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Abstract With the increased availability of chemical data in public databases, innovative techniques and algorithms have emerged for the analysis, exploration, visualization, and extraction of information from these data. One such technique is chemical grouping, where chemicals with common characteristics are categorized into distinct groups based on physicochemical properties, use, biological activity, or a combination. However, existing tools for chemical grouping often require specialized programming skills or the use of commercial software packages. To address these challenges, we developed a user-friendly chemical grouping workflow implemented in KNIME, a free, open-source, low/no-code, data analytics platform. The workflow serves as an all-encompassing tool, expertly incorporating a range of processes such as molecular descriptor calculation, feature selection, dimensionality reduction, hyperparameter search, and supervised and unsupervised machine learning methods, enabling effective chemical grouping and visualization of results. Furthermore, we implemented tools for interpretation, identifying key molecular descriptors for the chemical groups, and using natural language summaries to clarify the rationale behind these groupings. The workflow was designed to run seamlessly in both the KNIME local desktop version and KNIME Server WebPortal as a web application. It incorporates interactive interfaces and guides to assist users in a step-by-step manner. We demonstrate the utility of this workflow through a case study using an eye irritation and corrosion dataset. Scientific contributions This work presents a novel, comprehensive chemical grouping workflow in KNIME, enhancing accessibility by integrating a user-friendly graphical interface that eliminates the need for extensive programming skills. This workflow uniquely combines several features such as automated molecular descriptor calculation, feature selection, dimensionality reduction, and machine learning algorithms (both supervised and unsupervised), with hyperparameter optimization to refine chemical grouping accuracy. Moreover, we have introduced an innovative interpretative step and natural language summaries to elucidate the underlying reasons for chemical groupings, significantly advancing the usability of the tool and interpretability of the results.

Abstract While high circulating tumor DNA (ctDNA) levels are associated with poor survival for multiple cancers, variant-specific differences in the association of ctDNA levels and survival have not been examined. Here we investigate KRAS ctDNA (ctKRAS) variant-specific associations with overall and progression-free survival (OS/PFS) in first-line metastatic pancreatic ductal adenocarcinoma (mPDAC) for patients receiving chemoimmunotherapy (“PRINCE”, NCT03214250), and an independent cohort receiving standard of care (SOC) chemotherapy. For PRINCE, higher baseline plasma levels are associated with worse OS for ctKRAS G12D (log-rank p = 0.0010) but not G12V (p = 0.7101), even with adjustment for clinical covariates. Early, on-therapy clearance of G12D (p = 0.0002), but not G12V (p = 0.4058), strongly associates with OS for PRINCE. Similar results are obtained for the SOC cohort, and for PFS in both cohorts. These results suggest ctKRAS G12D but not G12V as a promising prognostic biomarker for mPDAC and that G12D clearance could also serve as an early biomarker of response.

Abstract The demand for open data and open science is on the rise, fueled by expectations from the scientific community, calls to increase transparency and reproducibility in research findings, and developments such as the Final Data Management and Sharing Policy from the U.S. National Institutes of Health and a memorandum on increasing public access to federally funded research, issued by the U.S. Office of Science and Technology Policy. This paper explores the pivotal role of data repositories in biomedical research and open science, emphasizing their importance in managing, preserving, and sharing research data. Our objective is to familiarize readers with the functions of data repositories, set expectations for their services, and provide an overview of methods to evaluate their capabilities. The paper serves to introduce fundamental concepts and community-based guiding principles and aims to equip researchers, repository operators, funders, and policymakers with the knowledge to select appropriate repositories for their data management and sharing needs and foster a foundation for the open sharing and preservation of research data.

Background:. Evidence-based medicine in plastic surgery is essential to provide optimal care to individual patients. Level of evidence (LOE) and number of citations are metrics used to gauge quality of research and impact within a field, respectively. The objective of this study was to determine an association between LOE and number of citations within recently published articles in Plastic and Reconstructive Surgery (PRS). Methods:. A review of original research articles published in PRS from January 2018 to June 2022 was performed. LOE was identified through the PRS website, and the number of citations identified via PubMed. Articles were further divided into sections of their corresponding topic. Results:. A total of 965 articles were reviewed, of which 21 (2.2%) were articles assigned level I evidence. There were 147 (15.2%) level II articles, 360 (37.3%) level III articles, 377 (39.1%) level IV articles, and 60 (6.2%) level V articles. The average number of citations per article was 2.72, and the average LOE of all included articles was 3.31. Level I articles had an average of 4.95 citations, whereas level II, III, IV, and V articles had averages of 2.95, 2.54, 2.64, and 2.71, respectively. Breast articles were cited on average 3.85 times each, more than any other type of article. Conclusions:. Our data show that articles assigned level I evidence in PRS trend toward higher numbers of citations compared with articles assigned lower LOEs. These findings should encourage investigators to publish high-quality research to advance the field of plastic surgery.

Objectives: To identify patient and process factors that contribute to the high cost of lung transplantation (LTx) in the perioperative period, which may allow transplant centers to evaluate situations in which transplantation is most cost-effective to inform judicious resource allocation, avoid futile care, and reduce costs. Methods: The MarketScan Research databases were used to identify 582 privately insured patients undergoing single or bilateral LTx between 2013 and 2019. The patients were subdivided into groups by disease etiology using the United Network of Organ Sharing classification system. Multivariable generalized linear models using a gamma distribution with a log link were fit to examine the associations between the etiology of lung disease and costs during the index admission, 3 months before admission, and 3 months after discharge. Results: Our results indicate that the index admission contributed the most to the total transplantation costs compared to the 3 months before admission and after discharge. The regression-adjusted mean index hospitalization cost was 35% higher for patients with pulmonary vascular disease compared to those with obstructive lung disease ($527,156 vs $389,055). The use of extracorporeal membrane oxygenation, mechanical ventilation, and surgical complications in the post-transplantation period were associated with higher costs during the index admission. Surprisingly, age ≥55 was associated with lower costs during the index admission. Conclusions: This analysis identifies pivotal factors influencing the high cost of LTx, emphasizing the significant impact of the index admission, particularly for patients with pulmonary vascular disease. These insights offer transplant centers an opportunity to enhance cost-effectiveness through judicious resource allocation and service bundling, ultimately reducing overall transplantation costs.

Abstract Submarine groundwater discharge (SGD) supplies nutrients, carbon, metals, and radionuclide tracers to estuarine and coastal waters. One aspect of SGD that is poorly recognized is its direct effect on dissolved oxygen (DO) demand in receiving waters, denoted here as SGD-OD. Sulfate-mediated oxidation of organic matter in salty coastal aquifers produces numerous reduced byproducts including sulfide, ammonia, dissolved organic carbon and nitrogen, methane, and reduced metals. When these byproducts are introduced to estuarine and coastal systems by SGD and are oxidized, they may substantially reduce the DO concentration in receiving waters and impact organisms living there. We consider six estuarine and coastal sites where SGD derived fluxes of reduced byproducts are well documented. Using data from these sites we present a semiquantitative model to estimate the effect of these byproducts on DO in the receiving waters. Without continued aeration with atmospheric oxygen, the study sites would have experienced periodic hypoxic conditions due to SGD-OD. The presence of H2S supplied by SGD could also impact organisms. This process is likely prevalent in other systems worldwide.

Abstract Critical loads (CLs) are frequently used to quantify terrestrial ecosystem impacts from nitrogen (N) deposition using ecological responses such as the growth and mortality of tree species. Typically, CLs are reported as a single value, with uncertainty, for an indicator across a species' entire range. Mediating factors such as climate and soil conditions can influence species' sensitivity to N, but the magnitudes of these effects are rarely calculated explicitly. Here, we quantify the spatial variability and estimation error in N CLs for the growth and survival of 10 different tree species while accounting for key environmental factors that mediate species sensitivity to N (e.g., soil characteristics). We used a bootstrapped machine learning approach to determine the level of N deposition at which a 1% decrease occurs in growth rate or survival probability at forest plot locations across the United States. We found minimal differences (8.5 kg N ha−1 year−1) within these regimes. We also evaluated the most important factors for predicting tree growth rates and mortality and found that climate, competition, and air pollution generally have the greatest influence on growth rates and survival probability. Lastly, we developed a new probability of exceedance metric for each species and found high likelihoods of exceedance across large portions (46%) of some species' ranges. Our analysis demonstrates that machine learning approaches provide a unique capability to: (1) quantify mediating factor influences on N sensitivity of trees, (2) estimate the error in local N CL estimates, and (3) generate localized N CLs with probabilities of exceedance for tree species.

Little is known about the interface between empathy and political skill in sales. This study develops a model to reflect these characteristics and their impact on performance. Results from a study of 240 B2B salespeople contradict the a priori assumption that empathy may not be positively related to sales performance and challenge existing stereotypes that salespeople are not empathetic. Importantly, the findings show sellers employing empathy can generate enhanced outcomes. Also, this study extends our understanding that utilizing political influence spreads the benefit of empathy beyond the impact itself. Politically skilled B2B salespeople can better understand and display their empathy and then persuade and direct customers to mutually advantageous decisions. The identification of new behavioral selling tools may benefit sellers as researchers gain further insight into maximizing selling behaviors.

Background: Ketamine has emerged as one of the most promising therapies for treatment-resistant depression. However, inter-individual variability in response to ketamine is still not well understood and it is unclear how ketamine’s molecular mechanisms connect to its neural and behavioral effects. Methods: We conducted a single-blind placebo-controlled study, with participants blinded to their treatment condition. 40 healthy participants received acute ketamine (initial bolus 0.23 mg/kg, continuous infusion 0.58 mg/kg/hr). We quantified resting-state functional connectivity via data-driven global brain connectivity and related it to individual ketamine-induced symptom variation and cortical gene expression targets. Results: We found that: (i) both the neural and behavioral effects of acute ketamine are multi-dimensional, reflecting robust inter-individual variability; (ii) ketamine’s data-driven principal neural gradient effect matched somatostatin (SST) and parvalbumin (PVALB) cortical gene expression patterns in humans, while the mean effect did not; and (iii) behavioral data-driven individual symptom variation mapped onto distinct neural gradients of ketamine, which were resolvable at the single-subject level. Conclusions: These results highlight the importance of considering individual behavioral and neural variation in response to ketamine. They also have implications for the development of individually precise pharmacological biomarkers for treatment selection in psychiatry. Funding: This study was supported by NIH grants DP5OD012109-01 (A.A.), 1U01MH121766 (A.A.), R01MH112746 (J.D.M.), 5R01MH112189 (A.A.), 5R01MH108590 (A.A.), NIAAA grant 2P50AA012870-11 (A.A.); NSF NeuroNex grant 2015276 (J.D.M.); Brain and Behavior Research Foundation Young Investigator Award (A.A.); SFARI Pilot Award (J.D.M., A.A.); Heffter Research Institute (Grant No. 1–190420) (FXV, KHP); Swiss Neuromatrix Foundation (Grant No. 2016–0111) (FXV, KHP); Swiss National Science Foundation under the framework of Neuron Cofund (Grant No. 01EW1908) (KHP); Usona Institute (2015 – 2056) (FXV). Clinical trial number: NCT03842800

Summary: Background: The Paediatric Difficult Intubation Collaborative identified multiple attempts and persistence with direct laryngoscopy as risk factors for complications in children with difficult tracheal intubations and subsequently engaged in initiatives to reduce repeated attempts and persistence with direct laryngoscopy in children. We hypothesised these efforts would lead to fewer attempts, fewer direct laryngoscopy attempts and decrease complications. Methods: Paediatric patients less than 18 years of age with difficult direct laryngoscopy were enrolled in the Paediatric Difficult Intubation Registry. We define patients with difficult direct laryngoscopy as those in whom (1) an attending or consultant obtained a Cormack Lehane Grade 3 or 4 view on direct laryngoscopy, (2) limited mouth opening makes direct laryngoscopy impossible, (3) direct laryngoscopy failed in the preceding 6 months, and (4) direct laryngoscopy was deferred due to perceived risk of harm or poor chance of success. We used a 5:1 propensity score match to compare an early cohort from the initial Paediatric Difficult Intubation Registry analysis (August 6, 2012–January 31, 2015, 785 patients, 13 centres) and a current cohort from the Registry (March 4, 2017–March 31, 2023, 3925 patients, 43 centres). The primary outcome was first attempt success rate between cohorts. Success was defined as confirmed endotracheal intubation and assessed by the treating clinician. Secondary outcomes were eventual success rate, number of attempts at intubation, number of attempts with direct laryngoscopy, the incidence of persistence with direct laryngoscopy, use of supplemental oxygen, all complications, and severe complications. Findings: First-attempt success rate was higher in the current cohort (42% vs 32%, OR 1.5 95% CI 1.3–1.8, p

Abstract Objective Duchenne muscular dystrophy (DMD) is an X‐linked disorder resulting in progressive muscle weakness and atrophy, cardiomyopathy, and in late stages, cardiorespiratory impairment, and death. As treatments for DMD have expanded, a DMD newborn screening (NBS) pilot study was conducted in New York State to evaluate the feasibility and benefit of NBS for DMD and to provide an early pre‐symptomatic diagnosis. Methods At participating hospitals, newborns were recruited to the pilot study, and consent was obtained to screen the newborn for DMD. The first‐tier screen measured creatine kinase‐MM (CK‐MM) in dried blood spot specimens submitted for routine NBS. Newborns with elevated CK‐MM were referred for genetic counseling and genetic testing. The latter included deletion/duplication analysis and next‐generation sequencing (NGS) of the DMD gene followed by NGS for a panel of neuromuscular conditions if no pathogenic variants were detected in the DMD gene. Results In the two‐year pilot study, 36,781 newborns were screened with CK‐MM. Forty‐two newborns (25 male and 17 female) were screen positive and referred for genetic testing. Deletions or duplications in the DMD gene were detected in four male infants consistent with DMD or Becker muscular dystrophy. One female DMD carrier was identified. Interpretation This study demonstrated that the state NBS program infrastructure and screening technologies we used are feasible to perform NBS for DMD. With an increasing number of treatment options, the clinical utility of early identification for affected newborns and their families lends support for NBS for this severe disease.

We present a dynamical study of 39 active Centaurs and 17 high-perihelion ( q > 4.5 au) Jupiter-family comets (JFCs) with a focus on investigating recent orbital changes as potential triggers for comet-like activity. We have identified a common feature in the recent dynamical histories of all active Centaurs and JFCs in our sample that is not present in the history of the majority of inactive population members: a sharp decrease in semimajor axis and eccentricity occurring within the past several hundred years prior to observed activity. We define these rapid orbital changes as “ a -jumps.” Our results indicate that these orbital reshaping events lead to shorter orbital periods and subsequently greater average per-orbit heating of Centaur nuclei. We suggest that the a -jumps could therefore be a major trigger of cometary activity on Centaurs and JFCs. Our results further imply that analyses of the recent dynamical histories could be used to identify objects that are currently active or may become active soon, where we have identified three such Centaurs with recent a -jumps that should be considered high-priority targets for observational monitoring to search for activity.

IntroductionX-linked PTCHD1 gene has recently been pointed as one of the most interesting candidates for involvement in neurodevelopmental disorders (NDs), such as intellectual disability (ID) and autism spectrum disorder (ASD). PTCHD1 encodes the patched domain-containing protein 1 (PTCHD1), which is mainly expressed in the developing brain and adult brain tissues. To date, major studies have focused on the biological function of the PTCHD1 gene, while the mechanisms underlying neuronal alterations and the cognitive-behavioral phenotype associated with mutations still remain unclear.MethodsWith the aim of incorporating information on the clinical profile of affected individuals and enhancing the characterization of the genotype–phenotype correlation, in this study, we analyze the clinical features of four individuals (two children and two adults) in which array-CGH detected a PTCHD1 deletion or in which panel for screening non-syndromal XLID (X-linked ID) detected a PTCHD1 gene variant. We define the neuropsychological and psychopathological profiles, providing quantitative data from standardized evaluations. The assessment consisted of clinical observations, structured interviews, and parent/self-reported questionnaires.ResultsOur descriptive analysis align with previous findings on the involvement of the PTCHD1 gene in NDs. Specifically, our patients exhibited a clinical phenotype characterized by psychomotor developmental delay- ID of varying severity. Interestingly, while ID during early childhood was associated with autistic-like symptomatology, this interrelation was no longer observed in the adult subjects. Furthermore, our cohort did not display peculiar dysmorphic features, congenital abnormalities or comorbidity with epilepsy.DiscussionOur analysis shows that the psychopathological and behavioral comorbidities along with cognitive impairment interfere with development, therefore contributing to the severity of disability associated with PTCHD1 gene mutation. Awareness of this profile by professionals and caregivers can promote prompt diagnosis as well as early cognitive and occupational enhancement interventions.

Coastal wetlands are hotspots of carbon sequestration, and their conservation and restoration can help to mitigate climate change. However, there remains uncertainty on when and where coastal wetland restoration can most effectively act as natural climate solutions (NCS). Here, we synthesize current understanding to illustrate the requirements for coastal wetland restoration to benefit climate, and discuss potential paths forward that address key uncertainties impeding implementation. To be effective as NCS, coastal wetland restoration projects will accrue climate cooling benefits that would not occur without management action (additionality), will be implementable (feasibility) and will persist over management-relevant timeframes (permanence). Several issues add uncertainty to understanding if these minimum requirements are met. First, coastal wetlands serve as both a landscape source and sink of carbon for other habitats, increasing uncertainty in additionality. Second, coastal wetlands can potentially migrate outside of project footprints as they respond to sea-level rise, increasing uncertainty in permanence. To address these first two issues, a system-wide approach may be necessary, rather than basing cooling benefits only on changes that occur within project boundaries. Third, the need for NCS to function over management-relevant decadal timescales means methane responses may be necessary to include in coastal wetland restoration planning and monitoring. Finally, there is uncertainty on how much data are required to justify restoration action. We summarize the minimum data required to make a binary decision on whether there is a net cooling benefit from a management action, noting that these data are more readily available than the data required to quantify the magnitude of cooling benefits for carbon crediting purposes. By reducing uncertainty, coastal wetland restoration can be implemented at the scale required to significantly contribute to addressing the current climate crisis.

ABSTRACTBackground United States (U.S.) census data from 2017 indicates that the percentage of persons born outside of the U.S. is increasing. However, no studies describe the amount of class time focused on immigrant and refugee health during medical school in the U.S. nor on incoming residents’ confidence in providing culturally sensitive care. The objective of this study is to characterize final-year medical students’ exposure to immigrant and refugee health and their confidence in caring for these populations.Methods A voluntary, cross-sectional survey was sent electronically to fourth-year medical students at twelve U.S. medical schools in 2020, with 707 respondents (46% response rate). Questions addressed respondents’ curricular exposure to immigrant and refugee health care during medical school and their confidence in providing culturally sensitive care. Chi-square tests were used to assess relationships between categorical variables, and odds ratios were calculated for dichotomized variables.Results Most students (70.6%) described insufficient class time dedicated to culturally sensitive care, and many (64.5%) reported insufficient clinical exposure in caring for immigrants/refugees. The odds that incoming residents felt ‘usually’ or ‘always’ confident in their ability to provide culturally sensitive care to immigrants and refugees were higher in those with more class time on culturally sensitive care (OR 5.2 [3.6–7.4]), those with more clinical opportunities to care for immigrants and refugees (OR 7.2 [5.1–10.2]), and those who participated in a domestic low-resource or international elective (OR 1.4 [1.02–1.9]). More than half (55.3%) of respondents reported feeling ‘not at all’ or only ‘sometimes’ confident in their ability to provide culturally sensitive care to immigrants/refugees.Conclusions Most fourth-year U.S. medical students entering residency feel unprepared to deliver culturally sensitive care to immigrants and refugees. This may be mediated by increased exposure to didactic curricula class time and/or experiential clinical activities, as those factors are associated with improved student confidence

Abstract Background Evaluating the impact of environmental exposures on organism health is a key goal of modern biomedicine and is critically important in an age of greater pollution and chemicals in our environment. Environmental health utilizes many different research methods and generates a variety of data types. However, to date, no comprehensive database represents the full spectrum of environmental health data. Due to a lack of interoperability between databases, tools for integrating these resources are needed. In this manuscript we present the Environmental Conditions, Treatments, and Exposures Ontology (ECTO), a species-agnostic ontology focused on exposure events that occur as a result of natural and experimental processes, such as diet, work, or research activities. ECTO is intended for use in harmonizing environmental health data resources to support cross-study integration and inference for mechanism discovery. Methods and findings ECTO is an ontology designed for describing organismal exposures such as toxicological research, environmental variables, dietary features, and patient-reported data from surveys. ECTO utilizes the base model established within the Exposure Ontology (ExO). ECTO is developed using a combination of manual curation and Dead Simple OWL Design Patterns (DOSDP), and contains over 2700 environmental exposure terms, and incorporates chemical and environmental ontologies. ECTO is an Open Biological and Biomedical Ontology (OBO) Foundry ontology that is designed for interoperability, reuse, and axiomatization with other ontologies. ECTO terms have been utilized in axioms within the Mondo Disease Ontology to represent diseases caused or influenced by environmental factors, as well as for survey encoding for the Personalized Environment and Genes Study (PEGS). Conclusions We constructed ECTO to meet Open Biological and Biomedical Ontology (OBO) Foundry principles to increase translation opportunities between environmental health and other areas of biology. ECTO has a growing community of contributors consisting of toxicologists, public health epidemiologists, and health care providers to provide the necessary expertise for areas that have been identified previously as gaps.

Aging is associated with a progressive decline of innate and adaptive immune responses, called immunosenescence. This phenomenon links to different multiple sclerosis (MS) disease courses among different age groups. While clinical relapse and active demyelination are mainly related to the altered adaptive immunity, including invasion of T- and B-lymphocytes, impairment of innate immune cell (e.g., microglia, astrocyte) function is the main contributor to disability progression and neurodegeneration. Most patients with MS manifest the relapsing-remitting phenotype at a younger age, while progressive phenotypes are mainly seen in older patients. Current disease-modifying therapies (DMTs) primarily targeting adaptive immunity are less efficacious in older patients, suggesting that immunosenescence plays a role in treatment response. This review summarizes the recent immune mechanistic studies regarding immunosenescence in patients with MS and discusses the clinical implications of these findings.

Primary mediastinal B-cell lymphoma (PMBCL) is a distinct clinicopathologic entity. Currently, there is a paucity of randomized prospective data to inform on optimal front-line chemoimmunotherapy (CIT) and use of consolidative mediastinal radiation (RT). To assess if distinct CIT approaches are associated with disparate survival outcomes, we performed a systematic review and meta-analysis comparing dose-intensive (DI-CIT) versus standard CIT for the front-line treatment of PMBCL. Standard approach (S-CIT) was defined as R-CHOP-21/CHOP-21, with or without RT. DI-CIT were defined as regimens with increased frequency, dose, and/or number of systemic agents. We reviewed data on 4,068 patients (2,517 DI-CIT; 1,551 S-CIT) with a new diagnosis of PMBCL. Overall survival for DI-CIT patients was 88% (95% CI: 85-90) compared to 80% for the S-CIT cohort (95% CI: 74-85). Meta-regression revealed an 8% overall survival (OS) benefit for the DI-CIT group (P

Inference of toxicological and mechanistic properties of untested chemicals through structural or biological similarity is a commonly employed approach for initial chemical characterization and hypothesis generation. We previously developed a web-based application, Tox21Enricher-Grails, on the Grails framework that identifies enriched biological/toxicological properties of chemical sets for the purpose of inferring properties of untested chemicals within the set. It was able to detect significantly overrepresented biological (e.g., receptor binding), toxicological (e.g., carcinogenicity), and chemical (e.g., toxicologically relevant chemical substructures) annotations within sets of chemicals screened in the Tox21 platform. Here, we present an R Shiny application version of Tox21Enricher-Grails, Tox21Enricher-Shiny, with more robust features and updated annotations. Tox21Enricher-Shiny allows users to interact with the web application component (available at http://hurlab.med.und.edu/Tox21Enricher/) through a user-friendly graphical user interface or to directly access the application’s functions through an application programming interface. This version now supports InChI strings as input in addition to CASRN and SMILES identifiers. Input chemicals that contain certain reactive functional groups (nitrile, aldehyde, epoxide, and isocyanate groups) may react with proteins in cell-based Tox21 assays: this could cause Tox21Enricher-Shiny to produce spurious enrichment analysis results. Therefore, this version of the application can now automatically detect and ignore such problematic chemicals in a user’s input. The application also offers new data visualizations, and the architecture has been greatly simplified to allow for simple deployment, version control, and porting. The application may be deployed onto a Posit Connect or Shiny server, and it uses Postgres for database management. As other Tox21-related tools are being migrated to the R Shiny platform, the development of Tox21Enricher-Shiny is a logical transition to use R’s strong data analysis and visualization capacities and to provide aesthetic and developmental consistency with other Tox21 applications developed by the Division of Translational Toxicology (DTT) at the National Institute of Environmental Health Sciences (NIEHS).

Background: Historically, diagnosis of urinary tract infections (UTIs) has been divided into 3 categories based on symptoms and urine culture results: not UTI, asymptomatic bacteriuria (ASB), or UTI. However, some populations (eg, older adults, catheterized patients) may not present with signs or symptoms referrable to the urinary tract or have chronic lower urinary tract symptoms (LUTS), making the diagnosis of UTI challenging. We sought to understand the clinical presentation of patients who receive urine tests in a cohort of diverse hospitals. Methods: This retrospective descriptive cohort study included all adult noncatheterized inpatient and ED encounters with paired urinalysis and urine cultures (24 hours apart) from 5 community and academic hospitals in 3 states (NC, VA, GA) between January 1, 2017, and December 31, 2019. Trained abstractors collected clinical and demographic data using a 60-question REDCap survey. The study group met with multidisciplinary experts (ID, geriatrics, urology) to define the “continuum of UTI” (Table 1), which includes 2 new categories: (1) LUTS to capture patients with chronic lower urinary tract symptoms and (2) bacteriuria of unclear significance (BUS) to capture patients who do not clinically meet criteria for ASB or UTI (eg, older adults who present with delirium and bacteriuria). The newly defined categories were compared to current guideline-based categories. We further compared ASB, BUS, and UTI categories using a lower bacterial threshold of 1,000 colony-forming units. Results: In total, 220,531 encounters met study criteria. After using a random number generator and removing duplicates, 3,392 encounters were included. Based on current IDSA guidelines, the prevalence of ASB was 32.1% (n = 975), and prevalence of patients with “not UTI” was 1,614 (53%). Applying the expert panel’s new “continuum of UTI” definitions, the prevalence of “not UTI” patients decreased to 1,147 (37.7%), due to reassignment of 467 patients (15.3%)to LUTS. The prevalence of ASB decreased by 24% due to reassignment to BUS. Lowering the bacterial threshold had a slight impact on the number of definitive UTIs (14.9 vs 15.9%) (Table 1). Conclusions: Our rigorous review of laboratory and symptom data from a diverse population dataset revealed that diagnostic uncertainty exists when assessing patients with suspicion for UTI. We propose moving away from dichotomous approach of ASB versus UTI and using the “continuum of UTI” for stewardship conversations. This approach will allow us to develop nuanced deprescribing interventions for patients with LUTS or BUS (eg, watchful waiting, shorter course therapy) that account for the unique characteristics of these populations.

The mission here is to see if we can find bound states for tachyons in some gravitational environment. That could provide an explanation for the phenomena called Dark Matter. Starting with the standard Schwarzschild metric in General Relativity, which is for a static and spherically symmetric source, it appears unlikely that such localized orbits exist. In this work, the usual assumption of isotropic pressure is replaced by a model that has different pressures in the radial and angular directions. This should be relevant to the study of neutrinos, especially if they are tachyons, in cosmological models. We do find an arrangement that allows bound orbits for tachyons in a galaxy. This is a qualitative breakthrough. Then we go on to estimate the numbers involved and find that we do have a fair quantitative fit to the experimental data on the Galaxy Rotation Curve. Additionally we are led to look in the neighborhood of a Black Hole and there we find novel orbits for tachyons.

Centaurs are small solar system objects on chaotic orbits in the giant planet region, forming an evolutionary continuum with the Kuiper Belt objects and Jupiter-family comets. Some Centaurs are known to exhibit cometary activity, though unlike comets, this activity tends not to correlate with heliocentric distance, and the mechanism behind it is currently poorly understood. We utilize serendipitous observations from the Asteroid Terrestrial-impact Last Alert System, Zwicky Transient Facility, Panoramic Survey Telescope and Rapid Response System, Dark Energy Survey, and Gaia in addition to targeted follow-up observations from the Las Cumbres Observatory, TRAnsiting Planets and PlanetesImals Small Telescope South (TRAPPIST-South), and Gemini North telescope to analyze an unexpected brightening exhibited by the known active Centaur (2060) Chiron in 2021. This is highly indicative of a cometary outburst. As of 2023 February, Chiron had still not returned to its prebrightening magnitude. We find Chiron's rotational lightcurve, phase curve effects, and possible high-albedo surface features to be unlikely causes of this observed brightening. We consider the most likely cause to be an epoch of either new or increased cometary activity, though we cannot rule out a possible contribution from Chiron's reported ring system, such as a collision of as-yet-unseen satellites shepherding the rings. We find no evidence for a coma in our Gemini or TRAPPIST-South observations, though this does not preclude the possibility that Chiron is exhibiting a coma that is too faint for observation or constrained to the immediate vicinity of the nucleus.

Abstract Macromolecular damage leading to cell, tissue and ultimately organ dysfunction is a major contributor to aging. Intracellular reactive oxygen species (ROS) resulting from normal metabolism cause most damage to macromolecules and the mitochondria play a central role in this process as they are the principle source of ROS. The relationship between naturally occurring variations in the mitochondrial (MT) genomes leading to correspondingly less or more ROS and macromolecular damage that changes the rate of aging associated organismal decline remains relatively unexplored. MT complex I, a component of the electron transport chain (ETC), is a key source of ROS and the NADH dehydrogenase subunit 5 (ND5) is a highly conserved core protein of the subunits that constitute the backbone of complex I. Using Daphnia as a model organism, we explored if the naturally occurring sequence variations in ND5 correlate with a short or long lifespan. Our results indicate that the short-lived clones have ND5 variants that correlate with reduced complex I activity, increased oxidative damage, and heightened expression of ROS scavenger enzymes. Daphnia offers a unique opportunity to investigate the association between inherited variations in components of complex I and ROS generation which affects the rate of aging and lifespan.

Detection and identification of species, subspecies or stocks of whales, dolphins and porpoises at sea remain challenging, particularly for cryptic or elusive species like beaked whales (Family: Ziphiidae). Here we investigated the potential for using an acoustically assisted sampling design to collect environmental (e)DNA from beaked whales on the U.S. Navy's Atlantic Undersea Test and Evaluation Center (AUTEC) in The Bahamas. During 12 days of August 2019, we conducted 9 small-boat surveys and collected 56 samples of seawater (paired subsamples of 1L each, including controls) using both a spatial collection design in the absence of visual confirmation of whales, and a serial collection design in the proximity of whales at the surface. There were 7 sightings of whales, including 11 Blainville's beaked whales (Mesoplodon densirostris). All whales were located initially with the assistance of information from a bottom-mounted acoustic array available on the AUTEC range. Quantification by droplet digital (dd)PCR from the four spatial design collections showed no samples of eDNA above the threshold of detection and none of these 20 samples yielded amplicons for conventional or next-generation sequencing. Quantification of the 31 samples from four serial collections identified 11 likely positive detections. eDNA barcoding by conventional sequencing and eDNA metabarcoding by next-generation sequencing confirmed species identification for 9 samples from three of the four serial collections. We further resolved five intra-specific variants (i.e., haplotypes), two of which showed an exact match to previously published haplotypes and three that have not been reported previously to the international repository, GenBank. A minimum spanning network of the five eDNA haplotypes, with all other published haplotypes of Blainville's beaked whales, suggested the potential for further resolution of differences between oceanic populations.

Abstract Background Patients with inflammatory bowel disease (IBD) have a high-life time risk undergoing abdominal surgery and are prone to develop incisional hernias (IH) in the postoperative course. Therefore, we investigated the role of IBD as perioperative risk factor in open ventral hernia repair (OVHR) as well as the impact of IBD on hernia recurrence during postoperative follow-up. Methods The postoperative course of 223 patients (Non-IBD (n = 199) and IBD (n = 34)) who underwent OVHR were compared by means of extensive group comparisons and binary logistic regressions. Hernia recurrence was investigated in the IBD group according to the Kaplan–Meier method and risk factors for recurrence determined by Cox regressions. Results General complications (≥ Clavien-Dindo I) occurred in 30.9% (72/233) and major complications (≥ Clavien-Dindo IIIb) in 7.7% (18/233) of the overall cohort with IBD being the single independent risk-factor for major complications (OR = 4.2, p = 0.007). Further, IBD patients displayed a recurrence rate of 26.5% (9/34) after a median follow-up of 36 months. Multivariable analysis revealed higher rates of recurrence in patients with ulcerative colitis (UC, 8/15, HR = 11.7) compared to patients with Crohn’s disease (CD, 1/19, HR = 1.0, p = 0.021). Conclusion IBD is a significant risk factor for major postoperative morbidity after OVHR. In addition, individuals with IBD show high rates of hernia recurrence over time with UC patients being more prone to recurrence than patients with CD.

Introduction A growing number of international studies have highlighted the adverse consequences of lived experience in the first thousand days of pregnancy and early life on the probability of stillbirth, child mortality, inadequate growth and healthy development during both childhood and adulthood. The lived experience of the fetus inside the womb and at the birth is strongly related to both maternal health during pregnancy and maternal exposure to a set of environmental factors known as ‘exposome’ characteristics, which include environmental exposure, health behaviours, living conditions, neighbourhood characteristics and socioeconomic profile. The aim of our project is to explore the relationships between exposome characteristics and the health status of pregnant women and their newborns. We are particularly interested in studying the relationships between the social inequality of adverse pregnancy outcomes and (1) short-term exposure to atmospheric pollution (MobiFem project) and (2) pregnancy lifestyle (EnviFem project).Methods and analysis Ours is a prospective, observational and multisite cohort study of pregnant women, involving one teaching hospital across two sites in the Strasbourg metropolitan area.The research team at University Hospital of Strasbourg (HUS) Health collects data on outcomes and individual characteristics from pregnancy registries, clinical records data and questionnaires administered via email to study participants. Recruitment began in February 2021 and will be complete by December 2021. Participants are recruited from first trimester antenatal ultrasound examinations (conducted on weekdays across both sites); each woman meeting our inclusion criteria enters the cohort at the end of her first trimester. Study participants receive a total of three online questionnaires covering sociodemographic characteristics, travel behaviour patterns and lifestyle. Participants complete these questionnaires at recruitment, during the second and third trimester. The level of personal exposure to air pollution is characterised using a dynamic spatiotemporal trajectory model that describes the main daily movements of pregnant women and the time spent in each place frequented. Univariate, multilevel and Bayesian model will be used to investigate the relationships between exposome characteristics and the health status of pregnant women and their newborns.Ethics and dissemination Our research was approved by the Commission de Protection des Personnes (CPP) Ile de France VI (Paris) on 9 December 2020 (File reference No. 20.09.15.41703 ID RCB: 2020-A02580-39 and No. 20 080–42137 IDRCB 2020-A02581-38). The Agence Nationale de Sécurité du Médicament was informed of it on 15 December 2020. Findings from the study will be disseminated through publications and international conferences and through presentation at meetings with local stakeholders, researchers and policy-makers.Trial registration numbers NCT04705272, NCT04725734

Abstract Background An increasing number of medical trainees across specialties desire and expect Global Health (GH) experiences during training. It is useful for residency programs to know the impact that offering GH opportunities has on resident recruitment. The study objectives were to explore the importance of GH opportunities in residency selection among fourth-year medical students, examine the relationship between interest in GH and career plans, and describe students’ perspectives on prior GH experiences. Methods The authors administered an electronic survey to all fourth-year medical students attending 12 different US institutions in February 2020. Data from the ten schools who were able to comply with the survey distribution methodology and with response rates above 25% were analyzed using descriptive statistics and Pearson’s correlation. Results A total of 707 fourth-year medical students from the included schools completed the survey out of 1554 possible students (46% response rate). One third of respondents ranked the presence of GH experiences in residency as moderately or very important and 26% felt that the presence of a formal GH curriculum was at least moderately important, with variation noted among specialties. After training, 65% of students envision practicing internationally in some capacity. A desire to care for underserved patients in their careers was significantly correlated with an interest in GH experiences during residency. Conclusions The opportunity to be involved in GH experiences during training can be an important factor for many medical students when considering residency choice, and the availability of these opportunities may be a valuable recruitment tool. Students valuing GH opportunities during residency are more interested in working with underserved populations in their future careers.

Abstract As Timor‐Leste nears the end of its petroleum‐exporting era, the transition to a sustainable economy has become even more challenging due to partisan political competition, disastrous flooding and the pandemic. This article describes the current economic context, and deteriorating trends. After a brief discussion of the political situation and the impacts of COVID‐19, it explores expenditure and income trends in recent state budgets, with a particular focus on dependency on oil and gas revenues and their investments, which pay for 80% of state spending and may run out within a decade. It then assesses in detail revenue prospects from current and future oil and gas activities, including Greater Sunrise and the planned Tasi Mane petroleum infrastructure project. The analysis shows that it is highly likely that resource revenue will continue to decline. Diversification is not an option; it is the only way forward.

After Timor-Leste restored independence in 2002, the new nation established a rigorous system to manage oil and gas revenues and activities, based on international best practice. Policymakers hoped that it would protect the small nation from the ‘resource curse’ which afflicts countries that depend on exporting non-renewable wealth. Within five years, petroleum exports were financing 85% of the state budget and comprised 75% of GDP. By 2021, with its known oil and gas reserves nearly depleted, Timor-Leste has made little progress toward diversifying into a sustainable economy or alleviating poverty and malnutrition. This paper explores what happened, and try to explain why well-intentioned legal and structural measures were not sufficient to avert the ‘paradox of plenty.’

Abstract Background National forest inventory and forest monitoring systems are more important than ever considering continued global degradation of trees and forests. These systems are especially important in a country like Bangladesh, which is characterised by a large population density, climate change vulnerability and dependence on natural resources. With the aim of supporting the Government’s actions towards sustainable forest management through reliable information, the Bangladesh Forest Inventory (BFI) was designed and implemented through three components: biophysical inventory, socio-economic survey and remote sensing-based land cover mapping. This article documents the approach undertaken by the Forest Department under the Ministry of Environment, Forests and Climate Change to establish the BFI as a multipurpose, efficient, accurate and replicable national forest assessment. The design, operationalization and some key results of the process are presented. Methods The BFI takes advantage of the latest and most well-accepted technological and methodological approaches. Importantly, it was designed through a collaborative process which drew from the experience and knowledge of multiple national and international entities. Overall, 1781 field plots were visited, 6400 households were surveyed, and a national land cover map for the year 2015 was produced. Innovative technological enhancements include a semi-automated segmentation approach for developing the wall-to-wall land cover map, an object-based national land characterisation system, consistent estimates between sample-based and mapped land cover areas, use of mobile apps for tree species identification and data collection, and use of differential global positioning system for referencing plot centres. Results Seven criteria, and multiple associated indicators, were developed for monitoring progress towards sustainable forest management goals, informing management decisions, and national and international reporting needs. A wide range of biophysical and socioeconomic data were collected, and in some cases integrated, for estimating the indicators. Conclusions The BFI is a new information source tool for helping guide Bangladesh towards a sustainable future. Reliable information on the status of tree and forest resources, as well as land use, empowers evidence-based decision making across multiple stakeholders and at different levels for protecting natural resources. The integrated socio-economic data collected provides information about the interactions between people and their tree and forest resources, and the valuation of ecosystem services. The BFI is designed to be a permanent assessment of these resources, and future data collection will enable monitoring of trends against the current baseline. However, additional institutional support as well as continuation of collaboration among national partners is crucial for sustaining the BFI process in future.

Abstract Background While much has been reported regarding the clinical course of COVID-19 in children, little is known regarding factors associated with organ dysfunction in pediatric COVID-19. We describe critical illness in pediatric patients with active COVID-19 and identify factors associated with PICU admission and organ dysfunction. This is a retrospective chart review of 77 pediatric patients age 1 day to 21 years admitted to two New York City pediatric hospitals within the Northwell Health system between February 1 and April 24, 2020 with PCR + SARS-CoV-2. Descriptive statistics were used to describe the hospital course and laboratory results and bivariate comparisons were performed on variables to determine differences. Results Forty-seven patients (61%) were admitted to the general pediatric floor and thirty (39%) to the PICU. The majority (97%, n = 75) survived to discharge, 1.3% (n = 1) remain admitted, and 1.3% (n = 1) died. Common indications for PICU admission included hypoxia (50%), hemodynamic instability (20%), diabetic ketoacidosis (6.7%), mediastinal mass (6.7%), apnea (6.7%), acute chest syndrome in sickle cell disease (6.7%), and cardiac dysfunction (6.7%). Of PICU patients, 46.7% experienced any significant organ dysfunction (pSOFA > = 2) during admission. Patients aged 12 years or greater were more likely to be admitted to a PICU compared to younger patients (p = 0.015). Presence of an underlying comorbidity was not associated with need for PICU admission (p = 0.227) or organ dysfunction (p = 0.87). Initial white blood cell count (WBC), platelet count, and ferritin were not associated with need for PICU admission. Initial C-reactive protein was associated with both need for PICU admission (p = 0.005) and presence of organ dysfunction (p = 0.001). Initial WBC and presenting thrombocytopenia were associated with organ dysfunction (p = 0.034 and p = 0.003, respectively). Conclusions Age over 12 years and initial CRP were associated with need for PICU admission in COVID-19. Organ dysfunction was associated with elevated admission CRP, elevated WBC, and thrombocytopenia. These factors may be useful in determining risk for critical illness and organ dysfunction in pediatric COVID-19.

Abstract Background Studies of agreement examine the distance between readings made by different devices or observers measuring the same quantity. If the values generated by each device are close together most of the time then we conclude that the devices agree. Several different agreement methods have been described in the literature, in the linear mixed modelling framework, for use when there are time-matched repeated measurements within subjects. Methods We provide a tutorial to help guide practitioners when choosing among different methods of assessing agreement based on a linear mixed model assumption. We illustrate the use of five methods in a head-to-head comparison using real data from a study involving Chronic Obstructive Pulmonary Disease (COPD) patients and matched repeated respiratory rate observations. The methods used were the concordance correlation coefficient, limits of agreement, total deviation index, coverage probability, and coefficient of individual agreement. Results The five methods generated similar conclusions about the agreement between devices in the COPD example; however, some methods emphasized different aspects of the between-device comparison, and the interpretation was clearer for some methods compared to others. Conclusions Five different methods used to assess agreement have been compared in the same setting to facilitate understanding and encourage the use of multiple agreement methods in practice. Although there are similarities between the methods, each method has its own strengths and weaknesses which are important for researchers to be aware of. We suggest that researchers consider using the coverage probability method alongside a graphical display of the raw data in method comparison studies. In the case of disagreement between devices, it is important to look beyond the overall summary agreement indices and consider the underlying causes. Summarising the data graphically and examining model parameters can both help with this.

Abstract Background Recent guidelines recommend consideration of germline testing for all newly diagnosed pancreatic ductal adenocarcinoma (PDAC). The primary aim of this study was to determine the burden of hereditary cancer susceptibility in PDAC. A secondary aim was to compare genetic testing uptake rates across different modes of genetic counselling. Patients and Methods All patients diagnosed with PDAC in the province of British Columbia, Canada referred to a population‐based hereditary cancer program were eligible for multi‐gene panel testing, irrespective of cancer family history. Any healthcare provider or patients themselves could refer. Results A total of 305 patients with PDAC were referred between July 2016 and January 2019. Two hundred thirty‐five patients attended a consultation and 177 completed index germline genetic testing. 25/177 (14.1%) of unrelated patients had a pathogenic variant (PV); 19/25 PV were in known PDAC susceptibility genes with cancer screening or risk‐reduction implications. PDAC was significantly associated with PV in ATM (OR, 7.73; 95% CI, 3.10 to 19.33, P = 6.14E‐05) when comparing age and gender and ethnicity‐matched controls tested on the same platform. The overall uptake rate for index testing was 59.2% and was significantly higher with 1‐on‐1 consultations and group consultations compared to telehealth consultations (88.9% vs 82.9% vs 61.8%, P

Abstract Background Point-of-care ultrasound (PoCUS) by emergency physicians for renal colic has been proposed as an alternative to computed tomography (CT) to avoid ionizing radiation exposure and shorten emergency department length of stay. Previous studies have employed experienced or credentialed ultrasonographers or required advanced ultrasound skills. We sought to measure the diagnostic accuracy of PoCUS by physicians with varied experience using a simplified binary outcome of presence or absence of hydronephrosis. Secondary outcomes include assessment as to whether the presence of hydronephrosis on PoCUS is predictive of complications, and to evaluate possible causes for the reduced diagnostic accuracy such as body mass index (BMI) and time between PoCUS and formal imaging, and scanner experience. Results 413 patients were enrolled in the study. PoCUS showed a specificity of 71.8% [95% CI 65.0, 77.9] and sensitivity of 77.1% [95% CI 70.9, 82.6]. Hydronephrosis on PoCUS was predictive of complications (relative risk 3.13; [95% CI 1.30, 7.53]). The time interval between PoCUS and formal imaging, BMI, and scanner experience did not influence the accuracy of PoCUS. Conclusions PoCUS for hydronephrosis in suspected renal colic has moderate accuracy when performed by providers with varied experience for the binary outcome of presence or absence of hydronephrosis. Hydronephrosis on PoCUS is associated with increased rates of complications. PoCUS for hydronephrosis is limited in its utility as a stand-alone test, however this inexpensive, readily available test may be useful in conjunction with clinical course to determine which patients would benefit from formal imaging or urologic consultation. ClinicalTrials.gov Identifier NCT01323842

The COVID-19 pandemic has had a negative impact on older persons who reside in long-term care settings, especially residents living with dementia. The physical and psychological burden of the current pandemic has also been felt by frontline caring staff including nurses caring for persons living with dementia. The aim of the study was to explore the experiences of nurses while caring for residents with dementia who resided in long-term dementia care units during the COVID-19 pandemic. Nine Maltese nurses working in dementia care units were interviewed during the month of February 2021. Following analysis of the transcripts, three themes were identified; ‘living the challenges of the pandemic’, ‘passing through a roller coaster of emotions’ and ‘building on personal and organisational resilience’. The participants lived through several challenges which in turn generated both positive and negative emotions. Moving forward through this period mostly relied on their coping strategies, how they negotiated infection control measures with the residents’ quality of life and how their organisation was able to provide quality dementia care pre-COVID-19. The study indicated how personal and organisational resilience could have influenced the participants’ experience of the pandemic and helped nursing staff in developing new ways of working.

Summary: Overlapping clinical phenotypes and an expanding breadth and complexity of genomic associations are a growing challenge in the diagnosis and clinical management of Mendelian disorders. The functional consequences and clinical impacts of genomic variation may involve unique, disorder-specific, genomic DNA methylation episignatures. In this study, we describe 19 novel episignature disorders and compare the findings alongside 38 previously established episignatures for a total of 57 episignatures associated with 65 genetic syndromes. We demonstrate increasing resolution and specificity ranging from protein complex, gene, sub-gene, protein domain, and even single nucleotide-level Mendelian episignatures. We show the power of multiclass modeling to develop highly accurate and disease-specific diagnostic classifiers. This study significantly expands the number and spectrum of disorders with detectable DNA methylation episignatures, improves the clinical diagnostic capabilities through the resolution of unsolved cases and the reclassification of variants of unknown clinical significance, and provides further insight into the molecular etiology of Mendelian conditions.

Abstract Background and Aim This study quantifies how changes in healthcare utilization and delivery during the first months of the COVID‐19 pandemic have altered the presentation, treatment, and management of patients with gastrointestinal (GI) malignancies within an academic health system. Methods and results Patients diagnosed with a GI malignancy (ICD10: C15‐C26) who received medical care within the health system during the observation period (first 44 weeks of 2019 and 2020) were identified for a retrospective cohort study. Deidentified patient encounter parameters were collected for this observation period and separated into pre‐pandemic (weeks 1–10) and early pandemic (weeks 11–20) study periods. Difference‐in‐difference analyses adjusted for week‐specific and year‐specific effects quantified the impact of the COVID‐19 pandemic on care delivery between pre‐pandemic and early pandemic study periods in 2020. Across all GI malignancies, the COVID‐19 pandemic has been associated with a significant decline in the number of patients with new patient visits (NPVs) (p = 1.2 × 10−4), Radiology encounters (p = 1.9 × 10−7), Surgery encounters (p = 1.6 × 10−3), Radiation Oncology encounters (p = 4.1 × 10−3), and infusion visits (6.1 × 10−5). Subgroup analyses revealed cancer‐specific variations in changes to delivery. Patients with colorectal cancer (CRC) had the most significant decrease in NPVs (p = 7.1 × 10−5), which was significantly associated with a concomitant decrease in colonoscopies performed during the early pandemic period (r2 = 0.722, p = 2.1 × 10−10). Conclusions The COVID‐19 pandemic has been associated with significant disruptions to care delivery. While these effects were appreciated broadly across GI malignancies, CRC, diagnosed and managed by periodic screening, has been affected most acutely.