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Abstract Mohs surgeons' fallibility is an important topic to explore. There are no studies on the role of cognitive biases in heuristic decision‐making within Mohs micrographic surgery (MMS) as a contributing factor in mistakes or errors of clinical judgement. We reviewed established cognitive biases applied to heuristics during the pre‐operative, intraoperative and reconstruction stages of MMS, and recommend conscious cognitive bias mitigating strategies for Mohs surgeons. Clinical errors/incidents may be reframed as opportunities to learn and develop, rather than evidence of competency or status. These experiences offer the opportunity to sharpen skills within metacognition and allow for more cognizant Mohs surgeons. We highly recommend all Mohs surgeons develop in‐depth knowledge and maintain awareness of cognitive biases throughout clinical practice, to enhance clinical performance.

ABSTRACT Bats are known to host zoonotic viruses, including henipaviruses that cause high fatality rates in humans (Nipah virus and Hendra virus). However, the determinants of zoonotic spillover are generally unknown, as the ecological and demographic drivers of viral circulation in bats are difficult to ascertain without longitudinal data. Here we analyse serological data collected from African straw‐coloured fruit bats (Eidolon helvum) in Ghana over the course of 2 years and across four sites, comprising three wild roosts and one captive colony. We focus on antibody affinity to five henipavirus antigens: Ghanaian bat henipavirus (GhV), Nipah virus (NiV), Hendra virus (HeV), Mojiang virus (MojV) and Cedar virus (CedV). In the wild roosts, we detected seasonal variations in henipavirus antibody binding, possibly associated with bat life‐history cycles and migration patterns. In the captive colony, we identified increases in antibody affinity levels among pregnant bats, suggesting possible shifts in the immune system during pregnancy. These bats then pass maternal antibodies to their pups, which wane before antibody affinity levels rise later in life following initial infections and/or reactivation of latent infections. These results improve our understanding of the links between bat ecology and viral circulation, including for GhV, a locally‐circulating African henipavirus.

Abstract Within the Industry 4.0 landscape, humans collaborate with cyber and physical elements to form human‐cyber‐physical systems (HCPS). These environments are increasingly complex and challenging workspaces due to increasing levels of automation and data availability. An effective system design requires suitable frameworks that consider human activities and needs whilst supporting overall system efficacy. Although several reviews of frameworks for technology were identified, none of these focused on the human in the system (moving towards Industry 5). The critical literature review presented provides a summary of HCPS frameworks, maps the considerations for a human in HCPS, and provides insight for future framework and system development. The challenges, recommendations, and areas for further research are discussed.

Abstract Objectives The aim was to assess the prevalence of never events (NEs) specific to urology in the United Kingdom and identify commonly occurring themes. Methods Data from the National Health Service (NHS) NEs website were obtained and all NEs from 2012 to 2022 were reviewed. Urology‐specific NEs were identified and further analysed in their respective categories. Data regarding the total number of surgical procedures performed in the NHS specific to each specialty were obtained via the NHS Hospital Episode Statistics website. Results There were 3972 NEs recorded over the 10‐year period with 95 (2.4%) of these as a result of urology surgery. The most common surgical intervention associated with a urological NE was ureteric stenting, which comprised 45/95 (47.4%) of all analysed NEs. These consisted of wrong site ureteric stent insertion (n = 29), wrong site ureteric stent removal (n = 9), wrong stent type (n = 5) and retained guidewires (n = 2). There were 7.14 million urology surgeries performed in the 10‐year period, and prevalence was 0.0013%. Conclusion NEs are fully preventable serious incidents in the NHS. This is the first study to investigate the prevalence of NEs in urology in the United Kingdom. This study demonstrates that in the last 10 years the prevalence of urology NEs is low at 0.0013%, with ureteric stent procedures accounting for more than half of the NEs. Urologists should be mindful of the potential for wrong site surgery in urologic stenting procedures.

Abstract The OPRM1 gene codes for the mu opioid receptor (MOR) and polymorphisms are associated with complex patient clinical responses. The most studied single nucleotide polymorphism (SNP) in OPRM1 is adenine (A) substituted by guanine (G) at position 118 (118A>G, rs1799971) leading to a substitution of asparagine (Asn) for aspartic acid (Asp) at position 40 in the N terminus of the resulting protein. To date, no structural explanation for the associated clinical responses resulting from the 118A>G polymorphism has been proposed. We utilized computational modeling paired with functional cellular assays to predict unstructured N‐ and C‐terminal regions of MOR‐1. Using molecular docking and post‐docking energy minimizations with morphine, we show that the extracellular substitution of Asn at position 40 alters the cytoplasmic C‐terminal conformation, while leaving the G‐protein binding interface unaffected. A real‐time BRET assay measuring G‐protein and β‐arrestin association with MOR r generated data that tested this prediction. Consistent with this in silico prediction, we show changes in morphine‐mediated β‐arrestin association with receptor variants with little change in morphine‐mediated G‐protein association comparing MOR‐1 wild type (WT) to MOR‐1118A>G. We tested the system with different opioid agonists, the OPRM1 118A>G SNP, and different MOR splice variants (MOR‐1 and MOR‐1O). These results are consistent with the observation that patients with the 118A>G OPRM1 allele respond more readily to fentanyl than to morphine. In conclusion, the 118A>G substitution alters receptor responses to opioids through variable C‐terminal domain movements that are agonist and splice variant dependent.

Societal Impact Statement Recognizing Loudetia‐dominated grasslands were widespread prior to human colonization highlights that open ecosystems were and continue to be an important component of Madagascar's biodiversity. A better understanding of the plant species that form grassland ecosystems is necessary for effective land management strategies that support livelihoods, but substantial financial and logistical barriers exist to implementing conservation genetic studies using contemporary genomic tools. Some challenges for population genetic analyses of non‐model polyploids lacking reference genomes can be ameliorated by developing computational resources that leverage a cost‐effective data generation strategy that requires no prior genetic knowledge of the target species. This may benefit conservation programs with small operating budgets while reducing uncertainty compared to status quo microsatellite assays. Summary The extent of Madagascar's grasslands prior to human colonization is unresolved. We used population genetic analyses of a broadly dominant C4 fire‐adapted grass, Loudetia simplex, as a proxy for estimating grassland change through time. We carefully examined the utility of target‐enrichment data for population genetics to make recommendations for conservation genetics. We explored the potential of estimating individual ploidy levels from target‐enrichment data and how assumptions about ploidy could affect analyses. We developed a novel bioinformatic pipeline to estimate ploidy and genotypes from target‐enrichment data. We estimated standard population genetic summary statistics in addition to species trees and population structure. Extended Bayesian skyline plots provided estimates of population size through time for empirical and simulated data. All Malagasy L. simplex individuals sampled in this study formed a clade and possibly indicated an ancestral Central Highland distribution of 800 m in altitude and above. Demographic models suggested grassland expansions occurred prior to the Last Interglacial Period and supported extensive grasslands prior to human colonization. Though there are limitations to target‐enrichment data for population genetic studies, we find that analyses of population structure are reliable. Genetic variation in L. simplex supports widespread grasslands in Madagascar prior to the more recent periods of notable paleoclimatic change. However, the methods explored here could not differentiate between paleoclimatic change near the Last Glacial Maximum and anthropogenic effects. Target‐enrichment data can be a valuable tool for analyses of population structure in the absence a reference genome.

Abstract Measuring vector–human contact in a natural setting can inform precise targeting of interventions to interrupt transmission of vector‐borne diseases. One approach is to directly match human DNA in vector bloodmeals to the individuals who were bitten using genotype panels of discriminative short tandem repeats (STRs). Existing methods for matching STR profiles in bloodmeals to the people bitten preclude the ability to match most incomplete profiles and multisource bloodmeals to bitten individuals. We developed bistro, an R package that implements three pre‐existing STR matching methods as well as the package's namesake, bistro, a new algorithm described here. bistro employs forensic analysis methods to calculate likelihood ratios and match human STR profiles in bloodmeals to people using a dynamic threshold. We evaluated the algorithm's accuracy and compared it to existing matching approaches using a publicly available panel of 188 single‐source and 100 multisource samples containing DNA from 50 known human sources. Then, we applied it to match 777 newly field‐collected mosquito bloodmeals to a database of 645 people. The R package implements four STR matching algorithms in user‐friendly functions with clear documentation. bistro correctly matched 99% (187/188) of profiles in single‐source samples, and 62% (224/359) of profiles from multisource samples, resulting in a sensitivity of 0.75 (vs.

Abstract Objectives With the legalization of cannabis in New Jersey on April 21, 2022, including the licensing of cannabis dispensaries, concerns have arisen about potential adverse events related to cannabis use. Here, we explore temporal trends and risk factors for cannabis‐related harm in both adult and pediatric cannabis‐related visits at a tertiary care academic institution. Methods We performed a retrospective chart review and temporal trend analysis via the electronic health record from May 1, 2019 to October 31, 2022, covering 2 years before, and 6 months after, cannabis legalization in New Jersey. The pediatric charts identified were analyzed for root causes of adverse events, and changes in the frequency of specific unsafe practices since cannabis legalization were tracked. Results We found that adult cannabis ED‐related visits significantly increased during the COVID‐19 pandemic and remained higher than pre‐pandemic levels for the remainder of the study periods, without a significant change upon legalization. Pediatric rates of cannabis‐related ED visits did not vary significantly during the study period. The vast majority of visits for children aged 0–12 years were related to accidental cannabis exposures—often a household member's edibles—whereas most visits for older children stemmed from intentional cannabis use. Conclusion This project highlights the unintended consequences of wider cannabis access in New Jersey. Notably, cannabis use increased even before its legalization, presumably in response to the COVID‐19 pandemic and its attendant mental health effects. Rates of cannabis use disorder and its highlight of other concurrent psychiatric disorders are important topics for both clinicians and lawmakers to consider.

Abstract Objectives Single‐use rhinolaryngoscopes were brought to market in 2019 as an alternative to traditional reusable scopes and have garnered interest across settings given portability and potential cost advantages. While single‐use was previously evaluated compared to traditional devices, the overall impact to the consult experience for both users and patients has not been captured. Methods Eighteen residents performed consults with both single‐use and reusable rhinolaryngoscope systems on alternating weeks. A five‐question cumulative survey administered across three assessment points over a 12‐week period using a five‐point rating system to rate favorability. Residents and patients also completed four‐point scale surveys following procedure(s) to capture the consult experience. Statistical analyses were performed to measure significance differences between survey responses between the two systems. Results Single‐use rhinolaryngoscopes received higher overall ratings compared with reusables across each metric captured including overall consult time (4.3 vs. 2.2, p

Abstract The once abundant delta smelt Hypomesus transpacificus is now on the verge of extinction. At the UC Davis Fish Conservation and Culture Laboratory, a refuge population has been maintained since 2008 as a safeguard against extinction and to breed and provide fish for research. Due to artificial aquaculture operations, it is assumed that the fish are impacted by life in captivity leading to questions about differences between cultured and captive wild fish. This study looked at the differences in fork length (FL), body weight (BW), fecundity (F) and condition factor (K) of cultured and wild (captive) delta smelt over the last 10 generations (2009–2018) to determine if there were any changes of life‐history traits between the two, which may indicate domestication. Results revealed that the cultured population had significantly higher FL, BW, F and K than the wild population. The correlation tests found significant positive relationships between all measured traits except FL and K of wild fish. Significant changes in the measured traits of the cultured population over time were found, whereas none was observed in most wild fish year‐classes. This study demonstrated changes of life‐history traits in a well‐managed fish population over 10 generations in captivity and provides critical information to the coming supplementation plan for the species.

Abstract Ice shelves are assumed to flow steadily from their grounding lines to the ice front. We report the detection of ice‐propagating extensional Lamb (plate) waves accompanied by pulses of permanent ice shelf displacement observed by co‐located Global Navigation Satellite System receivers and seismographs on the Ross Ice Shelf. The extensional waves and associated ice shelf displacement are produced by tidally triggered basal slip events of the Whillans Ice Stream, which flows into the ice shelf. The propagation velocity of 2,800 m/s is intermediate between shear and compressional ice velocities, with velocity and particle motions consistent with predictions for extensional Lamb waves. During the passage of the Lamb waves the entire ice shelf is displaced about 60 mm with a velocity more than an order of magnitude above its long‐term flow rate. Observed displacements indicate a peak dynamic strain of 10−7, comparable to that of earthquake surface waves that trigger ice quakes.

Abstract Introduction In November 2020, the FDA issued an emergency use authorization (EUA) for monoclonal antibody (mAb) therapy in patients with mild‐to‐moderate COVID‐19 at high risk for disease progression. Methods We retrospectively reviewed 38 adult hematology patients who received mAbs from 11/2020 to 2/2021. Results Thirty (79%) patients received bamlanivimab and 8 (21%) casirivimab‐imdevimab. Four (11%) patients were hospitalized due to COVID‐19, two (5%) progressed to severe disease and one patient (3%) died within 30 days from COVID‐19 disease. Most patients (n = 34, 89%) ultimately tested negative for SARS‐CoV‐2, with 34% (n = 13) clearing the virus within 14 days after mAb infusion. The median time to clearance of viral shedding was 25.5 days (range: 7–138). After mAb infusion, most patients with hematological malignancies (HM) (n = 10/15; 67%) resumed therapy for underlying disease with a median delay of 21.5 days (range: 12–42). We observed a significant difference in hospitalization among patients who received a HCT versus non‐HCT (0% n = 0/26 and 36% n = 4/11, respectively; p

Abstract Background In order to proliferate indefinitely, all tumors require a telomere maintenance mechanism. The expression of human telomerase reverse transcriptase (hTERT) enables telomere maintenance and provides cancer cells with limitless replicative potential. As such, it may serve as an attractive biomarker for oncogenic activity. This study explored whether a liquid biopsy that analyses blood derived exosomal hTERT transcript (e‐hTERT‐trans) may serve as such a biomarker in gliomas and meningiomas when compared to healthy controls. Methods Exosomes were isolated from the pre‐operative sera of patients' samples stored in the biobank of both Rabin and Sheba Medical Centers. The levels of e‐hTERT‐trans were measured in 81 healthy controls, 117 meningiomas, 17 low‐grade gliomas, and 61 glioblastomas. Clinical parameters of the patients were collected retrospectively and compared to the levels of the e‐hTERT‐trans. Results The upper normal limit of controls e‐hTERT‐trans was 1.85 relative quantitation (RQ). The rate of detection increased with rising tumor grade and correlated with tumor recurrence in meningiomas: mean RQ without recurrence (2.17 ± 11.7) versus with recurrence (3.59 ± 4.42; p = 0.002). In glioblastomas, preoperative measurements correlated with tumor volume and with the disease course on serial sampling. Conclusions We demonstrated for the first time that the expression of e‐hTERT‐trans transcript can be measured in the serum of primary brain tumors. This exosomal marker carries the potential to serve as a biomarker once used in conjunction with other clinical and radiological parameters. Future studies are required to investigate whether the sensitivity could be augmented and whether it can be implemented into routine patients care.

Abstract Immune checkpoint inhibitors (ICI), pembrolizumab and atezolizumab, were recently approved for treatment‐refractory triple‐negative breast cancer (TNBC), where those with Programmed death‐ligand 1 (PD‐L1) positive early‐stage disease had improved responses. ICIs are administered systemically in the clinic, however, reaching effective therapeutic dosing is challenging due to severe off‐tumor toxicities. As such, intratumoral (IT) injection is increasingly investigated as an alternative delivery approach. However, repeated administration, which sometimes is invasive, is required due to rapid drug clearance from the tumor caused by increased interstitial fluid pressure. To minimize off‐target drug biodistribution, we developed the nanofluidic drug‐eluting seed (NDES) platform for sustained intratumoral release of therapeutic via molecular diffusion. Here we compared drug biodistribution between the NDES, intraperitoneal (IP) and intratumoral (IT) injection using fluorescently labeled PD‐L1 monoclonal antibody (αPD‐L1). We used two syngeneic TNBC murine models, EMT6 and 4T1, that differ in PD‐L1 expression, immunogenicity, and transport phenotype. We investigated on‐target (tumor) and off‐target distribution using different treatment approaches. As radiotherapy is increasingly used in combination with immunotherapy, we sought to investigate its effect on αPD‐L1 tumor accumulation and systemic distribution. The NDES‐treated cohort displayed sustained levels of αPD‐L1 in the tumor over the study period of 14 days with significantly lower off‐target organ distribution, compared to the IP or IT injection. However, we observed differences in the biodistribution of αPD‐L1 across tumor models and with radiation pretreatment. Thus, we sought to extensively characterize the tumor properties via histological analysis, diffusion evaluation and nanoparticles contrast‐enhanced CT. Overall, we demonstrate that ICI delivery via NDES is an effective method for sustained on‐target tumor delivery across tumor models and combination treatments.

Background We tested the potential of the Secondary Manifestations of Arterial Disease (SMART2) risk score for use in patients undergoing coronary artery bypass grafting. Methods and Results We conducted an external validation of the SMART2 score in a racially diverse high‐risk national cohort (2010–2019) that underwent isolated coronary artery bypass grafting. We calculated the preoperative SMART2 score and modeled the 5‐year major adverse cardiovascular event (cardiovascular mortality+myocardial infarction+stroke) incidence. We evaluated SMART2 score discrimination at 5 years using c‐statistic and calibration with observed/expected ratio and calibration plots. We analyzed the potential clinical benefit using decision curves. We repeated these analyses in clinical subgroups, diabetes, chronic kidney disease, and polyvascular disease, and separately in White and Black patients. In 27 443 (mean age, 65 years; 10% Black individuals) US veterans undergoing coronary artery bypass grafting (2010–2019) nationwide, the 5‐year major adverse cardiovascular event rate was 25%; 27% patients were in high predicted risk (>30% 5‐year major adverse cardiovascular events). SMART2 score discrimination (c‐statistic: 64) was comparable to the original study (c‐statistic: 67) and was best in patients with chronic kidney disease (c‐statistic: 66). However, it underpredicted major adverse cardiovascular event rates in the whole cohort (observed/expected ratio, 1.45) as well as in all studied subgroups. The SMART2 score performed better in White than Black patients. On decision curve analysis, the SMART2 score provides a net benefit over a wide range of risk thresholds. Conclusions The SMART2 model performs well in a racially diverse coronary artery bypass grafting cohort, with better predictive capabilities at the upper range of baseline risk, and can therefore be used to guide secondary preventive pharmacotherapy.

Abstract Background We performed an integrated biomarker evaluation in pembrolizumab‐treated patients with R/M HNSCC enrolled in KEYNOTE‐012 or KEYNOTE‐055. The relationship between biomarkers and HPV status was explored. Methods We evaluated PD‐L1 (combined positive score [CPS]), TMB, T‐cell‐inflamed gene expression profile (TcellinfGEP), and HPV status. Associations between biomarkers were evaluated by logistic regression (ORR) and Cox regression (PFS, OS). Results Two hundred and fifty‐seven patients (KEYNOTE‐012, n = 106; KEYNOTE‐055, n = 151) had TMB data available; of these, 254 had PD‐L1 and 236 had TcellinfGEP. TMB, PD‐L1, and TcellinfGEP were each significantly associated with ORR (p

Abstract Background To stratify 10‐year survival outcomes by degree of social disparities in pediatric Wilms' tumor patients. We applied the Social Deprivation Index (SDI) to survival outcomes from the national SEER database to elucidate the effects of lower socioeconomics on cancer survival. Methods A retrospective cohort study was performed using the national Surveillance, Epidemiology, and End Results (SEER) oncology registry from 1975 to 2016 based on county‐level data. Pediatric patients (60th percentile/more deprived) or low‐risk (

Abstract Missing data create challenges in clinical research because they lead to loss of statistical power and potentially to biased results. Missing covariate data must be handled with suitable approaches to prepare datasets for pharmacometric analyses, such as population pharmacokinetic and pharmacodynamic analyses. To this end, various statistical methods have been widely adopted. Here, we introduce two machine‐learning (ML) methods capable of imputing missing covariate data in a pharmacometric setting. Based on a previously published pharmacometric analysis, we simulated multiple missing data scenarios. We compared the performance of four established statistical methods, listwise deletion, mean imputation, standard multiple imputation (hereafter “Norm”), and predictive mean matching (PMM) and two ML based methods, random forest (RF) and artificial neural networks (ANNs), to handle missing covariate data in a statistically plausible manner. The investigated ML‐based methods can be used to impute missing covariate data in a pharmacometric setting. Both traditional imputation approaches and ML‐based methods perform well in the scenarios studied, with some restrictions for individual methods. The three methods exhibiting the best performance in terms of least bias for the investigated scenarios are the statistical method PMM and the two ML‐based methods RF and ANN. ML‐based approaches had comparable good results to the best performing established method PMM. Furthermore, ML methods provide added flexibility when encountering more complex nonlinear relationships, especially when associated parameters are suitably tuned to enhance predictive performance.

Abstract Aim The Universal Definition of Heart Failure (UDHF) provides a framework for staging risk for HF events. It is not clear whether prognostic biomarkers have different meaning across UDHF stages. We sought to evaluate performance of biomarkers to predict HF events among high‐risk patients undergoing coronary and/or peripheral angiography categorized into UDHF stages. Methods One thousand two hundred thirty‐five individuals underwent coronary and/or peripheral angiography were enrolled. Study participants were categorized into UDHF Stage A (at risk), Stage B (pre‐HF), and Stage C or D (HF, including end stage) and grouped into Stage A/B and C/D. Biomarkers and clinical variables were used to develop prognostic models. Other measures examined included total HF hospitalizations. Results Over a median of 3.67 years of follow‐up, 155 cardiovascular (CV) deaths occurred, and 299 patients were hospitalized with acute HF. In patients with Stage A/B, galectin‐3 (HR = 1.52, P = 0.03), endothelin‐1 (HR = 2.16, P = 0.001), and N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP; HR = 1.43, P

Abstract Background Pathogenic germline mutations in several rare penetrant cancer predisposition genes are associated with an increased risk of aggressive prostate cancer (PC). Our objectives were to determine the prevalence of pathogenic germline mutations in men with low‐risk PC on active surveillance, and assess whether pathogenic germline mutations associate with grade reclassification or adverse pathology, recurrence, or metastases, in men treated after initial surveillance. Methods Men prospectively enrolled in the Canary Prostate Active Surveillance Study (PASS) were retrospectively sampled for the study. Germline DNA was sequenced utilizing a hereditary cancer gene panel. Mutations were classified according to the American College of Clinical Genetics and Genomics' guidelines. The association of pathogenic germline mutations with grade reclassification and adverse characteristics was evaluated by weighted Cox proportional hazards modeling and conditional logistic regression, respectively. Results Overall, 29 of 437 (6.6%) study participants harbored a pathogenic germline mutation of which 19 occurred in a gene involved in DNA repair (4.3%). Eight participants (1.8%) had pathogenic germline mutations in three genes associated with aggressive PC: ATM, BRCA1, and BRCA2. The presence of pathogenic germline mutations in DNA repair genes did not associate with adverse characteristics (univariate analysis HR = 0.87, 95% CI: 0.36–2.06, p = 0.7). The carrier rates of pathogenic germline mutations in ATM, BRCA1, and BRCA2did not differ in men with or without grade reclassification (1.9% vs. 1.8%). Conclusion The frequency of pathogenic germline mutations in penetrant cancer predisposition genes is extremely low in men with PC undergoing active surveillance and pathogenic germline mutations had no apparent association with grade reclassification or adverse characteristics.

Abstract Background and Aims Prostate cancer imposes a significant health burden, particularly in South America with its high incidence and mortality rates. This article explores the emergence of robot‐assisted radical prostatectomy (RARP) as a potential solution in the region. Methods This study relies on a comprehensive review of relevant literature. The analysis highlights the advantages of RARP, identifies impediments to its implementation, and proposes strategies to overcome these barriers. Results RARP demonstrates notable benefits, including improved functional outcomes, reduced complications, and minimized incisions. However, the integration of RARP in South America is hindered by challenges such as regional disparities, financial limitations, and data gaps. Limited healthcare infrastructure and a scarcity of skilled professionals further compound the issues. Conclusion Despite its potential, RARP faces obstacles to widespread adoption in South America. Strategic solutions encompassing technology investment, healthcare infrastructure enhancement, and workforce training are imperative. Overcoming these challenges can establish RARP as a crucial tool in managing prostate cancer in the region, ultimately enhancing patient care and treatment outcomes.

Abstract Over the past decades, superconducting qubits have emerged as one of the leading hardware platforms for realizing a quantum processor. Consequently, researchers have made significant effort to understand the loss channels that limit the coherence times of superconducting qubits. A major source of loss has been attributed to two level systems that are present at the material interfaces. It is recently shown that replacing the metal in the capacitor of a transmon with tantalum yields record relaxation and coherence times for superconducting qubits, motivating a detailed study of the tantalum surface. In this work, the chemical profile of the surface of tantalum films grown on c‐plane sapphire using variable energy X‐ray photoelectron spectroscopy (VEXPS) is studied. The different oxidation states of tantalum that are present in the native oxide resulting from exposure to air are identified, and their distribution through the depth of the film is measured. Furthermore, it is shown how the volume and depth distribution of these tantalum oxidation states can be altered by various chemical treatments. Correlating these measurements with detailed measurements of quantum devices may elucidate the underlying microscopic sources of loss.

Abstract Sequencing the human genome empowers translational medicine, facilitating transcriptome‐wide molecular diagnosis, pathway biology, and drug repositioning. Initially, microarrays are used to study the bulk transcriptome; but now short‐read RNA sequencing (RNA‐seq) predominates. Positioned as a superior technology, that makes the discovery of novel transcripts routine, most RNA‐seq analyses are in fact modeled on the known transcriptome. Limitations of the RNA‐seq methodology have emerged, while the design of, and the analysis strategies applied to, arrays have matured. An equitable comparison between these technologies is provided, highlighting advantages that modern arrays hold over RNA‐seq. Array protocols more accurately quantify constitutively expressed protein coding genes across tissue replicates, and are more reliable for studying lower expressed genes. Arrays reveal long noncoding RNAs (lncRNA) are neither sparsely nor lower expressed than protein coding genes. Heterogeneous coverage of constitutively expressed genes observed with RNA‐seq, undermines the validity and reproducibility of pathway analyses. The factors driving these observations, many of which are relevant to long‐read or single‐cell sequencing are discussed. As proposed herein, a reappreciation of bulk transcriptomic methods is required, including wider use of the modern high‐density array data—to urgently revise existing anatomical RNA reference atlases and assist with more accurate study of lncRNAs.

Abstract In skeletal muscle, CaV1.1 serves as the voltage sensor for both excitation‐contraction coupling (ECC) and L‐type Ca2+ channel activation. We have recently adapted the technique of action potential (AP) voltage clamp (APVC) to monitor the current generated by the movement of intramembrane voltage sensors (IQ) during single imposed transverse tubular AP‐like depolarization waveforms (IQAP). We now extend this procedure to monitoring IQAP, and Ca2+ currents during trains of tubular AP‐like waveforms in adult murine skeletal muscle fibers, and compare them with the trajectories of APs and AP‐induced Ca2+ release measured in other fibers using field stimulation and optical probes. The AP waveform remains relatively constant during brief trains (

Abstract Objective The objective of this study is to determine if Aquablation therapy can maintain its effectiveness in treating men with lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH) with large‐volume (80–150 cc) prostates at 3 years. Subjects and Methods One hundred one men with moderate‐to‐severe BPH symptoms and prostate volumes between 80 and 150 cc were enrolled in a prospective, nonrandomized, multicenter, international clinical trial in late 2017. Baseline, procedural, and follow‐up parameters were recorded at baseline and scheduled postoperative visits. IPSS, Qmax, and treatment failure are reported at 3 years. Results The mean prostate volume was 107 cc (range 80–150). Mean IPSS improved from 23.2 at baseline to 6.5 at 3 years (16.3‐point improvement, p

Glioblastoma (GBM) is the most common type of glioma and is uniformly fatal. Currently, tumour heterogeneity and mutation acquisition are major impedances for tailoring personalized therapy. We collected blood and tumour tissue samples from 25 GBM patients and 25 blood samples from healthy controls. Cell‐free DNA (cfDNA) was extracted from the plasma of GBM patients and from healthy controls. Tumour DNA was extracted from fresh tumour samples. Extracted DNA was sequenced using a whole‐genome sequencing procedure. We also collected 180 tumour DNA datasets from GBM patients publicly available at the TCGA/PANCANCER project. These data were analysed for mutations and gene–gene fusions that could be potential druggable targets. We found that plasma cfDNA concentrations in GBM patients were significantly elevated (22.6 ± 5 ng·mL−1), as compared to healthy controls (1.4 ± 0.4 ng·mL−1) of the same average age. We identified unique mutations in the cfDNA and tumour DNA of each GBM patient, including some of the most frequently mutated genes in GBM according to the COSMIC database (TP53, 18.75%; EGFR, 37.5%; NF1, 12.5%; LRP1B, 25%; IRS4, 25%). Using our gene–gene fusion database, ChiTaRS 5.0, we identified gene–gene fusions in cfDNA and tumour DNA, such as KDR–PDGFRA and NCDN–PDGFRA, which correspond to previously reported alterations of PDGFRA in GBM (44% of all samples). Interestingly, the PDGFRA protein fusions can be targeted by tyrosine kinase inhibitors such as imatinib, sunitinib, and sorafenib. Moreover, we identified BCR–ABL1 (in 8% of patients), COL1A1–PDGFB (8%), NIN–PDGFRB (8%), and FGFR1–BCR (4%) in cfDNA of patients, which can be targeted by analogues of imatinib. ROS1 fusions (CEP85L–ROS1 and GOPC–ROS1), identified in 8% of patient cfDNA, might be targeted by crizotinib, entrectinib, or larotrectinib. Thus, our study suggests that integrated analysis of cfDNA plasma concentration, gene mutations, and gene–gene fusions can serve as a diagnostic modality for distinguishing GBM patients who may benefit from targeted therapy. These results open new avenues for precision medicine in GBM, using noninvasive liquid biopsy diagnostics to assess personalized patient profiles. Moreover, repeated detection of druggable targets over the course of the disease may provide real‐time information on the evolving molecular landscape of the tumour.

Abstract The first line of treatment for most solid tumors is surgical resection of the primary tumor with adequate negative margins. Incomplete tumor resections with positive margins account for over 75% of local recurrences and the development of distant metastases. In cases of oral cavity squamous cell carcinoma (OSCC), the rate of successful tumor removal with adequate margins is just 50–75%. Advanced real‐time imaging methods that improve the detection of tumor margins can help improve success rates,overall safety, and reduce the cost. Fluorescence imaging in the second near‐infrared (NIR‐II) window has the potential to revolutionize the field due to its high spatial resolution, low background signal, and deep tissue penetration properties, but NIR‐II dyes with adequate in vivo performance and safety profiles are scarce. A novel NIR‐II fluorophore, XW‐03‐66, with a fluorescence quantum yield (QY) of 6.0% in aqueous media is reported. XW‐03‐66 self‐assembles into nanoparticles (≈80 nm) and has a systemic circulation half‐life (t1/2) of 11.3 h. In mouse models of human papillomavirus (HPV)+ and HPV‐ OSCC, XW‐03‐66 outperformed indocyanine green (ICG), a clinically available NIR dye, and enabled intraoperative NIR‐II image‐guided resection of the tumor and adjacent draining lymph node with negative margins. In vitro and in vivo toxicity assessments revealed minimal safety concerns for in vivo applications.

Abstract Background Alterations within large‐scale brain networks—namely, the default mode (DMN) and salience networks (SN)—are present among individuals with posttraumatic stress disorder (PTSD). Previous real‐time functional magnetic resonance imaging (fMRI) and electroencephalography neurofeedback studies suggest that regulating posterior cingulate cortex (PCC; the primary hub of the posterior DMN) activity may reduce PTSD symptoms and recalibrate altered network dynamics. However, PCC connectivity to the DMN and SN during PCC‐targeted fMRI neurofeedback remains unexamined and may help to elucidate neurophysiological mechanisms through which these symptom improvements may occur. Methods Using a trauma/emotion provocation paradigm, we investigated psychophysiological interactions over a single session of neurofeedback among PTSD (n = 14) and healthy control (n = 15) participants. We compared PCC functional connectivity between regulate (in which participants downregulated PCC activity) and view (in which participants did not exert regulatory control) conditions across the whole‐brain as well as in a priori specified regions‐of‐interest. Results During regulate as compared to view conditions, only the PTSD group showed significant PCC connectivity with anterior DMN (dmPFC, vmPFC) and SN (posterior insula) regions, whereas both groups displayed PCC connectivity with other posterior DMN areas (precuneus/cuneus). Additionally, as compared with controls, the PTSD group showed significantly greater PCC connectivity with the SN (amygdala) during regulate as compared to view conditions. Moreover, linear regression analyses revealed that during regulate as compared to view conditions, PCC connectivity to DMN and SN regions was positively correlated to psychiatric symptoms across all participants. Conclusion In summary, observations of PCC connectivity to the DMN and SN provide emerging evidence of neural mechanisms underlying PCC‐targeted fMRI neurofeedback among individuals with PTSD. This supports the use of PCC‐targeted neurofeedback as a means by which to recalibrate PTSD‐associated alterations in neural connectivity within the DMN and SN, which together, may help to facilitate improved emotion regulation abilities in PTSD.

Abstract Papua New Guinea (PNG) has a high HIV/AIDS prevalence and very high frequency of the CYP2B6 c.516G>T (rs3745274) variant. We have conducted the first investigation of the impact of c.516G>T and patient demographics on plasma efavirenz (EFV) and 8‐hydroxyefavirenz (8OH‐EFV) concentrations, metabolic ratio (8OH‐EFV/EFV) (MR), and their association with adverse effects, in PNG patients with HIV/AIDS. For 156 PNG patients with HIV/AIDS taking EFV 600 mg/day (for 3–156 months), plasma EFV and 8OH‐EFV concentrations were quantified, CYP2B6 c.516G>T genotyped, and demographic and self‐reported adverse effects data recorded. Genotype differences in EFV and 8OH‐EFV concentrations, MR, and percent within therapeutic range (1000–4000 ng/ml) were examined, in addition to EFV and 8OH‐EFV concentration differences between patients experiencing adverse effects. CYP2B6 c.516T allele frequency was 53%. Plasma EFV (p

Abstract Aim The aim of this study was to determine the causes of burnout syndrome and identify strategies to cope with them among nurses at high dependency unit if a regional Hospital in Ghana. Design A descriptive convenient and purposive cross‐sectional study design was used for this study. Methods The study involved 40 nurses in the high dependency unit of the Hospital. A Maslach Burnout Inventory (MBI) was adopted to measure burnout experienced by these nurses concentrating on feelings of being emotionally exhausted and lack of energy, depersonalization, feelings of impersonal response towards patients and personal achievement. Results 62.5% of the respondents were in the high emotional exhaustion, 55% scored high in the depersonalization section and 52.5% scored high in the personal achievement (competence) on the Maslach Burnout Inventory (MBI).

Abstract The origin of the Cameroon Volcanic Line (CVL), which is difficult to explain with traditional plate tectonics and mantle convection models because the volcanism does not display clear age progression, remains widely debated. Existing seismic tomography models show anomalously slow structure beneath the CVL, which some have interpreted to reflect upper mantle convective processes, possibly associated with edge‐driven flow related to the neighboring Congo Craton. However, mid‐ and lower mantle depths are generally not well resolved in these models, making it difficult to determine the extent of the anomalous CVL structure. Here, we present a new P‐wave velocity model for the African mantle, developed with the largest collection of travel‐time residuals recorded across the continent to date and an adaptive model parameterization. Our extensive data set and inversion method yield high resolution images of the mantle structure beneath western Africa, particularly at the critical mid‐ and lower mantle depths needed to further evaluate processes associated with the formation of the CVL. Our new model provides strong evidence for a connection between the African Large Low Velocity Province, centered in the lower mantle beneath southern Africa, and the continental portion of the CVL. We suggest that seismically slow material generated near the core‐mantle boundary beneath southern Africa moves northwestward under the Congo Craton. At the northern edge of the craton, the hot, buoyant material rises through the upper mantle, causing the CVL volcanism. Consequently, CVL magmatism can be linked to large‐scale mantle processes rooted in the deep mantle.

Abstract Study Objective To evaluate whether the introduction of a 1‐hour high‐sensitivity cardiac troponin‐T (hs‐TnT) pathway for patients who present to the emergency department (ED) with suspected acute coronary syndrome (ACS) improves ED patient flow without changing the rate of “missed” major adverse cardiac events (MACE), compared to use of conventional cardiac troponin with an associated 3‐hour pathway. Methods This was a prospective, uncontrolled observational study conducted before and after implementation of a 1‐hour hs‐TnT pathway at a high‐volume urban ED. Patients undergoing evaluation for ACS in the ED were enrolled during their initial visit and clinical outcomes were assessed at 30 and 90 days. Throughput markers were extracted from the electronic medical record and compared. The primary outcome was provider‐to‐disposition decision time. Results A total of 1892 patients were enrolled, 1071 patients while using conventional troponin and 821 after introduction of hs‐TnT. With the new assay and pathway, median interval between troponin tests decreased from 4.7 hours (interquartile range [IQR] 3.9–5.7 hours) to 2.3 hours (IQR 1.5–3.4 hours) (P < 0.001). However, there was no difference in median provider‐to‐disposition decision time, which measured 4.7 hours (IQR 2.9–7.2) and 4.8 hours (IQR 3.1–7.1) (P = 0.428) respectively. Total 30‐day MACE rate in discharged patients was low in both groups, occurring in only 4/472 (0.85%) encounters in the first cohort and 4/381 (1.0%) encounters in the second. Conclusion Introduction of a 1‐hour hs‐TnT ACS evaluation pathway reduced the troponin collection interval but did not reduce provider to disposition time. There was no difference in rate of 30‐day MACE in patients discharged from the ED.

Abstract Estimating and planning for the impacts of climate change on the biodiversity of protected areas is a major challenge for conservation managers. When these areas are topographically heterogenous and contain species' entire ranges, this challenge is exacerbated because the coarse spatial scales of Global Circulation Model projections provide limited information for within‐park management. South Africa's Table Mountain National Park, home to three endemic amphibian species in just ~24,500 hectares, provides a case study for identifying conservation needs under climate change. Selecting the park's herpetofauna as pilot taxa, we identified life history and demographic characteristics believed to make species more sensitive and less able to adapt to climate change. We organized these into assessment frameworks and, through a combination of literature review and expert elicitation, reviewed and used them to assess climate change vulnerability of 18 amphibian and 41 reptile species. The assessment highlighted that 73% and 67% of the park's reptile and amphibian species, respectively, had at least one high‐sensitivity and low‐adaptive capacity trait. Using ordinal and additive scoring methods, we identified the species most vulnerable to climate change and highlight the park areas containing their highest concentrations. These areas will be used to inform landscape‐scale management priorities and park use zones. The current IUCN Red List assessments for these species do not incorporate climate change vulnerability. Considering some species appear to be threatened by climate change, their conservation needs might be underestimated. Identifying the most vulnerable species and the mechanisms underpinning their vulnerability can guide the identification and prioritization of conservation needs, while the highlighted knowledge gaps inform priorities for monitoring and research. While comprehensive climate change adaptation planning for Table Mountain National Park requires additional assessment of other taxonomic groups, this trait‐based assessment example highlights a viable tool for assessing climate change vulnerability in protected areas.

Abstract We recently described the identification of a new class of small‐molecule activators of the mitochondrial protease ClpP. These compounds synthesized by Madera Therapeutics showed increased potency of cancer growth inhibition over the related compound ONC201. In this study, we describe chemical optimization and characterization of the next generation of highly potent and selective small‐molecule ClpP activators (TR compounds) and demonstrate their efficacy against breast cancer models in vitro and in vivo. We selected one compound (TR‐107) with excellent potency, specificity, and drug‐like properties for further evaluation. TR‐107 showed ClpP‐dependent growth inhibition in the low nanomolar range that was equipotent to paclitaxel in triple‐negative breast cancer (TNBC) cell models. TR‐107 also reduced specific mitochondrial proteins, including OXPHOS and TCA cycle components, in a time‐, dose‐, and ClpP‐dependent manner. Seahorse XF analysis and glucose deprivation experiments confirmed the inactivation of OXPHOS and increased dependence on glycolysis following TR‐107 exposure. The pharmacokinetic properties of TR‐107 were compared with other known ClpP activators including ONC201 and ONC212. TR‐107 displayed excellent exposure and serum t1/2 after oral administration. Using human TNBC MDA‐MB‐231 xenografts, the antitumor response to TR‐107 was investigated. Oral administration of TR‐107 resulted in a reduction in tumor volume and extension of survival in the treated compared with vehicle control mice. ClpP activation in vivo was validated by immunoblotting for TFAM and other mitochondrial proteins. In summary, we describe the identification of highly potent new ClpP agonists with improved efficacy against TNBC, through targeted inactivation of OXPHOS and disruption of mitochondrial metabolism.

Abstract Large‐scale biomonitoring of Arctic coastal marine communities is essential to track temporal changes in ecosystems. Despite the potential of environmental DNA (eDNA) as an innovative coastal biomonitoring tool, important questions remain pertaining to its temporal and spatial variation and how this may affect the evaluation of ecosystem changes over time in hydrodynamic ecosystems. In this study, we used eDNA metabarcoding of coastal water samples in two Canadian Arctic ports to evaluate the potential of eDNA to detect temporal transition in marine coastal communities. We sequenced eDNA from approximately 20 surface water samples collected each month (N ≈ 150 samples) covering the transition period between summer and late fall using four different universal primer pairs (two pairs of COI mitochondrial genes and two pairs of 18S rRNA genes). Our results from both primer pairs highlighted a significant transition from the summer to the fall marine community. We also observed a putative link between eDNA peaks of read abundance and timing for different life stages (e.g., spawning and larvae) of several species with the most abundant sequence reads. As such, our results show that temporal variation must be considered in ensuring comprehensive coastal biomonitoring with eDNA. Although much remains to be investigated about the ecology of eDNA, our results contribute to fundamental knowledge on the origin of eDNA and highlight the importance of considering temporal variation in developing guidance for coastal biomonitoring with this approach.

Abstract Determining the dynamics and sustainability of human interactions with threatened species is essential to inform evidence‐based conservation, but data can be challenging to collect across large areas and multiple user groups. Chinese giant salamanders Andrias spp. are critically depleted across China. Wild populations were exploited during the 20th century, and more recently to support a large‐scale farming industry. However, robust data remain largely unavailable on the timing of population declines in relation to changing human pressures, on primary drivers of exploitation, or on the effectiveness of conservation legislation. We conducted a series of large‐scale interview surveys across the range of giant salamanders in China, targeting potential rural and urban user groups, and stakeholders involved with giant salamander exploitation and policy management (comprising 2,932 rural households, 66 salamander farms, 115 county government officials and 835 urban consumers). Giant salamander populations were probably declining from at least the 1980s due to exploitation for food, and negative cultural values associated with these animals have not prevented rural consumption. There has been a major escalation in exploitation following the establishment of a large‐scale giant salamander farming industry in the 2000s. Our results demonstrate wide‐scale and largely unregulated illegal hunting to stock farms at a country‐wide scale in order to support demand by urban consumers for high‐prestige rare meat. We estimate there were at least 42,000 wild‐caught breeding adult giant salamanders and 164,000 wild‐caught subadults in farms across China at the time of our survey. Salamander farming probably poses unsustainable pressure on giant salamander populations. Existing legislation has clearly proved ineffective at preventing the stocking of farms with wild‐caught animals, and our findings highlight an important gap in the effectiveness of China's conservation protection for some of its highest‐priority threatened species. Tackling this problem will likely require multiple coordinated approaches, including enforcement of legislation, increased penalties for removing giant salamanders from the wild, permanent identification of captive‐bred giant salamanders, and consumer‐focused interventions to reduce urban demand. A free Plain Language Summary can be found within the Supporting Information of this article.

Objective: Scoping review of published literature to establish clinical characteristics and audiologic outcomes in patients diagnosed with Susac’s Syndrome(SS) who have undergone cochlear implantation (CI). Data sources: All published studies of CI in SS and contribution of two of our own patients who have not been reported previously. Methods: A comprehensive search of MEDLINE (via PubMed) was carried out in March 2020 using the following keywords and related entry terms: Susac’s Syndrome, Cochlear Implantation. Results: Our search identified a total of five case reports of CI in SS. With the addition of our two patients reported here, we analyzed characteristics and outcomes in seven patients. Mean age at implantation was 30 years old (range 19–46), with six women and one man implanted. Mean time from onset of hearing loss to implantation was 17 months (range three months to four years). Best reported postoperative speech understanding was reported via different metrics, with six of seven patients achieving open set speech scores of 90% or better, and one subject performing at 68%. Vestibular symptoms were present preoperatively in four of seven patients (57%), with vestibular testing reported in two patients, and showing vestibulopathy in one patient. No complications were reported following cochlear implantation. Conclusion: Cochlear implantation is a viable option for hearing rehabilitation in patients with SS, with levels of attainment of open set speech comparable to other populations of CI candidates.

Background Neurocritical care is routinely provided to patients post‐endovascular thrombectomy (EVT) for anterior large vessel occlusion strokes. We aim to study the relationship between immediate improvement in National Institutes of Health Stroke Scale (NIHSS) score on outcomes post‐EVT and potential implications for postprocedural care. Methods We performed a retrospective review of anterior circulation large vessel occlusion (internal carotid/proximal middle cerebral artery) patients undergoing EVT. Demographic, clinical, and imaging information was analyzed. Ultra‐early functional improvement (UEFI) was defined as NIHSS score

Aspirin-exacerbated respiratory disease (AERD) is frequently diagnosed in patients with severe type 2 airway inflammation presenting with nasal polyps and severe asthma. It has been associated with a recalcitrant course with high medical and surgical requirements. The advent of recent biological and other targeted treatments show promise in the medical management of patient with AERD. The goal of complete disease control where patients no longer require recurrent surgical procedures, systemic corticosteroid exposure and may live with a stable and relatively normal quality of life is now within reach. Further work is necessary to identify biomarkers predictive of treatment response.

Objective To determine whether training increases accuracy of self‐reported joint counts in people with rheumatoid arthritis (RA) and describe the knowledge and techniques for self‐examination of joints for reporting of RA disease activity. Methods This mixed‐methods study included 10 patients with RA and four rheumatologists. A rheumatologist presented about joint inflammation and disease monitoring in RA. Patients then self‐examined and reported 28‐tender joint count (28‐TJC) and 28‐swollen joint count (28‐SJC). Next, two paired rheumatologists examined patients and reported 28‐TJC and 28‐SJC. After watching a joint examination video for training physicians, patients discussed their training needs for self‐examination, with discussion analyzed using thematic analysis. Self‐examination techniques were determined by consensus. Finally, patients self‐examined and reported 28‐TJC and 28‐SJC. Reliability between the first and second patient‐reported 28‐TJCs and 28‐SJCs and rheumatologist pair‐reported 28‐TJC and 28‐SJC was determined with the intraclass coefficient. Results The reliability for patient self‐reported joint counts was higher for the 28‐TJC than for the 28‐SJC. Reliability improved following rheumatologist examination and training. Patients identified a preference for practical information rather than detailed information on joint anatomy and pathophysiology. Clear definitions of “swollen” and “tender” were important; patients found the concept of “tenderness” difficult. Techniques for self‐examination and reporting of joint counts were agreed on and demonstrated in an instructional video. Conclusion Training increased reliability of patient‐reported joint counts. Patients with RA identified important aspects of training for self‐examination and reporting of joint counts. An 8‐minute instructional video was codeveloped; the next step is the evaluation of the video’s impact on patient‐reported joint counts.

Abstract Severe and recurrent infections of the respiratory tract in early childhood constitute major risk factors for the development of bronchial hyper-responsiveness and obstructive respiratory diseases in later life. In the first years of life, the vast majority of respiratory tract infections (RTI) leading to wheezing and asthma are of a viral origin and severity and recurrence are the consequence of a greater exposure to infectious agents in a period when the immune system is still relatively immature. Therefore, boosting the efficiency of the host immune response against viral infections seems to be a rational preventative approach. In the last decades it has been demonstrated that living in farm environments, i.e. early-life exposure to microbes, may reduce the risk of allergic and infectious disorders, increasing the immune response efficacy. These findings have suggested that treatment with bacterial lysates could promote a nonspecific immunomodulation useful in the prevention of recurrent RTIs and of wheezing inception and persistence. Experimental and clinical studies showing the reduction of RTI frequency and severity in childhood and elucidating the involved mechanisms can support this hypothesis.

Abstract Background US research organizations increasingly are supporting patient and stakeholder engagement in health research with a goal of producing more useful, relevant and patient‐centered evidence better aligned with real‐world clinical needs. The Patient‐Centered Outcomes Research Institute (PCORI) engages patients, family caregivers and other health‐care stakeholders, including clinicians, payers and policymakers, as active partners in prioritizing, designing, conducting and disseminating research as a key strategy to produce useful evidence for health‐care decision making. Objective To inform effective engagement practices and policies, we sought to understand what motivates patients and caregivers to engage as partners on PCORI‐funded research projects and how such engagement changed their lives. Methods We conducted thematic analysis of open‐ended survey responses from 255 patients, family caregivers and individuals from advocacy and community‐based organizations who engaged as partners on 139 PCORI‐funded research projects focusing on a range of health conditions. Results Partners' motivations for engaging in research were oriented primarily towards benefiting others, including a desire to improve patients' lives and to support effective health‐care interventions. In addition to feeling they made a positive difference, many partners reported direct benefits from engagement, such as new relationships and improved health habits. Discussion and Conclusions By identifying patient and caregiver motivations for engaging in research partnerships and what they get out of the experience, our study may help research teams and organizations attract partners and foster more satisfying and sustainable partnerships. Our findings also add to evidence that engagement benefits the people involved as partners, strengthening the case for more widespread engagement.

Background Implantable cardioverter‐defibrillators (ICDs) are indicated in patients with severe left ventricular dysfunction, but many eligible patients do not receive them, especially women and Black patients. Our group had previously demonstrated that a best practice alert (BPA) improves overall rates of electrophysiology referrals and ICD implantations. This study examined the impact of a BPA by sex and race. Methods and Results This is a cluster randomized trial of cardiology (n=106) and primary care (n=89) providers who were randomized to receive (BPA, n=93) or not receive (No BPA, n=102) the alert and managed 1856 patients meeting primary prevention criteria for ICD implantation (965 BPA and 891 No BPA). After a median follow up of 34 months, 630 (34%) patients were referred to electrophysiology, and 522 (28%) patients received an ICD. Compared with the No BPA arm, patients in the BPA arm saw a modest differential increase in the rate of electrophysiology referrals at 18 months in men (+4%) compared with women (+7%) but a profound increase in Black patients (+16%) compared with White patients (+2%), thus closing the sex and race gaps. Similar trends were noted for rates of ICD implantation. Conclusions Use of a BPA improves rates of electrophysiology referrals and ICD implantations in all comers with severe cardiomyopathy and no prior ventricular arrhythmias but has a more pronounced impact in women and Black patients. The use of a BPA at the point of care is an effective tool in the fight against sex and race inequities in health care.

Abstract Background Intrinsic connectivity networks, including the default mode network (DMN), are frequently disrupted in individuals with posttraumatic stress disorder (PTSD). The posterior cingulate cortex (PCC) is the main hub of the posterior DMN, where the therapeutic regulation of this region with real‐time fMRI neurofeedback (NFB) has yet to be explored. Methods We investigated PCC downregulation while processing trauma/stressful words over 3 NFB training runs and a transfer run without NFB (total n = 29, PTSD n = 14, healthy controls n = 15). We also examined the predictive accuracy of machine learning models in classifying PTSD versus healthy controls during NFB training. Results Both the PTSD and healthy control groups demonstrated reduced reliving symptoms in response to trauma/stressful stimuli, where the PTSD group additionally showed reduced symptoms of distress. We found that both groups were able to downregulate the PCC with similar success over NFB training and in the transfer run, although downregulation was associated with unique within‐group decreases in activation within the bilateral dmPFC, bilateral postcentral gyrus, right amygdala/hippocampus, cingulate cortex, and bilateral temporal pole/gyri. By contrast, downregulation was associated with increased activation in the right dlPFC among healthy controls as compared to PTSD. During PCC downregulation, right dlPFC activation was negatively correlated to PTSD symptom severity scores and difficulties in emotion regulation. Finally, machine learning algorithms were able to classify PTSD versus healthy participants based on brain activation during NFB training with 80% accuracy. Conclusions This is the first study to investigate PCC downregulation with real‐time fMRI NFB in both PTSD and healthy controls. Our results reveal acute decreases in symptoms over training and provide converging evidence for EEG‐NFB targeting brain networks linked to the PCC.

Abstract Introduction Recent advances in generating massive single‐cell/nucleus transcriptomic data have shown great potential for facilitating the identification of cell type–specific Alzheimer's disease (AD) pathobiology and drug‐target discovery for therapeutic development. Methods We developed The Alzheimer's Cell Atlas (TACA) by compiling an AD brain cell atlas consisting of over 1.1 million cells/nuclei across 26 data sets, covering major brain regions (hippocampus, cerebellum, prefrontal cortex, and so on) and cell types (astrocyte, microglia, neuron, oligodendrocytes, and so on). We conducted nearly 1400 differential expression comparisons to identify cell type–specific molecular alterations (e.g., case vs healthy control, sex‐specific, apolipoprotein E (APOE) ε4/ε4, and TREM2 mutations). Each comparison was followed by protein‐protein interaction module detection, functional enrichment analysis, and omics‐informed target and drug (over 700,000 perturbation profiles) screening. Over 400 cell‐cell interaction analyses using 6000 ligand‐receptor interactions were conducted to identify the cell‐cell communication networks in AD. Results All results are integrated into TACA (https://taca.lerner.ccf.org/), a new web portal with cell type–specific, abundant transcriptomic information, and 12 interactive visualization tools for AD. Discussion We envision that TACA will be a highly valuable resource for both basic and translational research in AD, as it provides abundant information for AD pathobiology and actionable systems biology tools for drug discovery. Highlights We compiled an Alzheimer's disease (AD) brain cell atlas consisting of more than 1.1 million cells/nuclei transcriptomes from 26 data sets, covering major brain regions (cortex, hippocampus, cerebellum) and cell types (e.g., neuron, oligodendrocyte, astrocyte, and microglia). We conducted over 1400 differential expression (DE) comparisons to identify cell type–specific gene expression alterations. Major comparison types are (1) AD versus healthy control; (2) sex‐specific DE, (3) genotype‐driven DE (i.e., apolipoprotein E [APOE] ε4/ε4 vs APOE ε3/ε3; TREM2R47H vs common variants) analysis; and (4) others. Each comparison was further followed by (1) human protein‐protein interactome network module analysis, (2) pathway enrichment analysis, and (3) gene‐set enrichment analysis. For drug screening, we conducted gene set enrichment analysis for all the comparisons with over 700,000 drug perturbation profiles connecting more than 10,000 human genes and 13,000 drugs/compounds. A total of over 400 analyses of cell‐cell interactions against 6000 experimentally validated ligand‐receptor interactions were conducted to reveal the disease‐relevant cell‐cell communications in AD.

Abstract “In what circumstances would you want this AI to make decisions on your behalf?” We have been investigating how to enable a user of an Artificial Intelligence‐powered system to answer questions like this through a series of empirical studies, a group of which we summarize here. We began the series by (a) comparing four explanation configurations of saliency explanations and/or reward explanations. From this study we learned that, although some configurations had significant strengths, no one configuration was a clear “winner.” This result led us to hypothesize that one reason for the low success rates Explainable AI (XAI) research has in enabling users to create a coherent mental model is that the AI itself does not have a coherent model. This hypothesis led us to (b) build a model‐based agent, to compare explaining it with explaining a model‐free agent. Our results were encouraging, but we then realized that participants' cognitive energy was being sapped by having to create not only a mental model, but also a process by which to create that mental model. This realization led us to (c) create such a process (which we term After‐Action Review for AI or “AAR/AI”) for them, integrate it into the explanation environment, and compare participants' success with AAR/AI scaffolding vs without it. Our AAR/AI studies' results showed that AAR/AI participants were more effective assessing the AI than non‐AAR/AI participants, with significantly better precision and significantly better recall at finding the AI's reasoning flaws.

Abstract We have located 117 previously undetected seismic events mainly occurring between 2015 and 2017 that originated from glacial, tectonic, and volcanic processes in central West Antarctica using data recorded on Polar Earth Observing Network (POLENET/ANET) and UK Antarctic Network (UKANET) seismic stations. The seismic events, with local magnitudes (ML) ranging from 1.1 to 3.5, are predominantly clustered in four geographic regions; the Ellsworth Mountains, Thwaites Glacier, Pine Island Glacier, and Mount Takahe. Eighteen of the events are in the Ellsworth Mountains and can be attributed to a mixture of glacial and tectonic processes. The largest event noted in this study was a mid‐crustal (∼19 km focal depth; ML 3.5) normal mechanism earthquake beneath Thwaites Glacier. We also located 91 glacial events near the grounding zones of Thwaites Glacier and Pine Island Glacier that are predominantly associated with time periods of significant calving activity. Eight events, likely arising from volcano‐tectonic processes, occurred beneath Mount Takahe. Using Pn travel times from the seismic events, we find laterally variable uppermost mantle structure in central West Antarctica. On average, the Ellsworth Mountains are underlain by a faster mantle lid (VPn = ∼8.4 km/s) compared to the Amundsen Sea Embayment region (VPn = ∼8.1 km/s). Within the Amundsen Sea Embayment itself, we find mantle lid velocities ranging from ∼8.05 to 8.18 km/s. Laterally heterogeneous uppermost mantle structure, indicative of variable thermal and rheological structure, likely influences both geothermal heat flux and glacial isostatic adjustment spatial patterns and rates within central West Antarctica.

Abstract Inaccurate taxonomic assessment of threatened populations can hinder conservation prioritization and management, with human‐mediated population movements obscuring biogeographic patterns and confounding reconstructions of evolutionary history. Giant salamanders were formerly distributed widely across China, and are interpreted as a single species, Andrias davidianus. Previous phylogenetic studies have identified distinct Chinese giant salamander lineages but were unable to associate these consistently with different landscapes, probably because population structure has been modified by human‐mediated translocations for recent commercial farming. We investigated the evolutionary history and relationships of allopatric Chinese giant salamander populations with Next‐Generation Sequencing methods, using historical museum specimens and late 20th‐century samples, and retrieved partial or near‐complete mitogenomes for 17 individuals. Samples from populations unlikely to have been affected by translocations form three clades from separate regions of China, spatially congruent with isolation by either major river drainages or mountain ranges. Pliocene–Pleistocene divergences for these clades are consistent with topographic modification of southern China associated with uplift of the Qinghai‐Tibet Plateau. General Mixed Yule Coalescent model analysis indicates that these clades represent separate species: Andrias davidianus (Blanchard, 1871) (northern Yangtze/Sichuan), Andrias sligoi (Boulenger, 1924) (Pearl/Nanling), and an undescribed species (Huangshan). Andrias sligoi is possibly the world's largest amphibian. Inclusion of additional reportedly wild samples from areas of known giant salamander exploitation and movement leads to increasing loss of biogeographic signal. Wild Chinese giant salamander populations are now critically depleted or extirpated, and conservation actions should be updated to recognize the existence of multiple species.