Thresholds for adding degraded tropical forest to the conservation estate.

Logged and disturbed forests are often viewed as degraded and depauperate environments compared with primary forest. However, they are dynamic ecosystems1 that provide refugia for large amounts of biodiversity2,3, so we cannot afford to underestimate their conservation value4. Here we present empirically defined thresholds for categorizing the conservation value of logged forests, using one of the most comprehensive assessments of taxon responses to habitat degradation in any tropical forest environment. We analysed the impact of logging intensity on the individual occurrence patterns of 1,681 taxa belonging to 86 taxonomic orders and 126 functional groups in Sabah, Malaysia. Our results demonstrate the existence of two conservation-relevant thresholds. First, lightly logged forests (<29% biomass removal) retain high conservation value and a largely intact functional composition, and are therefore likely to recover their pre-logging values if allowed to undergo natural regeneration. Second, the most extreme impacts occur in heavily degraded forests with more than two-thirds (>68%) of their biomass removed, and these are likely to require more expensive measures to recover their biodiversity value. Overall, our data confirm that primary forests are irreplaceable5, but they also reinforce the message that logged forests retain considerable conservation value that should not be overlooked.

Mapping of long interspersed element-1 (L1) insertions by TIPseq provides information about sub chromosomal genetic variation in human embryos.

PURPOSE: Retrotransposons play important roles during early development when they are transiently de-repressed during epigenetic reprogramming. Long interspersed element-1 (L1), the only autonomous retrotransposon in humans, comprises 17% of the human genome. We applied the Single Cell Transposon Insertion Profiling by Sequencing (scTIPseq) to characterize and map L1 insertions in human embryos. METHODS: Sixteen cryopreserved, genetically tested, human blastocysts, were accessed from consenting couples undergoing IVF at NYU Langone Fertility Center. Additionally, four trios (father, mother, and embryos) were also evaluated. scTIPseq was applied to map L1 insertions in all samples, using L1 locations reported in the 1000 Genomes as controls. RESULTS: Twenty-nine unknown and unique insertions were observed in the sixteen embryos. Most were intergenic; no insertions were located in exons or immediately upstream of genes. The location or number of unknown insertions did not differ between euploid and aneuploid embryos, suggesting they are not merely markers of aneuploidy. Rather, scTIPseq provides novel information about sub-chromosomal structural variation in human embryos. Trio analyses showed a parental origin of all L1 insertions in embryos. CONCLUSION: Several studies have measured L1 expression at different stages of development in mice, but this study for the first time reports unknown insertions in human embryos that were inherited from one parent, confirming no de novo L1 insertions occurred in parental germline or during embryogenesis. Since one-third of euploid embryo transfers fail, future studies would be useful for understanding whether these sub-chromosomal genetic variants or de novo L1 insertions affect embryo developmental potential.

Cerebrospinal Creatine Kinase BB Isoenzyme: A Biomarker for Predicting Outcome After Cardiac Arrest.

BACKGROUND: Cerebrospinal fluid creatine kinase BB isoenzyme (CSF CK-BB) after cardiac arrest (CA) has been shown to have a high positive predictive value for poor neurological outcome, but it has not been evaluated in the setting of targeted temperature management (TTM) and modern CA care. We aimed to evaluate CSF CK-BB as a prognostic biomarker after CA. METHODS: We performed a retrospective cohort study of patients with CA admitted between 2010 and 2020 to a three-hospital health system who remained comatose and had CSF CK-BB assayed between 36 and 84 h after CA. We examined the proportion of patients at hospital discharge who achieved favorable or intermediate neurological outcome, defined as Cerebral Performance Category score of 1-3, compared with those with poor outcome (Cerebral Performance Category score 4-5) for various CSF CK-BB thresholds. We also evaluated additive value of bilateral absence of somatosensory evoked potentials (SSEPs). RESULTS: Among 214 eligible patients, the mean age was 54.7 ± 4.8 years, 72% of patients were male, 33% were nonwhite, 17% had shockable rhythm, 90% were out-of-hospital CA, and 83% received TTM. A total of 19 (9%) awakened. CSF CK-BB ≥ 230 U/L predicted a poor outcome at hospital discharge, with a specificity of 100% (95% confidence interval [CI] 82-100%) and sensitivity of 69% (95% CI 62-76%). When combined with bilaterally absent N20 response on SSEP, specificity remained 100% while sensitivity increased to 80% (95% CI 73-85%). Discordant CK-BB and SSEP findings were seen in 13 (9%) patients. CONCLUSIONS: Cerebrospinal fluid creatine kinase BB isoenzyme levels accurately predicted poor neurological outcome among CA survivors treated with TTM. The CSF CK-BB cutoff of 230 U/L optimizes sensitivity to 69% while maintaining a specificity of 100%. CSF CK-BB could be a useful addition to multimodal neurological prognostication after CA.

A Bayesian non-stationary heteroskedastic time series model for multivariate critical care data.

We propose a multivariate GARCH model for non-stationary health time series by modifying the observation-level variance of the standard state space model. The proposed model provides an intuitive and novel way of dealing with heteroskedastic data using the conditional nature of state-space models. We follow the Bayesian paradigm to perform the inference procedure. In particular, we use Markov chain Monte Carlo methods to obtain samples from the resultant posterior distribution. We use the forward filtering backward sampling algorithm to efficiently obtain samples from the posterior distribution of the latent state. The proposed model also handles missing data in a fully Bayesian fashion. We validate our model on synthetic data and analyze a data set obtained from an intensive care unit in a Montreal hospital and the MIMIC dataset. We further show that our proposed models offer better performance, in terms of WAIC than standard state space models. The proposed model provides a new way to model multivariate heteroskedastic non-stationary time series data. Model comparison can then be easily performed using the WAIC.

Leveraging High-Resolution Ion Mobility-Mass Spectrometry for Cyclic Peptide Soft Spot Identification.

Cyclic peptides are an important class of molecules that gained significant attention in the field of drug discovery due to their unique pharmacological characteristics and enhanced proteolytic stability. Yet, gastrointestinal degradation remains a major hurdle in the discovery of orally bioavailable cyclic peptides. Soft spot identification (SSID) of the regions in the cyclic peptide sequence susceptible to amide hydrolysis by proteases is used in the discovery stage to guide medicinal chemistry design. SSID can be an arduous task, traditionally performed using liquid chromatography-tandem mass spectrometry (LC-MS/MS), often resulting in complex and time-consuming manual analysis, particularly when isomeric linear peptide metabolites chromatographically coelute. Here, we present an alternative orthogonal approach that entails a high-resolution ion mobility (HRIM) system based on Structures for Lossless Ion Manipulation (SLIM) technology interfaced with quadrupole time-of-flight (QTOF) mass spectrometry to address some of the challenges associated with SSID. Two strategies were used to resolve linear isomeric peptide metabolites: labeled and label-free, both utilizing the HRIM platform. The label-free strategy leverages negative polarity to ionize the isomers which achieves better separation of the gas phase ions in the ion mobility (IM) dimension as compared to positive polarity, which is a more conventional approach when studying proteins and peptides. The second approach uses an isotope-labeled dimethyl tag on the terminal amine group, acting as a "shift reagent" to influence the mobility of isomers in the positive mode. This method resulted in baseline separation for the isomers of interest and produced unique product ions in the fragmentation spectra for unambiguous soft spot identification. Both label-free and labeled strategies demonstrated the ability to solve the challenges associated with SSID for cyclic peptides.

Canada's approach to SARS-CoV-2 sero-surveillance: Lessons learned for routine surveillance and future pandemics.

SETTING: In Canada's federated healthcare system, 13 provincial and territorial jurisdictions have independent responsibility to collect data to inform health policies. During the COVID-19 pandemic (2020-2023), national and regional sero-surveys mostly drew upon existing infrastructure to quickly test specimens and collect data but required cross-jurisdiction coordination and communication. INTERVENTION: There were 4 national and 7 regional general population SARS-CoV-2 sero-surveys. Survey methodologies varied by participant selection approaches, assay choices, and reporting structures. We analyzed Canadian pandemic sero-surveillance initiatives to identify key learnings to inform future pandemic planning. OUTCOMES: Over a million samples were tested for SARS-CoV-2 antibodies from 2020 to 2023 but siloed in 11 distinct datasets. Most national sero-surveys had insufficient sample size to estimate regional prevalence; differences in methodology hampered cross-regional comparisons of regional sero-surveys. Only four sero-surveys included questionnaires. Sero-surveys were not directly comparable due to different assays, sampling methodologies, and time-frames. Linkage to health records occurred in three provinces only. Dried blood spots permitted sample collection in remote populations and during stay-at-home orders. IMPLICATIONS: To provide timely, high-quality information for public health decision-making, routine sero-surveillance systems must be adaptable, flexible, and scalable. National capability planning should include consortiums for assay design and validation, defined mechanisms to improve test capacity, base documents for data linkage and material transfer across jurisdictions, and mechanisms for real-time communication of data. Lessons learned will inform incorporation of a robust sero-survey program into routine surveillance with strategic sampling and capacity to adapt and scale rapidly as a part of a comprehensive national pandemic response plan.

RéSUMé: CONTEXTE: Au Canada, où le système de santé est fédéré, les 13 juridictions provinciales et territoriales ont la responsabilité individuelle de recueillir les données qui leur permettent d'élaborer leurs politiques de santé. Lors de la pandémie de COVID-19 (2020­2023), pour réaliser les enquêtes de séroprévalence à l'échelle régionale et nationale, les autorités ont principalement utilisé l'infrastructure existante pour pouvoir analyser les échantillons et recueillir des données rapidement, mais cela a également nécessité de la communication et de la coordination entre les différentes juridictions. INTERVENTION: Au Canada, il y a eu quatre enquêtes nationales et sept enquêtes régionales sur la séroprévalence du SARS-CoV-2 dans la population générale. Les méthodologies utilisées différaient selon la méthode de sélection des participants, le choix des tests d'analyses et les structures de rapports. Nous avons analysé la façon dont ces enquêtes avaient été réalisées afin d'en dégager des éléments essentiels qui permettront de planifier pour les futures pandémies. RéSULTATS: Entre 2020 et 2023, plus d'un million d'échantillons, répartis en 11 ensembles de données distincts, ont été analysés afin de rechercher la présence d'anticorps au SARS-CoV-2. Dans la plupart des enquêtes nationales, la taille de l'échantillon était insuffisante pour pouvoir estimer la prévalence à l'échelle régionale. La disparité des méthodologies utilisées a entravé la comparaison des enquêtes régionales. Seules quatre enquêtes fournissaient les données recueillies à partir des questionnaires. Il a été impossible de comparer les enquêtes entre elles en raison de la diversité des tests d'analyse utilisés, des méthodes d'échantillonnage et de la durée des enquêtes. Seules trois provinces avaient couplé leurs données avec les archives médicales. Pour réaliser les enquêtes dans les populations éloignées et lors des périodes de confinement, la méthode d'analyse sur gouttes de sang séché a été utilisée. CONCLUSION: Afin de pouvoir fournir, en temps et en heure, des données de haute qualité pour la prise de décisions en matière de santé publique, un système de sérosurveillance continuelle doit être adaptable, modulable et évolutif. En cas de pandémie, un plan national doit prévoir des consortiums pour la conception et la validation des tests d'analyse, des moyens d'amélioration de la capacité de dépistage, des documents de base pour le couplage des données, un mode de transfert du matériel entre les différentes juridictions et des moyens pour une communication en temps réel des données. Les leçons tirées de cette analyse permettront de mettre en place un solide programme d'enquêtes de séroprévalence au sein des systèmes de sérosurveillance continuelle, et que ce programme sera accompagné d'une stratégie d'échantillonnage et d'un plan d'intervention national, rapide et complet en cas de pandémie.

Effect of Data-Processing Methods on Acceleration Summary Metrics of GNSS Devices in Elite Australian Football.

This study aimed to measure the differences in commonly used summary acceleration metrics during elite Australian football games under three different data processing protocols (raw, custom-processed, manufacturer-processed). Estimates of distance, speed and acceleration were collected with a 10-Hz GNSS tracking technology device from fourteen matches of 38 elite Australian football players from one team. Raw and manufacturer-processed data were exported from respective proprietary software and two common summary acceleration metrics (number of efforts and distance within medium/high-intensity zone) were calculated for the three processing methods. To estimate the effect of the three different data processing methods on the summary metrics, linear mixed models were used. The main findings demonstrated that there were substantial differences between the three processing methods; the manufacturer-processed acceleration data had the lowest reported distance (up to 184 times lower) and efforts (up to 89 times lower), followed by the custom-processed distance (up to 3.3 times lower) and efforts (up to 4.3 times lower), where raw data had the highest reported distance and efforts. The results indicated that different processing methods changed the metric output and in turn alters the quantification of the demands of a sport (volume, intensity and frequency of the metrics). Coaches, practitioners and researchers need to understand that various processing methods alter the summary metrics of acceleration data. By being informed about how these metrics are affected by processing methods, they can better interpret the data available and effectively tailor their training programs to match the demands of competition.

Circulating Tumor DNA Predicts Early Recurrence Following Locoregional Therapy for Oligometastatic Colorectal Cancer.

(1) Background: Local therapies offer a potentially curative approach for patients with oligometastatic colorectal cancer (CRC). An evidence-based consensus recommendation for systemic therapy following definitive locoregional therapy is lacking. Tumor-informed circulating tumor DNA (ctDNA) might provide information to help guide management in this setting. (2) Methods: A multi-institutional retrospective study was conducted, including patients with CRC that underwent curative-intent locoregional therapy to an isolated site of metastatic disease, followed by tumor-informed ctDNA assessment. The Kaplan-Meier method and log-rank tests were used to compare disease-free survival based on ctDNA results. ctDNA test performance was compared to carcinoembryonic antigen (CEA) test results using McNemar's test. (3) Results: Our study cohort consisted of 87 patients treated with locoregional interventions who underwent ctDNA testing. The initial ctDNA test post-intervention was positive in 28 patients and negative in 59 patients. The median follow-up time was 14.0 months. Detectable ctDNA post-intervention was significantly associated with early disease recurrence, with a median disease-free survival (DFS) of 6.63 months compared to 21.30 months in ctDNA-negative patients (p < 0.001). ctDNA detected a numerically higher proportion of recurrences than CEA (p < 0.097). Post-intervention systemic therapy was not associated with improved DFS (p = 0.745). (4) Conclusions: ctDNA results are prognostically important in oligometastatic CRC, and further prospective studies are urgently needed to define its role in guiding clinical decisions.

What is associated with painful polyneuropathy? A cross-sectional analysis of symptoms and signs in patients with painful and painless polyneuropathy.

ABSTRACT: It is still unclear how and why some patients develop painful and others painless polyneuropathy. The aim of this study was to identify multiple factors associated with painful polyneuropathies (NeuP). A total of 1181 patients of the multicenter DOLORISK database with painful (probable or definite NeuP) or painless (unlikely NeuP) probable or confirmed neuropathy were investigated clinically, with questionnaires and quantitative sensory testing. Multivariate logistic regression including all variables (demographics, medical history, psychological symptoms, personality items, pain-related worrying, life-style factors, as well as results from clinical examination and quantitative sensory testing) and machine learning was used for the identification of predictors and final risk prediction of painful neuropathy. Multivariate logistic regression demonstrated that severity and idiopathic etiology of neuropathy, presence of chronic pain in family, Patient-Reported Outcomes Measurement Information System Fatigue and Depression T-Score, as well as Pain Catastrophizing Scale total score are the most important features associated with the presence of pain in neuropathy. Machine learning (random forest) identified the same variables. Multivariate logistic regression archived an accuracy above 78%, random forest of 76%; thus, almost 4 out of 5 subjects can be classified correctly. This multicenter analysis shows that pain-related worrying, emotional well-being, and clinical phenotype are factors associated with painful (vs painless) neuropathy. Results may help in the future to identify patients at risk of developing painful neuropathy and identify consequences of pain in longitudinal studies.

Numerical model for electrogenic transport by the ATP-dependent potassium pump KdpFABC.

In vitro assays of ion transport are an essential tool for understanding molecular mechanisms associated with ATP-dependent pumps. Because ion transport is generally electrogenic, principles of electrophysiology are applicable, but conventional tools like patch-clamp are ineffective due to relatively low turnover rates of the pumps. Instead, assays have been developed to measure either voltage or current generated by transport activity of a population of molecules either in cell-derived membrane fragments or after reconstituting purified protein into proteoliposomes. In order to understand the nuances of these assays and to characterize effects of various operational parameters, we have developed a numerical model to simulate data produced by two relevant assays: fluorescence from voltage-sensitive dyes and current recorded by capacitive coupling on solid supported membranes. Parameters of the model, which has been implemented in Python, are described along with underlying principles of the computational algorithm. Experimental data from KdpFABC, a K+ pump associated with P-type ATPases, are presented, and model parameters have been adjusted to mimic these data. In addition, effects of key parameters such as nonselective leak conductance and turnover rate are demonstrated. Finally, simulated data are used to illustrate the effects of capacitive coupling on measured current and to compare alternative methods for quantification of raw data.

Efficacy of commercial recombinant HVT vaccines against a North American clade 2.3.4.4b H5N1 highly pathogenic avian influenza virus in chickens.

The outbreak of clade 2.3.4.4b H5 highly pathogenic avian influenza (HPAI) in North America that started in 2021 has increased interest in applying vaccination as a strategy to help control and prevent the disease in poultry. Two commercially available vaccines based on the recombinant herpes virus of turkeys (rHVT) vector were tested against a recent North American clade 2.3.4.4b H5 HPAI virus isolate: A/turkey/Indiana/22-003707-003/2022 H5N1 in specific pathogen free white leghorn (WL) chickens and commercial broiler chickens. One rHVT-H5 vaccine encodes a hemagglutinin (HA) gene designed by the computationally optimized broadly reactive antigen method (COBRA-HVT vaccine). The other encodes an HA gene of a clade 2.2 virus (2.2-HVT vaccine). There was 100% survival of both chicken types COBRA-HVT vaccinated groups and in the 2.2-HVT vaccinated groups there was 94.8% and 90% survival of the WL and broilers respectively. Compared to the 2.2-HVT vaccinated groups, WL in the COBRA-HVT vaccinated group shed significantly lower mean viral titers by the cloacal route and broilers shed significantly lower titers by the oropharyngeal route than broilers. Virus titers detected in oral and cloacal swabs were otherwise similar among both vaccine groups and chicken types. To assess antibody-based tests to identify birds that have been infected after vaccination (DIVA-VI), sera collected after the challenge were tested with enzyme-linked lectin assay-neuraminidase inhibition (ELLA-NI) for N1 neuraminidase antibody detection and by commercial ELISA for detection of antibodies to the NP protein. As early as 7 days post challenge (DPC) 100% of the chickens were positive by ELLA-NI. ELISA was less sensitive with a maximum of 75% positive at 10DPC in broilers vaccinated with 2.2-HVT. Both vaccines provided protection from challenge to both types of chickens and ELLA-NI was sensitive at identifying antibodies to the challenge virus therefore should be evaluated further for DIVA-VI.

An evaluation of the outcomes associated with peritoneal catheter use in neonates undergoing cardiac surgery: A multicenter study.

Objective: The study objective was to determine if intraoperative peritoneal catheter placement is associated with improved outcomes in neonates undergoing high-risk cardiac surgery with cardiopulmonary bypass. Methods: This propensity score-matched retrospective study used data from 22 academic pediatric cardiac intensive care units. Consecutive neonates undergoing Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery category 3 to 5 cardiac surgery with cardiopulmonary bypass at centers participating in the NEonatal and Pediatric Heart Renal Outcomes Network collaborative were studied to determine the association of the use of an intraoperative placed peritoneal catheter for dialysis or passive drainage with clinical outcomes, including the duration of mechanical ventilation. Results: Among 1490 eligible neonates in the NEonatal and Pediatric Heart Renal Outcomes Network dataset, a propensity-matched analysis was used to compare 395 patients with peritoneal catheter placement with 628 patients without peritoneal catheter placement. Time to extubation and most clinical outcomes were similar. Postoperative length of stay was 5 days longer in the peritoneal catheter placement cohort (17 vs 22 days, P = .001). There was a 50% higher incidence of moderate to severe acute kidney injury in the no-peritoneal catheter cohort (12% vs 18%, P = .02). Subgroup analyses between specific treatments and in highest risk patients yielded similar associations. Conclusions: This study does not demonstrate improved outcomes among neonates with placement of a peritoneal catheter during cardiac surgery. Outcomes were similar apart from longer hospital stay in the peritoneal catheter cohort. The no-peritoneal catheter cohort had a 50% higher incidence of moderate to severe acute kidney injury (12% vs 18%). This analysis does not support indiscriminate peritoneal catheter use, although it may support the utility for postoperative fluid removal among neonates at risk for acute kidney injury. A multicenter controlled trial may better elucidate peritoneal catheter effects.

Hepatitis B Virus in People who Inject Drugs and Men who Have Sex With Men With HIV in India: A Cross-sectional Study.

Background: People with HIV (PWH) who are coinfected with hepatitis B virus (HBV) have a higher risk of mortality compared with PWH alone. Populations such as people who inject drugs (PWID) and men who have sex with men (MSM) are particularly at high risk for HBV acquisition; yet, limited epidemiological data from these populations exist on HBV prevalence from low- and middle-income country settings (LMICs). Methods: We characterized the prevalence and correlates of HBV serological markers in a sample of PWID and MSM with HIV recruited across 15 Indian cities using hepatitis B surface antigen (HBsAg), hepatitis B core antibody (anti-HBc), and hepatitis B surface antibody (anti-HBs). Testing of stored specimens for the presence of these markers was performed on the Abbott ARCHITECT i1000 as per the manufacturer's instructions. Correlates of ever being infected with HBV (reactive for anti-HBc and/or HBsAg) and chronic HBV (reactive for HBsAg) among those ever infected were assessed using univariable and multivariable multilevel logistic regression models accounting for site-level clustering. Results: A total of 2198 (95%) of the 2314 participants recruited for the trial were screened for HBV markers. The median age among the PWID and MSM participants was 30 and 32 years, respectively. The prevalence of ever being infected with HBV was 75.6% vs 46.9% in PWID vs MSM, respectively (P < .01); prevalence of chronic infection was also higher in PWID vs MSM (14.1% vs 9.5%; P < .01). Correlates of ever being infected with HBV among PWID included unstable housing (adjusted odds ratio [aOR], 5.02) and sharing injection paraphernalia (aOR, 2.70), and among MSM, correlates included history of injection drug use (aOR, 4.87) and gender identity. The prevalence of isolated core (anti-HBc in the absence of anti-HBs) was 34.7% vs 29.4% in PWID vs MSM (P < .05). Vaccination serostatus was <10% in both populations. Conclusions: In this large sample of PWID and MSM with HIV, we observed a high prevalence of serology consistent with HBV infection and low vaccination, highlighting the need for routine screening and catch-up vaccination. The high prevalence of isolated anti-HBc reactivity highlights the need to understand the risk of reactivation with this serological pattern.

Methods to Screen the Adhesion of Fish Cells on Plant-, Algal- and Fungal-Derived Biomaterials.

Cellular agriculture, an alternative and innovative approach to sustainable food production, has gained momentum in recent years. However, there is limited research into the production of cultivated seafood. Here, we investigated the ability of fish mackerel cells (Scomber scombrus) to adhere to plant, algal and fungal-based biomaterial scaffolds, aiming to optimize the cultivation of fish cells for use in cellular agriculture. A mackerel cell line was utilized, and metabolic assays and confocal imaging were utilized to track cell adhesion, growth, and differentiation on the different biomaterials. The mackerel cells adhered and grew on gelatin (positive control), zein, and soy proteins, as well as on alginate, chitosan, and cellulose polysaccharides. The highest adhesion and growth were on the zein and chitosan substrates, apart from the gelatin control. These findings provide a blueprint to enhance scaffold selection and design, contributing to the broader field of cellular agriculture through the development of scalable and eco-conscious solutions for meeting the growing global demand for seafood.

A Doctor of Pharmacy Curriculum Revision Process Focused on Curricular Overload.

OBJECTIVE: The objective is to describe the impact of a curricular revision process using the 8-step Kotter change model to decrease curricular overload in a PharmD program at a public, research-intensive school of pharmacy. METHODS: In alignment with the 8-step Kotter Change Model, the first step was to create urgency for change, which was supported by calls to action to address curricular overload. Next, a coalition of change leaders was formed, who developed seven curriculum renewal targets to collectively address curricular overload. This vision was communicated at faculty meetings throughout the change process, with requests for feedback. Five curricular working groups were formed to empower action based on their charges. Quick wins were created by early adopters, which built momentum and led to a more streamlined course change process. Lastly, making changes stick requires ongoing evaluation. RESULTS: In total, required didactic credits were reduced from 92.6 to 79 and didactic courses were reduced from 31 to 23, while ensuring that all required content remained. For many courses, contact hours were also reduced to align with allotted credit hours. Obstacles and challenges were encountered along the way, and a collaborative approach to finding solutions proved beneficial. CONCLUSION: Key recommendations for implementing curricular changes to address overload include having a change model in place, and identifying change leaders to support change and address faculty concerns efficiently. Effective communication through repetition of messaging is critical. Although change is complex, leaning into it with patience and perseverance can lead to success.

A Nationwide Analysis of Complications, Reoperations and Cost of Wide-Awake Flexor Tendon Repairs.

INTRODUCTION: Some papers suggest that wide-awake flexor tendon repair (FTR) may reduce rates of postoperative tendon gapping and rupture due to improved intraoperative testing of the repair. The current study is a nationwide cohort study comparing FTRs performed wide-awake and with traditional anesthesia. METHODS: Patients undergoing zone II FTR between 2010-2022 were identified in PearlDiver. Exclusion criteria were other tendon repairs, concomitant treatment for vascular injury, fracture, dislocation or amputation, inpatient or office surgery, age <18 years and <1 year of follow-up. Patients were stratified by anesthesia technique: traditional anesthesia (general anesthesia, monitored anesthesia care, regional blocks) or wide-awake. Patients were matched based on age, sex, Elixhauser Comorbidity Index (ECI) score, geographical region, insurance coverage, number of tendon repairs and presence of concomitant nerve repair. 30-day wound complications, emergency department visits and readmissions and 1-year reoperations were identified. Total reimbursement for surgery was determined. RESULTS: Each matched cohort included 2,563 patients. Wide-awake patients had fewer 30-day emergency department visits (2.7% vs 4.8%). There were no differences in 30-day wound complications or readmissions. There was no difference in 1-year reoperations for rupture or for stiffness. Multivariable linear regression identified wide-awake surgery to be a significantly associated with lower total reimbursement. CONCLUSIONS: Performing digital FTR using wide-awake techniques can reduce costs, but the hypothesis that wide-awake repairs may reduce rates of tendon rupture was not supported by the current study.

The Tissue Systems Pathology Test Objectively Risk-Stratifies Patients With Barrett's Esophagus: Results From a Multicenter US Clinical Experience Study.

BACKGROUND: Barrett's esophagus (BE) is a diagnosis of esophageal intestinal metaplasia, which can progress to esophageal adenocarcinoma (EAC), and guidelines recommend endoscopic surveillance for early detection and treatment of EAC. However, current practices have limited effectiveness in risk-stratifying patients with BE. AIM: This study aimed to evaluate use of the TSP-9 test in risk-stratifying clinically relevant subsets of patients with BE in clinical practice. METHODS: TSP-9 results for tests ordered by 891 physicians for 8080 patients with BE with clinicopathologic data were evaluated. Orders were from nonacademic (94.3%) and academic (5.7%) settings for nondysplastic BE (NDBE; n=7586; 93.9%), indefinite for dysplasia (IND, n=312, 3.9%), and low-grade dysplasia (LGD, n=182, 2.3%). RESULTS: The TSP-9 test scored 83.2% of patients with low risk, 10.6% intermediate risk, and 6.2% high risk, respectively, for progression to HGD/EAC within 5 years. TSP-9 provided significant risk-stratification independently of clinicopathologic features, within NDBE, IND, and LGD subsets, male and female, and short- and long-segment subsets of patients. TSP-9 identified 15.3% of patients with NDBE as intermediate/high-risk for progression, which was 6.4 times more than patients with a pathology diagnosis of LGD. Patients with NDBE who scored intermediate or high risk had a predicted 5-year progression risk of 8.1% and 15.3%, respectively, which are similar to and higher than published progression rates in patients with BE with confirmed LGD. CONCLUSIONS: The TSP-9 test identified a high-risk subset of patients with NDBE who were predicted to progress at a higher rate than confirmed LGD, enabling early detection of patients requiring management escalation to reduce the incidence of EAC. TSP-9 scored the majority of patients with NDBE as low risk, providing support to adhere to 3- to 5-year surveillance per guidelines.

A Biochemical and Biophysical Analysis of the Interaction of nsp9 with nsp12 from SARS-CoV-2-Implications for Future Drug Discovery Efforts.

The ongoing global pandemic of the coronavirus 2019 (COVID-19) disease is caused by the virus SARS-CoV-2, with very few highly effective antiviral treatments currently available. The machinery responsible for the replication and transcription of viral RNA during infection is made up of several important proteins. Two of these are nsp12, the catalytic subunit of the viral polymerase, and nsp9, a cofactor of nsp12 involved in the capping and priming of viral RNA. While several recent studies have determined the structural details of the interaction of nsp9 with nsp12 in the context of RNA capping, very few biochemical or biophysical details are currently available. In this study, we have used a combination of surface plasmon resonance (SPR) experiments, size exclusion chromatography (SEC) experiments, and biochemical assays to identify specific nsp9 residues that are critical for nsp12 binding as well as RNAylation, both of which are essential for the RNA capping process. Our data indicate that nsp9 dimerization is unlikely to play a significant functional role in the virus. We confirm that a set of recently discovered antiviral peptides inhibit nsp9-nsp12 interaction by specifically binding to nsp9; however, we find that these peptides do not impact RNAylation. In summary, our results have important implications for future drug discovery efforts to combat SARS-CoV-2 and any newly emerging coronaviruses.

Electrostatic Surface Potentials and Chalcogen-Bonding Motifs of Substituted 2,1,3-Benzoselenadiazoles Probed via 77Se Solid-State NMR Spectroscopy.

Chalcogen bonds (ChB) are moderately strong, directional, and specific non-covalent interactions that have garnered substantial interest over the last decades. However, ChB applications are currently hampered by a lack of methods to characterize and control chalcogen bonds. We report on the influence of various substituents (halogens, cyano, and methyl groups) on the observed self-complementary ChB networks of 2,1,3-benzoselenadiazoles. From molecular electrostatic potential calculations, we show that the electrostatic surface potentials (ESP) of the σ-holes on selenium are largely influenced by the electron-withdrawing character of these substituents. Structural analyses via X-ray diffraction reveal a variety of ChB geometries and binding modes that are rationalized via the computed ESP maps, although the structure of 5,6-dimethyl-2,1,3-benzoselenadiazole also demonstrates the influence of steric interactions. 77Se solid-state magic-angle spinning NMR spectroscopy, in particular the analysis of the selenium chemical shift tensors, is found to be an effective probe able to characterize both structural and electrostatic features of these self-complementary ChB systems. We find a positive correlation between the value of the ESP maxima at the σ-holes and the experimentally measured 77Se isotropic chemical shift, while the skew of the chemical shift tensor is established as a metric which is reflective of the ChB binding motif.

Aberrant bowel movement frequencies coincide with increased microbe-derived blood metabolites associated with reduced organ function.

Bowel movement frequency (BMF) directly impacts the gut microbiota and is linked to diseases like chronic kidney disease or dementia. In particular, prior work has shown that constipation is associated with an ecosystem-wide switch from fiber fermentation and short-chain fatty acid production to more detrimental protein fermentation and toxin production. Here, we analyze multi-omic data from generally healthy adults to see how BMF affects their molecular phenotypes, in a pre-disease context. Results show differential abundances of gut microbial genera, blood metabolites, and variation in lifestyle factors across BMF categories. These differences relate to inflammation, heart health, liver function, and kidney function. Causal mediation analysis indicates that the association between lower BMF and reduced kidney function is partially mediated by the microbially derived toxin 3-indoxyl sulfate (3-IS). This result, in a generally healthy context, suggests that the accumulation of microbiota-derived toxins associated with abnormal BMF precede organ damage and may be drivers of chronic, aging-related diseases.