Search

Abstract Aims Intra‐aortic balloon pump (IABP) devices are commonly used in patients with heart failure related cardiogenic shock (HF‐CS), including those with out‐of‐proportion right ventricular (RV) dysfunction. Pulmonary artery pulsatility index (PAPi) is a haemodynamic surrogate for RV performance. We aimed to assess short‐term haemodynamic changes in patients with HF‐CS following IABP support stratified by baseline PAPi. Methods and results This is a single‐centre study of 67 consecutive patients with HF‐CS who underwent IABP placement between 2020 and 2022. The primary aim was haemodynamic changes of specific variables on pulmonary artery catheter monitoring over 72 h following IABP placement. Secondary aims were clinically significant changes in diuretic regimens, changes in inotropes or vasopressors at 72 h following IABP, along with clinical outcomes. Prior to IABP placement, 57% of the total cohort (median age 59 years [48, 69], 31% female) had Society of Cardiovascular Angiography and Interventions Stage C HF‐CS. Thirty‐eight (56%) patients had a PAPi

Abstract Light affects the cellular iron (Fe) requirement of phytoplankton because of its presence in major photosynthetic proteins. Thus, interactions between variable Fe concentrations and light intensities could restrict photosynthetic carbon fixation in the ocean. Here we show a narrowing of the optimal light range for growth of a marine cyanobacterium, Prochlorococcus strain NATL1A, a member of LLI ecotype, under Fe limitation. The response of the cells to variations in Fe and light involved differential changes in the cellular content of low‐Fe photosystem II (PSII) and Fe‐rich photosystem I (PSI), and associated up to 23‐fold changes in PSII : PSI ratios, showing an unprecedented extreme plasticity of the photosynthetic apparatus. Our study demonstrated the physiological effects of Fe and light interactions on this low‐light‐adapted Prochlorococcus strain, and increases our understanding of the reasons for the wide distribution of this and possibly other Prochlorococcus strains in the ocean.

Abstract Background Olutasidenib is a potent, selective, oral, small molecule inhibitor of mutant IDH1 (mIDH1) which induced durable remissions in high-risk, relapsed/refractory (R/R) mIDH1 AML patients in a phase 1/2 trial. We present a pooled analysis from multiple cohorts of the phase 1/2 trial of patients with R/R AML who received combination olutasidenib and azacitidine therapy. Methods Adult patients with mIDH1 R132 AML received 150 mg olutasidenib twice daily plus standard-of-care azacitidine (OLU + AZA) and were evaluated for response and safety. Results Sixty-seven patients with R/R mIDH1 R132 AML received combination OLU + AZA. Median age was 66 years (range 28–82) and 54% were male. Most patients (83%) had 2 + prior regimens, including a hypomethylating agent in 40%, IDH1 inhibitor therapy in 31% (olutasidenib in 24%), and hematopoietic stem cell transplant in 10%. Cytogenetic risk was intermediate in 72%, poor in 18% and unknown in 10%. CR/CRh was achieved in 21/67 (31%; 95% CI 21–44) patients, with a median duration of 14.7 months (95% CI 4.6-not reached). CR was achieved in 18/67 (27%; 95% CI 17–39) patients, with median duration of 20.3 months (95% CI 3.7-not reached). Overall response (partial remission or better) was achieved in 34/67 (51%; 95% CI 38–63) patients. Median overall survival was 12.9 months (95% CI 18.7–19.3). In a subset analysis excluding patients who had prior OLU exposure (N = 51), CR/CRh was achieved in 19/51 (37%; 95% CI 24–52) patients, CR was achieved in 16/51 (31%; 95% CI 19–46), and overall response was achieved in 30/51 (59%; 95% CI 44–72). In patients who achieved CR/CRh and were transfusion-dependent at baseline, transfusion independence (RBC and platelets) was achieved in 64% (7/11) and 57% (4/7) of patients, respectively. The most common Grade 3 or 4 adverse events (> 20% patients) were decreased platelet count (37%), red blood cell count (25%), and neutrophil count (24%). Six patients (9%) experienced differentiation syndrome. Four (6%) discontinued treatment due to an adverse event. Conclusions Olutasidenib plus azacitidine induced high response rates and durable remissions with a tolerable side effect profile in patients with R/R AML with diverse treatment histories. The results represent another therapeutic option for patients with mIDH1 AML who may benefit from a targeted therapy. Trial registration NCT02719574.

Background: Friction is the primary cause of notching in reverse shoulder arthroplasty during internal, external rotation (IR/ER), and extension (EXT). To address notching, glenosphere eccentricity (ECC) was introduced. The primary objective of this study was to investigate different positions of glenosphere ECC to determine whether there is an optimal position for impingement-free range of motion. Methods: In this computer model study, 10 female CTs were analyzed and EXT, ER, IR, and adduction simulated (18 models.) A 135° stem with a +10° liner (145°) was combined with a 25-mm standard/or +3-mm lateralized baseplate (BP) and a 36-mm +2-mm eccentric glenosphere in 4 ECC positions (50° posterior; 30° posterior; 30° anterior; 50° anterior) from the reference position 0° neutral (10 models). Additionally, a concentric 39-mm glenosphere was tested (+2 models). A 0° insert, 135° neck shaft angle (NSA), was tested with a 25-mm standard/or +3-mm BP for 3 configurations (30° posterior; neutral; 39 mm; +6 models). Results: Compared to the 0° neutral reference position, 30° posterior dialing improved the mean ER (group 145°: 40° vs. 38°, group 145° + 3: 51° vs. 49°, both P

Abstract Historically, CLL prognostication relied on disease burden, reflected in clinical stage. Later, chromosome abnormalities and genomics suggested several CLL subtypes which were aligned with response to therapy. Gene expression profiling data identified pathways associated with CLL progression. We hypothesized that transcriptome and proteome may identify functional omics associated with CLL nosology. As a test cohort, we utilized publicly available treatment-naïve CLL transcriptomics data (n = 130) and did consensus clustering that identified BTK-expression-based clusters. The BTK-High and BTK-Low clusters were validated in public and our in-house databases (n = >550 CLL patients). To associate with functional relevance, we took samples from 151 previously treated patient with CLL and analyzed them using RNA sequencing and reverse-phase protein array. Transcript levels were strongly correlated with BTK protein levels. BTK-High subtype showed increased CCL3/CCL4 levels and disease burden such as high WBC. BTK-Low subtype showed down-regulated mRNA/proteins of DNA-repair pathway and increased DNA-damage-response, which may have contributed to enrichment of inflammatory pathway. BTK-Low subtype was rich in proapoptotic gene and protein expression and relied less on BCR pathway. High-BTK subgroup was enriched in replication/repair pathway and transcription machinery. In conclusion, profiling of 5 datasets of ~700 patients revealed unique BTK-associated expression clusters in CLL.

Abstract Background There are avoidable differences (i.e., inequities) in the prevalence and distribution of chronic pain across diverse populations, as well as in access to and outcomes of pain management services. Digital pain self-reporting tools have the potential to reduce or exacerbate these inequities. This study aimed to better understand how to optimise the health equity impact of digital pain self-reporting tools on people who are experiencing (or are at risk of) digital pain inequities. Methods This was a qualitative study, guided by the Health Equity Impact Assessment tool—digital health supplement (HEIA-DH). We conducted three scoping focus groups with multiple stakeholders to identify the potential impacts of digital pain self-reporting tools and strategies to manage these impacts. Each group focused on one priority group experiencing digital pain inequities, including older adults, ethnic minorities, and people living in socio-economically deprived areas. A fourth consensus focus group was organised to discuss and select impact management strategies. Focus groups were audio-recorded, transcribed verbatim, and analysed using a framework approach. We derived codes, grouped them under four pre-defined categories from the HEIA-DH, and illustrated them with participants’ quotes. Results A total of fifteen people living with musculoskeletal pain conditions and thirteen professionals took part. Participants described how digital pain self-reports can have a positive health equity impact by better capturing pain fluctuations and enriching patient-provider communication, which in turn can enhance clinical decisions and self-management practices. Conversely, participants identified that incorrect interpretation of pain reports, lack of knowledge of pain terminologies, and digital (e.g., no access to technology) and social (e.g., gender stereotyping) exclusions may negatively impact on people’s health equity. The participants identified 32 strategies, of which 20 were selected as being likely to mitigate these negative health equity impacts. Example strategies included, e.g., option to customise self-reporting tools in line with users’ personal preferences, or resources to better explain how self-reported pain data will be used to build trust. Conclusion Linked to people’s personal and social characteristics, there are equity-based considerations for developing accessible digital pain self-reporting tools, as well as resources and skills to enable the adoption and use of these tools among priority groups. Future research should focus on implementing these equity-based considerations or strategies identified by our study and monitoring their impact on the health equity of people living with chronic pain.

Abstract Background Precise estimates of risk-adjusted increases in postoperative length of stay (LOS) associated with postoperative complications across a range of complications and operations are not available in the existing literature. Methods Associations between preoperative characteristics, postoperative complications and postoperative LOS were tested using medians, interquartile ranges, and nonparametric rank sum tests in a retrospective cohort study using the 2005–2018 American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) dataset. A negative binomial model was used with postoperative LOS as the dependent variable and preoperative characteristics and postoperative complications as independent variables. The model was applied to estimate each patient’s postoperative LOS with and without each postoperative complication to measure the association between each complication and risk-adjusted change in postoperative LOS. Results A total of 4,495,582 patients were included. After risk-adjustment, occurrence of each postoperative complication was associated with significantly increased postoperative LOS (between + 3.9 and + 20.1 days, p

Abstract Background Management of rheumatoid arthritis (RA) relies on symptoms reported by patients during infrequent outpatient clinic visits. These reports are often incomplete and inaccurate due to poor recall, leading to suboptimal treatment decisions and outcomes. Asking people to track symptoms in-between visits and integrating the data into clinical pathways may improve this. However, knowledge on how to implement this into practice and its impact on services and outcomes remains scarce in RA. Therefore, we evaluate the comparative effectiveness and cost-effectiveness of integrated symptom tracking in people with RA over and above usual care, while generating insights on factors for successful implementation. Methods In this superiority stepped wedge cluster-randomized controlled trial with continuous recruitment short exposure design, 16 rheumatology outpatient departments (clusters) recruit a total of 732 people with active RA. They initially offer clinic visits according to standard of care before switching in pairs to visits with integrated symptom tracking. Clusters switch in randomized order every 3 weeks. Integrated symptom tracking consists of (1) a mobile app for patients to track their symptoms daily and other RA aspects weekly/monthly, and (2) an interactive dashboard visualizing the app data, which healthcare professionals access from their electronic health record system. Clinic visits happen according to usual practice, with tracked symptom data only reviewed during visits. Our primary outcome is a difference in marginal mean disease activity score at 12 ± 3 months between standard of care and integrated symptom tracking, after accounting for baseline values, cluster, and other covariates. Secondary outcomes include patient-reported disease activity, quality of life and quality-adjusted life-years, medication/resource use, consultation and decision-making experience, self-management, and illness perception. We also conduct interviews and observations as part of a parallel process evaluation to gather information on implementation. Discussion Our trial will generate high-quality evidence of comparative and cost-effectiveness of integrated symptom tracking compared to standard of care in people with RA, with our process evaluation delivering knowledge on successful implementation. This optimizes the chances of integrated symptom tracking being adopted more widely if we find it is (cost-) effective. Trial registration Registered 4-Jun-2024 on https://www.isrctn.com/ , ISRCTN51539448. Trial open science framework repository https://osf.io/sj9ha/ .

Abstract Background HIV treatment programs in Africa have implemented centralized testing for routine viral load monitoring (VLM), which may result in specimen processing delays inhibiting timely return of viral load results. Decentralized, point-of-care (PoC) VLM is a promising tool for expediting HIV clinical decision-making but remains unavailable in most African settings. We qualitatively explored the perceived feasibility and appropriateness of PoC VLM to address gaps along the viral load monitoring continuum in rural Uganda. Methods Between May and September 2022, we conducted 15 in-depth interviews with HIV clinicians (facility in-charges, clinical officers, nurses, counselors) and six focus group discussions with 47 peer health workers from three south-central Ugandan districts. Topics explored centralized VLM implementation and opportunities/challenges to optimizing routine VLM implementation with PoC testing platforms. We explored perspectives on PoC VLM suitability and feasibility using iterative thematic analysis. Applying the Framework Method, we then mapped salient constraints and enablers of PoC VLM to constructs from the Consolidated Framework for Implementation Research. Results Clinicians and peers alike emphasized centralized viral load monitoring’s resource-intensiveness and susceptibility to procedural/infrastructural bottlenecks (e.g., supply stockouts, testing backlogs, community tracing of clients with delayed VLM results), inhibiting timely clinical decision-making. Participants reacted enthusiastically to the prospect of PoC VLM, anticipating accelerated turnarounds in specimen processing, shorter and/or fewer client encounters with treatment services, and streamlined efficiencies in HIV care provision (including expedited VLM-driven clinical decision-making). Anticipated constraints to PoC VLM implementation included human resource requirements for processing large quantities of specimens (especially when machinery require repair), procurement and maintenance costs, training needs in the existing health workforce for operating point-of-care technology, and insufficient space in lower-tier health facilities to accommodate installation of new laboratory equipment. Conclusions Anticipated implementation challenges, primarily clustering around resource requirements, did not diminish enthusiasm for PoC VLM monitoring among rural Ugandan clinicians and peer health workers, who perceived PoC platforms as potential solutions to existing inefficiencies within the centralized VLM ecosystem. Prioritizing PoC VLM rollout in facilities with available resources for optimal implementation (e.g., adequate physical and fiscal infrastructure, capacity to manage high specimen volumes) could help overcome anticipated barriers to decentralizing viral load monitoring.

Abstract Cotton is the most common natural fibre used in textile manufacture, used alone or with other fibres to create a wide range of fashion clothing and household textiles. Most of these textiles are cleaned using detergents and domestic or commercial washing machines using processes that require many chemicals and large quantities of water and energy. Enzymes can reduce this environmental footprint by enabling effective detergency at reduced temperatures, mostly by directly attacking substrates present in the soils. In the present study, we report the contribution of a cleaning cellulase enzyme based on the family 44 glycoside hydrolase (GH) endo-beta-1,4-glucanase from Paenibacillus polymyxa. The action of this enzyme on textile fibres improves laundry detergent performance in several vectors including soil anti-redeposition, dye transfer inhibition and stain removal. Molecular probes are used to study how this enzyme is targeting both amorphous cellulose and xyloglucan on textile fibres and the relationship between textile surface effects and observed performance benefits.

BackgroundThere is no neoadjuvant immunotherapy for early-stage oral cancer patients. We report a single-arm, open-label, pilot clinical trial assessing the efficacy and safety of topical toll-like receptor-7 (TLR-7) agonist, imiquimod, utilized in a neoadjuvant setting in early-stage oral squamous cell carcinoma (OSCC).MethodsThe primary endpoint is reduction in tumor cell counts assessed by quantitative multiplex immunofluorescence and the immune-related pathologic response. The secondary endpoint is safety.Results60% of patients experienced a 50% reduction or greater in tumor cell count post-treatment (95% CI = 32% to 84%). Similarly, 60% of patients had immune-related major pathologic response (irMPR) with two complete pathologic responses, and 40% had partial response (PR) with the percent residual viable tumor ranging from 25% to 65%. An increase in functional helper and cytotoxic T-cells significantly contributed to a reduction in tumor (R=0.54 and 0.55, respectively). The treatment was well tolerated with the application site mucositis being the most common adverse event (grades 1-3), and no grade 4 life-threatening event. The median follow-up time was 17 months (95% CI = 16 months - not reached), and one-year recurrence-free survival was 93% of evaluable patients.ConclusionNeoadjuvant imiquimod immunotherapy could be safe and promising regimen for early-stage oral cancer.Trial registrationClinicalTrials.gov, Identifier NCT04883645.

BACKGROUND:. Accurate assessment of oxygen delivery relative to oxygen demand is crucial in the care of a critically ill patient. The central venous oxygen saturation (Svo2) enables an estimate of cardiac output yet obtaining these clinical data requires invasive procedures and repeated blood sampling. Interpretation remains subjective and vulnerable to error. Recognition of patient’s evolving clinical status as well as the impact of therapeutic interventions may be delayed. OBJECTIVE:. The predictive analytics algorithm, inadequate delivery of oxygen (IDo2) index, was developed to noninvasively estimate the probability of a patient’s Svo2 to fall below a preselected threshold. DERIVATION COHORT:. A retrospective multicenter cohort study was conducted using data temporally independent from the design and development phase of the IDo2 index. VALIDATION COHORT:. A total of 20,424 Svo2 measurements from 3,018 critically ill neonates, infants, and children were retrospectively analyzed. Collected data included vital signs, ventilator data, laboratory data, and demographics. PREDICTION MODEL:. The ability of the IDo2 index to predict Svo2 below a preselected threshold (30%, 40%, or 50%) was evaluated for discriminatory power, range utilization, and robustness. RESULTS:. Area under the receiver operating characteristic curve (AUC) was calculated for each index threshold. Datasets with greater amounts of available data had larger AUC scores. This was observed across each configuration. For the majority of thresholds, Svo2 values were observed to be significantly lower as the IDo2 index increased. CONCLUSIONS:. The IDo2 index may inform decision-making in pediatric cardiac critical care settings by providing a continuous, noninvasive assessment of oxygen delivery relative to oxygen demand in a specific patient. Leveraging predictive analytics to guide timely patient care, including support for escalation or de-escalation of treatments, may improve care delivery for patients and clinicians.

Background:. This study evaluated the sensory and breast pain outcomes in inferior versus superomedial pedicle breast reduction. Methods:. Twenty patients undergoing the inferior pedicle technique were matched to 20 patients undergoing the superomedial pedicle technique based on age, BMI, and resection weight. Patients were evaluated preoperatively and postoperatively at 1, 3, 6, and 12 months. Monofilament testing was performed on the nipple-areola complex (NAC) and surrounding breast. Patient-reported outcomes included nipple and breast sensation (5-point Likert scale), pain intensity (0–10), and the Patient-reported Outcome Measurement Information System Neuropathic Pain Quality scale. Results:. At the NAC, mean monofilament values and patient-reported sensation were significantly better in the inferior versus the superomedial pedicle group at 1 and 3 months postoperatively (P < 0.05) and comparable at 6 and 12 months (P > 0.05). At 12 months, 72.5% of patients reported complete (5 of 5) nipple sensation (77.5% inferior versus 67.5% superomedial, P > 0.05). At the breast, the mean monofilament values and patient-reported sensation were similar between pedicle groups throughout follow-up. At 12 months, 82.5% of the patients reported complete (5 of 5) breast sensation (85.0% inferior versus 80% superomedial, P > 0.05). Rates of postoperative breast pain were similar between groups throughout follow-up (P > 0.05). At 12 months, 25% of patients reported breast pain, with neuropathic qualities in 85% of cases. Conclusions:. The inferior pedicle may allow for earlier restoration of quantitative and patient-reported NAC sensation, but long-term sensation is comparable between techniques. A quarter of patients reported persistent breast pain regardless of the pedicle type.

Background:. Most patients undergoing breast surgery with free nipple grafts lose nipple erection (NE) function. This study aimed to evaluate the effect of nerve preservation and reconstruction with targeted nipple–areola complex reinnervation (TNR) on NE following gender-affirming mastectomy with free nipple grafting. Methods:. Patients undergoing gender-affirming mastectomy with free nipple grafts were prospectively enrolled. Subjects who underwent TNR were compared with controls who did not undergo TNR. Postoperative patient-reported NE function was scored using a 4-point Likert scale. Objective NE evaluation consisted of the change in areola circumference and nipple height following cold application using a thermal device and 3-dimensional imaging. Results:. Twenty patients (11 subjects and 9 controls) with comparable age, body mass index, and mastectomy weight were included. At an average follow-up of 16.8 (±7.0) months, significantly more subjects reported NE than controls (72.8% versus 38.9%, P = 0.03), with a higher median NE score (3 [range 1–4] versus 1 [range 1–2], P = 0.0005). Following cold application, subjects had a greater mean reduction in areola circumference (−4.16 ± 3.3 versus −1.67 ± 1.9 mm, P = 0.02) and a greater mean increase in nipple height (+0.86 ± 0.8 versus +0.37±0.3 mm, P = 0.04) compared with controls. Improved patient-reported NE function correlated with better cold detection thresholds (P = 0.01). Conclusions:. TNR was associated with improved patient-reported and objective NE following gender-affirming mastectomy. Improved NE correlated with improved cold detection, suggesting the role of both sensory and autonomic innervation in mediating NE.

Background: Per- and polyfluoroalkyl substances (PFAS) are a class of widespread persistent chemicals, which may have obesogenic effects during the fetal period. This study investigated the long-term association of maternal plasma PFAS concentrations at delivery and their mixture with child body mass index (BMI) and the risk of Overweight or Obesity (OWO) at the age of 2–18 years. Methods: The study included 1189 mother–child dyads from the prospective Boston Birth Cohort. Eight PFAS were measured in maternal plasma samples collected 24–72 h after delivery. Outcomes were BMI Z-score and OWO status of children at 2–18 years. The exposure-outcome associations were evaluated with linear and modified Poisson mixed-effects regression for individual PFAS and Bayesian kernel machine regression and quantile-based g-computation models for PFAS mixture. We explored the effect modification by maternal pre-pregnancy OWO, child age, sex, and race. Results: Maternal plasma samples had PFAS detection frequencies from 87 % to 100 % and geometric means ranging from 0.11 to 3.67 ng/mL. PFHpS and PFHxS were associated with higher child BMI Z-score. Such associations were stronger in children aged 6–12 years and 13–18 years than in 2–5 years. Stratified by maternal pre-pregnancy OWO, significant associations of the PFAS mixture with child BMI Z-score were only found in children of non-OWO mothers. In children aged 13–18 years, children with both high maternal plasma PFDeA, PFNA, and PFOA concentrations and maternal OWO had the highest risks of OWO compared to children with either only. Such synergistic effects were not found in younger children. Conclusions: Early life exposure to individual PFAS and their mixture were associated with a higher risk of childhood OWO, with stronger associations observed in older child age groups and in children of non-OWO mothers. Synergistic effects of PFAS exposures and maternal pre-pregnancy OWO became evident in adolescence.

Multiple sclerosis (MS) is an autoimmune disease of the brain and spinal cord with both inflammatory and neurodegenerative features. Although advances in imaging techniques, particularly magnetic resonance imaging (MRI), have improved the process of diagnosis, its cause is unknown, a cure remains elusive and the evidence base to guide treatment is lacking. Computational techniques like machine learning (ML) have started to be used to understand MS. Published MS MRI-based computational studies can be divided into five categories: automated diagnosis; differentiation between lesion types and/or MS stages; differential diagnosis; monitoring and predicting disease progression; and synthetic MRI dataset generation. Collectively, these approaches show promise in assisting with MS diagnosis, monitoring of disease activity and prediction of future progression, all potentially contributing to disease management. Analysis quality using ML is highly dependent on the dataset size and variability used for training. Wider public access would mean larger datasets for experimentation, resulting in higher-quality analysis, permitting for more conclusive research. This narrative review provides an outline of the fundamentals of MS pathology and pathogenesis, diagnostic techniques and data types in computational analysis, as well as collating literature pertaining to the application of computational techniques to MRI towards developing a better understanding of MS.

The NANOGrav 15 yr data provide compelling evidence for a stochastic gravitational-wave (GW) background at nanohertz frequencies. The simplest model-independent approach to characterizing the frequency spectrum of this signal consists of a simple power-law fit involving two parameters: an amplitude A and a spectral index γ . In this Letter, we consider the next logical step beyond this minimal spectral model, allowing for a running (i.e., logarithmic frequency dependence) of the spectral index, ${\gamma }_{{\rm{run}}}(f)=\gamma +\beta \mathrm{ln}\left(f/{f}_{{\rm{ref}}}\right)$ . We fit this running-power-law (RPL) model to the NANOGrav 15 yr data and perform a Bayesian model comparison with the minimal constant-power-law (CPL) model, which results in a 95% credible interval for the parameter β consistent with no running, $\beta \in \left[-0.80,2.96\right]$ , and an inconclusive Bayes factor, ${ \mathcal B }\left({\rm{RPL}}\,{\rm{versus}}\,{\rm{CPL}}\right)=0.69\pm 0.01$ . We thus conclude that, at present, the minimal CPL model still suffices to adequately describe the NANOGrav signal; however, future data sets may well lead to a measurement of nonzero β . Finally, we interpret the RPL model as a description of primordial GWs generated during cosmic inflation, which allows us to combine our results with upper limits from Big Bang nucleosynthesis, the cosmic microwave background, and LIGO–Virgo–KAGRA.

A dual phase boride and carbide ceramic with the nominal composition (Ti0.2Zr0.2Hf0.2Nb0.2Ta0.2)B2 and (Ti0.2Zr0.2Hf0.2Nb0.2Ta0.2)C was prepared by reactive synthesis and consolidated by spark plasma sintering. The resulting microstructure contained about 30% (in volume) boride and 70% carbide. Compositional inhomogeneities were observed within single grains that had core-shell structures and preferential accumulation of specific metals in the boride or carbide phases. Specifically, Ti and Nb had higher concentrations in the boride, whereas Hf and Ta in the carbide. The Zr concentration was relatively equally distributed in the two phases. The dual phase ceramic had additional, distinctive features including nanosized inclusions, possibly related to local miscibility gaps and supersaturation, linear defects, and strain due to adjustment of the crystal structure. As a consequence, the fracture mode was transgranular with the crack path deviated by these nanometric microstructure alterations. Nanoindentation under 5 mN measured higher hardness and modulus for the boride, 30 GPa and 525 GPa, as compared to the carbide phase, 22 GPa and 425 GPa, due to a higher concentration of dislocation tangles and strains deriving from the introduction of metals with different sizes (and properties) in a less compliant hexagonal lattice.

Purpose: To assess the feasibility of a second-generation (44-channel) suprachoroidal retinal prosthesis for provision of functional vision in recipients with end-stage retinitis pigmentosa (RP) over 2.7 years. Design: Prospective, single-arm, unmasked interventional clinical trial. Participants: Four participants, with advanced RP and bare-light perception vision. Methods: The 44-channel suprachoroidal retinal prosthesis was implanted in the worse-seeing eye. Device stability, functionality, and adverse events were investigated at approximately 12-week intervals up to 140 weeks (2.7 years) postdevice activation. Main Outcome Measures: Serious adverse event (SAE) reporting, visual response outcomes, functional vision outcomes, and quality-of-life outcomes. Results: All 4 participants (aged 39–66 years, 3 males) were successfully implanted in 2018, and there were no device-related SAEs over the duration of the study. A mild postoperative subretinal hemorrhage was detected in 2 recipients, which cleared spontaneously within 2 weeks. OCT confirmed device stability and position under the macula. Improvements in localization abilities were demonstrated for all 4 participants in screen-based, tabletop, and orientation and mobility tasks. In addition, 3 of 4 participants recorded improvements in motion discrimination and 2 of 4 participants recorded substantial improvements in spatial discrimination and identification of tabletop objects. Participants reported their unsupervised use of the device included exploring new environments, detecting people, and safely navigating around obstacles. A positive effect of the implant on participants’ daily lives in their local environments was confirmed by an orientation and mobility assessor and participant self-report. Emotional well-being was not impacted by device implantation or usage. Conclusions: The completed clinical study demonstrates that the suprachoroidal prosthesis raises no safety concerns and provides improvements in functional vision, activities of daily living, and observer-rated quality of life. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Introduction Long-term conditions are a major burden on health systems. One way to facilitate more research and better clinical care among patients with long-term conditions is to collect accurate data on their daily symptoms (patient-generated health data) using wearable technologies. Whilst evidence is growing for the use of wearable technologies in single conditions, there is less evidence of the utility of frequent symptom tracking in those who have more than one condition. Aims To explore patient views of the acceptability of collecting daily patient-generated health data for three months using a smartwatch app. Methods Watch Your Steps was a longitudinal study which recruited 53 patients to track over 20 symptoms per day for a 90-day period using a study app on smartwatches. Semi-structured interviews were conducted with a sub-sample of 20 participants to explore their experience of engaging with the app. Results In a population of older people with multimorbidity, patients were willing and able to engage with a patient-generated health data app on a smartwatch. It was suggested that to maintain engagement over a longer period, more ‘real-time’ feedback from the app should be available. Participants did not seem to consider the management of more than one condition to be a factor in either engagement or use of the app, but the presence of severe or chronic pain was at times a barrier. Conclusion This study has provided preliminary evidence that multimorbidity was not a major barrier to engagement with patient-generated health data via a smartwatch symptom tracking app.

Idiopathic arrhythmias originating from the mitral and tricuspid annuli are commonly encountered in clinical practice. This review focuses on distinguishing features of ventricular arrhythmias arising from these structures and the importance of distinguishing idiopathic arrhythmias from those associated with structural heart disease. Each region along the mitral and tricuspid annuli (including the cardiac crux and para-Hisian region) is then discussed separately, with a particular emphasis on the ablation strategies and pitfalls for each. Although this review series is centred around idiopathic ventricular arrhythmias, the strategies for ablation techniques in these regions are broadly applicable.

BackgroundThe sinoatrial node (SN) generates the heart rate (HR). Its spontaneous activity is regulated by a complex interplay between the modulation by the autonomic nervous system (ANS) and intrinsic factors including ion channels in SN cells. However, the systemic and intrinsic regulatory mechanisms are still poorly understood. This study aimed to elucidate the sex-specific differences in heart morphology and SN function, particularly focusing on basal HR, expression and function of hyperpolarization-activated HCN4 and HCN1 channels and mRNA abundance of ion channels and mRNA abundance of ion channels contributing to diastolic depolarization (DD) and spontaneous action potentials (APs).MethodsBody weight, heart weight and tibia length of 2- to 3-month-old male and female mice were measured. Conscious in-vivo HR of male and female mice was recorded via electrocardiography (ECG). Unconscious ex-vivo HR, stroke volume (SV) and ejection fraction (EF) were recorded via echocardiography. Ex-vivo HR was measured via Langendorff apparatus. Volume of atria, ventricles and whole hearts were measured from the ex-vivo hearts by microcomputed tomography (micro-CT). Immunohistochemistry targeting HCN4 and HCN1 was conducted in the SN and RA tissues from both male and female hearts. The funny current (If) of SN cells in 1 nM and following wash-on of 1 μM isoproterenol (ISO) were recorded via whole cell patch clamp. The APs of SN tissue were recorded via sharp microelectrode and optical mapping of membrane voltage. The relative abundance of mRNAs was measured in male and female mice by qPCR.ResultsHeart weight to tibia length ratio and heart volume of females were significantly smaller than males. Unconscious in-vivo HR in male mice was higher than that in females. Conscious in-vivo HR, ex-vivo HR, SV, and EF showed no notable difference between male and female mice. Immunohistochemistry revealed HCN4, HCN1, and the sum of HCN4 and HCN1, expression in the SN was notably elevated compared with the RA in both male and females, but there was no sex difference in these channels expression. There were also no significant sex differences in the V0.5 of If in SN cells in the presence of 1 nM ISO, however wash-on 1 μM ISO in the same cells induced a significantly increased shift of V0.5 to more positive voltages in males than in females. The expression of mRNA coding for adrenergic receptor beta-1 (Adrb1) and cholinergic receptors muscarinic 2 (chrm2) in male mice was higher compared with that in female mice. Early diastolic depolarization (EDD) rate in APs from peripheral SN (pSN) from male mice were higher than these in female mice. Mice of both sexes showed equivalent frequency of SN APs and spatial localization of the leading site in control, and similar significant response to ISO 100 nM superfusion.ConclusionMales display faster in-vivo HR, but not ex-vivo HR, than females associated with increased expression of Adrb1 in male versus female. This suggests a possible difference in the β-adrenergic modulation in males and females, possibly related to the greater ISO response of If observed in cells from males. The role of hormonal influences or differential expression of other ion channels may explain these sex-specific variations in HR dynamics. Further investigations are necessary to pinpoint the precise molecular substrates responsible for these differences.

ABSTRACTOn 13 October 2023, the National Directorate for Livestock Development in Mozambique was notified of a suspected outbreak of avian influenza in commercial layers. Samples were screened by real-time and conventional RT–PCR and were positive for both H7 and N6. Full genome sequences were obtained for three representative samples. Sequence analysis of the H7 cleavage site confirmed that the viruses were highly pathogenic (i.e. 333- PEPPKGPRFRR/GLF-346). In addition, the H7 and N6 sequences were highly similar (from 99.4-99.5% and 99.6-99.7% for the HA gene and the NA gene, respectively) to the sequences of a H7N6 virus identified in the Republic of South Africa in May 2023 indicating a similar origin of the viruses. The identification of H7N6 HPAIV in Mozambique has important implications for disease management and food security in the region.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy that is refractory to immune checkpoint inhibitor therapy. However, intratumoral T-cell infiltration correlates with improved overall survival (OS). Herein, we characterized the diversity and antigen specificity of the PDAC T-cell receptor (TCR) repertoire to identify novel immune-relevant biomarkers. Demographic, clinical, and TCR-beta sequencing data were collated from 353 patients across three cohorts that underwent surgical resection for PDAC. TCR diversity was calculated using Shannon Wiener index, Inverse Simpson index, and “True entropy.” Patients were clustered by shared repertoire specificity. TCRs predictive of OS were identified and their associated transcriptional states were characterized by single-cell RNAseq. In multivariate Cox regression models controlling for relevant covariates, high intratumoral TCR diversity predicted OS across multiple cohorts. Conversely, in peripheral blood, high abundance of T-cells, but not high diversity, predicted OS. Clustering patients based on TCR specificity revealed a subset of TCRs that predicts OS. Interestingly, these TCR sequences were more likely to encode CD8+ effector memory and CD4+ T-regulatory (Tregs) T-cells, all with the capacity to recognize beta islet-derived autoantigens. As opposed to T-cell abundance, intratumoral TCR diversity was predictive of OS in multiple PDAC cohorts, and a subset of TCRs enriched in high-diversity patients independently correlated with OS. These findings emphasize the importance of evaluating peripheral and intratumoral TCR repertoires as distinct and relevant biomarkers in PDAC.

Viral vectors are an active area of research and development to treat diseases of the central nervous system (CNS). However, systemic delivery of large-molecular weight biologics is complicated by limited crossing of the blood-brain barrier, immunological clearance from the circulation, off-target effects, and systemic or organ toxicity. Local drug delivery can mitigate these obstacles, however, the drug must still be distributed over sufficiently large tissue volume to achieve the desired efficacy. In the field of drug delivery, quantitative, high resolution spatial analysis of drug distribution in the brain and other organs poses a challenge. To address this issue, we introduce a computational pipeline to reconstruct and quantify 3D distribution of locally delivered viral vectors from 2D microscopy images of subsampled brain sections. This pipeline, which combined existing and newly developed machine-learning and other computational tools, effectively removed false positive artifacts abundant in large-scale images of uncleared tissue sections, and subsampling adequately predicted the dispersion of model viral vectors from the point of local drug delivery. Furthermore, the pipeline successfully captured differences in the distribution of adeno virus (AdV) and adeno-associated virus (AAV) vectors exhibiting varying sizes and transport properties. Notably, the proposed method is directly applicable to the distribution studies of therapeutics in large animal models. Thus, our developed pipeline is an accessible tool that can aid the research and development of local drug delivery strategies for the treatment of CNS diseases with viral vectors and potentially other therapeutics.

Introduction: Left-sided gallbladder (LSG) is a rare anatomic variant in the pediatric population where the gallbladder lies to the left of the round ligament. The diagnosis of LSG is often made intraoperatively as preoperative imaging has poor sensitivity for detection. As LSG is also associated with biliary and vascular anatomic variation, lack of familiarity with these anatomic variants can lead to higher rates of bleeding and bile duct injury. Case presentation: A 17-year-old previously healthy male with history of scoliosis and sickle cell trait was referred for surgical management of symptomatic cholelithiasis. The patient had presented with multiple transient episodes of severe epigastric pain and nausea with ultrasound findings of cholelithiasis. There was no comment on the ultrasound report of any anatomic variation or abnormal location of the gallbladder. However, review of the imaging demonstrated a gallbladder that was situated on the left side of the liver and medial to ligamentum teres hepatis (round ligament). During the laparoscopic cholecystectomy, we confirmed that the gallbladder was located to the left of the round ligament and inferior to segment III of the liver. A retrograde top-down approach was utilized to clearly delineate the cystic artery and duct. The cystic artery was identified by its entry point into the gallbladder crossing anterior to the common bile duct in a right-to-left fashion. The cystic duct was identified and noted to drain into the right-side of the common hepatic duct. Due to clear delineation of the gallbladder anatomy with this approach, intraoperative cholangiography or fluorescence cholangiography were not utilized. He was discharged on postoperative day one without any complications. Conclusion: LSG is associated with biliary and vascular anomalies, which may lead to intraoperative complications. Therefore, the biliary anatomy should be clearly elucidated prior to proceeding with cholecystectomy in cases of LSG.

Abstract Background Severe psychomotor agitation and aggression often require immediate pharmacological intervention, but clear evidence-based recommendations for choosing among the multiple options are lacking. To address this gap, we plan a systematic review and individual-participant-data network meta-analysis to investigate their comparative effectiveness in real-world emergency settings with increased precision. Methods We will include randomized controlled trials investigating intramuscular or intravenous pharmacological interventions, as monotherapy or in combination, in adults with severe psychomotor agitation irrespective of the underlying diagnosis and requiring rapid tranquilization in general or psychiatric emergency settings. We will exclude studies before 2002, those focusing on specific reasons for agitation and placebo-controlled trials to avoid concerns related to the transitivity assumption and potential selection biases. We will search for eligible studies in BIOSIS, CENTRAL, CINAHL Plus, Embase, LILACS, MEDLINE via Ovid, PubMed, ProQuest, PsycINFO, ClinicalTrials.gov, and WHO-ICTRP. Individual-participant data will be requested from the study authors and harmonized into a uniform format, and aggregated data will also be extracted from the studies. At least two independent reviewers will conduct the study selection, data extraction, risk-of-bias assessment using RoB 2, and applicability evaluation using the RITES tool. The primary outcome will be the number of patients achieving adequate sedation within 30 min after treatment, with secondary outcomes including the need for additional interventions and adverse events, using odds ratios as the effect size. If enough individual-participant data will be collected, we will synthesize them in a network meta-regression model within a Bayesian framework, incorporating study- and participant-level characteristics to explore potential sources of heterogeneity. In cases where individual-participant data are unavailable, potential data availability bias will be explored, and models allowing for the inclusion of studies reporting only aggregated data will be considered. We will assess the confidence in the evidence using the Confidence in Network Meta-Analysis (CINeMA) approach. Discussion This individual-participant-data network meta-analysis aims to provide a fine-tuned synthesis of the evidence on the comparative effectiveness of pharmacological interventions for severe psychomotor agitation in real-world emergency settings. The findings from this study can greatly be provided clearer evidence-based guidance on the most effective treatments. Systematic review registration PROSPERO CRD42023402365.

Abstract Background Digital technologies, such as wearable devices and smartphone applications (apps), can enable the decentralisation of clinical trials by measuring endpoints in people’s chosen locations rather than in traditional clinical settings. Digital endpoints can allow high-frequency and sensitive measurements of health outcomes compared to visit-based endpoints which provide an episodic snapshot of a person’s health. However, there are underexplored challenges in this emerging space that require interdisciplinary and cross-sector collaboration. A multi-stakeholder Knowledge Exchange event was organised to facilitate conversations across silos within this research ecosystem. Methods A survey was sent to an initial list of stakeholders to identify potential discussion topics. Additional stakeholders were identified through iterative discussions on perspectives that needed representation. Co-design meetings with attendees were held to discuss the scope, format and ethos of the event. The event itself featured a cross-disciplinary selection of talks, a panel discussion, small-group discussions facilitated via a rolling seating plan and audience participation via Slido. A transcript was generated from the day, which, together with the output from Slido, provided a record of the day’s discussions. Finally, meetings were held following the event to identify the key challenges for digital endpoints which emerged and reflections and recommendations for dissemination. Results Several challenges for digital endpoints were identified in the following areas: patient adherence and acceptability; algorithms and software for devices; design, analysis and conduct of clinical trials with digital endpoints; the environmental impact of digital endpoints; and the need for ongoing ethical support. Learnings taken for next generation events include the need to include additional stakeholder perspectives, such as those of funders and regulators, and the need for additional resources and facilitation to allow patient and public contributors to engage meaningfully during the event. Conclusions The event emphasised the importance of consortium building and highlighted the critical role that collaborative, multi-disciplinary, and cross-sector efforts play in driving innovation in research design and strategic partnership building moving forward. This necessitates enhanced recognition by funders to support multi-stakeholder projects with patient involvement, standardised terminology, and the utilisation of open-source software.

Abstract High frequencies of stem-like memory T cells in infusion products correlate with superior patient outcomes across multiple T cell therapy trials. Herein, we analyzed a published CRISPR activation screening to identify transcriptional regulators that could be harnessed to augment stem-like behavior in CD8+ T cells. Using IFN-γ production as a proxy for CD8+ T cell terminal differentiation, LMO4 emerged among the top hits inhibiting the development of effectors cells. Consistently, we found that Lmo4 was downregulated upon CD8+ T cell activation but maintained under culture conditions facilitating the formation of stem-like T cells. By employing a synthetic biology approach to ectopically express LMO4 in antitumor CD8+ T cells, we enabled selective expansion and enhanced persistence of transduced cells, while limiting their terminal differentiation and senescence. LMO4 overexpression promoted transcriptional programs regulating stemness, increasing the numbers of stem-like CD8+ memory T cells and enhancing their polyfunctionality and recall capacity. When tested in syngeneic and xenograft tumor models, LMO4 overexpression boosted CD8+ T cell antitumor immunity, resulting in enhanced tumor regression. Rather than directly modulating gene transcription, LMO4 bound to JAK1 and potentiated STAT3 signaling in response to IL-21, inducing the expression of target genes (Tcf7, Socs3, Junb, and Zfp36) crucial for memory responses. CRISPR/Cas9-deletion of Stat3 nullified the enhanced memory signature conferred by LMO4, thereby abrogating the therapeutic benefit of LMO4 overexpression. These results establish LMO4 overexpression as an effective strategy to boost CD8+ T cell stemness, providing a new synthetic biology tool to bolster the efficacy of T cell-based immunotherapies.

Abstract How prostate cancer cells and their precursors mediate changes in the tumor microenvironment (TME) to drive prostate cancer progression is unclear, in part due to the inability to longitudinally study the disease evolution in human tissues. To overcome this limitation, we perform extensive single-cell RNA-sequencing (scRNA-seq) and molecular pathology of the comparative biology between human prostate cancer and key stages in the disease evolution of a genetically engineered mouse model (GEMM) of prostate cancer. Our studies of human tissues reveal that cancer cell-intrinsic activation of MYC signaling is a common denominator across the well-known molecular and pathological heterogeneity of human prostate cancer. Cell communication network and pathway analyses in GEMMs show that MYC oncogene-expressing neoplastic cells, directly and indirectly, reprogram the TME during carcinogenesis, leading to a convergence of cell state alterations in neighboring epithelial, immune, and fibroblast cell types that parallel key findings in human prostate cancer.

Abstract Background Honey bees are the principal commercial pollinators. Along with other arthropods, they are increasingly under threat from anthropogenic factors such as the incursion of invasive honey bee subspecies, pathogens and parasites. Better tools are needed to identify bee subspecies. Genomic data for economic and ecologically important organisms is increasing, but in its basic form its practical application to address ecological problems is limited. Results We introduce HBeeID a means to identify honey bees. The tool utilizes a knowledge-based network and diagnostic SNPs identified by discriminant analysis of principle components and hierarchical agglomerative clustering. Tests of HBeeID showed that it identifies African, Americas-Africanized, Asian, and European honey bees with a high degree of certainty even when samples lack the full 272 SNPs of HBeeID. Its prediction capacity decreases with highly admixed samples. Conclusion HBeeID is a high-resolution genomic, SNP based tool, that can be used to identify honey bees and screen species that are invasive. Its flexible design allows for future improvements via sample data additions from other localities.

Abstract Large-density functional theory (DFT) databases are a treasure trove of energies, forces, and stresses that can be used to train machine-learned interatomic potentials for atomistic modeling. Herein, we employ structural relaxations from the AFLOW database to train moment tensor potentials (MTPs) for four carbide systems: CHfTa, CHfZr, CMoW, and CTaTi. The resulting MTPs are used to relax ~6300 random symmetric structures, and are subsequently improved via active learning to generate robust potentials (RP) that can relax a wide variety of structures, and accurate potentials (AP) designed for the relaxation of low-energy systems. This protocol is shown to yield convex hulls that are indistinguishable from those predicted by AFLOW for the CHfTa, CHfZr, and CTaTi systems, and in the case of the CMoW system to predict thermodynamically stable structures that are not found within AFLOW, highlighting the potential of the employed protocol within crystal structure prediction. Relaxation of over three hundred (Mo1−x W x )C stoichiometry crystals first with the RP then with the AP yields formation enthalpies that are in excellent agreement with those obtained via DFT.

Abstract Background Canine acaricides with rapid onset and sustained activity can reduce pathogen transmission risk and enhance pet owner experience. This randomized, complete block design, investigator-masked study compared the speed of kill of Amblyomma americanum provided by three monthly-use isoxazoline-containing products. Methods Eight randomized beagles per group were treated (day 0), per label, with sarolaner (combined with moxidectin and pyrantel, Simparica Trio™), afoxolaner (NexGard™), or lotilaner (Credelio™), or remained untreated. Infestations with 50 adult A. americanum were conducted on days − 7, − 2, 21, and 28, and tick counts were performed on day − 5 (for blocking), and at 4, 8, 12, 24, 48, and 72 h following treatment and subsequent infestations. Efficacy calculations were based on geometric mean live tick counts. A linear mixed model was used for between-group comparisons. Results On day 0, only lotilaner significantly reduced an A. americanum infestation by 12 h (43.3%; P = 0.002). Efficacy of lotilaner and afoxolaner at 24 h post-treatment was 95.3% and 97.6%, respectively, both significantly different from sarolaner (74%) (P = 0.002, P

Objective: To evaluate the completeness and reliability of recurrence data from an institutional cancer registry for patients with head and neck cancer. Patients and Methods: Recurrence information was collected by radiation oncology and otolaryngology researchers. This was compared with the institutional cancer registry for continuous patients treated with radiation therapy for head and neck cancer at a tertiary cancer center. The sensitivity and specificity of institutional cancer registry data was calculated using manual review as the gold standard. False negative recurrences were compared to true positive recurrences to assess for differences in patient characteristics. Results: A total of 1338 patients who were treated from January 1, 2010, through December 31, 2017, were included in a cancer registry and underwent review. Of them, 375 (30%) had confirmed cancer recurrences, 45 (3%) had concern for recurrence without radiologic or pathologic confirmation, and 31 (2%) had persistent disease. Most confirmed recurrences were distant (37%) or distant plus locoregional (29%), whereas few were local (11%), regional (9%), or locoregional (14%) alone. The cancer registry accuracy was 89.4%, sensitivity 61%, and specificity 99%. Time to recurrence was associated with registry accuracy. True positives had recurrences at a median of 414 days vs 1007 days for false negatives. Conclusion: Currently, institutional cancer registry recurrence data lacks the required accuracy for implementation into studies without manual confirmation. Longer follow-up of cancer status will likely improve sensitivity. No identified differences in patients accounted for differences in sensitivity. New, ideally automated, data abstraction tools are needed to improve detection of cancer recurrences and minimize manual chart review.

Abstract Intra-abdominal infections (IAIs) are an important cause of morbidity and mortality in hospital settings worldwide. The cornerstones of IAI management include rapid, accurate diagnostics; timely, adequate source control; appropriate, short-duration antimicrobial therapy administered according to the principles of pharmacokinetics/pharmacodynamics and antimicrobial stewardship; and hemodynamic and organ functional support with intravenous fluid and adjunctive vasopressor agents for critical illness (sepsis/organ dysfunction or septic shock after correction of hypovolemia). In patients with IAIs, a personalized approach is crucial to optimize outcomes and should be based on multiple aspects that require careful clinical assessment. The anatomic extent of infection, the presumed pathogens involved and risk factors for antimicrobial resistance, the origin and extent of the infection, the patient’s clinical condition, and the host’s immune status should be assessed continuously to optimize the management of patients with complicated IAIs.

Objectives: Postoperative atrial fibrillation (POAF) is the most common perioperative arrhythmia. The association of POAF with negative short-term outcomes after cardiac surgery is well understood; however, the association of POAF with long-term morbidity and mortality is not well described. We compared the risk of long-term clinical outcomes (up to 9 years postdischarge) in patients with and without POAF following open-chest cardiac surgery. Methods: This observational, retrospective cohort study used data from the Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies (SWEDEHEART) Swedish Cardiac Surgery Registry and National Board of Health and Welfare. Patients aged 55 to 90 years who underwent open-chest coronary artery bypass and/or valvular surgery between 2010 and 2019 were included. Clinical outcomes were adjusted for differences in baseline demographics and clinical history using multivariable Cox regression. Results: A total of 30,870 patients with a mean age of 69.2 years were included in the study (no POAF, n = 20,734; POAF, n = 10,136). The median follow-up was 4.6 years. After adjustment, POAF was associated with a significantly higher risk of recurrent atrial fibrillation (hazard ratio [HR], 2.30; 95% CI, 2.21-2.41), heart failure (HR, 1.17; 95% CI, 1.10-1.25), chronic kidney disease (HR, 1.15; 95% CI, 1.07-1.24), all-cause mortality (HR, 1.11; 95% CI, 1.04-1.18), and cardiovascular mortality (HR, 1.16; 95% CI, 1.06-1.26). POAF was also associated with a numerically higher risk of ischemic stroke and major bleed, but these findings were not statistically significant after adjustment. Conclusions: These data provide further insight into the long-term clinical outcomes associated with POAF in patients undergoing cardiac surgery.

Mounting evidence suggests that the tissue inhibitor of metalloproteinases-2 (TIMP2) can reduce tumor burden and metastasis. However, the demonstration of such anti-tumor activity and associated mechanisms using in vivo tumor models is lacking. The effects of a Timp2 functional mutation and administration of recombinant TIMP2 were examined in both orthotopic and heterotopic murine models of lung cancer using C57Bl/6 syngeneic Lewis Lung 2-luciferase 2 cells (LL2-Luc2) cells. Mice harboring a functional mutation of TIMP2 (mT2) display markedly increased primary lung tumor growth, increased mortality, enriched vasculature, and enhanced infiltration of pro-tumorigenic, immunosuppressive myeloid cells. Treatment with recombinant TIMP2 reduced primary tumor growth in both mutant and wild-type (wt) mice. Comparison of transcriptional profiles of lung tissues from tumor-free, wt versus mT2 mice reveals only minor changes. However, lung tumor-bearing mice of both genotypes demonstrate significant genotype-dependent changes in gene expression following treatment with TIMP. In tumor-bearing wt mice, TIMP2 treatment reduced the expression of upstream oncogenic mediators, whereas treatment of mT2 mice resulted in an immunomodulatory phenotype. A heterotopic subcutaneous model generating metastatic pulmonary tumors demonstrated that daily administration of recombinant TIMP2 significantly reduces the expression of heat shock proteins, suggesting a reduction of cell-stress responses. In summary, we describe how TIMP2 exerts novel, anti-tumor effects in a murine model of lung cancer and that rTIMP2 treatment supports a normalizing effect on the tumor microenvironment. Our findings show that TIMP2 treatment demonstrates significant potential as an adjuvant in the treatment of NSCLC.

Soil-plant-atmosphere conditions in crop fields can differ substantially from those at the nearest weather station, creating uncertainty in crop management decisions and scientific analyses. To reduce this uncertainty, CRopland Observatory NOdeS (CRONOS) were developed to monitor soil water content, green canopy cover (GCC), and atmospheric conditions in crop fields. Here we evaluate the accuracy and reliability of first-generation CRONOS systems and compare CRONOS data to data from the nearest permanent weather station. CRONOS stations were installed in three winter wheat (Triticum aestivum) fields across Oklahoma, USA. Each was equipped with a cosmic-ray neutron sensor to measure soil water content, a camera to monitor GCC, and an all-in-one weather station. Validation sampling showed that CRONOS stations accurately determined field-scale average soil water content, with a mean absolute difference (MAD) of 0.025 cm3cm-3 and a Nash-Sutcliffe Efficiency (NSE) of 0.742. Greater discrepancies existed between CRONOS GCC estimates and field-scale average GCC, with an MAD of 11% and NSE of 0.67. There was generally strong agreement between CRONOS atmospheric data and data from a collocated, high quality weather station, with NSE values ≥ 0.95 for measurements of air temperature and atmospheric pressure, but slightly poorer agreement for precipitation, solar radiation, relative humidity, and wind speed (NSE values ≥ 0.73). The reliability of the CRONOS cameras needs to be improved because 43% of the scheduled images were missing or unsuitable for GCC analysis, but the reliability of the other sensors was high with ≥ 98% valid observations. Overall, CRONOS stations show good potential to improve monitoring of the soil-plant-atmosphere continuum in cropland.

Proliferative verrucous leukoplakia (PVL) is an aggressive and distinct type of oral precancerous lesion characterized by warty surfaced white plaque diffusely involving oral mucosa. Surgical excision is the treatment of choice. However, PVL has persistent and recurrent growth patterns, requiring multiple surgical procedures. Surgical intervention is especially challenging if PVL extends between teeth limiting access. These interproximally located lesions have a high propensity to undergo malignant transformation. We report a case of a 53-year-old man with recurrent PVL diffusely covering the maxillary and mandibular gingiva. Despite complete surgical excisions, PVL recurred, and a focal area in the interproximal mandibular gingiva progressed to invasive squamous cell carcinoma requiring marginal resection. The remaining PVL areas were treated with topical imiquimod (toll-like receptor 7 agonist) for six months, resulting in complete clinical and histological resolution. Topical agents can cover a larger surface area and penetrate in between interproximal areas. Importantly, it allows for maximal local exposure with minimal systemic toxicity, essential for long-term treatment and prophylactic use of the agent to prevent relapse.

Bruton tyrosine kinase inhibitors (BTKi) have transformed the treatment of B-cell malignancies, but intolerance has often led to their discontinuation. The phase 1/2 BRUIN study evaluated pirtobrutinib, a highly selective non-covalent (reversible) BTKi, in patients with R/R B-cell malignancies (NCT03740529). Pirtobrutinib was investigated in 127 patients with intolerance to at least one prior BTKi therapy in the absence of progressive disease. The most common adverse event (AE) leading to BTKi discontinuation was cardiac disorders (n=40, 31.5%), specifically atrial fibrillation (n=30, 23.6%). The median follow-up was 17.4 months and the median time on pirtobrutinib was 15.3 months. The most common reasons for pirtobrutinib discontinuation were progressive disease (26.8%), AE (10.2%), or death (5.5%). The most frequent treatment-emergent AEs were fatigue (39.4%) and neutropenia (37.0%). Among patients who discontinued a prior BTKi for a cardiac issue, 75% had no recurrence of their cardiac AE. No patient discontinued pirtobrutinib for the same AE that led to discontinuation of the prior BTKi. In 78 CLL/SLL and 21 MCL patients intolerant to prior BTKi, ORR to pirtobrutinib was 76.9% and 81.0%, respectively. Median PFS for CLL/SLL was 28.4 months and was not estimable for MCL. These results suggest that pirtobrutinib was safe, well-tolerated, and an efficacious option in patients with prior BTKi-intolerance.

Background: The pathophysiology of protracted symptoms after COVID-19 is unclear. This study aimed to determine if long-COVID is associated with differences in baseline characteristics, markers of white matter diffusivity in the brain, and lower scores on objective cognitive testing. Methods: Individuals who experienced COVID-19 symptoms for more than 60 days post-infection (long-COVID) (n = 56) were compared to individuals who recovered from COVID-19 within 60 days of infection (normal recovery) (n = 35). Information regarding physical and mental health, and COVID-19 illness was collected. The National Institute of Health Toolbox Cognition Battery was administered. Participants underwent magnetic resonance imaging (MRI) with diffusion tensor imaging (DTI). Tract-based spatial statistics were used to perform a whole-brain voxel-wise analysis on standard DTI metrics (fractional anisotropy, axial diffusivity, mean diffusivity, radial diffusivity), controlling for age and sex. NIH Toolbox Age-Adjusted Fluid Cognition Scores were used to compare long-COVID and normal recovery groups, covarying for Age-Adjusted Crystallized Cognition Scores and years of education. False discovery rate correction was applied for multiple comparisons. Results: There were no significant differences in age, sex, or history of neurovascular risk factors between the groups. The long-COVID group had significantly (p < 0.05) lower mean diffusivity than the normal recovery group across multiple white matter regions, including the internal capsule, anterior and superior corona radiata, corpus callosum, superior fronto-occiptal fasciculus, and posterior thalamic radiation. However, the effect sizes of these differences were small (all β 0.05). Conclusions: Differences in diffusivity between long-COVID and normal recovery groups were found on only one DTI metric. This could represent subtle areas of pathology such as gliosis or edema, but the small effect sizes and non-specific nature of the diffusion indices make pathological inference difficult. Although long-COVID patients reported many neuropsychiatric symptoms, significant differences in objective cognitive performance were not found.

BackgroundAlthough many people are supportive of their deidentified health care data being used for research, concerns about privacy, safety, and security of health care data remain. There is low awareness about how data are used for research and related governance. Transparency about how health data are used for research is crucial for building public trust. One proposed solution is to ensure that affected communities are notified, particularly marginalized communities where there has previously been a lack of engagement and mistrust. ObjectiveThis study aims to explore patient and public perspectives on the use of deidentified data from electronic health records for musculoskeletal research and to explore ways to build and sustain public trust in health data sharing for a research program (known as “the Data Jigsaw”) piloting new ways of using and analyzing electronic health data. Views and perspectives about how best to engage with local communities informed the development of a public notification campaign about the research. MethodsQualitative methods data were generated from 20 semistructured interviews and 8 focus groups, comprising 48 participants in total with musculoskeletal conditions or symptoms, including 3 carers. A presentation about the use of health data for research and examples from the specific research projects within the program were used to trigger discussion. We worked in partnership with a patient and public involvement group throughout the research and cofacilitated wider community engagement. ResultsRespondents were supportive of their health care data being shared for research purposes, but there was low awareness about how electronic health records are used for research. Security and governance concerns about data sharing were noted, including collaborations with external companies and accessing social care records. Project examples from the Data Jigsaw program were viewed positively after respondents knew more about how their data were being used to improve patient care. A range of different methods to build and sustain trust were deemed necessary by participants. Information was requested about: data management; individuals with access to the data (including any collaboration with external companies); the National Health Service’s national data opt-out; and research outcomes. It was considered important to enable in-person dialogue with affected communities in addition to other forms of information. ConclusionsThe findings have emphasized the need for transparency and awareness about health data sharing for research, and the value of tailoring this to reflect current and local research where residents might feel more invested in the focus of research and the use of local records. Thus, the provision for targeted information within affected communities with accessible messages and community-based dialogue could help to build and sustain public trust. These findings can also be extrapolated to other conditions beyond musculoskeletal conditions, making the findings relevant to a much wider community.

Reptile feeding strategies encompass a wide variety of diets and accompanying diversity in methods for subduing prey. One such strategy, the use of venom for prey capture, is found in living reptile clades like helodermatid (beaded) lizards and some groups of snakes, and venom secreting glands are also present in some monitor lizards and iguanians. The fossil record of some of these groups shows strong evidence for venom use, and this feeding strategy also has been hypothesized for a variety of extinct reptiles (e.g., archosauromorphs, anguimorphs, and a sphenodontian). However, evidence of systems for venom delivery in extinct groups and its evolutionary origins has been scarce, especially when based on more than isolated teeth. Here, we describe a potentially venomous new reptile, Microzemiotes sonselaensis gen. et sp. nov., from a partial left dentary recovered from the Sonsela Member of the Chinle Formation (middle Norian, Upper Triassic) of northeastern Arizona, U.S.A. The three dentary teeth have apices that are distally reclined relative to their bases and the tip of the posteriormost tooth curves mesially. The teeth show subthecodont implantation and are interspaced by empty sockets that terminate above the Meckelian canal, which is dorsoventrally expanded posteriorly. Replacement tooth sockets are positioned distolingually to the active teeth as in varanid-like replacement. We identify this new specimen as a diapsid reptile based on its monocuspid teeth that lack carinae and serrations. A more exclusive phylogenetic position within Diapsida is not well supported and remains uncertain. Several features of this new taxon, such as the presence of an intramandibular septum, are shared with some anguimorph squamates; however, these likely evolved independently. The teeth of the new taxon are distinctively marked by external grooves that occur on the entire length of the crown on the labial and lingual sides, as seen in the teeth of living beaded lizards. If these grooves are functionally similar to those of beaded lizards, which use the grooves to deliver venom, this new taxon represents the oldest known reptile where venom-conducting teeth are preserved within a jaw. The teeth of the new species are anatomically distinct from and ~10x smaller than those of the only other known Late Triassic hypothesized venomous reptile, Uatchitodon, supporting venom use across multiple groups of different body size classes. This new species represents the third Late Triassic reptile species to possibly have used envenomation as a feeding (and/or defensive) strategy, adding to the small number of venomous reptiles known from the Mesozoic Era.