qualitative evidence highlights the limitations of these. Future research should focus on using robust case ascertainment criteria in a community setting. Quantification of the burden of disease can be used to inform health policy and planning, for this understudied condition.

Abstract Background Potentially preventable complications are monitored as part of the Maryland Hospital Acquired Conditions Program and are used to adjust hospital reimbursement. Few studies have evaluated racial-ethnic disparities in potentially preventable complications. Our study objective was to explore whether racial-ethnic disparities in potentially preventable complications after Cesarean delivery exist in Maryland. Methods We performed a retrospective observational cohort study using data from the Maryland Health Services Cost Review Commission database. All patients having Cesarean delivery, who had race-ethnicity data between fiscal years 2016 and 2020 were included. Multivariable logistic regression modeling was performed to estimate risk-adjusted odds of having a potentially preventable complication in patients of different race-ethnicity. Results There were 101,608 patients who had Cesarean delivery in 33 hospitals during the study period and met study inclusion criteria. Among them, 1,772 patients (1.7%), experienced at least one potentially preventable complication. Patients who had a potentially preventable complication were older, had higher admission severity of illness, and had more government insurance. They also had more chronic hypertension and pre-eclampsia (both P

Objective: To determine whether CT-to-body divergence can be overcome to improve the diagnostic yield of peripheral pulmonary nodules with the combination of shape-sensing robotic-assisted bronchoscopy (SSRAB) and portable 3-dimensional (3D) imaging. Patients and Methods: A single-center, prospective, pilot study was conducted from February 9, 2021, to August 4, 2021, to evaluate the combined use of SSRAB and portable 3D imaging to visualize tool-in-lesion as a correlate to diagnostic yield. Results: Thirty lesions were subjected to biopsy in 17 men (56.7%) and 13 women (43.3%). The median lesion size was 17.5 mm (range, 10-30 mm), with the median airway generation of 7 and the median distance from pleura of 14.9 mm. Most lesions were in the upper lobes (18, 60.0%). Tool-in-lesion was visualized at the time of the procedure in 29 lesions (96.7%). On the basis of histopathologic review, 22 (73.3%) nodules were malignant and 6 (20.0%) were benign. Two (6.7%) specimens were suggestive of inflammation, and the patients elected observation. The mean number of spins was 2.5 (±1.6) with a mean fluoroscopy time of 8.7 min and a mean dose area product of 50.3 Gy cm2 (±32.0 Gy cm2). There were no episodes of bleeding or pneumothorax. The diagnostic yield was 93.3%. Conclusion: This pilot study shows that the combination of mobile 3D imaging and SSRAB of pulmonary nodules appears to be safe and feasible. In conjunction with appropriate anesthetic pathways, nodule motion and divergence can be overcome in most patients. Trial Registration: https://clinicaltrials.gov Identifier NCT04740047

Candia auris is an emerging human pathogenic yeast; yet, despite phenotypic attributes and genomic evidence suggesting that it probably emerged from a natural reservoir, we know nothing about the environmental phase of its life cycle and the transmission pathways associated with it. The thermotolerant characteristics of C. auris have been hypothesised to be an environmental adaptation to increasing temperatures due to global warming (which may have facilitated its ability to tolerate the mammalian thermal barrier that is considered a protective strategy for humans against colonisation by environmental fungi with pathogenic potential). Thus, C. auris may be the first human pathogenic fungus to have emerged as a result of climate change. In addition, the release of antifungal chemicals, such as azoles, into the environment (from both pharmaceutical and agricultural sources) is likely to be responsible for the environmental enrichment of resistant strains of C. auris; however, the survival and dissemination of C. auris in the natural environment is poorly understood. In this paper, we critically review the possible pathways through which C. auris can be introduced into the environment and evaluate the environmental characteristics that can influence its persistence and transmission in natural environments. Identifying potential environmental niches and reservoirs of C. auris and understanding its emergence against a backdrop of climate change and environmental pollution will be crucial for the development of effective epidemiological and environmental management responses.

BackgroundMany older adults now use technologies such as wearable devices and telehealth services to support their health and well-being while living independently at home. However, older adults vary in how they use these technologies, and there is a lack of knowledge regarding the motivations that influence their acceptance and use of health-related technologies in home environments. ObjectiveThis study aimed to understand the types of technologies that older adults use to support their health and the factors that motivate them to use their chosen technologies to support their health. In addition, we aimed to understand the factors that enable the effective use of technologies for health self-management and to identify the barriers that can negatively affect the adoption of technologies. MethodsA total of 22 older adults participated in semistructured interviews regarding their experiences of using technologies for health self-management. Interview transcripts were analyzed through an in-depth thematic analysis. ResultsThe interviews revealed that a range of technologies, such as videoconferencing software, fitness trackers, and other devices, were being used by older adults to support their health. Interviews showed that participants were motivated to use technologies to monitor health issues, to stay active and connected, and to record and change their behavior in the light of foreseen risks related to their future health status. Enablers that facilitated the effective use of technologies include social and organizational influence, convenient access to health care and safety provided by the technology, and easy setup and low cost of the technology. Barriers include information overload and a sense of futility about future health decline; telehealth being an inadequate substitute for in-person consultation; concerns about trust related to privacy and accuracy; and technologies being stigmatizing, uncomfortable to use, expensive, and unfamiliar. ConclusionsThis study suggested that older adults were using a variety of technologies to prevent or prepare for future health decline, evidencing a resilient attitude toward health and aging. In addition, older adults were willing to continue using the technology when there was a perceived need. The enabler mentioned by most participants was the social and organizational influence that included health care staff, family, friends, and organizations. This analysis provides a better understanding of how older adults use technologies to support their health and can guide the provision of appropriate health technologies for them.

The use of Information and Communication Technologies (ICTs) for people with Neurodevelopmental Disorders (NDD) is increasing; however, it is currently hard to assess its quality as there are issues regarding the lack of consensus on how to design these technologies. Here, using a Delphi method, we built a trans-ICTs inventory named the Design ICT Inventory (DICTI) to guide and gauge design in the 4 main ICTs dedicated to people with NDD (serious game/App, robotics, video modeling, augmentative and alternative communication). After two rounds with feedback from 12 experts, we obtained consensus and agreement for each of the 13 items of the inventory: customization; feedback; rewards; contextualized learning; enhance motivation; manage difficulty; increasing accessibility; clarity of instruction and content; attention capacity; clear goals; minimalistic graphics and audio; human interaction; and trustworthy. The DICTI provides an easy tool to use in order to assess the design of ICTs. Future research is needed to ensure the inter-reliability of the inventory and its relevance in assessing ICT.

IntroductionRepetitive, subconcussive events may adversely affect the brain and cognition during sensitive periods of development. Prevention of neurocognitive consequences of concussion in high school football is therefore an important public health priority. We aimed to identify the player positions and demographic, behavioral, cognitive, and impact characteristics that predict the frequency and acceleration of head impacts in high school football players.MethodsIn this prospective study, three cohorts of adolescent male athletes (N = 53, 28.3% Hispanic) were recruited over three successive seasons in a high school American football program. Demographic and cognitive functioning were assessed at baseline prior to participating in football. Helmet sensors recorded impact frequency and acceleration. Each head impact was captured on film from five different angles. Research staff verified and characterized on-field impacts. Player-level Poisson regressions and year-level and impact-level linear mixed-effect models were used to determine demographic, behavioral, cognitive, and impact characteristics as predictors of impact frequency and acceleration.Results4,678 valid impacts were recorded. Impact frequency positively associated with baseline symptoms of hyperactivity-impulsivity [β(SE) = 1.05 impacts per year per unit of symptom severity (1.00), p = 0.01] and inattentiveness [β(SE) = 1.003 impacts per year per T-score unit (1.001), p = 0.01]. Compared to quarterbacks, the highest acceleration impacts were sustained by kickers/punters [β(SE) = 21.5 g's higher (7.1), p = 0.002], kick/punt returners [β(SE) = 9.3 g's higher (4.4), p = 0.03], and defensive backs [β(SE) = 4.9 g's higher (2.5), p = 0.05]. Impacts were more frequent in the second [β(SE) = 33.4 impacts (14.2), p = 0.02)] and third [β(SE) = 50.9 impacts (20.1), p = 0.01] year of play. Acceleration was highest in top-of-the-head impacts [β(SE) = 4.4 g's higher (0.8), pConclusionIncluding screening questions for Attention-Deficit/Hyperactivity Disorder in pre-participation evaluations can help identify a subset of prospective football players who may be at risk for increased head impacts. Position-specific strategies to modify kickoffs and correct tackling and blocking may also reduce impact burden.

SARS-CoV-2 spread rapidly, causing millions of deaths across the globe. As a result, demand for medical supplies and personal protective equipment (PPE) surged and supplies dwindled. Separate entirely, hospital-acquired infections have become commonplace and challenging to treat. To explore the potential of novel sterilization techniques, this study evaluated the disinfection efficacy of Fathhome's ozone-based, dry-sanitizing device by dose and time response. Inactivation of human pathogens was tested on non-porous (plastic) surfaces. 95.42–100% inactivation was observed across all types of vegetative microorganisms and 27.36% inactivation of bacterial endospores tested, with no residual ozone detectable after completion. These results strongly support the hypothesis that Fathhome's commercial implementation of gas-based disinfection is suitable for rapid decontamination of a wide variety of pathogens on PPE and other industrially relevant materials.

The opportunistic yeast Candida albicans and lactic acid bacteria Enterococcus faecalis are frequently co-isolated from various infection sites on the human body, suggesting a common interkingdom interaction. While some reports suggest an antagonism, the reason for their co-isolation therefore remains unclear. The purpose of this study was to undertake a detailed characterisation of this dual-species interaction. We used standard biofilm characterisation methodologies alongside an RNASeq analysis to assess the response of C. albicans to E. faecalis. We evaluated the relevance of pH to dual-species biofilm interactions and demonstrated that E. faecalis rapidly and significantly impacted C. albicans morphogenesis and biofilm formation, which was mirrored by levels of gene expression. These transcripts were enriched in amino acids biosynthesis and metabolism pathways in co-cultures, a finding that guided our investigation into pH related mechanism. We were able to demonstrate the direct role of E. faecalis induced low pH, which inhibited C. albicans hyphal morphogenesis and biofilm formation. The results suggest that the anti-candidal effect of E. faecalis is not based solely on a single mechanism, instead it may involve various mechanisms, which collectively reflects the complexity of interaction between C. albicans and E. faecalis and impacts treatment outcomes.

Abstract Background The gut microbiome is altered in patients with inflammatory bowel disease, yet how these alterations contribute to intestinal inflammation is poorly understood. Murine models have demonstrated the importance of the microbiome in colitis since colitis fails to develop in many genetically susceptible animal models when re-derived into germ-free environments. We have previously shown that Wiskott-Aldrich syndrome protein (WASP)-deficient mice (Was −/− ) develop spontaneous colitis, similar to human patients with loss-of-function mutations in WAS. Furthermore, we showed that the development of colitis in Was −/− mice is Helicobacter dependent. Here, we utilized a reductionist model coupled with multi-omics approaches to study the role of host-microbe interactions in intestinal inflammation. Results Was −/− mice colonized with both altered Schaedler flora (ASF) and Helicobacter developed colitis, while those colonized with either ASF or Helicobacter alone did not. In Was −/− mice, Helicobacter relative abundance was positively correlated with fecal lipocalin-2 (LCN2), a marker of intestinal inflammation. In contrast, WT mice colonized with ASF and Helicobacter were free of inflammation and strikingly, Helicobacter relative abundance was negatively correlated with LCN2. In Was −/− colons, bacteria breach the mucus layer, and the mucosal relative abundance of ASF457 Mucispirillum schaedleri was positively correlated with fecal LCN2. Meta-transcriptomic analyses revealed that ASF457 had higher expression of genes predicted to enhance fitness and immunogenicity in Was −/− compared to WT mice. In contrast, ASF519 Parabacteroides goldsteinii’s relative abundance was negatively correlated with LCN2 in Was −/− mice, and transcriptional analyses showed lower expression of genes predicted to facilitate stress adaptation by ASF519 in Was −/− compared to WT mice. Conclusions These studies indicate that the effect of a microbe on the immune system can be context dependent, with the same bacteria eliciting a tolerogenic response under homeostatic conditions but promoting inflammation in immune-dysregulated hosts. Furthermore, in inflamed environments, some bacteria up-regulate genes that enhance their fitness and immunogenicity, while other bacteria are less able to adapt and decrease in abundance. These findings highlight the importance of studying host-microbe interactions in different contexts and considering how the transcriptional profile and fitness of bacteria may change in different hosts when developing microbiota-based therapeutics. Video abstract

The structural condition of hydroelectric tunnels is important to the overall performance, safety, and longevity of generating stations. Significant effort is required to inspect, monitor, and maintain these tunnels. Photogrammetry is an effective method of collecting highly accurate visual and spatial data. However, it also presents the complex challenge of positioning a camera at thousands of difficult-to-reach locations throughout the large and varying-diameter tunnels. A semi-automated robotic camera positioning system was developed to enhance the collection of images within hydroelectric tunnels for photogrammetric inspections. A continuous spiral image network was developed to optimize the collection speed within the bounds of photography and capture-in-motion constraints. The positioning system and image network optimization reduce the time and effort required while providing the ability to adapt to different and varying tunnel diameters. To demonstrate, over 28,000 images were captured at a ground sampling distance of 0.4 mm in the 822 m long concrete-lined section of the Grand Falls Generating Station intake tunnel.

Abstract Study objective Digital nerve blocks (DNBs) provide local anesthesia for minor procedures of the digits. Several DNB techniques have been described, but it is unclear which technique provides adequate anesthesia with the least pain. DNB techniques can be grouped into a dorsal approach, which requires 2 injections, versus 3 different types of volar approaches, which require a single injection. We performed a meta‐analysis to compare DNB techniques with respect to time to anesthesia (TTA), duration of anesthesia (DOA), and pain of injection. We also reviewed data on degree and distribution of anesthesia and discuss the techniques preferred by study participants and clinicians performing injections. Data Sources We searched MEDLINE, EMBASE, and CENTRAL databases with terms “digital block,” “digital nerve block,” “local anesthetic,” “local anesthesia,” “lidocaine,” and/or “bupivacaine.” Study Selection Randomized controlled trials (RCTs) were prioritized, though high‐quality prospective cohort studies were also eligible. All included studies evaluated DNB techniques or anesthetics. There were 23 papers (21 RCTs, 2 prospective descriptive studies) included. Data Extraction DNBs studied included dorsal ring block, traditional dorsal block, transthecal block, modified transthecal block, and volar subcutaneous digital blocks. Outcomes measured included TTA, DOA, pain of injection scores, and degree of anesthesia. Results Overall, mean TTA was 4.5 minutes (95% confidence interval [CI] 3.5, 5.6), mean DOA was 187 minutes (95% CI 104.3, 269.7), and mean pain score was 2.1 out of 10 (95% CI 1.3, 2.8) without significant differences between studies or techniques. Conclusions There were no significant differences in the outcomes of TTA, DOA, and pain of injection between different DNB techniques. Single‐injection volar approaches may be preferred by participants and clinicians over dorsal approaches that require 2 injections, particularly with respect to pain. However, 2‐injection dorsal approaches may have better coverage of the proximal dorsal surface based on degree and distribution of anesthesia.

Exploring austere environments required a reimagining of resource acquisition and utilization. Cyanobacterial in situ resources utilization (ISRU) and biological life support system (BLSS) bioreactors have been proposed to allow crewed space missions to extend beyond the temporal boundaries that current vehicle mass capacities allow. Many cyanobacteria and other microscopic organisms evolved during a period of Earth’s history that was marked by very harsh conditions, requiring robust biochemical systems to ensure survival. Some species work wonderfully in a bioweathering capacity (siderophilic), and others are widely used for their nutritional power (non-siderophilic). Playing to each of their strengths and having them grow and feed off of each other is the basis for the proposed idea for a series of three bioreactors, starting from regolith processing and proceeding to nutritional products, gaseous liberation, and biofuel production. In this paper, we discuss what that three reactor system will look like, with the main emphasis on the nutritional stage.

Abstract Background Helping Babies Breathe (HBB) is a life-saving program that has helped reduce neonatal morbidity and mortality, but knowledge and skills retention after training remains a significant challenge for sustainability of impact. User-centred design (UCD) can be used to develop solutions to target knowledge and skills maintenance. Methods We applied a process of UCD beginning with understanding the facilitators of, and barriers to, learning and retaining HBB knowledge and skills. HBB Master Trainers and frontline HBB providers participated in a series of focus group discussions (FGDs) to uncover the processes of skills acquisition and maintenance to develop a mobile application called “HBB Prompt”. Themes derived from each FGD were identified and implications for development of the HBB Prompt app were explored, including feasibility of incorporating strategies into the format of an app. Data analysis took place after each iteration in Phase 1 to incorporate feedback and improve subsequent versions of HBB Prompt. Results Six HBB trainers and seven frontline HBB providers participated in a series of FGDs in Phase 1 of this study. Common themes included lack of motivation to practise, improving confidence in ventilation skills, ability to achieve the Golden Minute, fear of forgetting knowledge or skills, importance of feedback, and peer-to-peer learning. Themes identified that were not feasible to address pertained to health system challenges. Feedback about HBB Prompt was generally positive. Based on initial and iterative feedback, HBB Prompt was created with four primary functions: Training Mode, Simulation Mode, Quizzes, and Dashboard/Scoreboard. Conclusions Developing HBB Prompt with UCD to help improve knowledge and skills retention was feasible and revealed key concepts, including drivers for successes and challenges faced for learning and maintaining HBB skills. HBB Prompt will be piloted in Phase 2 of this study, where knowledge and skills retention after HBB training will be compared between an intervention group with HBB Prompt and a control group without the app. Trial registration Clinicaltrials.gov (NCT03577054). Retrospectively registered July 5, 2018, https://clinicaltrials.gov/ct2/show/study/NCT03577054 .

Digital trace data from search engines lacks information about the experiences of the individuals generating the data. Here the authors link search data and human computation to build a tracking model of influenza-like illness.

BackgroundLittle is known about the effects of social exclusion on youth with bipolar disorder (BD). Understanding these effects and the functional neural correlates of social exclusion in youth with BD may establish differences from healthy youth and help identify areas of intervention.MethodsWe investigated brain function in 19 youth with BD and 14 age and gender matched healthy control (HC) participants while performing Cyberball, an fMRI social exclusion task. Whole brain activation, region-of-interest, and functional connectivity were compared between groups and examined with behavioral measures.ResultsCompared with the HC group, youth with BD exhibited greater activation in the left fusiform gyrus (FFG) during social exclusion. Functional connectivity between the left FFG and the posterior cingulate/precuneus was significantly greater in the HC compared with the BD group. For the HC group only, age and subjective distress during Cyberball significantly predicted mean FFG activation. No significant differences in distress during social exclusion were found between groups.ConclusionAlthough preliminary due to small sample size, these data suggest that youth with BD process social exclusion in a manner that focuses on basic visual information while healthy youth make use of past experiences to interpret current social encounters. This difference may account for the social cognitive issues experienced by youth with BD, which can lead to more severe anxiety and mood symptoms.

Background: The Centers for Disease Control and Prevention have declared that the United States is amidst a continuing opioid epidemic, with drug overdose–related death tripling between 1999 and 2014. Among the 47,055 overdose-related deaths that occurred in 2014, 28,647 (60.9%) of them involved an opioid. Methods: To determine if there are specific trends in opioid prescribing practices of specific groups of surgeons to better describe any regional or subspecialty trends that exist, the Part D Prescriber Public Use File was used to evaluate all prescription drug orders for Medicare beneficiaries with a Part D prescription drug plan for the 2015 calendar year. Only those providers with the specialty description corresponding to a surgical specialty were included in this study, using the provider's Part B claims. Results: A total of 65,277,932 claims made to Part D by 90,253 surgeons in the 2015 service year were analyzed in this study, demonstrating statistically significant differences in the opioid prescribing practices of surgeons from different states, cities, practice settings, and subspecialties (P

Engineered proteins are increasingly being required to function or pass through environmental stresses for which the underlying protein has not evolved. A major example in health are antibody therapeutics, where a low pH step is used for purification and viral inactivation. In order to develop a computational model for analysis of pH-stability, predictions are compared with experimental data for the relative pH-sensitivities of antibody domains. The model is then applied to proteases that have evolved to be functional in an acid environment, showing a clear signature for low pH-dependence of stability in the neutral to acidic pH region, largely through reduction of salt-bridges. Interestingly, an extensively acidic protein surface can maintain contribution to structural stabilisation at acidic pH through replacement of basic sidechains with polar, hydrogen-bonding groups. These observations form a design principle for engineering acid-stable proteins.

We study policies aimed at discouraging behavior that produces negative externalities, and their differential gender impact. Using driving as an application, we carry out an experiment where slowest vehicles are the safest choice, whereas faster driving speeds lead to higher potential payoffs but higher probabilities of accidents. Faster speeds have a personal benefit but create a negative externality. We consider four experimental policy conditions: a baseline situation, a framing condition in which drivers are suggested that driving fast violates a social norm, and two punishment conditions, one exogenous and one endogenous. We find that the most effective policies use different framing and endogenously determined punishment mechanisms (to fast drivers by other drivers). These policies are only effective for female drivers which leads to substantial gender payoff differences. Our data suggest that these results arise from differences in social norms across genders, thus opening the way to designing more effective policies.

BackgroundMitigation measures for the first wave of the COVID-19 pandemic and burden on health systems created challenges for pre-exposure prophylaxis (PrEP) service delivery. We examined PrEP uptake in PEPFAR programs before and after the start of the COVID-19 pandemic.MethodsWe studied two PEPFAR program monitoring indicators, using routine Monitoring, Evaluation, Reporting (MER) indicators capturing uptake of PrEP (PrEP_NEW) and overall use of PrEP (PrEP_CURR). We also analyzed descriptive program narratives to understand successes and challenges field teams encountered after the start of the COVID-19 pandemic. To assess changes in coverage of PrEP across 21 countries, we calculated the "PrEP to need ratio" (PnR) using a published methodology. We defined the pre-COVID time period as April 1, 2019 -March 31, 2020 and the COVID time period as April 1, 2020 -March 31, 2021.FindingsThe total number of persons who initiated PrEP increased by 157% from 233,250 in the pre-COVID-19 period compared with 599,935 in the COVID-19 period. All countries, except five, noted significant increases in PrEP uptake. PrEP uptake among adolescent girls and young women (AGYW) increased by 159% from 80,452 AGYW in the pre-COVID-19 period to 208,607 AGYW in the COVID-19 period. There were 77,430 key populations (KP) initiated on PrEP in the pre-COVID-19 period and 209,114 KP initiated in the COVID-19 period (a 170% increase). The PnR increased 214% in the COVID-19 period across all PEPFAR-supported countries. Adaptations, such as multi-month dispensing (MMD) of PrEP; virtual demand creation activities; decentralized, community-based and virtual service delivery, were implemented to maintain PrEP services.ConclusionsPEPFAR programs continued to maintain and initiate new clients on PrEP despite the challenges posed by the COVID-19 pandemic. Adaptations such as MMD of PrEP and use of technology were vital in expanding service delivery and increasing PrEP coverage.FundingThis project has been supported by the U.S. President's Emergency Plan for AIDS Relief.

Candida albicans is an opportunistic pathogen found throughout multiple body sites and is frequently co-isolated from infections of the respiratory tract and oral cavity with Staphylococcus aureus. Herein we present the first report of the effects that S. aureus elicits on the C. albicans transcriptome. Dual-species biofilms containing S. aureus and C. albicans mutants defective in ALS3 or ECE1 were optimised and characterised, followed by transcriptional profiling of C. albicans by RNA-sequencing (RNA-seq). Altered phenotypes in C. albicans mutants revealed specific interaction profiles between fungus and bacteria. The major adhesion and virulence proteins Als3 and Ece1, respectively, were found to have substantial effects on the Candida transcriptome in early and mature biofilms. Despite this, deletion of ECE1 did not adversely affect biofilm formation or the ability of S. aureus to interact with C. albicans hyphae. Upregulated genes in dual-species biofilms corresponded to multiple gene ontology terms, including those attributed to virulence, biofilm formation and protein binding such as ACE2 and multiple heat-shock protein genes. This shows that S. aureus pushes C. albicans towards a more virulent genotype, helping us to understand the driving forces behind the increased severity of C. albicans-S. aureus infections.

This study explores the impacts of the COVID-19 pandemic and the Maryland stay-at-home order on fruit and vegetable farmers in Maryland. Focusing on farms’ direct-to-consumer marketing channels, we aim to characterize the diversity of farm responses and identify practices that facilitated adaptation. This research is grounded in the socio-ecological systems framework, which emphasizes the interconnection between social and ecological systems and characterizes the dual-driving forces that impact food producers and their livelihood. The study team conducted interviews with 20 Maryland farm owners/managers who grow and sell produce. The semistructured interviews includ­ed questions relating to production practices, sales and marketing, and resilience. The interviewer fol­lowed up with probes to understand the dimen­sions of response diversity and adaptive capacity. Interviews were transcribed verbatim, and responses were analyzed using the framework approach. In the context of a global pandemic, community supported agriculture (CSA), farmers markets, and pick-your-own channels provided a high degree of stability and financial security. No farmer reported relying solely on intermediated markets (e.g., restaurants, grocery stores, institu­tions). Distribution channels that incorporated an online marketplace offering prepacked pre-orders were a notable strength of highly adaptive Mary­land produce farmers. Farmers reported that expanding established CSAs was an important method for reallocating produce originally intended to be sold to reduced/terminated marketing chan­nels. Common challenges among farmers included increased administrative workload, concerns asso­ciated with raising food prices during a crisis, and environmental concerns about the use of additional packaging. We describe a range of adaptive behav­iors that aided farmers in withstanding shocks.

ABSTRACT Despite the strikingly high worldwide prevalence of vulvovaginal candidiasis (VVC), treatment options for recurrent VVC (RVVC) remain limited, with many women experiencing failed clinical treatment with frontline azoles. Further, the cause of onset and recurrence of disease is largely unknown, with few studies identifying potential mechanisms of treatment failure. This study aimed to assess a panel of clinical samples from healthy women and those with RVVC to investigate the influence of Candida, the vaginal microbiome, and how their interaction influences disease pathology. 16S rRNA sequencing characterized disease by a reduction in specific health-associated Lactobacillus species, such as Lactobacillus crispatus, coupled with an increase in Lactobacillus iners. In vitro analysis showed that Candida albicans clinical isolates are capable of heterogeneous biofilm formation, and we found the presence of hyphae and C. albicans aggregates in vaginal lavage fluid. Additionally, the ability of Lactobacillus to inhibit C. albicans biofilm formation and biofilm-related gene expression was demonstrated. Using RNA sequencing technology, we were able to identify a possible mechanism by which L. crispatus may contribute to re-establishing a healthy vaginal environment through amino acid acquisition from C. albicans. This study highlights the potential formation and impact of Candida biofilms in RVVC. Additionally, it suggests that RVVC is not entirely due to an arbitrary switch in C. albicans from commensal to pathogen and that understanding interactions between this yeast and vaginal Lactobacillus species may be crucial to elucidating the cause of RVVC and developing appropriate therapies. IMPORTANCE RVVC is a significant burden, both economically and for women's health, but its prevalence is poorly documented globally due to the levels of self-treatment. Identifying triggers for development and recurrence of VVC and the pathogenesis of the microbes involved could considerably improve prevention and treatment options for women with recurrent, azole-resistant cases. This study therefore aimed to examine the interkingdom dynamics from healthy women and those with RVVC using next-generation sequencing techniques and to further investigate the molecular interactions between C. albicans and L. crispatus in a relevant biofilm coculture system.

Abstract Background We introduce BPG, a framework for generating publication-quality, highly-customizable plots in the R statistical environment. Results This open-source package includes multiple methods of displaying high-dimensional datasets and facilitates generation of complex multi-panel figures, making it suitable for complex datasets. A web-based interactive tool allows online figure customization, from which R code can be downloaded for integration with computational pipelines. Conclusion BPG provides a new approach for linking interactive and scripted data visualization and is available at http://labs.oicr.on.ca/boutros-lab/software/bpg or via CRAN at https://cran.r-project.org/web/packages/BoutrosLab.plotting.general