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Objective: The effects of Coronavirus disease 2019 (COVID-19) infection and altered processes of care on nonelective coronary artery bypass grafting (CABG) outcomes remain unknown. We hypothesized that patients with COVID-19 infection would have longer hospital lengths of stay and greater mortality compared with COVID-negative patients, but that these outcomes would not differ between COVID-negative and pre-COVID controls. Methods: The National COVID Cohort Collaborative 2020-2022 was queried for adult patients undergoing CABG. Patients were divided into COVID-negative, COVID-active, and COVID-convalescent groups. Pre-COVID control patients were drawn from the National Surgical Quality Improvement Program database. Adjusted analysis of the 3 COVID groups was performed via generalized linear models. Results: A total of 17,293 patients underwent nonelective CABG, including 16,252 COVID-negative, 127 COVID-active, 367 COVID-convalescent, and 2254 pre-COVID patients. Compared to pre-COVID patients, COVID-negative patients had no difference in mortality, whereas COVID-active patients experienced increased mortality. Mortality and pneumonia were higher in COVID-active patients compared to COVID-negative and COVID-convalescent patients. Adjusted analysis demonstrated that COVID-active patients had higher in-hospital mortality, 30- and 90-day mortality, and pneumonia compared to COVID-negative patients. COVID-convalescent patients had a shorter length of stay but a higher rate of renal impairment. Conclusions: Traditional care processes were altered during the COVID-19 pandemic. Our data show that nonelective CABG in patients with active COVID-19 is associated with significantly increased rates of mortality and pneumonia. The equivalent mortality in COVID-negative and pre-COVID patients suggests that pandemic-associated changes in processes of care did not impact CABG outcomes. Additional research into optimal timing of CABG after COVID infection is warranted.

Abstract Aims This study aimed to assess the effectiveness of adaptive servo‐ventilation (ASV) for lowering hypoxaemic burden components in heart failure with reduced ejection fraction (HFrEF) patients. Methods and results Fifty‐six stable HFrEF patients with left ventricular ejection fraction ≤ 40 were randomized to receive either ASV (n = 27; 25 males) or optimal medical management or optimal medical management alone (n = 29; 26 males). Patients underwent overnight polysomnography at baseline and a 12 week follow‐up visit. We quantified hypoxaemic as time spent at

East Coast Fever (ECF) is a disease affecting cattle in sub-Saharan Africa, caused by the tick-borne Apicomplexan pathogen Theileria parva. The disease is a major problem for cattle farmers in affected regions and there are few methods of control, including a complex infection and treatment vaccine, expensive chemotherapy, and the more widespread tick control through acaricides. New intervention strategies are, therefore, sorely needed. Benzoxaboroles are a versatile class of boron-heterocyclic compounds with demonstrable pharmacological activity against a diverse group of pathogens, including those related to T. parva. In this study, the in vitro efficacy of three benzoxaboroles against the intracellular schizont stage of T. parva was investigated using a flow cytometry approach. Of the benzoxaboroles tested, only one showed any potency, albeit only at high concentrations, even though there is high protein sequence similarity in the CPSF3 protein target compared to other protozoan pathogen species. This finding suggests that benzoxaboroles currently of interest for the treatment of African animal trypanosomiasis, toxoplasmosis, cryptosporidiosis and malaria may not be suitable for the treatment of ECF. We conclude that testing of further benzoxaborole compounds is needed to fully determine whether any lead compounds can be identified to target T. parva.

Background and Aim: The prevalence of depressive symptoms and major depressive disorder is high among adults living with HIV. Depressive symptoms are associated with increased cardiovascular disease risk. This study examined the association between depressive symptoms and echocardiographic indices of left ventricular diastolic dysfunction (LVDD) among men and women living with and without HIV. Methods: Cross-sectional analysis included individuals in the Multicenter AIDS Cohort Study (MACS) and Women’s Interagency HIV Study (WIHS) who participated in transthoracic echocardiogram substudies and completed measures of depressive symptoms at the same visit as, or up to 6 months prior to, the transthoracic echocardiogram visit. Participants had helper T cells (CD4) >350 cells/mm3 and HIV RNA viral load less than 499 copies/mL. The presence of LVDD was defined according to the Characterizing Heart Function on Antiretroviral Therapy (CHART) criteria. Secondary outcomes were continuous values of each component of the CHART criteria: left ventricular ejection fraction >50%, septal e’ velocity, lateral e’ velocity, left atrial volume index, left ventricular mass index, and relative wall thickness. Logistic and linear regression were used to adjust for sociodemographic, behavioural, cardiometabolic, and HIV-related factors. Results: Among 874 men (51% with HIV) and 1,191 women (76% with HIV), in whom the overall prevalence of LVDD was 22.5% and depressive symptoms 30.8%, depressive symptoms were not significantly associated with LVDD. The associations between individual LVDD components and depression were in the small to medium range, though generally not significant. Conclusion: Findings warrant further research regarding the association between LVDD and depressive symptoms in the era of combination antiretroviral therapy.

Sweet cherry (Prunus avium) production relies on modern growing practices like polytunnel coverings to improve yields but this may interrupt arthropod-mediated ecosystem services. The distribution of beneficial arthropods (natural enemies and flower visitors) and the ecosystem services they provide may be affected under polytunnel systems, especially at orchard edges. Across 10 commercial cherry orchards grown in polytunnels, we explored how wildflower strips mitigated edge effects on beneficial arthropods and pest regulation and pollination services. In each orchard, we established a standard wildflower strip (SWS; single cut at the end of the season) and an actively managed wildflower strip (AMWS; regularly cut at 20 cm height) between tree rows and compared this to a conventional control strip (CS). We recorded natural enemies in alleyways and cherry trees post-cherry anthesis (flowering) and flower visitors during and post-cherry anthesis at different distances from the orchard edge (2017–2019). In 2019, we deployed insect prey bait cards in trees to measure pest regulation services and recorded fruit quality (2017–2019) and fruit set (2018–2019) to measure pollination services. Distance from the orchard edge did not affect natural enemy density or diversity in any year or under any alleyway treatment, but pest regulation services decreased towards orchard centres with CS (by 33.0% reduction). Flower visitor density (−34% individuals) and diversity declined with distance from the edge during cherry anthesis. For post-cherry anthesis, marginal negative edge effects were observed for flower visitor density and diversity and behaviour. Overall, fruit set decreased towards the orchard centre while fruit quality increased. Our results suggest that wildflower strips are an effective tool to mitigate edge effects on pest regulation services but have limited effects on flower visitors and pollination.

Purpose: To compare osteochondral defect size measurements and characteristics across magnetic resonance imaging (MRI) and arthroscopy and at the time of osteochondral allograft (OCA) transplantation or autologous chondrocyte implantation (ACI). Methods: Patients who underwent ACI and OCA transplantation at a single institution between 2015 and 2019 were retrospectively identified. Patients were excluded if they had severe osteoarthritis, MRI scans were not available for review, surgical records did not include defect sizing necessary for analysis, or operative reports were not available. Osteochondral lesion characteristics including size were collected preoperatively by MRI and arthroscopy and at the time of definitive open surgical intervention. Subgroup analysis was performed comparing measurement techniques depending on the corrective surgical approach used, as well as depending on the mechanism of chondral injury, to determine whether these factors had any effect on the ability of arthroscopy or MRI to predict graft size. Results: Overall, 136 chondral lesions were addressed, with restoration procedures in 117 patients (mean age, 32.5 years). The average difference between the final graft size and the lesion area measured with index arthroscopy was 116 mm2, whereas the average difference between the final graft size and the lesion size measured with preoperative MRI was 182 mm2 (P < .001). Depending on surgical technique, measurements with MRI were more similar to the final graft size when a patient underwent OCA transplantation versus ACI (P = .007). Depending on the mechanism of injury, MRI measurements of lesions were closer to the graft area when lesions resulted from trauma (P = .047). Conclusions: Chondral lesion size as determined by preoperative MRI is less accurate than arthroscopic measurement. The mechanism of injury leading to chondral damage and degree of damage may influence the ability of MRI and arthroscopy to accurately measure chondral lesions and predict the final graft size used in surgical correction. Level of Evidence: Level III, retrospective cohort study.

Purpose: To objectively assess the accuracy of socket measurements taken during cruciate ligament reconstruction using a retrograde reaming technique. Methods: Six complete knee sawbone specimens were used to ream anterior and posterior cruciate ligament sockets in the femur and tibia in a retrograde fashion using a standard retrograde reaming device. The longest and shortest sides of the sockets were measured using a ruler. One-sided Wilcoxon signed-rank sum tests were used to evaluate whether the actual measured socket length matched the estimated length set on the drill guide. Results: One fellowship-trained surgeon reamed 24 total sockets in sawbone specimens using guides. Statistical analysis revealed a significant difference between the estimated measurement and the actual shortest tunnel length in each of the sockets. The median short side socket lengths were shorter than their respective intended depths by 4 mm for the femoral anterior cruciate ligament socket, 6 mm for the femoral posterior cruciate ligament socket, 6 mm for the tibial anterior cruciate ligament socket, and 4.5 mm for the tibial posterior cruciate ligament socket. All differences were significant at α = 0.05. Conclusions: The estimated cruciate socket lengths reamed during ligament reconstruction using a retrograde reamer and standard intra-articular measuring instrumentation were greater than the actual measured socket lengths. Clinical Relevance: Successful cruciate ligament reconstruction relies on accurate socket measurements. This study examined the accuracy of commercially available cruciate ligament socket drill guides and the implications for clinical practice, to include graft-tunnel mismatch and surface area available for healing. Surgeons may consider reaming slightly longer than estimated sockets when performing all-inside cruciate ligament reconstructions to ensure appropriate socket depth for graft fixation.

Abstract Background Radon is a radioactive gas and a major risk factor for lung cancer (LC). Methods We investigated the dose–response relationship between radon and LC risk in the International Lung Cancer Consortium with 8927 cases and 5562 controls from Europe, North America, and Israel, conducted between 1992 and 2016. Spatial indoor radon exposure in the residential area (sIR) obtained from national surveys was linked to the participants' residential geolocation. Parametric linear and spline functions were fitted within a logistic regression framework. Results We observed a non‐linear spatial‐dose response relationship for sIR

Abstract Permafrost influences 25% of land in the Northern Hemisphere, where it stabilizes the ground beneath communities and infrastructure and sequesters carbon. However, the coevolution of permafrost, river dynamics, and vegetation in Arctic environments remains poorly understood. As rivers meander, they erode the floodplain at cutbanks and build new land through bar deposition, creating sequences of landforms with distinct formation ages. Here we mapped these sequences along the Koyukuk River floodplain, Alaska, analyzing permafrost occurrence, and landform and vegetation types. We used radiocarbon and optically stimulated luminescence (OSL) dating to develop a floodplain age map. Deposit ages ranged from modern to 10 ka, with more younger deposits near the modern channel. Permafrost rapidly reached 50% areal extent in all deposits older than 200 years then gradually increased up to ∼85% extent for deposits greater than 4 Kyr old. Permafrost extent correlated with increases in black spruce and wetland abundance, as well as increases in permafrost extent within wetland, and shrub and scrub vegetation classes. We developed an inverse model to constrain permafrost formation rate as a function of air temperature. Permafrost extent initially increased by ∼25% per century, in pace with vegetation succession, before decelerating to

The Mount Meager Volcanic Complex (Q̓welq̓welústen) is an active glacier-capped volcanic massif in the Garibaldi Volcanic Belt (British Columbia) and the only known glaciovolcanic cave system in North America steadily releasing sulfur-rich gases. In September 2022, leveraging specialized cave explorer expertise, the fumarole-carved ice cave at the Job Glacier on Mt. Meager was surveyed. Direct measurements of fumarolic gas concentrations were taken at the source, with H2S >200 ppm, SO2 >100 ppm, CO2 ∼5,200 ppm, and CO ∼230 ppm. Snowpack and fumarole-associated sediments were characterized for microbial diversity, functional potential, and biogeochemistry including measurements of nutrients, major ions, dissolved organic and inorganic carbon concentrations as well as the stable isotope compositions of carbon, sulfur, hydrogen and oxygen. Green algae (Chlorophyta) dominated the snowpack, consistent with other Pacific Northwest glaciers. Representatives of Firmicutes were the most abundant bacterial sequences detected in our samples, contrasting with other glacier and snowpack samples which harbor abundant Sphingobacteria, Betaproteobacteria, and Alphaproteobacteria. Sediments and water collected inside the cave were mostly high in SO42- (5.3–185.2 mg/L) and acidic (pH = 3.6–6.0), while most other major anions and cations were below detection of the method used. Snow at the cave entrance had more SO42- (0.08 mg/L) and lower pH (5.9) than snow collected at a distance (SO42- undetectable, pH 7.6), suggesting influence by fumarole exhalations. Negative δ13C values of organic matter (−29.0‰ to −26.1‰, respectively) in sediments suggest in-situ microbial carbon transformations, findings that are supported by the presence of genes encoding complete heterotrophic and autotrophic carbon transformation pathways. The δ34S value of H2S was ∼0‰, suggesting a deep magmatic origin; however, both sulfur-oxidizing and sulfate-reducing microbial phyla were present in the sediment samples as were genes encoding both dissimilatory sulfur-oxidizing and sulfate-reducing pathways. Metagenomic data suggest diverse chemosynthetic lifestyles in the cave microbial community. This study provides insight on the microbiomes associated with a sulfidic glaciovolcanic system and identifies unique analog features for icy celestial bodies like Saturn’s moon Enceladus, where cryovolcanic activity may carry biomarkers from the subsurface and deposit them on surface ice.

IntroductionEndothelial function is significantly impaired in patients with SLE compared to healthy controls. Elevated activation of the mammalian target of rapamycin complex 1 (mTORC1) is reported in humans and mice with SLE. However, it is unclear if elevated mTORC1 in SLE contributes to impaired mitophagy and endothelial dysfunction. Therefore, we tested the hypothesis that inhibiting mTORC1 with rapamycin would increase mitophagy and attenuate endothelial dysfunction and inflammatory responses in SLE.MethodsNine-week-old female lupus-prone (MRL/lpr) and healthy control (MRL/MpJ) mice were randomly assigned into rapamycin treatment (lpr_Rapamycin and MpJ_Rapamycin) or control (lpr_Control and MpJ_Control) groups. Rapamycin was injected i.p. 3 days per week for 8 weeks. After 8 weeks, endothelium-dependent vasorelaxation to acetylcholine (ACh) and endothelium-independent vasorelaxation to sodium nitroprusside (SNP) were measured in thoracic aortas using a wire myograph.ResultsMTORC1 activity was increased in aorta from lpr mice as demonstrated by increased phosphorylation of s6rp and p70s6k and significantly inhibited by rapamycin (s6rp, p < 0.0001, p70s6k, p = 0.04, respectively). Maximal responses to Ach were significantly impaired in lpr_Control (51.7% ± 6.6%) compared to MpJ_Control (86.7% ± 3.6%) (p < 0.0001). Rapamycin prevented endothelial dysfunction in the thoracic aorta from lupus mice (lpr_Rapamycin) (79.6% ± 4.2%) compared to lpr_Control (p = 0.002). Maximal responses to SNP were not different across groups. Phosphorylation of endothelial nitric oxide synthase also was 42% lower in lpr_Control than MpJ_Control and 46% higher in lpr_Rapamycin than lpr_Control. The inflammatory marker, vascular cell adhesion protein 1 (Vcam 1), was elevated in aorta from lupus mice compared with healthy mice (p = 0.001), and significantly reduced with Rapamycin treatment (p = 0.0021). Mitophagy markers were higher in lupus mice and reduced by rapamycin treatment, suggesting altered mitophagy in lpr mice.ConclusionCollectively, these results demonstrate the beneficial effects of inhibiting mTORC1 on endothelial function in SLE mice and suggest inflammation and altered mitophagy contribute to endothelial dysfunction in SLE.

Abstract Reversible axonal swelling and brainstem auditory evoked potential (BAEP) changes were observed in standard chronic (9‐month) toxicology studies in dogs treated with ritlecitinib, an oral Janus kinase 3/tyrosine kinase expressed in hepatocellular carcinoma family kinase inhibitor, at exposures higher than the approved 50‐mg human dose. To evaluate the clinical relevance of the dog toxicity finding, this phase 2a, double‐blind study assessed BAEP changes and intraepidermal nerve fiber (IENF) histology in adults with alopecia areata treated with ritlecitinib. Patients were randomized to receive oral ritlecitinib 50 mg once daily (QD) with a 4‐week loading dose of 200 mg QD or placebo for 9 months (placebo‐controlled phase); they then entered the active‐therapy extension and received ritlecitinib 50 mg QD (with a 4‐week loading dose of 200 mg in patients switching from placebo). Among the 71 patients, no notable mean differences in change from baseline (CFB) in Waves I–V interwave latency (primary outcome) or Wave V amplitude on BAEP at a stimulus intensity of 80 dB nHL were observed in the ritlecitinib or placebo group at Month 9, with no notable differences in interwave latency or Wave V amplitude between groups. The CFB in mean or median IENF density and in percentage of IENFs with axonal swellings was minimal and similar between groups at Month 9. Ritlecitinib treatment was also not associated with an imbalanced incidence of neurological and audiological adverse events. These results provide evidence that the BAEP and axonal swelling finding in dogs are not clinically relevant in humans.

Contamination of poultry products by Salmonella enterica serovar Typhimurium (STm) is a major cause of foodborne infections and outbreaks. This study aimed to assess the diversity and antimicrobial resistance (AMR) carriage of STm in three chicken processing plants using genomic sequencing. It also aimed to investigate whether any particular strain types were associated with cases of human illness. Multilevel genome typing (MGT) was used to analyze 379 STm isolates from processed chicken carcasses. The diversity of chicken STm sequence types (STs) increased from MGT1 (2 STs) to MGT9 (257 STs). STs at MGT5 to MGT9 levels that were unique to one processing plant and shared among the processing plants were identified, likely reflecting the diversity of STm at their farm source. Fifteen medium resolution MGT5 STs matched those from human infections in Australia and globally. However, no STs matched between the chicken and human isolates at high resolution levels (MGT8 or MGT9), indicating the two STm populations were phylogenetically related but were unlikely to be directly epidemiologically linked. AMR genes were rare, with only a blaTEM-1 gene carried by a 95 kb IncI1 Alpha plasmid being identified in 20 isolates. In conclusion, subpopulations that were widespread in processing plants and had caused human infections were described using MGT5 STs. In this STM population, AMR was rare with only sporadic resistance to a single drug class observed. The genomic analysis of STm from chicken processing plants in this study provided insights into STm that contaminate meat chickens early in the food production chain.

The criteria for the progression of hits in the discovery of leads for human African trypanosomiasis (HAT), a neglected disease caused by the microbial eukaryote Trypanosoma brucei, are not standardized. Hits are advanced upon meeting thresholds for drug-like molecules. Following those principles, pharmacokinetics (Cmax and AUC0–6h) and anti-trypanosome characteristics predicted the arrest of T. brucei proliferation in mice by three curaxins. Unexpectedly, while CBL0137 cured HAT in a mouse model, CBL0174 and CBL0187—structural analogs of CBL0137 with similar drug-like properties—failed to control T. brucei division. We here propose an alternative strategy that integrates physicochemical, metabolic, pharmacokinetic, pharmacodynamic, tissue distribution, and trypanocidality parameters into calculating a score for ranking compounds in hit-to-lead campaigns. Data from our studies of curaxins support the feasibility of this goal. Serum dropped the anti-trypanosome potency of CBL0174 and CBL0187 considerably. Delayed trypanocidal concentrations (DTC25 and DTC90) were used to study modes of curaxin actions in trypanosomes. Efficacy of CBL0137 in mice correlated with (i) a high AUC0–6h:DTC90 ratio, (ii) blocking of transferrin endocytosis, and (iii) the inhibition of protein synthesis. Hydroxylation of the carbazole prevented CBL0137 from inhibiting endocytosis of transferrin. The multiparametric score “Curaxin HAT lead efficacy (CHLE)” score was calculated using pharmacokinetic, physicochemical, metabolic, brain exposure, and pharmacodynamic data; CBL0137 was the highest scoring hit. Complementing these observations and predictive of performance of curaxins in mice, CBL0137, but not CBL0174 or CBL0187, was trypanocidal after the exposure of trypanosomes to AUC0–6h amounts of the hits for 6 hours in vitro. We discuss a role for CHLE scores in ranking curaxins for anti-HAT lead discovery. The principles used to develop CHLE scores may be used to calculate new ones for other scaffolds during the discovery of leads for HAT or other infectious diseases.

In advanced photonics, there is a growing interest in piezochromic luminescent materials that exhibit multicolor switching, driven by their potential applications in optical recording, memory, and sensors. Here, the piezochromic behavior of 2,4,6‐triphenylpyrylium tetrachloroferrate (Py‐FeCl4) under high pressures from 0 to 9 GPa is reported. The observed multicolor changing properties of Py‐FeCl4 (yellow–orange–red–maroon–black) are found to be fully reversible upon decompression to ambient conditions. The mechanism of Py‐FeCl4 piezochromism is investigated via Raman, infrared, and UV–vis spectroscopy combined with powder X‐ray Diffraction. The absence of structural phase transitions as well as the abrupt shifts of bandgap values together with characteristic Raman and IR peaks within 0‐9 GPa suggests that the Py‐FeCl4 multicoloring switching behavior is driven by an electron transfer between the inorganic FeCl4− anion and the organic pyrylium cation. The obtained results demonstrate that Py‐FeCl4 dye is a good candidate for developing high‐pressure sensing technologies designed to function in extreme environments. Moreover, due to the inherent role of molecular‐structure relationships in the pyrylium salt's photophysical properties, findings suggest the potential discovery of piezochromic behavior in other pyrylium compounds.

PURPOSEWomen living with HIV (WLWH) experience decreased breast cancer survival. We sought to determine whether WLWH surviving breast cancer also experienced different quality of life (QOL) gain.METHODSWomen who enrolled in the Thabatse Cancer Cohort across oncology centers in Botswana for the initial treatment of stage I-III breast cancer from October 2010 to February 2022 were included. Exclusion criteria were no documented definitive therapy and incomplete data at treatment end or 24 ± 3 months after treatment. QOL was measured quarterly using the SF-8 questionnaire. G methods using weighted exposure and outcome modules were used to mitigate potential bias from imbalances in demographic and cancer characteristics by HIV status. Primary analysis was change in physical component summary (PCS) and mental component summary (MCS) from treatment end to 24 months after treatment for WLWH compared with women without HIV.RESULTSOf 603 women enrolled, the final analysis included 298, comprising 85 WLWH and 213 women without HIV. Most common reasons for exclusion were no documented definitive treatment (n = 114) and death before 21 months after treatment (n = 137). WLWH were younger, were less wealthy, and had more estrogen receptor/progesterone receptor positive tumors. Overall, PCS and MCS significantly increased from treatment end to 24 months after treatment, from 50.8 to 52.8 and 51.8 to 53.7, respectively. There was no difference in the change of the PCS or MCS with HIV infection, 2.2 (95% CI, –0.4 to 4.9) and 0.6 (95% CI, –1.7 to 2.9), respectively.CONCLUSIONHIV infection did not impede QOL gain at 24 months after treatment in women surviving breast cancer. Further work is needed to clarify the role of HIV on specific treatment-related morbidities and in other malignancies.

BackgroundEmerging adults (EAs; age 18-30 years) with type 1 diabetes (T1D) have more challenges with diabetes management and glycemic control than other age groups. Living in a rural community introduces additional unique diabetes care challenges due to limited access to specialty care and ancillary support services. Yet, few interventions have been developed to improve diabetes management in rural-dwelling EAs with T1D. ObjectiveThis study aimed to understand the diabetes management experiences of older adolescents and EAs (age 16-25 years) with T1D living in a rural area and to assess their perceptions of the acceptability of 4 fully automated mobile health (mHealth) interventions to support diabetes management. MethodsEAs were identified by clinical staff through convenience sampling. In total, 8 EAs participated in 1 focus group and 1 EA completed an individual interview; all data were collected over Zoom. Facilitators explored EAs’ experiences living in a rural community with T1D and discussed EAs’ impressions of, feedback on, and recommendations for improving 4 mHealth interventions to meet the specific needs of EAs with T1D living in rural communities. Discussions were transcribed and analyzed using conventional content analysis. ResultsIn total, 9 EAs (aged 18.8, SD 2.7 years; 5, 56% men; 8, 89% White) with a duration of diabetes of 8.6 (SD 4.3) years participated. They described experiences with diabetes stigma (attributing diabetes to poor lifestyle choices) and feelings of self-consciousness (hyperawareness) in their rural communities. They attributed these experiences to the small size of their communities (“everyone knows”) and community members’ lack of knowledge about diabetes (unable to differentiate between type 1 and type 2 diabetes). In contrast, EAs reported high levels of social support for diabetes and diabetes care from family, friends, and other community members, but low support for medical needs. The location of their diabetes care providers and the limited accessibility of diabetes-specific and general medical care services in their local community created a challenging medical care context. Overall, EAs found mHealth interventions appealing due to their digital delivery and highlighted features that increased accessibility (voiceovers and simple, jargon-free language), individualization (ability to tailor intervention content and delivery), and applicability to their own lives and other EAs with T1D (relatability of vignettes and other content). EAs suggestions for improving the interventions included more opportunities to tailor the interventions to their preferences (greater frequency and duration, ability to adapt content to emerging needs), increasing opportunities for peer support within the interventions (friend and significant other as identified support person, connecting with peers beyond their local community), and making the tone of intervention components more casual and engaging. ConclusionsmHealth interventions aligned with EAs’ needs and preferences are a promising strategy to support EAs in communities where social support and resources might be limited. Trial RegistrationN/A, not a clinical trial

Single lung transplantation (SLTx) has been used to treat end-stage lung disease. A common complication after SLTx is hyperinflation of the native emphysematous lung (NLH). Previous attempts to reduce the NLH have been tried using surgery, endoscopic valves, etc. with variable outcomes. Lung volume reduction coils can be used for treating hyperinflation in emphysema patients irrespective of collateral ventilation (CV). We here report a case of native lung hyperinflation in SLTx treated with lung volume reduction coils. This treatment appears to be a safe treatment option when dealing with CV-positive NLH in SLTx recipients.

Background: Wild-type transthyretin amyloidosis (ATTRwt amyloidosis) is primarily diagnosed in elderly men but diagnoses in younger patients and women have recently increased. Objectives: The purpose of this study was to examine age- and sex-related differences in patients with ATTRwt amyloidosis enrolled in the THAOS (Transthyretin Amyloidosis Outcomes Survey). Methods: THAOS was a global, longitudinal, observational survey of patients with transthyretin amyloidosis, including both hereditary and wild-type disease, and asymptomatic carriers of pathogenic transthyretin gene variants. Patient characteristics at enrollment were analyzed by age at enrollment and sex (data cutoff date: August 1, 2022). Results: Of 1,251 patients with ATTRwt amyloidosis, 13.7%, 49.1%, 34.5%, and 2.8% were aged

Summary: Background: An increasing number of countries have or are considering legalizing cannabis. One concern is that legalization of cannabis will result in increased cannabis use and in turn a higher prevalence of anxiety disorders. We examined changes in emergency department (ED) visits for anxiety disorders with cannabis involvement in Ontario, over a period that involved medical and non-medical cannabis legalization. Methods: This repeated cross-sectional population-based study identified all ED visits for anxiety disorders from residents of Ontario, Canada aged 10–105 between 2008 and 2022 (n = 15.7 million individuals). We used interrupted time series analyses to examine immediate and gradual changes in cannabis-involvement and alcohol-involvement (control condition) over four policy periods: medical cannabis legalization (January 2008–November 2015), expanded medical access (December 2015–September 2018), non-medical cannabis legalization with restrictions (October 2018–February 2020), and commercialization which overlapped with the COVID-19 pandemic (March 2020–December 2022). Poisson models were used to generate incidence rate ratios with 95% confidence intervals. Findings: Over the 14-year study, there were 438,700 individuals with one or more ED visits for anxiety disorders of which 3880 (0.89%) individuals had cannabis involvement and 6329 (1.45%) individuals had alcohol involvement. During the commercialization/COVID-19 period monthly rates of anxiety disorders with cannabis-involvement were 156% higher (0.11 vs 0.29 per 100,000 individuals) relative to the pre-legalization period, compared to a 27% increase for alcohol-involvement (0.27 vs 0.35 per 1100,000 individuals). Rates of anxiety ED visits with cannabis involvement per 100,000 individuals increased gradually over the study period with no immediate or gradual changes after expanded medical access, legalization with restrictions or commercialization/COVID-19. However, during the commercialization/COVID-19 period there were large declines in total anxiety disorder ED visits and anxiety disorder ED visits with alcohol-involvement. Consequently, during this period there was an immediate 31.4% relative increase in the proportion of anxiety visits with cannabis-involvement (incidence rate ratio [IRR], 1.31; 95% CI 1.05–1.65). Interpretation: We found large relative increases in anxiety disorder ED visits with cannabis involvement over a 14-year period involving medical and non-medical cannabis legalization. These findings may reflect increasing anxiety disorder problems from cannabis use, increasing self-medication of anxiety disorders with cannabis use, or both. The proportion of anxiety ED visits with cannabis involvement increased during the final period of the study but could have been the results of the market commercialization, COVID-19 or both and ongoing monitoring is indicated. Funding: Canadian Institutes of Health Research (grant #452360).

Introduction: Emerging literature links fatherhood to men's health but lacks comprehensive assessment of health outcomes, especially among multiethnic populations. This study's objective was to evaluate the associations of fatherhood (age at onset and status) with cardiovascular health scores, incident cardiovascular disease, cardiovascular disease death, and all-cause mortality, examining differences by race/ethnicity. Methods: The study sample included men from Multi-Ethnic Study of Atherosclerosis, prospective cohort study that enrolled adults aged 45–84 years without known cardiovascular disease at baseline. Cardiovascular health was defined using the American Heart Association's Life's Essential 8 scores (0–100), excluding sleep (cardiovascular health score). Results: In this sample of 2,814 men, mean age at cardiovascular health assessment was 62.2 years, 82% were fathers, 24% self-identified as Black, 13% self-identified Chinese, 22% self-identified Hispanic, and 41% self-identified White. Fathers who were aged 35 years (adjusted mean score of 61.1 vs 64.7 [p=0.01] and 61.0 vs 64.7 [p

This study analyzes immune responses to SARS-CoV-2 vaccination and infection, including asymptomatic cases, focusing on infection risks during the Omicron wave, particularly among high-risk healthcare workers. In the KoCo-Impf study, we monitored 6088 vaccinated participants in Munich aged 18 and above. From 13 May to 31 July 2022, 2351 participants were follow-uped. Logistic regression models evaluated primary, secondary, and breakthrough infections (BTIs). Roche Elecsys® Anti-SARS-CoV-2 assays detected prior infections (via anti-Nucleocapsid antibodies) and assessed vaccination/infection impact (via anti-Spike antibodies) using dried blood spots. Our findings revealed an anti-Nucleocapsid seroprevalence of 44.1%. BTIs occurred in 38.8% of participants, with reinfections in 48.0%. Follow-up participation was inversely associated with current smoking and non-vaccination, while significantly increasing with age and receipt of three vaccine doses. Larger household sizes and younger age increased infection risks, whereas multiple vaccinations and older age reduced them. Household size and specific institutional subgroups were risk factors for BTIs. The anti-Nucleocapsid value prior to the second infection was significantly associated with reinfection risk. Institutional subgroups influenced all models, underscoring the importance of tailored outbreak responses. The KoCo-Impf study underscores the importance of vaccination, demographic factors, and institutional settings in understanding SARS-CoV-2 infection risks during the Omicron wave.

EELS-DARTS is a simulator designed for autonomy development and analysis of large degree of freedom snake-like robots for space exploration. A detailed description of the EELS-DARTS simulator design is presented. This includes the versatile underlying multibody dynamics representation used to model a variety of distinct snake robot configurations as well as an anisotropic friction model for describing screw–ice interaction. Additional simulation components such as graphics, importable terrain, joint controllers, and perception are discussed. Methods for setting up and running simulations are discussed, including how a snake robot’s autonomy stack closes the commands and information loop with the simulation via ROS. Multiple use cases are described to illustrate how the simulation is used to aid and inform robot design, autonomy development, and field test use throughout the project’s life cycle. A validation analysis of the screw–ice contact model is performed for the surface mobility case. Lastly, an overview of simulation use for planning operations during a recent field test to the Athabasca Glacier in Canada is discussed.

At the beginning of the COVID-19 pandemic, the Georgia Institute of Technology made the decision to keep the university doors open for on-campus attendance. To manage COVID-19 infection rates, internal resources were applied to develop and implement a mass asymptomatic surveillance program. The objective was to identify infections early for proper follow-on verification testing, contact tracing, and quarantine/isolation as needed. Program success depended on frequent and voluntary sample collection from over 40,000 students, faculty, and staff personnel. At that time, the nasopharyngeal (NP) swab, not saliva, was the main accepted sample type for COVID-19 testing. However, due to collection discomfort and the inability to be self-collected, the NP swab was not feasible for voluntary and frequent self-collection. Therefore, saliva was selected as the clinical sample type and validated. A saliva collection kit and a sample processing and analysis workflow were developed. The results of a clinical sample-type comparison study between co-collected and matched NP swabs and saliva samples showed 96.7% positive agreement and 100% negative agreement. During the Fall 2020 and Spring 2021 semesters, 319,988 samples were collected and tested. The program resulted in maintaining a low overall mean positivity rate of 0.78% and 0.54% for the Fall 2020 and Spring 2021 semesters, respectively. For this high-throughput asymptomatic COVID-19 screening application, saliva was an exceptionally good sample type.

Heusler compounds with semiconducting properties represent an important class of functional materials. Usually, research on these systems is guided by simple electron-counting rules, such as the Slater-Pauling principle. Here, we report on the discovery of Heusler-type semiconductors, significantly deviating from the Slater-Pauling rule. We theoretically predict the occurrence of nonmagnetic semiconducting ground states in various highly off-stoichiometric full-Heusler alloys, where self-substitution leads to a band-gap opening. This unexpected trend is confirmed experimentally by thermoelectric transport measurements on a multitude of Fe_{2−2x}V_{1−x}Al_{1+3x} samples with up to 20% substitution of Fe and V atoms. The band-gap opening leads to an exceptionally large Seebeck coefficient in p-type Fe_{2}VAl thermoelectrics, previously limited by bipolar conduction and low-density-of-states effective mass. Consequently, our work presents a paradigm to tune the band gap of Heusler compounds by self-substitution and introduces a hitherto unexplored class of semiconductors with exceptional thermoelectric properties, offering significant potential for advancements in energy science and sustainable-energy technologies.

We numerically study the relaxation dynamics of impurity-host systems, focusing on the presence of long-lived metastable states in the nonequilibrium dynamics after an initial excitation of the impurities. In generic systems, an excited impurity coupled to a large bath at zero temperature is expected to relax and approach its ground state over time. However, certain exceptional cases exhibit metastability, where the system remains in an excited state on timescales largely exceeding the typical relaxation time. We study this phenomenon for three prototypical impurity models: a tight-binding quantum model of independent spinless fermions on a lattice with two stub impurities, a classical-spin Heisenberg model with two weakly coupled classical impurity spins, and a tight-binding quantum model of independent electrons with two classical impurity spins. Through numerical integration of the fundamental equations of motion, we find that all three models exhibit similar qualitative behavior: complete relaxation for nearest-neighbor impurities and incomplete or strongly delayed relaxation for next-nearest-neighbor impurities. The underlying mechanisms leading to this behavior differ between models and include impurity-induced bound states, emergent approximately conserved local observables, and exact cancellation of local and nonlocal dissipation effects.

We present a genome assembly from an individual Tridacna derasa (the smooth giant clam; Mollusca; Bivalvia;Cardiida; Cardiidae). The genome sequence is 1,060.2 megabases in span. Most of the assembly is scaffolded into 18 chromosomal pseudomolecules. The mitochondrial genome has also been assembled and is 24.95 kilobases in length. Gene annotation of this assembly on Ensembl identified 19,638 protein coding genes.

We present a genome assembly from an individual Fragum sueziense (the heart cockle; Mollusca; Bivalvia; Cardiida; Cardiidae). The genome sequence is 1,206.1 megabases in span. Most of the assembly is scaffolded into 19 chromosomal pseudomolecules. The mitochondrial genome has also been assembled and is 92.77 kilobases in length. Gene annotation of this assembly on Ensembl identified 70,309 protein-coding genes.

In view of the rise of drug-resistant tuberculosis and difficult-to-treat related diseases caused by non-tuberculous mycobacteria, there is an urgent need for antimycobacterial drug discovery. Nα-aroyl-N-aryl-phenylalanine amides (AAPs) have been identified as antimycobacterial agents and are subject to lead optimization. The aim of the present study is to evaluate the impact of N-aryl ortho cyano substitution in a lead compound on the crystal and molecular structure and its in vitro activity against Mycobacterium abscessus. The title AAP can be conveniently synthesized from N-Boc-protected d-phenylalanine in two amide coupling steps using a previously established racemization-free method. Two polymorphic forms in the solid-state are described, as discovered by X-ray and electron diffraction. The introduction of a cyano group in the ortho position of the AAP N-aryl ring, however, leads to loss of in vitro activity against M. abscessus subsp. abscessus.

Background: Ventilator associated pneumonia (VAP) is associated with significant rates of morbidity and all-cause mortality. Active VAP surveillance can identify risk factors for which targeted preventive measures can be implemented. However, surveillance efforts are complicated by challenges associated with accurate VAP diagnosis. We aimed to improve the accuracy and automation of existing VAP diagnostic algorithms to better identify patients at risk. Methods: The study was conducted at NYU Langone Health from June 2022 through December 2023. We created a semi-automated VAP surveillance system using the Centers for Disease Control & Prevention (CDC) ventilator associated event (VAE) definition as a base framework (Figure 1). We modified this definition to include additional elements, such as having a sputum culture ordered within 48 hours of worsening oxygen status, regardless of culture result. Using this algorithm—followed by manual clinician reviews—we retrospectively assessed possible VAP cases to determine the ability of our surveillance system to correctly identify VAP. Results: Of the 123 possible VAP cases identified through our automated system, 75 (61%) were correctly diagnosed as VAP after clinical review. This reflects a rate of 1.5 infections per 1000 ventilation days across the system and 1.85 infections per 100 patients ventilated for greater than 2 days. Of the 48 remaining patients without VAP after clinical review, 25% (n=12) were characterized as having hospital-acquired pneumonia, 21% (n=10) as acute respiratory distress syndrome or infection at another site and 10% (n=5) as pulmonary embolism/infarction. Among all patients identified through this automated system (VAP and non-VAP), 53% experienced in-hospital death. Discussion: Our automated VAP surveillance algorithm identified 123 cases of potential VAP, 61% of which were consistent with a clinical diagnosis of VAP upon manual chart review. Our VAP rate of 1.5 infections per 1000 ventilation days was similar to published rates at other North American hospital systems. The high in-hospital mortality rate among these patients highlights the need for improved surveillance systems and earlier interventions to reduce the risk of VAP. There are several limitations to the CDC’s VAE definition, including its requirement of a positive microbiologic culture and focus on sputum quality. This potentially misses cases of culture-negative VAP in patients receiving antibiotics prior to sputum collection. Our goal is to continue to validate and improve our algorithm’s ability to correctly identify patients with clinical VAP, so that targeted prevention efforts can be focused upon the patients with the highest risk for poor outcomes.

Background: Using antibiotics without medical guidance (non-prescription use) is a potential safety threat to individual and public health. Patients' situations can impact their intentions to use non-prescription antibiotics in the future (intended use). This survey (1) explores the dimensionality of 13 predefined situations to identify ‘summary factor,’ which include conceptually similar situations that influence patients’ intended use of non-prescription antibiotics, and (2) identifies the sociodemographic predictors associated with these summary factors. Methods: A cross-sectional survey was conducted from January 2020–June 2021 in the waiting rooms of six safety-net primary care clinics and two private emergency departments. We used principal component analysis as a data reduction technique and confirmed the factor structure of the situations (identifying three situational summary factors). Multivariate linear regression identified the sociodemographic predictors (e.g., age, gender, race, education, insurance, healthcare system, language preference, birth country, and health literacy) associated with each summary factor. Results: Of the 564 patients surveyed, the majority were female (72%), Hispanic or Latinx (47%), college-educated (44%), and received public health insurance (e.g., Medicaid or County Financial Assistance) (56%). The largest proportion of patients endorsed intended non-prescription antibiotic use for situations involving high doctor visit costs (29.8%), having leftover prescription antibiotics (50.4%), and experiencing symptom relief with prior use of antibiotics (47.5%) (Figure 1). We identified three situational summary factors: (1) perceived barriers to a doctor visit and receiving a prescription (Cronbach’s alpha [α]=0.96), (2) convenience and accessibility of non-prescription antibiotics (α=0.81), and (3) previous symptom relief with antibiotics (α=0.95). After controlling for gender, race, education, insurance, language preference, birth country, and health literacy, our multivariate regression results revealed that younger patients (P < 0 .04) and patients attending the safety-net health system (P < 0 .001) had more intended use of non-prescription antibiotics for all three summary factors (Figure 2). Conclusions: Our study revealed that younger patients and individuals receiving care from the safety-net clinics had an increased risk of intended non-prescription antibiotic use across all summary factors. Future stewardship interventions should consider the types of situations that drive patients' decisions to use antibiotics without a prescription. Interventions aimed at reducing barriers to healthcare (e.g., high costs and long waits associated with doctor appointments) and educating individuals on the risks associated with inappropriate antibiotic use while providing alternative (non-antibiotic) treatment options may reduce antibiotic use and antimicrobial resistance. Acknowledgments: This work is supported by grant number R01HS026901 from AHRQ and NRSA T-32 (6T32HC10031).

Background: Administrative tasks are an increasing burden for primary care doctors globally and linked to burnout. Many tasks occur during consultations. They cause interruptions with possible effects on patients’ and doctors’ experiences and care. The burden and typology of interruptions of doctors in primary care consultations have not been studied in South Africa. Given the link between administrative loads and burnout, describing the extent of these interruptions would help. This study’s aim was to assess the extent of interruptions on primary care doctors in the Western Cape. Methods: This was a descriptive cross-sectional survey. Doctors from rural and urban primary care clinics in the Western Cape answered an online self-administered survey on the types of interruptions experienced during consultations. Interruptions were categorised and their prevalence calculated. Clinical and non-clinical interruption categories were compared. Results: There were 201 consultations from 30 doctors. Most interruptions were from retrieving and recording the current patient’s information (93.0%), paperwork for other patients (50.7%), and telephone calls about the current patient (41.8%). Other prevalent interruptions were for emergencies (39.8%) and acquiring consumables (37.3%). The median (interquartile range [IQR]) of four (2–4) interruption types per consultation was higher than global settings. Conclusion: Doctors experienced many interruptions during consultations. Their wide range included interruptions unrelated to the current patient. Contribution: This study adds insights from the global south on clinicians’ administrative burden. It elaborates on the types of activities that interrupt consultations in an upper-middle income primary care setting. Exploration of interventions to decrease this burden is suggested.

Abstract Gut bacterial communities provide flexibility to hosts during dietary changes. Despite the increasing number of studies exploring the associations between broader dietary guilds of mammalian hosts and their gut bacteria, it is generally unclear how diversity and variability in consumed diets link to gut bacterial taxa in wild non‐primate mammals, particularly in omnivores. Here, we contribute to filling this gap by exploring consumed diets and gut bacterial community compositions with metabarcoding of faecal samples for two African mammals, Civettictis civetta and Genetta spp., from the family Viverridae. For each individual sample, we characterised bacterial communities and identified dietary taxa by sequencing vertebrate, invertebrate and plant markers. This led us to establish diet compositions that diverged from what has previously been found from visual identification methods. Specifically, while the two genera have been categorised into the same dietary guild, we detected more animal dietary items than plant items in C. civetta, while in Genetta spp., we observed the opposite. We further found that individuals with similar diets have similar gut bacterial communities within both genera. This association tended to be driven by specific links between dietary items and gut bacterial genera, rather than communities as a whole, implying diet‐driven selection for specific gut microbes in individual wild hosts. Our findings underline the importance of molecular tools for improving characterisations of omnivorous mammalian diets and highlight the opportunities for simultaneously disentangling links between diets and gut symbionts. Such insights can inform robustness and flexibility in host‐microbe symbioses to dietary change associated with seasonal and habitat changes.

Foot-and-mouth disease (FMD) is a highly infectious and endemic disease in Lao PDR. However, surveillance is weak, and outbreaks are not routinely reported. To address this, serum samples were routinely collected from cattle and buffalo from provincial abattoirs between November 2021 and December 2022. A total of 2,663 serum samples were collected from large ruminants (n = 1,625 cattle; n = 1,038 buffalo) from 17 provinces. Samples were tested for specific antibodies directed against FMD non-structural protein (NSP) to determine the proportion of animals exposed to FMD virus. In addition to sampling from abattoirs, further independent data was collected to report clinical signs and outcomes from 94 districts in 12 northern provinces. These incident reports were recorded by district staff using a Google Form and summarised monthly in the National Animal Disease Reporting System. Information was collected on species, incident date, herd size, location and which clinical signs the animals presented. Overall, 46% of the tested animals returned a positive result using ID Screen® FMD NSP Competition ELISA. Results from serological testing were then compared with reported clinical signs from the same district. In districts reporting ‘mouth problems’ (regardless of other clinical signs) the median FMD seroprevalence was 49.7%, compared to 31.6% in districts not reporting mouth problems (p = 0.021). This finding suggests that reporting clinical cases of ‘mouth problems’ could be a potential predictor of FMD infection at a district level in cattle and buffalo in Lao PDR. Furthermore, in districts reporting ‘fever’, ‘mouth problems’, and ‘nose/mouth secretions’ together, the median FMD seroprevalence was 46.2%, compared to 24.4% in districts not reporting these signs (p = 0.033). In districts reporting ‘mouth problems’ and ‘nose/mouth secretions’ the median FMD seroprevalence was 49.4%, compared to 25.5% in districts not reporting these signs (p = 0.037). In districts reporting both ‘fever’ and ‘mouth problems,’ the median FMD seroprevalence was 46.4% compared to 25% in districts not reporting these signs (p = 0.017). Based on serological data generated by abattoir surveillance, this study identified clinical signs most predictive of FMD seroprevalence. These novel findings can be used to guide passive surveillance efforts in the future specifically in northern Laos and help support improved FMD surveillance more broadly in FMD endemic countries in Southeast Asia.

ABSTRACT Bacterial chromosomal type I toxin-antitoxin systems consist of a small protein, typically under 60 amino acids, and a small RNA (sRNA) that represses toxin translation. These gene pairs have gained attention over the last decade for their contribution to antibiotic persistence and phage tolerance in bacteria. However, biological functions for many remain elusive as gene deletions often fail to produce an observable phenotype. For many pairs, it is still unknown when the toxin and/or antitoxin gene are natively expressed within the bacterium. We examined sequence conservation of three type I toxin-antitoxin systems, tisB/istR-1, shoB/ohsC, and zor/orz, in over 2,000 Escherichia coli strains, including pathogenic and commensal isolates. Using our custom database, we found that these gene pairs are widespread across E. coli and have expression potential via BLASTn. We identified an alternative, dominant sequence variant of TisB and confirmed that it is toxic upon overproduction. Additionally, analyses revealed a highly conserved sequence in the zorO mRNA untranslated region that is required for full toxicity. We further noted that over 30% of E. coli genomes contain an orz antitoxin gene only and confirmed its expression in a representative strain: the first confirmed report of a type I antitoxin without its cognate toxin. Our results add to our understanding of these systems, and our methodology is applicable for other type I loci to identify critical regulatory and functional features.IMPORTANCEChromosomal type I toxin-antitoxins are a class of genes that have gained increasing attention over the last decade for their roles in antibiotic persistence which may contribute to therapeutic failures. However, the control of many of these genes and when they function have remained elusive. We demonstrate that a simple genetic conservation-based approach utilizing free, publicly available data yields known and novel insights into the regulation and function of three chromosomal type I toxin-antitoxins in Escherichia coli. This study also provides a framework for how this approach could be applied to other genes of interest.

BackgroundA large number of modifiable and measurable daily actions are thought to impact mental health. The “Things You Do” refers to 5 types of daily actions that have been associated with mental health: healthy thinking, meaningful activities, goals and plans, healthy habits, and social connections. Previous studies have reported the psychometric properties of the Things You Do Questionnaire (TYDQ)–21-item (TYDQ21). The 21-item version, however, has an uneven distribution of items across the 5 aforementioned factors and may be lengthy to administer on a regular basis. ObjectiveThis study aimed to develop and evaluate a brief version of the TYDQ. To accomplish this, we identified the top 10 and 15 items on the TYDQ21 and then evaluated the performance of the 10-item and 15-item versions of the TYDQ in community and treatment-seeking samples. MethodsUsing confirmatory factor analysis, the top 2 or 3 items were used to develop the 10-item and 15-item versions, respectively. Model fit, reliability, and validity were examined for both versions in 2 samples: a survey of community adults (n=6070) and adults who completed an assessment at a digital psychology service (n=14,878). Treatment responsivity was examined in a subgroup of participants (n=448). ResultsParallel analysis supported the 5-factor structure of the TYDQ. The brief (10-item and 15-item) versions were associated with better model fit than the 21-item version, as revealed by its comparative fit index, root-mean-square error of approximation, and Tucker-Lewis index. Configural, metric, and scalar invariance were supported. The 15-item version explained more variance in the 21-item scores than the 10-item version. Internal consistency was appropriate (eg, the 15-item version had a Cronbach α of >0.90 in both samples) and there were no marked differences between how the brief versions correlated with validated measures of depression or anxiety symptoms. The measure was responsive to treatment. ConclusionsThe 15-item version is appropriate for use as a brief measure of daily actions associated with mental health while balancing brevity and clinical utility. Further research is encouraged to replicate our psychometric evaluation in other settings (eg, face-to-face services). Trial RegistrationAustralian New Zealand Clinical Trials Registry ACTRN12613000407796; https://tinyurl.com/2s67a6ps

Background Limited data exist for management strategies targeting immunotherapy-related enteritis (irEnteritis). Systemic corticosteroids are commonly used but often are limited by adverse events. Enteric corticosteroids such as budesonide offer an attractive alternative; however, the ileocolonic release of enteric-coated budesonide has limited utility for diffuse enteritis. Open-capsule budesonide (OCB) is a novel therapeutic approach that offers drug delivery throughout the small bowel. We report outcomes in patients treated with OCB for confirmed or suspected irEnteritis.Methods This retrospective cohort included all individuals treated with OCB for irEnteritis at Memorial Sloan Kettering from July 2018 to August 2023. Primary outcomes included clinical response, clinical remission, and corticosteroid-free remission following OCB. Secondary outcomes were OCB-related adverse events and efficacy by gastrointestinal toxicity location.Results 19 patients (53% female) with irEnteritis were treated with OCB. All patients presented with diarrhea; 15 (79%) reported anorexia with median 6 kg weight loss. 17 patients (89%) underwent esophagogastroduodenoscopy with biopsies revealing enteritis in all; 8 (42%) had concomitant colitis. 15 (79%) patients were treated previously with systemic corticosteroids: 8 (53%) were corticosteroid-dependent while 7 (47%) demonstrated non-response. 18 patients (95%) achieved clinical response, 15 (79%) attained clinical remission, and 11 (58%) had corticosteroid-free remission. Response to OCB was rapid with improvement noted after a median 4 days. 14 (74%) patients restored their pre-irEnteritis weight by OCB cessation. One mild, self-resolving adverse event was reported.Conclusions OCB is a safe and effective therapy for irEnteritis. OCB avoids systemic immunosuppression and successfully achieves clinical response and remission even in patients previously nonresponsive to systemic corticosteroids. Future studies are needed to optimize indications and duration.

Abstract Background and Aims High tissue sodium accumulation and intermuscular adipose tissue (IMAT) are associated with aging, type 2 diabetes, and chronic kidney disease. In this study, we aim to investigate whether high lower‐extremity tissue sodium accumulation relates to IMAT quantity and whether systemic inflammatory mediators and adipocytokines contribute to such association. Methods Tissue sodium content and IMAT accumulation (percentage of IMAT area to muscle area) were measured in 83 healthy individuals using sodium imaging (23Na‐MRI) and proton (1H‐MRI) imaging of the calf. Insulin sensitivity was assessed by glucose disposal rate (GDR) measured with the hyperinsulinemic‐euglycemic clamp. Results Median (interquartile range) muscle and skin sodium contents were 16.6 (14.9, 19.0) and 12.6 (10.9, 16.7) mmol/L, respectively. Median IMAT was 3.69 (2.80, 5.37) %. In models adjusted for age, sex, BMI, GDR, adiponectin, and high‐sensitivity C‐reactive protein, increasing tissue sodium content was significantly associated with higher IMAT quantity (p = 0.018 and 0.032 for muscle and skin tissue sodium, respectively). In subgroup analysis stratified by sex, skin sodium was significantly associated with IMAT only among men. In interaction analysis, the association between skin sodium and IMAT was greater with increasing levels of high‐sensitivity C‐reactive protein and interleukin‐6 (p for interaction = 0.022 and 0.006, respectively). Conclusions Leg muscle and skin sodium are associated with IMAT quantity among healthy individuals. The relationship between skin sodium and IMAT may be mediated by systemic inflammation.

BackgroundThe Maslach Burnout Inventory-General Survey (MBI-GS) stands as the preeminent tool for assessing burnout across various professions. Although the MBI-GS9 emerged as a derivative of the MBI-GS and has seen extensive use over several years, a comprehensive examination of its psychometric properties has yet to be undertaken.MethodsThis study followed the Standards for Educational and Psychological Testing guidelines to validate the MBI-GS9. Employing a combined approach of classical test theory and item response theory, particularly Rasch analysis, within an integrated framework, the study analyzed data from 16,132 participants gathered between 2005 and 2015 by the Centre for Organizational Research at Acadia University.ResultsThe findings revealed that the MBI-GS9 exhibited satisfactory reliability and validity akin to its predecessor, the MBI-GS. Across its three dimensions, Cronbach’s α and omega coefficients ranged from 0.84 to 0.91. Notably, the MBI-GS9 displayed no floor/ceiling effects and demonstrated good item fit, ordered threshold, acceptable person and item separation and reliability, clear item difficulty hierarchy, and a well-distributed item threshold. However, the results suggested a recommended minimum sample size of 350 to mitigate potential information loss when employing the MBI-GS9. Beyond this threshold, the observed mean difference between the MBI-GS and MBI-GS9 held minimal practical significance. Furthermore, measurement equivalence tests indicated that the MBI-GS9 maintained an equivalent three-factor structure and factor loadings across various gender, age, and continent groups, albeit with inequivalent latent values across continents.ConclusionIn sum, the MBI-GS9 emerges as a reliable and valid alternative to the MBI-GS, particularly when utilized within large, diverse samples across different age and gender demographics. However, to address potential information loss, a substantial sample size is recommended when employing the MBI-GS9. In addition, for cross-cultural comparisons, it is imperative to initially assess equivalence across different language versions at both the item and scale levels.

Background MecROX is a mechanistic sub-study of the UK-ROX trial which was designed to evaluate the clinical and cost-effectiveness of a conservative approach to oxygen therapy for invasively ventilated adults in intensive care. This is based on the scientific rationale that excess oxygen is harmful. Epithelial cell damage with alveolar surfactant deficiency is characteristic of hyperoxic acute lung injury. Additionally, hyperoxaemia (excess blood oxygen levels) may exacerbate whole-body oxidative stress leading to cell death, autophagy, mitochondrial dysfunction, bioenergetic failure and multi-organ failure resulting in poor clinical outcomes. However, there is a lack of in-vivo human models evaluating the mechanisms that underpin oxygen-induced organ damage in mechanically ventilated patients. Aim The aim of the MecROX mechanistic sub-study is to assess lung surfactant composition and global systemic redox status to provide a mechanistic and complementary scientific rationale to the UK-ROX trial findings. The objectives are to quantify in-vivo surfactant composition, synthesis, and metabolism with markers of oxidative stress and systemic redox disequilibrium (as evidenced by alterations in the ‘reactive species interactome’) to differentiate between groups of conservative and usual oxygen targets. Methods and design After randomisation into the UK-ROX trial, 100 adult participants (50 in the conservative and 50 in usual care group) will be recruited at two trial sites. Blood and endotracheal samples will be taken at 0, 48 and 72 hours following an infusion of 3 mg/kg methyl-D9-choline chloride. This is a non-radioactive, stable isotope of choline (vitamin), which has been extensively used to study surfactant phospholipid kinetics in humans. This study will mechanistically evaluate the in-vivo surfactant synthesis and breakdown (by hydrolysis and oxidation), oxidative stress and redox disequilibrium from sequential plasma and bronchial samples using an array of analytical platforms. We will compare conservative and usual oxygenation groups according to the amount of oxygen administered. Trial registration: ISRCTN ISRCTN61929838, 27/03/2023 https://doi.org/10.1186/ISRCTN61929838.

Apolipoprotein AV (APOA5) deficiency causes hypertriglyceridemia in mice and humans. For years, the cause remained a mystery, but the mechanisms have now come into focus. Here, we review progress in defining APOA5’s function in plasma triglyceride metabolism. Biochemical studies revealed that APOA5 binds to the angiopoietin-like protein 3/8 complex (ANGPTL3/8) and suppresses its ability to inhibit the activity of lipoprotein lipase (LPL). Thus, APOA5 deficiency is accompanied by increased ANGPTL3/8 activity and lower levels of LPL activity. APOA5 deficiency also reduces amounts of LPL in capillaries of oxidative tissues (e.g., heart, brown adipose tissue). Cell culture experiments revealed the likely explanation: ANGPTL3/8 detaches LPL from its binding sites on the surface of cells, and that effect is blocked by APOA5. Both the low intracapillary LPL levels and the high plasma triglyceride levels in Apoa5−/− mice are normalized by recombinant APOA5. Carboxyl-terminal sequences in APOA5 are crucial for its function; a mutant APOA5 lacking 40-carboxyl-terminal residues cannot bind to ANGPTL3/8 and lacks the ability to change intracapillary LPL levels or plasma triglyceride levels in Apoa5−/− mice. Also, an antibody against the last 26 amino acids of APOA5 reduces intracapillary LPL levels and increases plasma triglyceride levels in wild-type mice. An inhibitory ANGPTL3/8-specific antibody functions as an APOA5-mimetic reagent, increasing intracapillary LPL levels and lowering plasma triglyceride levels in both Apoa5−/− and wild-type mice. That antibody is a potentially attractive strategy for treating elevated plasma lipid levels in human patients.

BackgroundSIOP-CNS-GCT-II European trial was opened for the treatment of patients of any age with central nervous system germ cell tumour (CNS-GCT). Four courses of pre-irradiation chemotherapy were delivered. The influence of patient age on chemotherapy related acute toxicity (CRAT) was assessed.MethodsCRAT was analysed according to age-groups: children (aged ≤11 years), adolescents (aged 12-17 years), adults (aged ≥18 years) and to chemotherapy type: CarboPEI (alternating etoposide-carboplatin/etoposide-ifosfamide) for non-metastatic germinoma; PEI (cisplatin-etoposide-ifosfamide) for standard-risk non-germinomatous GCT (NGGCT); PEI and high-dose PEI (HD-PEI), for high-risk or poorly responsive NGGCTs.Results296 patients were assessable for CRAT: 105 children, 121 adolescents, 70 adults (max age: 41 years). Median cumulative doses/m² of chemotherapy were similar among age-groups. The proportion of germinoma over NGGCT (and accordingly use of CarboPEI chemotherapy) was higher in the adult groups (79%) versus the other two groups (62%). Delay in chemotherapy ≥7 days was noticed in 27%, 38%, and 19% of children, adolescents, and adults, respectively. Grade ≥3 haematological and non-haematological adverse events (AEs) were observed in 94%/31%, 97%/36%, and 77%/21% of children, adolescents, and adults, respectively. No toxic death was reported. Grade ≥3 AEs and delayed chemotherapies were significantly rarer in adults when compared with adolescents, even when adjusted on chemotherapy type: odds ratio: 0.1 [95%CI 0.02-0.4], and 0.2 [95%CI 0.1-0.4] in the group treated with CarboPEI.ConclusionAdult patients can be treated safely with a chemotherapy intensive protocol, with even less toxicity than that observed in adolescents. Further work is required to understand age-related differences regarding toxicity.

Single-cell technologies allow us to gain insights into cellular processes at unprecedented resolution. In stem cell and developmental biology snapshot data allow us to characterize how the transcriptional states of cells change between successive cell types. Here, we show how approximate Bayesian computation (ABC) can be employed to calibrate mathematical models against single-cell data. In our simulation study, we demonstrate the pivotal role of the adequate choice of distance measures appropriate for single-cell data. We show that for good distance measures, notably optimal transport with the Sinkhorn divergence, we can infer parameters for mathematical models from simulated single-cell data. We show that the ABC posteriors can be used (i) to characterize parameter sensitivity and identify dependencies between different parameters and (ii) to construct representations of the Waddington or epigenetic landscape, which forms a popular and interpretable representation of the developmental dynamics. In summary, these results pave the way for fitting mechanistic models of stem cell differentiation to single-cell data.

The gut microbiome plays a significant role in the pathogenesis of pancreatic ductal adenocarcinoma (PDAC), influencing oncogenesis, immune responses, and treatment outcomes. Studies have identified microbial species like Porphyromonas gingivalis and Fusobacterium nucleatum, that promote PDAC progression through various mechanisms. Additionally, the gut microbiome affects immune cell activation and response to immunotherapy, including immune checkpoint inhibitors and CAR-T therapy. Specific microbes and their metabolites play a significant role in the effectiveness of immune checkpoint inhibitors (ICIs). Alterations in the gut microbiome can either enhance or diminish responses to PD-1/PD-L1 and CTLA-4 blockade therapy. Additionally, bacterial metabolites like trimethylamine N-oxide (TMAO) and lipopolysaccharide (LPS) impact antitumor immunity, offering potential targets to augment immunotherapy responses. Modulating the microbiome through fecal microbiota transplantation, probiotics, prebiotics, dietary changes, and antibiotics shows promise in PDAC treatment, although outcomes are highly variable. Dietary modifications, particularly high-fiber diets and specific fat consumption, influence microbiome composition and impact cancer risk. Combining microbiome-based therapies with existing treatments holds potential for improving PDAC therapy outcomes, but further research is needed to optimize their effectiveness.

Rhincodon typus, or the whale shark, is the largest extant fish in the world and is classified as endangered on the IUCN’s Red List. Due to their enormous size and conservation status, whale sharks are rarely housed in aquaria. Here we present a behavioral analysis culminating from a large effort by 89 observers from 2008–2012 to study four R. typus (ID codes: AL, TA, TR, YU) longitudinally in an aquarium setting. We found that relatively simple behavioral metrics such as swim speed, depth occupation, swimming direction, and lead-follow interactions demonstrated R. typus individual variation and responses to habitat changes. All sharks displayed increased swim speeds 30-minutes before regimented feed times, when there was scent of food being fed to other animals in the habitat. Consistently in the habitat, one male shark (YU) was recorded swimming more at depth, faster, almost exclusively clockwise, and engaged in fewer close proximity interactions with others than expected by chance. In contrast, a larger female shark (AL) was observed swimming the slowest, at the surface more than others, led other sharks more than she followed, and had strong lead-follow interactions with another shark of the opposite sex (TA). TA and TR did not differ from each other in depth profiles or speed, but did differ in their proclivity to lead or follow. Depth preferences and lead-follow interactions suggest some partitioning of the habitat and the possibility of social hierarchy in this species. These results represent the first longitudinal behavioral analysis of aquarium R. typus, offering meaningful similarities and contrasts to field observations.

IntroductionPatients with cirrhosis undergoing liver transplantation frequently exhibit systemic inflammation, coagulation derangements, and edema, indicating endothelial dysfunction. This syndrome may worsen after ischemia–reperfusion injury of the liver graft, coincident with organ dysfunction that worsens patient outcomes. Little is known about changes in endothelial permeability during liver transplantation. We hypothesized that sera from these patients would increase permeability in cultured human endothelial cells ex vivo.MethodsAdults with cirrhosis presenting for liver transplantation provided consent for blood collection during surgery. Sera were prepared at five time points spanning the entire operation. The barrier function of human pulmonary microvascular endothelial cells in culture was assessed by transendothelial resistance measured using the ECIS ZΘ system. Confluent cells from two different endothelial cell donors were stimulated with human serum from liver transplant patients. Pooled serum from healthy men and purified inflammatory agonists served as controls. The permeability response to serum was quantified as the area under the normalized resistance curve. Responses were compared between time points and analyzed for associations with clinical characteristics of liver transplant patients and their grafts.ResultsLiver transplant sera from all time points during surgery-induced permeability in both endothelial cell lines. The magnitude of permeability change was heterogeneous between patients, and there were differences in the effects of sera on the two endothelial cell lines. In one of the cell lines, the severity of liver disease was associated with greater permeability at the start of surgery. In the same cell line, serum collected 15 min after liver reperfusion induced significantly more permeability as compared to that collected at the start of surgery. Early postreperfusion sera from patients undergoing living donor transplants induced more permeability than sera from deceased donor transplants. Sera from two exemplary cases of patients on preoperative dialysis, and one patient with an unexpectedly long warm ischemia time of the liver graft, induced exaggerated and prolonged endothelial permeability.DiscussionSerum from patients with cirrhosis undergoing liver transplantation induces permeability of cultured human pulmonary microvascular endothelial cells. Increased endothelial permeability during liver transplantation may contribute to organ injury and present a target for future therapeutics.

We have recently shown that cancer cells of various origins take up extracellular citrate through the plasma membrane citrate carrier (pmCiC), a specific plasma membrane citrate transporter. Extracellular citrate is required to support cancer cell metabolism, in particular fatty acid synthesis, mitochondrial activity, protein synthesis and histone acetylation. In addition, cancer cells tend to acquire a metastatic phenotype in the presence of extracellular citrate. Our recent study also showed that cancer-associated stromal cells synthesise and release citrate and that this process is controlled by cancer cells. In the present study, we evaluated the expression of pmCiC, fibroblast activation protein-α (FAP) and the angiogenesis marker cluster of differentiation 31 (CD31) in human cancer tissues of different origins. In the cohort studied, we found no correlation between disease stage and the expression of FAP or CD31. However, we have identified a clear correlation between pmCiC expression in cancer cells and cancer-associated stroma with tumour stage. It can be concluded that pmCiC is increased in cancer cells and in cancer-supporting cells in the tumour microenvironment at the later stages of cancer development, particularly at the metastatic sites. Therefore, pmCiC expression has the potential to serve as a prognostic marker, although further studies are needed.