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Purpose: Removal of clinically benign eyelid margin lesions is frequently desired for cosmetic concerns. Although surgical excision remains the standard therapy for such lesions, it carries the risk of unfavorable outcomes. Hence, this study aimed to evaluate a more aesthetic technique entailing a posterior lamellar wedge resection of lower eyelid margin lesions through an infraciliary incision. Methods: A retrospective review of patients who underwent posterior lamellar wedge resection for benign lower eyelid margin lesions between May 2017 and June 2022 was performed. Patient satisfaction using the visual analog score (VAS) and cosmetic outcomes using the Strasser score. Results: Forty-two patients met the inclusion criteria (61.9% female, mean age: 46.8 years). Nevus was the most frequent histologic diagnosis (57.1%). Furthermore, 66.7% of lesions extended to the back of the lid margin. The mean defect size was 5.8 mm (range: 3.5–8 mm). The mean follow-up interval was 24.1 months (range: 6–60 months). Thirty-two (76.2%) eyelids had scores indicating an excellent result, and 10 (23.8%) patients had a good result. The mean patient satisfaction VAS score for the eyelid appearance was 96 (range: 70–100). There were no cases of recurrence of resected lesions. No further surgery was performed on the operated eyelid for any reason during the follow-up period. Conclusion: Posterior lamellar wedge resection for lower eyelid margin lesions was associated with excellent cosmetic outcomes, high patient satisfaction, and minimal adverse events.

Purpose: While testosterone therapy can improve the various pathologies associated with adult-onset testosterone deficiency (TD), Summary of Product Characteristics (SPC) of five testosterone preparations caution that treatment may be associated with hypertension. This paper evaluates the impact of testosterone undecanoate (TU) on blood pressure (BP) in men with adult-onset TD. Materials and Methods: Of 737 men with adult-onset TD in an on-going, observational, prospective, cumulative registry, we studied changes in BP using non-parametric sign-rank tests at final assessment and fixed time points. We used multiple regression analysis to establish factors (baseline BP, age, change/baseline waist circumference [WC] and hematocrit [HCT] and follow-up) potentially associated with BP change in men on TU. Results: TU was associated with significant reductions in systolic, diastolic BP and pulse pressure, regardless of antihypertensive therapy (at baseline or during follow-up), larger reductions were seen with concurrent antihypertensive therapy. In men never on antihypertensive agents, median changes (interquartile range [IQR]) in systolic BP, diastolic BP and pulse pressure were -12.5 (-19.0, -8.0), -8.0 (-14.0, -3.0), and -6.0 (-10.0, -1.0) mmHg, respectively at final assessment, with only baseline BP values inversely associated with these changes (HCT and WC were not significantly associated). In men not on TU, systolic BP, diastolic BP, and pulse pressure significantly increased. In the TU treated men only 1 of the 152 men (not on antihypertensive agents at baseline) were started on antihypertensives during follow-up. In contrast 33 of the 202 men on antihypertensives (at baseline or follow-up) had the antihypertensive agent discontinued by the end of the follow-up. Conclusions: TU was associated with lowering of BP during follow-up irrespective of antihypertensive therapy, with greater reductions in men with higher baseline BP. In the context of SPC warnings, our long-term data provide reassurance on the effect of TU on BP.

Abstract Brain resection is curative for a subset of patients with drug resistant epilepsy but up to half will fail to achieve sustained seizure freedom in the long term. There is a critical need for accurate prediction tools to identify patients likely to have recurrent postoperative seizures. Results from preclinical models and intracranial EEG in humans suggest that the window of time immediately before and after a seizure (“peri-ictal”) represents a unique brain state with implications for clinical outcome prediction. Using a dataset of 294 patients who underwent temporal lobe resection for seizures, we show that machine learning classifiers can make accurate predictions of postoperative seizure outcome using 5 min of peri-ictal scalp EEG data that is part of universal presurgical evaluation (AUC 0.98, out-of-group testing accuracy > 90%). This is the first approach to seizure outcome prediction that employs a routine non-invasive preoperative study (scalp EEG) with accuracy range likely to translate into a clinical tool. Decision curve analysis (DCA) shows that compared to the prevalent clinical-variable based nomogram, use of the EEG-augmented approach could decrease the rate of unsuccessful brain resections by 20%.

Abstract During summer, ammonia emissions in Southeast Asia influence air pollution and cloud formation. Convective transport by the South Asian monsoon carries these pollutant air masses into the upper troposphere and lower stratosphere (UTLS), where they accumulate under anticyclonic flow conditions. This air mass accumulation is thought to contribute to particle formation and the development of the Asian Tropopause Aerosol Layer (ATAL). Despite the known influence of ammonia and particulate ammonium on air pollution, a comprehensive understanding of the ATAL is lacking. In this modelling study, the influence of ammonia on particle formation is assessed with emphasis on the ATAL. We use the EMAC chemistry-climate model, incorporating new particle formation parameterisations derived from experiments at the CERN CLOUD chamber. Our diurnal cycle analysis confirms that new particle formation mainly occurs during daylight, with a 10-fold enhancement in rate. This increase is prominent in the South Asian monsoon UTLS, where deep convection introduces high ammonia levels from the boundary layer, compared to a baseline scenario without ammonia. Our model simulations reveal that this ammonia-driven particle formation and growth contributes to an increase of up to 80% in cloud condensation nuclei (CCN) concentrations at cloud-forming heights in the South Asian monsoon region. We find that ammonia profoundly influences the aerosol mass and composition in the ATAL through particle growth, as indicated by an order of magnitude increase in nitrate levels linked to ammonia emissions. However, the effect of ammonia-driven new particle formation on aerosol mass in the ATAL is relatively small. Ammonia emissions enhance the regional aerosol optical depth (AOD) for shortwave solar radiation by up to 70%. We conclude that ammonia has a pronounced effect on the ATAL development, composition, the regional AOD, and CCN concentrations.

Abstract Ryugu is the C-type asteroid from which material was brought to Earth by the Hayabusa2 mission. A number of individual grains and fine-grained samples analysed so far for noble gases have indicated that solar wind and planetary (known as P1) noble gases are present in Ryugu samples with concentrations higher than those observed in CIs, suggesting the former to be more primitive compared to the latter. Here we present results of analyses of three fine-grained samples from Ryugu, in one of which Xe concentration is an order of magnitude higher than determined so far in other samples from Ryugu. Isotopically, this Xe resembles P1, but with a much stronger isotopic fractionation relative to solar wind and significantly lower 36Ar/132Xe ratio than in P1. This previously unknown primordial noble gas component (here termed P7) provides clues to constrain how the solar composition was fractionated to form the planetary components.

Abstract Aspects of the acute experience induced by the serotonergic psychedelic psilocybin predict symptomatic relief in multiple psychiatric disorders and improved well-being in healthy participants, but whether these therapeutic effects are immediate or are based on memories of the experience is unclear. To examine this, we co-administered psilocybin (25 mg) with the amnestic benzodiazepine midazolam in 8 healthy participants and assayed the subjective quality of, and memory for, the dosing-day experience. We identified a midazolam dose that allowed a conscious psychedelic experience to occur while partially impairing memory for the experience. Furthermore, midazolam dose and memory impairment tended to associate inversely with salience, insight, and well-being induced by psilocybin. These data suggest a role for memory in therapeutically relevant behavioral effects occasioned by psilocybin. Because midazolam blocks memory by blocking cortical neural plasticity, it may also be useful for evaluating the contribution of the pro-neuroplastic properties of psychedelics to their therapeutic activity.

Rosai-Dorfman disease (RDD) is a nonmalignant disease of histiocyte proliferation. RDD usually presents with painless cervical lymphadenopathy, although extranodal involvement can occur. Cardiac involvement was reported in

An artificial intelligence-based geostatistical optimization algorithm was developed to upgrade a test Iranian aquifer’s existing groundwater monitoring network. For that aquifer, a preliminary study revealed that a Multi-Layer Perceptron Artificial Neural Network (MLP-ANN) more accurately determined temporally average water table elevations than geostatistical kriging, spline, and inverse distance weighting. Because kriging is usually used in that area for water table estimation, the developed algorithm used MLP-ANN to guide kriging, and Genetic Algorithm (GA) to determine locations for new monitoring well location(s). For possible annual fiscal budgets allowing 1–12 new wells, 12 sets of optimal new well locations are reported. Each set has the locations of new wells that would minimize the squared difference between the time-averaged heads developed by kriging versus MLP-ANN. Also, to simultaneously consider local expertise, the algorithm used fuzzy inference to quantify an expert’s satisfaction with the number of new wells. Then, the algorithm used symmetric bargaining (Nash, Kalai–Smorodinsky, and area monotonic) to present an upgradation strategy that balanced professional judgment and heuristic optimization. In essence, the algorithm demonstrates the systematic application of relatively new computational practices to a common situation worldwide.

Abstract Primates must adapt to changing environments by optimizing their behavior to make beneficial choices. At the core of adaptive behavior is the orbitofrontal cortex (OFC) of the brain, which updates choice value through direct experience or knowledge-based inference. Here, we identify distinct neural circuitry underlying these two separate abilities. We designed two behavioral tasks in which two male macaque monkeys updated the values of certain items, either by directly experiencing changes in stimulus-reward associations, or by inferring the value of unexperienced items based on the task’s rules. Chemogenetic silencing of bilateral OFC combined with mathematical model-fitting analysis revealed that monkey OFC is involved in updating item value based on both experience and inference. In vivo imaging of chemogenetic receptors by positron emission tomography allowed us to map projections from the OFC to the rostromedial caudate nucleus (rmCD) and the medial part of the mediodorsal thalamus (MDm). Chemogenetic silencing of the OFC-rmCD pathway impaired experience-based value updating, while silencing the OFC-MDm pathway impaired inference-based value updating. Our results thus demonstrate dissociable contributions of distinct OFC projections to different behavioral strategies, and provide new insights into the neural basis of value-based adaptive decision-making in primates.

Abstract Background People with dementia and severe challenging behavior in the Netherlands can be temporarily admitted to highly specialized units when their behavior is not manageable in regular dementia special care units (DSCUs). With scarce evidence available for the treatment of these patients, treatment in these units is in a pioneering phase. To gain more insight into these units, this study investigated organizational characteristics, i.e. admission and discharge characteristics, staffing, the physical environment, and the management of severe challenging behavior. Methods Three data collection methods were used: 1) a digital questionnaire to be completed by the unit manager, 2) an interview with the physician responsible for medical care and often another practitioner, and 3) an observation of the physical environment for which the OAZIS-dementia questionnaire was used. Descriptive analysis was used for quantitative data and thematic analysis for qualitative data, after which data was interpreted together. Thirteen units participated, with their sizes ranging from 10 to 28 places. Results Patients were mainly admitted from regular DSCUs, home or mental health care, and discharged to regular DSCUs. A multidisciplinary team comprising at least an elderly care physician or geriatrician, psychologist, and nursing staff member and other therapists as needed provided the treatment. Nursing staff hours per patient considerably differed among units. Nursing staff played a central role in the treatment. Competences such as reflectiveness on one’s own behavior, and being able to cope with stressful situations were described as relevant for nursing staff. Investing in a stable nursing staff team was described as important. The units varied in whether their work-up was more intuitive or methodological. In the diagnostic phase, observation together with an extensive analysis of the patient’s biography was essential. The units used a broad variety of interventions, and all paid attention to sensory stimuli. In the observation of the physical environment, the safety scored well and domesticity relatively low. Conclusion Highly specialized units show strong heterogeneity in organizational characteristics and management, which can be understood in the light of the pioneering phase. Despite this, similarities were found in nursing staff roles, frequent multidisciplinary evaluation, and attention to sensory stimuli.

Abstract Neural processing of rewarding stimuli involves several distinct regions, including the nucleus accumbens (NAc). The majority of NAc neurons are GABAergic projection neurons known as medium spiny neurons (MSNs). MSNs are broadly defined by dopamine receptor expression, but evidence suggests that a wider array of subtypes exist. To study MSN heterogeneity, we analyzed single-nucleus RNA sequencing data from the largest available rat NAc dataset. Analysis of 48,040 NAc MSN nuclei identified major populations belonging to the striosome and matrix compartments. Integration with mouse and human data indicated consistency across species and disease-relevance scoring using genome-wide association study results revealed potentially differential roles for MSN populations in substance use disorders. Additional high-resolution clustering identified 34 transcriptomically distinct subtypes of MSNs definable by a limited number of marker genes. Together, these data demonstrate the diversity of MSNs in the NAc and provide a basis for more targeted genetic manipulation of specific populations.

Objectives: The role of timing of coronary artery bypass grafting after acute myocardial infarction on early and late outcomes remains uncertain. Methods: We reviewed 1631 consecutive adult patients who underwent isolated coronary artery bypass grafting with information on timing of acute myocardial infarction. Early and late mortality were compared between patients receiving coronary artery bypass grafting within 24 hours after acute myocardial infarction, between 1 and 7 days after acute myocardial infarction, and more than 7 days after acute myocardial infarction. Sensitivity analyses were performed in subgroups of patients with ST-segment elevation myocardial infarction or non–ST-segment elevation myocardial infarction, and other high-risk groups. Results: A total of 124 patients (5.7%) underwent coronary artery bypass grafting within 24 hours, 972 patients (51.2%) received coronary artery bypass grafting between 1 and 7 days after acute myocardial infarction, and 535 patients (43.2%) underwent coronary artery bypass grafting more than 7 days after acute myocardial infarction. Overall operative mortality was 2.7% with comparable adjusted early mortality among 3 groups. Over a median follow-up of 13.5 years (interquartile range, 8.9-17.1), compared with patients receiving coronary artery bypass grafting between 1 and 7 days after acute myocardial infarction, those receiving coronary artery bypass grafting at 7 days had greater adjusted risk for late overall mortality (hazard ratio, 1.39, 95% CI, 1.16-1.67; P 7 days had a higher risk of late mortality [hazard ratio, 1.38, 95% CI, 1.14-1.67, P

Abstract The purpose of this study is to examine the effect of early incomplete follow-up on overall survival among stage I lung cancer patients. Patients with clinical stage I lung cancer at our institution between 2007 and 2016 were identified (N = 1111). Exclusions included

Abstract Many health insurance markets are organized by principles of regulated competition. Regulators of these markets typically apply risk equalization (aka risk adjustment) and risk sharing to mitigate risk selection. Risk equalization and risk sharing can have various positive and negative effects on efficiency and fairness. This paper provides a comprehensive framework for ex-ante evaluation of these effects. In a first step, we distinguish 22 potential effects. In a second step, we summarize and discuss quantitative measures used for evaluating risk equalization and risk sharing schemes in academic research. To underline the relevance of our work, we compare our framework with an existing framework that was previously used in the Dutch regulated health insurance market. We conclude that this framework is incomplete and uses inappropriate measures. To avoid suboptimal policy choices, we recommend policymakers (1) to consider the entire spectrum of potential effects and (2) to select their measures carefully.

Abstract The ongoing international negotiations on a global plastics treaty will have pivotal implications for future efforts to transform the plastic economy. This is essential since the current use of plastic in the economy impacts the environment beyond the planetary carrying capacity. To ensure that the forthcoming Treaty can provide the foundation for this transition, the best available science must be made available in the negotiations, but with no formal scientific mechanism to inform the negotiations process, this is not ensured. The Scientists’ Coalition for an Effective Plastic Treaty serves as an example of how the global scientific community has self-organized and come together to address this task, working with five different categories of science-policy communication. The Scientists’ Coalition’s work is made transparent here with the hope that it can inspire organization of scientific input into other future policy areas.

Abstract In the face of increasing antimicrobial tolerance and resistance there is a global obligation to optimise oral antimicrobial dosing strategies including narrow spectrum penicillins, such as penicillin-V. We conducted a randomised, crossover study in healthy volunteers to characterise the influence of probenecid on penicillin-V pharmacokinetics and estimate the pharmacodynamics against Streptococcus pneumoniae. Twenty participants took six doses of penicillin-V (250 mg, 500 mg or 750 mg four times daily) with and without probenecid. Total and free concentrations of penicillin-V and probenecid were measured at two timepoints. A pharmacokinetic model was developed, and the probability of target attainment (PTA) calculated. The mean difference (95% CI) between penicillin-V alone and in combination with probenecid for serum total and free penicillin-V concentrations was significantly different at both timepoints (total: 45 min 4.32 (3.20–5.32) mg/L p

Abstract The construction of sub‐daily pressure series is described for the cities of London (GB) and Paris (FR). The series extend back 1692 and 1748, respectively, and as such they represent two of the longest sub‐daily series of barometric pressure available. These series are updated from the previously documented London and Paris daily series and offer more homogeneous series, and in the case of the London series a more temporally complete sequence of data. A pairwise homogenization procedure has been applied to the two series alongside the long series of pressure that exists for De Bilt (NL). The De Bilt series has been available for some time in the International Surface Pressure Dataset (ISPD), but further quality control and homogeneity‐checking procedures have been applied to the data in this paper and therefore the three series are released together in this dataset. The series are of immediate interest for understanding changes to storm activity across the English Channel and North Atlantic region over an extended timeframe but may also be assimilated into reanalysis datasets such as the 20th‐century reanalysis.

Abstract Background With its minimally invasive approach, laparoscopic surgery has transformed the medical landscape. As the demand for these procedures escalates, there is a pressing need for adept surgeons trained in laparoscopic techniques. However, current training often falls short of catering to medical school education. This study evaluates the impact of a custom-designed laparoscopic training workshop on medical students’ surgical skills and career aspirations. Methods This prospective experimental study was conducted at the E-Da hospital in Kaohsiung City, Taiwan. Medical students from Taiwanese medical schools undergoing Clerk 5, Clerk 6, and Postgraduate Year 1 and 2 were invited to participate. Medical students (n = 44) underwent an endoscopic skill training workshop consisting of lectures, box training, and live tissue training. The trainees performed multiple tasks before and after training using our objective evaluation system. The primary outcome was assessed before and after training through a questionnaire assessing the influence of training on students’ interest in surgery as a career. The secondary outcome measured improvement in skill acquisition, comparing the task completion time pre- and post-workshop. For the primary outcome, descriptive statistics were used to summarize the questionnaire responses, and paired t-tests were performed to determine significant changes in interest levels post-workshop. For the secondary outcome, paired t-tests were used to compare the time recorded pre- and post-training. Results Post-training, participants exhibited significant proficiency gains, with task completion times reducing notably: 97 s (p = 0.0015) for Precision Beads Placement, 88.5 s (p

Abstract Background Traumatic brain injury (TBI) causes neuroinflammation and can lead to long-term neurological dysfunction, even in cases of mild TBI (mTBI). Despite the substantial burden of this disease, the management of TBI is precluded by an incomplete understanding of its cellular mechanisms. Sphingolipids (SPL) and their metabolites have emerged as key orchestrators of biological processes related to tissue injury, neuroinflammation, and inflammation resolution. No study so far has investigated comprehensive sphingolipid profile changes immediately following TBI in animal models or human cases. In this study, sphingolipid metabolite composition was examined during the acute phases in brain tissue and plasma of mice following mTBI. Methods Wildtype mice were exposed to air-blast-mediated mTBI, with blast exposure set at 50-psi on the left cranium and 0-psi designated as Sham. Sphingolipid profile was analyzed in brain tissue and plasma during the acute phases of 1, 3, and 7 days post-TBI via liquid-chromatography-mass spectrometry. Simultaneously, gene expression of sphingolipid metabolic markers within brain tissue was analyzed using quantitative reverse transcription-polymerase chain reaction. Significance (P-values) was determined by non-parametric t-test (Mann–Whitney test) and by Tukey’s correction for multiple comparisons. Results In post-TBI brain tissue, there was a significant elevation of 1) acid sphingomyelinase (aSMase) at 1- and 3-days, 2) neutral sphingomyelinase (nSMase) at 7-days, 3) ceramide-1-phosphate levels at 1 day, and 4) monohexosylceramide (MHC) and sphingosine at 7-days. Among individual species, the study found an increase in C18:0 and a decrease in C24:1 ceramides (Cer) at 1 day; an increase in C20:0 MHC at 3 days; decrease in MHC C18:0 and increase in MHC C24:1, sphingomyelins (SM) C18:0, and C24:0 at 7 days. Moreover, many sphingolipid metabolic genes were elevated at 1 day, followed by a reduction at 3 days and an absence at 7-days post-TBI. In post-TBI plasma, there was 1) a significant reduction in Cer and MHC C22:0, and an increase in MHC C16:0 at 1 day; 2) a very significant increase in long-chain Cer C24:1 accompanied by significant decreases in Cer C24:0 and C22:0 in MHC and SM at 3 days; and 3) a significant increase of C22:0 in all classes of SPL (Cer, MHC and SM) as well as a decrease in Cer C24:1, MHC C24:1 and MHC C24:0 at 7 days. Conclusions Alterations in sphingolipid metabolite composition, particularly sphingomyelinases and short-chain ceramides, may contribute to the induction and regulation of neuroinflammatory events in the early stages of TBI, suggesting potential targets for novel diagnostic, prognostic, and therapeutic strategies in the future.

Abstract Background Evidence on the effectiveness of multidomain lifestyle interventions to prevent cognitive decline in older people without dementia is mixed. Embedded in the World-Wide FINGERS initiative, FINGER-NL aims to investigate the effectiveness of a 2-year multidomain lifestyle intervention on cognitive functioning in older Dutch at risk individuals. Methods Multi-center, randomized, controlled, multidomain lifestyle intervention trial with a duration of 24 months. 1210 adults between 60–79 years old with presence of ≥ 2 modifiable risk factors and ≥ 1 non-modifiable risk factor for cognitive decline were recruited between January 2022 and May 2023 via the Dutch Brain Research Registry and across five study sites in the Netherlands. Participants were randomized to either a high-intensity or a low-intensity intervention group. The multidomain intervention comprises a combination of 7 lifestyle components (physical activity, cognitive training, cardiovascular risk factor management, nutritional counseling, sleep counseling, stress management, and social activities) and 1 nutritional product (Souvenaid®) that could help maintain cognitive functioning. The high-intensity intervention group receives a personalized, supervised and hybrid intervention consisting of group meetings (on-site and online) and individual sessions guided by a trained lifestyle coach, and access to a digital intervention platform that provides custom-made training materials and selected lifestyle apps. The low-intensity intervention group receives bi-monthly online lifestyle-related health advice via the digital intervention platform. Primary outcome is 2-year change on a cognitive composite score covering processing speed, executive function, and memory. Results Within 17 months, participant recruitment has been successfully completed (N = 1210; mean age: 67.7 years (SD: 4.6); 64% female). Modifiable risk factors commonly present at baseline were physical inactivity (89%), low mental/cognitive activity (50%), low social engagement (39%), hypertension (39%) and high alcohol consumption (39%). The mean body mass index of participants was 28.3 (SD: 4.2) and the total serum cholesterol was 5.4 mmol/L (SD: 1.2). Conclusions Baseline lifestyle and clinical measurements showed successful recruitment of participants with sufficient potential for prevention. Results of FINGER-NL will provide further insight into the efficacy of a multidomain lifestyle intervention to prevent cognitive decline in older adults. Trial registration ClinicalTrials.gov (ID: NCT05256199)/2022–01-11.

The formation of contrail ice particles under the conditions observed during the ECLIF2/ND‑MAX flight campaign was simulated to understand two specific aspects of the contrail measurements. In both the experimental results and the simulations, fewer ice particles formed than were present in the soot (non-volatile Particulate Matter: nvPM) emissions' full distribution. This is due to the larger particles being more effective in capturing water vapor and growing, even though all the particles are active ice nuclei. These results suggest that, under the contrail forming conditions of ECLIF2/ND‑MAX, 85 % or less of the activated nvPM particles can grow to contrail ice particles.The lowest nvPM concentration point (SAF2) was also the lowest Fuel Sulfur Content (FSC) point. This point seems to deviate from the line defined by the other points and the deviation can be simulated by assuming that only 60 % of the nvPM particles are activated. Due to uncertainties in the data and simulation, this observation is far from conclusive, but strongly suggests that the low FSC of the SAF2 case may be starting to indicate a lowering of the activation of the emitted nvPM for contrail formation.These results suggest that further field campaigns would be valuable to measure the effect of FSC on contrail formation when the FSC is significantly below 10 ppmm and that careful experiments with FSC of below 0.1 ppmm, and preferably below 0.05 ppmm, would be needed to fully explore the role FSC has in activating the nvPM particles for contrail formation.

Background: Dementia poses a significant global health challenge. Anthocyanins neutralize free radicals, modulate signaling pathways, inhibit pro-inflammatory genes, and suppress cytokine production and may thus have positive cognitive effects in people at increased risk of dementia. We aim to investigate the effects of purified anthocyanins on cognitive function in people at increased risk of dementia according to their inflammation status based on blood-based inflammatory biomarkers. Methods: This is a secondary analysis of a 24-week randomized, double-blind, placebo-controlled trial. Cluster analysis was performed to categorize two groups based on their individual inflammatory biomarker profile using multiplex sandwich ELISA for the quantitative measurement of cytokines. Descriptive statistics and longitudinal models assessed cognitive outcomes. The primary comparison was the group difference at week 24 based on a modified intention-to-treat analysis. Results: Cluster analysis revealed two distinct inflammatory biomarker profiles. In Cluster 1 (high levels of inflammation biomarkers), anthocyanin treatment showed a statistically significant improvement on cognitive function compared to placebo at 24 weeks. No significant differences were observed in Cluster 2 (low levels of inflammation biomarkers). The demographic characteristics, cognitive scores, and biomarker distributions were similar between treatment groups at baseline. However, cluster 1 exhibited higher BMI, diabetes prevalence, medication usage, and lower HDL cholesterol levels. Conclusion: Individuals with elevated levels of inflammation markers benefited from anthocyanin treatment to enhance cognitive performance, whereas those with lower levels did not. The anti-inflammatory and antioxidant properties of anthocyanins make them a promising intervention, and future prospective trials in people with increased inflammation are warranted.

Surfactant corrosion inhibition performance in water–oil environments is influenced by complex relationships between their physical properties, solution chemistry and interfacial characteristics. The existence of polar heads/nonpolar tails influences both the preferential distribution of the surfactant between the two media as well as the phase in which micellisation occurs. Both phenomena affect the efficiency of the surfactant inhibitor and its adsorption at the metal-solution interface. To demonstrate the complexity of such interactions, the effect of brine salinity on the critical micelle concentration (CMC) and partitioning/distribution behaviour of a quaternary amine corrosion inhibitor (alkyldimethylbenzylhexadecylammonium chloride, or BAC-C16) in a brine and toluene system (at 1:1 ratio) was explored. All experiments were conducted at 50 °C and pH4 over varying salinities (0.1, 1 and 10 wt%) of NaCl brine. Both CMC and partitioning characteristics of BAC-C16 are significantly affected by aqueous phase salinity, with an inversion of the partitioning response observed between concentrations of 0.1 and 1 wt% NaCl. The effect of BAC-C16 partitioning/distribution behaviour on corrosion inhibitor performance was examined using rotating cylinder electrode experiments. The results illustrate that in order to establish the true corrosion inhibition behaviour, consideration of the chemical distribution characteristics is crucial.

Abstract Hand osteoarthritis (OA) is an irreversible degenerative condition causing chronic pain and impaired functionality. Existing treatment options are often inadequate. Cannabidiol (CBD) has demonstrated analgesic and anti-inflammatory effects in preclinical models of arthritis. In this open-label feasibility trial, participants with symptomatically active hand OA applied a novel transdermal CBD gel (4% w/w) three times a day for four weeks to their most painful hand. Changes in daily self-reported pain scores were measured on a 0–10 Numeric Pain Rating Scale (NPRS). Hand functionality was determined via daily grip strength measures using a Bluetooth equipped squeeze ball and self-report questionnaire. Quality of life (QoL) ratings around sleep, anxiety, stiffness and fatigue were also measured. All self-report measures and grip strength data were gathered via smartphone application. Urinalysis was conducted at trial end to determine systemic absorption of CBD. Eighteen participants were consented and 15 completed the trial. Pain ratings were significantly reduced over time from pre-treatment baseline including current pain (− 1.91 ± 0.35, p

Abstract Background Clinicians and public health professionals have allocated resources to curb opioid over-prescription and address psychological needs among patients with musculoskeletal pain. However, associations between psychological distress, risk of surgery, and opioid prescribing among those with hip pathologies remain unclear. Methods Using a retrospective cohort study design, we identified patients that were evaluated for hip pain from January 13, 2020 to October 27, 2021. Patients’ surgical histories and postoperative opioid prescriptions were extracted via chart review. Risk of hip surgery within one year of evaluation was analyzed using multivariable logistic regression. Multivariable linear regression was employed to predict average morphine milligram equivalents (MME) per day of opioid prescriptions within the first 30 days after surgery. Candidate predictors included age, gender, race, ethnicity, employment, insurance type, hip function and quality of life on the International Hip Outcome Tool (iHOT-12), and psychological distress phenotype using the OSPRO Yellow Flag (OSPRO-YF) Assessment Tool. Results Of the 672 patients, n = 350 (52.1%) underwent orthopaedic surgery for hip pain. In multivariable analysis, younger patients, those with TRICARE/other government insurance, and those with a high psychological distress phenotype had higher odds of surgery. After adding iHOT-12 scores, younger patients and lower iHOT-12 scores were associated with higher odds of surgery, while Black/African American patients had lower odds of surgery. In multivariable analysis of average MME, patients with periacetabular osteotomy (PAO) received opioid prescriptions with significantly higher average MME than those with other procedures, and surgery type was the only significant predictor. Post-hoc analysis excluding PAO found higher average MME for patients undergoing hip arthroscopy (compared to arthroplasty or other non-PAO procedures) and significantly lower average MME for patients with public insurance (Medicare/Medicaid) compared to those with private insurance. Among those only undergoing arthroscopy, older age and having public insurance were associated with opioid prescriptions with lower average MME. Neither iHOT-12 scores nor OSPRO-YF phenotype assignment were significant predictors of postoperative mean MME. Conclusions Psychological distress characteristics are modifiable targets for rehabilitation programs, but their use as prognostic factors for risk of orthopaedic surgery and opioid prescribing in patients with hip pain appears limited when considered alongside other commonly collected clinical information such as age, insurance, type of surgery pursued, and iHOT-12 scores.

Abstract Purpose To analyze the clinicopathological characteristics and surgical outcomes of patients with Wolfring gland ductal cysts (WGDCs). Methods A retrospective, consecutive, interventional comparative case series was performed over a period of 7 years. Data on demographic and clinical characteristics, pathological findings and outcomes of surgically excised cysts were collected. A comparison between the transconjunctival and transcutaneous approaches was also assessed. Results Forty-eight patients (48 eyelids) were included in the final analysis. The most common presenting symptom was painless eyelid swelling (81.3%). The median symptom duration was 11.5 months (IQR, 18.25). The upper eyelid was involved in 31 (64.6%) patients, 29/31 of whom had cysts in a medial or centromedial location. Forty-five (93.8%) cysts were bluish gray and transilluminable with clear contents on lid eversion and a median largest dimension of 22 mm (IQR, 8). A transverse conjunctival fibrotic band was observed along the proximal tarsal border in the cyst area in all patients. Signs of chronic trachoma were noted in 38 (79.2%) patients. Preoperative significant ptosis was present in 28/31 (90.3%) of the upper eyelid cysts. Thirty cysts (62.5%) were excised through the skin, and 18 cysts (37.5%) were excised transconjunctivally. Intraoperative cyst rupture, the need for conjunctival grafting and postoperative residual upper lid ptosis were significantly greater in the transconjunctival group (p = 0.009, p

Papillary fibroelastomas (PFEs) are small, slowly growing benign cardiac tumors with clinically significant risk of embolization. Surgical excision is the definitive treatment of symptomatic PFE and is conventionally performed through a median sternotomy. In this study, we report a series of 12 patients, who underwent robotic-assisted PFE removal at the Mayo Clinic. PFE involved the mitral valve, left atrium, and tricuspid valve. No major complications occurred after the procedure, and most patients were discharged 4 days after the surgery. On follow-up, 1 patient demonstrated pericarditis.

Abstract Information from a variety of sources has suggested that increased storminess was experienced across the British Isles in the late eighteenth/early nineteenth century. However, it is not clear how stormy that period was relative to current conditions. Using newly recovered barometric pressure data that extend back to 1748 we have constructed a measure of geostrophic wind speed for the English Channel region using a pressure-triangle approach. We show that the 1790−1820s was a period of increased storminess across the region. This storminess extended throughout the year, which is different to comparable increases observed since the 1990s, which were confined to the winter season. While a strengthened North Atlantic jet stream is implicated in both periods, in the earlier period it is likely that the storm track shifted slightly to a more southerly location. We discuss the potential forcing mechanisms responsible for the changes in storminess over this multi-century timeframe.

Abstract The continuing and rapid emergence of antibiotic resistance (AMR) calls for innovations in antimicrobial therapies. A promising, ‘re-emerging’ approach is the application of bacteriophage viruses to selectively infect and kill pathogenic bacteria, referred to as phage therapy. In practice, phage therapy is personalized and requires companion diagnostics to identify efficacious phages, which are then formulated into a therapeutic cocktail. The predominant means for phage screening involves optical-based assays, but these methods cannot be carried out in complex media, such as colored solutions, inhomogeneous mixtures, or high-viscosity samples, which are often conditions encountered in vivo. Moreover, these assays cannot distinguish phage binding and lysis parameters, which are important for standardizing phage cocktail formulation. To address these challenges, we developed Phage-layer Interferometry (PLI) as a companion diagnostic. Herein, PLI is assessed as a quantitative phage screening method and prototyped as a bacterial detection platform. Importantly, PLI is amenable to automation and is functional in complex, opaque media, such as baby formula. Due to these newfound capabilities, we foresee immediate and broad impact of PLI for combating AMR and protecting against foodborne illnesses.

A lithium-ion battery is a rechargeable battery that uses the reversible reduction of lithium ions to store energy and is the predominant battery type in many industrial and consumer electronics. The lithium-ion batteries are essential to ensure they operate safely. We conducted an exposure assessment five days after a fire in a battery-testing facility. We assessed some of the potentially hazardous materials after a lithium-ion battery fire. We sampled total suspended particles, hydrogen fluoride, and lithium with real-time monitoring of particulate matter (PM) 1, 2.5, and 10 micrometers (μm). The area sampling results indicated that primary potential hazardous materials such as dust, hydrogen fluoride, and lithium were below the recommended limits suggested by the Korean Ministry of Labor and the American Conference of Governmental Industrial Hygienists Threshold Limit Values. Based on our assessment, workers were allowed to return to work.

Aims: Medullary carcinoma of the colon is a rare subtype of adenocarcinoma, first described in 1999. Clinically known to have a favourable prognosis in comparison to poorly differentiated cancers, it is associated with deficient mismatch repair. This is an observational single center study of patients with medullary cancer, and comparison with the current literature. Methods: We performed a search of the pathological database at our institution for medullary adenocarcinomas between the years of 2016–2023 and reviewed their clinical information to collect all relevant data including patient history, hospital admissions. surgery and clinic visits. We then performed a literature search using Pubmed for search terms medullary cancer/carcinoma of the colon/colorectum. Results: 11 patients were found in our database, 34 studies in the literature, 19 retrospective cohort studies (3144 patients) and 13 case reports. 81.8% (vs. 73.22% in cohort studies) were female patients. 8/11 patients' tumours had lympho-vascular invasion with 2/11 perineural involvement. Immunohistochemistry demonstrated 11/11 patients’ tumours with MLH1 and PMS2 loss, and presence of MSH2 and MSH6. Cohort studies demonstrated 302/1897 (15.92%) tumours had perineural invasion with 1133/2151 (52.67%) demonstrating lympho-vascular invasion. MLH1 testing was available for 192 patients, with 93.75% having loss of MLH1. Conclusion: Our cohort of medullary cancer patients were similar to that in the literature, with regards to demographics, staging and tumour characteristics. A longer follow-up time is required for our cohort to analyze long term survival outcomes.

Objective: Osteoarthritis management programs (OAMPs) have become a more common way to deliver patient-centered care. However, there is limited information on real-world use of these programs to guide implementation, payment policy, accessibility, and scaling in the United States. This paper describes 5-year use metrics for the Duke Joint Health Program, an OAMP embedded within a US academic health system. Method: This analysis includes patients referred into the Program between October 2017 and April 2022. We generated descriptive statistics of referral and enrollment totals, demographics and patient-reported measures of enrollees, retention and healthcare use metrics (e.g., office visit frequency), and data capture rates for patient-reported outcomes. Results: During the study period, 6863 patients were referred to the program and 4162 (61 ​%) enrolled. We observed statistically significant differences between those who did and did not enroll by age (mean difference ​± ​SE: 2.49 ​± ​2.8 years), sex (70.0 ​% vs 67.7 ​% female), race (65.1 ​% vs 55.3 ​% Caucasian/White), employment status (50.0 ​% vs 40.2 ​% retired), and insurance type (53.5 ​% vs 47.0 ​% Medicare). The median (Q1, Q3) number of visits was 2 (1, 4) and ranged from 1 to 67. The median (Q1, Q3) number of days from first to last program visit was 23 (0, 84) days. Questionnaire completion rates were 72 ​% at baseline, 46 ​% at 6 weeks, 39 ​% at 3 months, and 40 ​% at 6 and 12 months. Conclusion: Findings can guide the planning, development, and implementation of future OAMPs and inform policies to ensure programs are accessible and equitable.

Background: We aimed to assess perioperative changes in fibrinogen in the cerebrospinal fluid (CSF), their association with markers of blood–brain barrier breakdown and neuroinflammation, and their association with postoperative delirium severity. Methods: We conducted a secondary analysis of the Interventions for Postoperative Delirium-Biomarker 2 (IPOD-B2, NCT02926417) study, a prospective observational cohort study. We included 24 patients aged >21 yr undergoing aortic aneurysm repair. CSF samples were obtained before (n=24) and after surgery (n=13), with some participants having multiple postoperative samples. Our primary outcome was the perioperative change in CSF fibrinogen. Delirium was assessed using the Delirium Rating Scale-Revised-98. Results: CSF fibrinogen increased after surgery (P

Background Timely diagnosis and treatment of inflammatory bowel disease (IBD) may improve clinical outcomes.Objective Examine associations between time to diagnosis, patterns of prior healthcare use, and clinical outcomes in IBD.Design Using the Clinical Practice Research Datalink we identified incident cases of Crohn’s disease (CD) and ulcerative colitis (UC), diagnosed between January 2003 and May 2016, with a first primary care gastrointestinal consultation during the 3-year period prior to IBD diagnosis. We used multivariable Cox regression to examine the association of primary care consultation frequency (n=1, 2, >2), annual consultation intensity, hospitalisations for gastrointestinal symptoms, and time to diagnosis with a range of key clinical outcomes following diagnosis.Results We identified 2645 incident IBD cases (CD: 782; UC: 1863). For CD, >2 consultations were associated with intestinal surgery (adjusted HR (aHR)=2.22, 95% CI 1.45 to 3.39) and subsequent CD-related hospitalisation (aHR=1.80, 95% CI 1.29 to 2.50). For UC, >2 consultations were associated with corticosteroid dependency (aHR=1.76, 95% CI 1.28 to 2.41), immunomodulator use (aHR=1.68, 95% CI 1.24 to 2.26), UC-related hospitalisation (aHR=1.43, 95% CI 1.05 to 1.95) and colectomy (aHR=2.01, 95% CI 1.22 to 3.27). For CD, hospitalisation prior to diagnosis was associated with CD-related hospitalisation (aHR=1.30, 95% CI 1.01 to 1.68) and intestinal surgery (aHR=1.71, 95% CI 1.13 to 2.58); for UC, it was associated with immunomodulator use (aHR=1.42, 95% CI 1.11 to 1.81), UC-related hospitalisation (aHR=1.36, 95% CI 1.06 to 1.95) and colectomy (aHR=1.54, 95% CI 1.01 to 2.34). For CD, consultation intensity in the year before diagnosis was associated with CD-related hospitalisation (aHR=1.19, 95% CI 1.12 to 1.28) and intestinal surgery (aHR=1.13, 95% CI 1.03 to 1.23); for UC, it was associated with corticosteroid use (aHR=1.08, 95% CI 1.04 to 1.13), corticosteroid dependency (aHR=1.05, 95% CI 1.00 to 1.11), and UC-related hospitalisation (aHR=1.12, 95% CI 1.03 to 1.21). For CD, time to diagnosis was associated with risk of CD-related hospitalisation (aHR=1.03, 95% CI 1.01 to 1.68); for UC, it was associated with reduced risk of UC-related hospitalisation (aHR=0.83, 95% CI 0.70 to 0.98) and colectomy (aHR=0.59, 95% CI 0.43 to 0.80).Conclusion Electronic records contain valuable information about patterns of healthcare use that can be used to expedite timely diagnosis and identify aggressive forms of IBD.

This study investigates the dynamics of collaborative characteristics, interpersonal reactivity, and disaster situation responses in non-face-to-face settings, a response mechanism increasingly relevant in the wake of prolonged pandemics. By examining a group of 123 university students engaged in a seven-week non-face-to-face collaborative project, the research identifies relational patterns between collaborative traits such as regulation and efficacy, interpersonal empathy, and responses to disaster situations. The research methodology employs a sophisticated analytical framework comprising factor and canonical correlation analyses to identify how empathy and collaborative efficacy significantly related with disaster response in online collaborations. The mediation and moderation models analyzed confirm mutual mediation effects of collaborative regulation and interpersonal reactivity on situational empathy without significant moderation effects. This suggests there were direct causal relationships of collaborative regulation, collaborative efficacy, interpersonal reactivity on situational empathy. The findings underscore the pivotal role of empathy in collaboration during disasters offering a nuanced understanding of the social and psychological underpinnings that enable collective responses to crises in environments lacking physical interaction and illuminating the critical role of collaborative and interpersonal skills in such settings.

Climate change creates a leverage point in plant breeding. We must rethink the way we employ plant breeding, utilize genetic diversity, and prioritize edible plant production across the landscape. A long-term strategy to ‘redirect’ the process of crop domestication that prioritizes the generation of abiotic and biotic stress-tolerant cultivars is needed. A proposed neo-domestication strategy is presented as a case study. It entails the re-domestication of chile by retro-crossing of modern plant cultivars with landraces and a desert-adapted wild relative. An organized, collaborative effort could reintroduce stress tolerance genes that will render new cultivars more tolerant to challenges imposed by climate change. Purposeful populations generated using a broad spectrum of genetic diversity could also provide the basis for an evolutionary–participatory plant breeding process. The process must recognize the need for a paradigm shift in our resource allocation and breeding strategies. To succeed, a shared vision for neo-domestication of chile must recognize the importance of human cultural values and the need for sustained cooperation among stakeholders.

Abstract End users of single‐use plastics can help minimize their contribution to plastic pollution via mindful purchasing and waste management. These behaviors can be impacted via behavior change interventions in various key sectors of society. This review set out to summarize recent (2015–2023) peer‐reviewed evidence on interventions aimed at changing the plastic consumption, recycling, and/or littering behaviors of individuals across four sectors: business and retail, tourism and leisure, schools and education, and communities. Systematic literature searches were conducted across multiple databases and resulted in the inclusion of 92 intervention studies. Information on intervention strategy and effectiveness was extracted, and the studies were assessed for risk of bias. Intervention descriptions and outcomes were coded into five intervention categories (informational, contextual, prompts, social, and personal strategies) and synthesized qualitatively to inform future practice in an accessible manner. Although nearly half of the reviewed studies were assessed as having moderate‐to‐high risk of bias (e.g., lacked reliability assessment of outcome measures), limiting confidence in the documented findings, the review concludes that different strategies work in different sectors. For example, informational strategies showed mostly promising results in most sectors, but had mixed effectiveness in the education sector, while contextual modifications were effective across sectors.

PurposeTo demonstrate and evaluate factors contributing to near-cures in patients with Gadolinium Deposition Disease (GDD) undergoing intravenous (IV) DTPA chelation.MethodsPatients who had undergone or are currently undergoing DTPA chelation for GDD were included in this report based on their medical records that showed their perceived improvement was at least 80% back to normal. A survey was developed that included factors commonly reported by patients treated in one clinic to determine if these ‘near-cured’ (pre-MRI baseline health) individuals possessed certain factors and lacked others. The anonymized survey was emailed to these individuals by the principal treating physician, the only investigator not blinded to the subjects. This report describes clinical documentation of patient status and their underlying factors in individuals treated by the primary author, and no research was performed. The survey was sent to sixteen individuals; Fourteen patients completed it (10 females; 41.1 ± 11.2 y/o).ResultsThe most common factor was the administration of ≤5 lifetime doses of a Gadolinium-Based Contrast Agents (GBCA) (12/14). Unconfounded agents triggering GDD were seen in nine subjects. Most subjects (12/14) initiated chelation in the first year after the causative GBCA, and most (11/14) underwent ≤10 chelations with DTPA. Good healthcare status prior to MRI was observed in 5 subjects. The majority (11/14) described their immune status as strong. Severe physical disability prior to chelation was seen in 1.ConclusionSubjects with GDD can experience near-cure with IV DTPA chelation. Factors surveyed that predict near-cure include the start of chelation in the first year, few GBCA administrations, and good health status before MRI with GBCA injection. Nonetheless, a few patients with predictors of less successful outcomes still experienced near-cure.

In recent years, there has been a paradigm shift with regards to ageing, challenging its traditional perception as an inevitable and natural process. Researchers have collectively identified hallmarks of ageing, nine of which were initially proposed in 2013 and expanded in 2023 to include disabled macroautophagy, chronic inflammation, and dysbiosis, enhancing our understanding of the ageing process at microscopic, cellular, and system-wide levels. Strategies to manipulate these hallmarks present opportunities for slowing, preventing, or reversing age-related diseases, thereby promoting longevity. The interdependence of these hallmarks underscores the necessity of a comprehensive, systems-based approach to address the complex processes contributing to ageing. As a primary risk factor for various diseases, ageing diminishes healthspan, leading to extended periods of compromised health and multiple age-related conditions towards the end of life. The significant gap between healthspan and lifespan holds substantial economic and societal implications. The inaugural Longevity Med Summit (4–5 May 2023, Cascais, Portugal) provided an international forum to discuss the academic and industry landscape of healthy longevity research, preventive medicine and clinical practice to enhance healthspan.

Abstract The firn layer covers 98% of Antarctica's ice sheets, protecting underlying glacial ice from the external environment. Accurate measurement of firn properties is essential for assessing cryosphere mass balance and climate change impacts. Characterizing firn structure through core sampling is expensive and logistically challenging. Seismic surveys, which translate seismic velocities into firn densities, offer an efficient alternative. This study employs Distributed Acoustic Sensing technology to transform an existing fiber‐optic cable near the South Pole into a multichannel, low‐maintenance, continuously interrogated seismic array. The data resolve 16 seismic wave propagation modes at frequencies up to 100 Hz that constrain P and S wave velocities as functions of depth. Using co‐located geophones for ambient noise interferometry, we resolve very weak radial anisotropy. Leveraging nearby SPICEcore firn density data, we find prior empirical density‐velocity relationships underestimate firn air content by over 15%. We present a new empirical relationship for the South Pole region.

Objective It is unclear whether widespread use of biologics is reducing inflammatory bowel disease (IBD) surgical resection rates. We designed a population-based study evaluating the impact of early antitumour necrosis factor (TNF) on surgical resection rates up to 5 years from diagnosis.Design We evaluated all patients with IBD diagnosed in Cardiff, Wales 2005–2016. The primary measure was the impact of early (within 1 year of diagnosis) sustained (at least 3 months) anti-TNF compared with no therapy on surgical resection rates. Baseline factors were used to balance groups by propensity scores, with inverse probability of treatment weighting (IPTW) methodology and removing immortal time bias. Crohn’s disease (CD) and ulcerative colitis (UC) with IBD unclassified (IBD-U) (excluding those with proctitis) were analysed.Results 1250 patients were studied. For CD, early sustained anti-TNF therapy was associated with a reduced likelihood of resection compared with no treatment (IPTW HR 0.29 (95% CI 0.13 to 0.65), p=0.003). In UC including IBD-U (excluding proctitis), there was an increase in the risk of colectomy for the early sustained anti-TNF group compared with no treatment (IPTW HR 4.6 (95% CI 1.9 to 10), p=0.001).Conclusions Early sustained use of anti-TNF therapy is associated with reduced surgical resection rates in CD, but not in UC where there was a paradoxical increased surgery rate. This was because baseline clinical factors were less predictive of colectomy than anti-TNF usage. These data support the use of early introduction of anti-TNF therapy in CD whereas benefit in UC cannot be assessed by this methodology.

Background Days alive out of hospital (DAOH) is an objective and patient‐centered net benefit end point. There are no assessments of DAOH in clinical trials of interventions for atrial fibrillation (AF), and it is not known whether this end point is of clinical utility in these populations. Methods and Results ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) was an international double‐blind, double‐dummy randomized clinical trial that compared rivaroxaban with warfarin in patients with atrial fibrillation at increased risk for stroke. We assessed DAOH using investigator‐reported event data for up to 12 months after randomization in ROCKET AF. We assessed DAOH overall, by treatment group, and by subgroup, including age, sex, and comorbidities, using Poisson regression. The mean±SD number of days dead was 7.3±41.2, days hospitalized was 1.2±7.2, and mean DAOH was 350.7±56.2, with notable left skew. Patients with comorbidities had fewer DAOH overall. There were no differences in DAOH by treatment arm, with mean DAOH of 350.6±56.5 for those randomized to rivaroxaban and 350.7±55.8 for those randomized to warfarin (P=0.86). A sensitivity analysis found no difference in DAOH not disabled with rivaroxaban versus warfarin (DAOH not disabled, 349.2±59.5 days and 349.1 days±59.3 days, respectively, P=0.88). Conclusions DAOH did not identify a treatment difference between patients randomized to rivaroxaban versus warfarin. This may be driven in part by the low overall event rates in atrial fibrillation anticoagulation trials, which leads to substantial left skew in measures of DAOH.

Macrophages play essential roles in maintaining tissue homeostasis and immune defence. However, their extensive infiltration into tumours has been linked to adverse outcomes in multiple human cancers. Within the tumour microenvironment (TME), tumour-associated macrophages (TAMs) promote tumour growth and metastasis, making them prime targets for cancer immunotherapy. Recent single-cell analysis suggest that proliferating TAMs accumulate in human cancers, yet their origins and differentiation pathways remain uncertain. Here, we show that a subpopulation of CD163+ TAMs proliferates in situ within the TME of melanoma, lung cancer, and breast cancer. Consistent with their potential role in suppressing anti-tumour activities of T cells, CD163+ TAMs express a range of potent immunosuppressive molecules, including PD-L1, PD-L2, IL-10, and TGF-β. Other phenotypic markers strongly suggested that these cells originate from CD14+ CCR2+ monocytes, a cell population believed to have minimal capacity for proliferation. However, we demonstrate in vitro that certain myelopoietic cytokines commonly available within the TME induce robust proliferation of human monocytes, especially the combination of interleukin 3 (IL-3) and Macrophage Colony-Stimulating Factor 1 (M-CSF). Monocytic cells cultured with these cytokines efficiently modulate T cell proliferation, and their molecular phenotype recapitulates that of CD163+ TAMs. IL-3-driven proliferation of monocytic cells can be completely blocked by IL-4, associated with the induction of CDKN1A, alongside the upregulation of transcription factors linked to dendritic cell function, such as BATF3 and IRF4. Taken together, our work suggests several novel therapeutic routes to reducing immunosuppressive TAMs in human tumours, from blocking chemokine-mediated recruitment of monocytes to blocking their proliferation.

Introduction: Pneumoperitoneum in neonates is an ominous sign of gastrointestinal (GI) perforation which often requires emergent surgical intervention. Although Meckel's diverticulum (MD) is the most common congenital anomaly of the GI tract, spontaneous MD perforation leading to pneumoperitoneum in the immediate postnatal period is an extremely rare occurrence. This report describes the case of a perforated MD presenting as pneumoperitoneum on day of life (DOL) one. Case presentation: A 1-day-old 36 week gestational age male presented with acute abdominal distention and guarding upon examination. Two-view abdominal radiographs revealed pneumoperitoneum without pneumatosis intestinalis, portal venous gas, or bowel dilation. Exploratory laparotomy was performed and bilious ascites was encountered – secondary to a perforated MD in the distal ileum. The perforated MD and adjacent small bowel were resected and a double-barrel ileostomy was created. He recovered successfully and without complication in the acute postoperative period. Histopathologic findings were consistent with a perforated MD with ectopic pancreatic tissue. Conclusion: This rare case highlights the importance of early surgical intervention for neonates with pneumoperitoneum secondary to a perforated MD. Heightened clinical suspicion for a perforated MD should be considered among term/late preterm neonates presenting with pneumoperitoneum and low suspicion for necrotizing enterocolitis.

Summary: Although glutamine addiction in cancer cells is extensively reported, there is controversy on the impact of glutamine metabolism on the immune cells within the tumor microenvironment (TME). To address the role of extracellular glutamine, we enzymatically depleted circulating glutamine using PEGylated Helicobacter pylori gamma-glutamyl transferase (PEG-GGT) in syngeneic mouse models of breast and colon cancers. PEG-GGT treatment inhibits growth of cancer cells in vitro, but in vivo it increases myeloid-derived suppressor cells (MDSCs) and has no significant impact on tumor growth. By deriving a glutamine depletion signature, we analyze diverse human cancers within the TCGA and illustrate that glutamine depletion is not associated with favorable clinical outcomes and correlates with accumulation of MDSC. Broadly, our results help clarify the integrated impact of glutamine depletion within the TME and advance PEG-GGT as an enzymatic tool for the systemic and selective depletion (no asparaginase activity) of circulating glutamine in live animals.

Abstract There is limited information on changes of pasture mineral concentrations over the long-term in response to liming. A long-term field experiment was conducted to assess the influence of lime application on (a) changes in pasture mineral composition over time; and (b) key pasture mineral concentrations and ratios important to animal health. Perennial and annual pastures with or without lime application were sampled annually over 12 years and analysed for macro- and micro-minerals. Mineral ratios and indices were calculated to assess the potential impact on animal health. Liming increased the concentrations of calcium, sodium and silicon, but decreased the concentrations of micro-nutrients including copper, zinc and manganese. The same trend was found in both annual and perennial pastures although there were some fluctuations between years. Liming increased the calcium:phosphorus ratio and the dietary cation–anion difference but reduced the tetany index on both annual and perennial pastures. These findings suggest a potential benefit to improve animal health outcomes for some disorders on the limed pastures. However, the reduced concentrations of some trace elements following liming potentially decreases antioxidant capacity and requires further research.

Abstract Background Torpedo maculopathy (TM) is a rare, congenital condition characterized by an oval-shaped, chorioretinal lesion in the temporal macula of unknown etiology. To our knowledge, the longest reported follow-up of TM is 5 years. Herein we report 10 years of follow-up on two patients with TM to further characterize the long-term natural history of the condition. Case reports Two patients with torpedo maculopathy were examined at baseline and then again at 5 years and 10 years from baseline. Eyes were evaluated using color fundus photography, automated perimetry, fundus autofluorescence and spectral domain optical coherence tomography. Visual function of both patients remained stable throughout the observation period. In case 1, there was no evidence of change in lesion morphology over the 10 year observation period. Case 2 showed progression of cystic degeneration of the neurosensory retina within the torpedo lesion. Case 1 reported a history of supernumerary teeth and underwent gene sequence with deletion/duplication analyses of the APC gene but no clinically significant variants were detected. Conclusions Our findings support the position that TM is a nonprogressive condition with long-term stability of visual function. Genetic analysis of case 1 failed to detect any association with Gardner syndrome.

Abstract Solid-state superionic conductors (SSICs) are promising alternatives to liquid electrolytes in batteries and other energy storage technologies. The rational design of SSICs and ultimately their deployment in battery technologies is hindered by the lack of a thorough understanding of their ion conduction mechanisms. In SSICs containing molecular ions, rotational dynamics couple with translational diffusion to create a paddle-wheel effect that facilitates conduction. The paddle-wheel mechanism explains many important features of molecular SSICs, but an explanation for ion conduction and anharmonic lattice dynamics in SSICs composed of monatomic ions is still needed. We predict that ion conduction in the classic SSIC AgI involves electronic paddle-wheels, rotational motion of localized electron pairs that couples to and facilitates ion diffusion. The electronic paddle-wheel mechanism creates a universal perspective for understanding ion conductivity in both monatomic and molecular SSICs that will create design principles for engineering solid-state electrolytes from the electronic level up to the macroscale.