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Abstract The cation-independent mannose 6-phosphate receptor (CI-MPR) is clinically significant in the treatment of patients with lysosomal storage diseases because it functions in the biogenesis of lysosomes by transporting mannose 6-phosphate (M6P)-containing lysosomal enzymes to endosomal compartments. CI-MPR is multifunctional and modulates embryonic growth and fetal size by downregulating circulating levels of the peptide hormone insulin-like growth factor 2 (IGF2). The extracellular region of CI-MPR comprises 15 homologous domains with binding sites for M6P-containing ligands located in domains 3, 5, 9, and 15, whereas IGF2 interacts with residues in domain 11. How a particular ligand affects the receptor’s conformation or its ability to bind other ligands remains poorly understood. To address these questions, we purified a soluble form of the receptor from newborn calf serum, carried out glycoproteomics to define the N-glycans at its 19 potential glycosylation sites, probed its ability to bind lysosomal enzymes in the presence and absence of IGF2 using surface plasmon resonance, and assessed its conformation in the presence and absence of IGF2 by negative-staining electron microscopy and hydroxyl radical protein footprinting studies. Together, our findings support the hypothesis that IGF2 acts as an allosteric inhibitor of lysosomal enzyme binding by inducing global conformational changes of CI-MPR.

Abstract Background Chronic overlapping pain conditions (COPCs), pain-related conditions that frequently occur together, may occur in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and could impact illness severity. This study aimed to identify comorbid COPCs in patients with ME/CFS and evaluate their impact on illness severity. Methods We used data from 923 participants in the Multi-Site Clinical Assessment of ME/CFS study, conducted in seven U.S. specialty clinics between 2012 and 2020, who completed the baseline assessment (595 ME/CFS and 328 healthy controls (HC)). COPCs included chronic low back pain (cLBP), chronic migraine/headache (cMHA), fibromyalgia (FM), interstitial cystitis/irritable bladder (IC/IB), irritable bowel syndrome (IBS), temporomandibular disorder (TMD). Illness severity was assessed through questionnaires measuring symptoms and functioning. Multivariate analysis of variance and analysis of covariance models were used for analyses. Log-binomial regression analyses were used to compute prevalence of COPCs and prevalence ratios (PR) between groups with 95% confidence intervals. Both unadjusted and adjusted results with age and sex are presented. Results 76% of participants with ME/CFS had at least one COPCs compared to 17.4% of HC. Among ME/CFS participants, cMHA was most prevalent (48.1%), followed by FM (45.0%), cLBP (33.1%), and IBS (31.6%). All individual COPCs, except TMD, were significantly more frequent in females than males. The unadjusted PR (ME/CFS compared to HC) was highest for FM [147.74 (95% confidence interval (CI) = 20.83-1047.75], followed by cLBP [39.45 (12.73-122.27)], and IC/IB [13.78 (1.88-101.24)]. The significance and order did not change after age and sex adjustment. The COPC comorbidities of cLBP and FM each had a significant impact on most health measures, particularly in pain attributes (Cohen’s d effect size 0.8 or larger). While the impact of COPC comorbidities on non-pain attributes and quality of life measures was less pronounced than that on pain, statistically significant differences between ME/CFS participants with and without COPCs were still evident. Conclusions More than 75% of ME/CFS participants had one or more COPCs. Multiple COPCs further exacerbated illness severity, especially among females with ME/CFS. Assessment and management of COPCs may help improve the health and quality of life for patients with ME/CFS.

Abstract Infections with Enterobacterales (E) are increasingly difficult to treat due to antimicrobial resistance. After ceftriaxone replaced chloramphenicol (CHL) as empiric therapy for suspected sepsis in Malawi in 2004, extended-spectrum beta-lactamase (ESBL)-E rapidly emerged. Concurrently, resistance to CHL in Escherichia coli and Klebsiella spp. decreased, raising the possibility of CHL re-introduction. However, many phenotypically susceptible isolates still carry CHL acetyltransferase (cat) genes. To understand the molecular mechanisms and stability of this re-emerging CHL susceptibility we use a combination of genomics, phenotypic susceptibility assays, experimental evolution, and functional assays for CAT activity. Here, we show that of 840 Malawian E. coli and Klebsiella spp. isolates, 31% have discordant CHL susceptibility genotype–phenotype, and we select a subset of 42 isolates for in-depth analysis. Stable degradation of cat genes by insertion sequences leads to re-emergence of CHL susceptibility. Our study suggests that CHL could be reintroduced as a reserve agent for critically ill patients with ESBL-E infections in Malawi and similar settings and highlights the ongoing challenges in inferring antimicrobial resistance from sequence data.

We embed an object with a singular horizon structure, reminiscent of (but fundamentally different from, except in a limiting case) a black hole event horizon, in an expanding, spherically symmetric, homogeneous, Universe that has a positive cosmological constant. Conformal representation is discussed. There is a temperature/pressure singularity and a corresponding scalar curvature singularity at the horizon. The expanding singular horizon ultimately bounds the entire spacetime manifold. It is is preceded by an expanding light front, which separates the spacetime affected by the singularity from that which is not yet affected. An appropriately located observer in front of the light front can have a Hubble–Lemaître constant that is consistent with that currently observed.

Introduction Home-based, virtually-supported care models may represent the most efficient and scalable approach to delivering prehabilitation services. However, virtual approaches to prehabilitation are understudied. This manuscript describes the protocol for an internal pilot randomised controlled trial of a virtually-delivered, multimodal prehabilitation intervention.Methods and analysis We will conduct a pragmatic, individual patient, internal pilot randomised controlled trial of home-based, virtually supported, multimodal prehabilitation compared with standard perioperative care in adults undergoing elective, inpatient thoracic, abdominal, pelvic and vascular surgery at five Canadian hospitals. Participants will be partially blinded; clinicians and outcome assessors will be fully blinded. The intervention consists of 3–12 weeks of a home-based, multimodal (exercise, nutrition and psychosocial support) prehabilitation programme supported through an online platform. The primary feasibility outcomes and their progression targets are (1) monthly recruitment of>6 participants at each centre, (2) intervention adherence of>75%, (3) retention of>90% of participants at the patient-reported primary outcome point of 30-days after surgery and (4) elicitation of patient, clinician and researcher-identified barriers to our pragmatic trial. A sample size of 144 participants will be adequate to estimate recruitment, adherence and retention rates with acceptable precision. All participants will be followed to either death or up to 1 year. As an internal pilot, if no substantive changes to the trial or intervention design are required, pilot participant outcome data will migrate, unanalysed by allocation, to the future full-scale trial.Ethics and dissemination Ethical approval has been granted by Clinical Trials Ontario (Project ID: 4479) and our ethics review board (Protocol Approval #20230399–01T). Results will be disseminated through presentations at scientific conferences, peer-reviewed publications, partner organisations and engagement of social and traditional media.Trial registration number ClinicalTrials.gov identifier NCT06042491. Protocol, V.1.2, dated 6 June 2024.

IntroductionPatients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) experience cognitive problems with attention, information processing speed, working memory, learning efficiency, and executive function. Commonly, patients report worsening of cognitive symptoms over time after physical and/or cognitive challenges. To determine, monitor, and manage longitudinal decrements in cognitive function after such exposures, it is important to be able to screen for cognitive dysfunction and changes over time in clinic and also remotely at home. The primary objectives of this paper were: (1) to determine whether a brief computerized cognitive screening battery will detect differences in cognitive function between ME/CFS and Healthy Controls (HC), (2) to monitor the impact of a full-day study visit on cognitive function over time, and (3) to evaluate the impact of exercise testing on cognitive dysfunction.MethodsThis cognitive sub-study was conducted between 2013 and 2019 across seven U.S. ME/CFS clinics as part of the Multi-Site Clinical Assessment of ME/CFS (MCAM) study. The analysis included 426 participants (261 ME/CFS and 165 HC), who completed cognitive assessments including a computerized CogState Brief Screening Battery (CBSB) administered across five timepoints (T0-T4) at the start of and following a full day in-clinic visit that included exercise testing for a subset of participants (182 ME/CFS and 160 HC). Exercise testing consisted of ramped cycle ergometry to volitional exhaustion. The primary outcomes are performance accuracy and latency (performance speed) on the computerized CBSB administered online in clinic (T0 and T1) and at home (T2-T4).ResultsNo difference was found in performance accuracy between ME/CFS and HCs whereas information processing speed was significantly slower for ME/CFS at most timepoints with Cohen’s d effect sizes ranging from 0.3–0.5 (p < 0.01). The cognitive decline over time on all CBSB tasks was similar for patients with ME/CFS independent of whether exercise testing was included in the clinic visit.ConclusionThe challenges of a clinic visit (including cognitive testing) can lead to further cognitive deficits. A single short session of intense exercise does not further reduce speed of performance on any CBSB tasks.

Abstract A straightforward nebulized spray system is designed to explore the hydrogenation of carbon dioxide (CO2) within water microdroplets surrounded by different gases such as carbon dioxide, nitrogen, oxygen, and compressed air. The collected droplets are analyzed using water‐suppressed nuclear magnetic resonance (NMR). Formate anion (HCOO−), acetate anion (CH3COO−), ethylene glycol (HOCH2CH2OH), and methane (CH4) are detected when water is nebulized. This pattern persisted when the water is saturated with CO2, indicating that CO2 in the nebulizing gas triggers the formation of these small organics. In a pure CO2 atmosphere, the formate anion concentration is determined to be ≈70 µm, referenced to dimethyl sulfoxide, which has been introduced as an internal standard in the collected water droplets. This study highlights the power of water microdroplets to initiate unexpected chemistry for the transformation of CO2 to small organic compounds.

Living in an area with good availability and accessibility of residential green spaces such as parks, woodlands, and residential gardens can improve mental health and reduce the global disease burden. Unlike for physical health, it is not well understood if mental health and green space associations might be modified by local area deprivation. Existing evidence for this association comes from cross-sectional studies, widely considered vulnerable to confounding and bias. Individual time-invariant mental health status, personality, and other factors may result in positive effect modification on green space and mental health associations in more deprived areas. We use fixed-effects models that remove time-invariant confounding by calculating differences within-persons to eliminate this bias and add to the existing evidence. We modelled changes in mental health status, green space, and deprivation (relative to the within-person mean) within 54,666 individuals with a combined total of 300,710 mental health scores from one of the world’s largest panel surveys: “Understanding Society” in the UK. We found a positive effect of increasing residential green space on mental health and this was positively modified and intensified by area deprivation before and after adjusting for confounding. Our results support providing green space to protect against the negative impact of socioeconomic deprivation on health, particularly for those moving from a less deprived to a more deprived area.

To date, little is known about the mechanisms of rejection in vascularized composite allotransplantation, particularly for antibody mediated rejection. Additionally, no clear guidelines exist for the diagnosis and management of antibody-mediated rejection in vascularized composite allotransplantation. A systematic review of electronic databases (Embase and PubMed) was conducted to evaluate the relationship of donor specific antibodies and C4d deposition in correlation with cellular rejection following hand and face transplantation reported by centers between 1998 and July 2023. We extracted data on serum donor specific antibodies at the time of biopsy proven rejection according to Banff classification and C4d staining of target tissues. Mann-Whitney U tests were performed to compare rejection grade between groups divided by status of C4d deposition and serum donor specific antibodies, and Fisher's Exact test was used to assess association between the two markers. This review adhered to PRISMA guidelines. A total of 26 patients (5 face, 21 hand) were identified and data on 90 acute rejection episodes with information on Banff grade, donor specific antibody status, and C4d deposition were available. Donor specific antibodies were found to be associated with higher rejection grade (p = 0.005). C4d was not found to be associated with higher rejection grade (p = 0.33). Finally, no significant association was found between concurrent status of the two markers (p = 0.23). These findings suggest that the presence of donor specifc antibodies may be associated with higher grades of acute cellular rejection following hand and face transplantation. More consistent reporting on rejection episodes is needed in order to better understand antibody-mediated rejection in vascularized composite allotransplantation.

Modified Vaccinia Ankara Bavarian Nordic (MVA-BN) as a smallpox and mpox vaccine has been approved in its liquid-frozen (LF) formulation in the US, Canada, and EU. A freeze-dried (FD) formulation may offer additional benefits, such as a longer shelf life and reduced dependence on cold chain storage and transport. In a phase 2 clinical trial, 651 vaccinia-naïve participants were vaccinated with two doses of MVA-BN LF or FD, 4 weeks apart. The objectives were to compare MVA-BN FD with LF in terms of vaccine-induced immune responses, safety, and reactogenicity. Non-inferiority of the immune response was assessed by the 95% CI of the geometric mean ratios. Both formulations induced robust vaccinia-specific humoral and cellular immune responses. At peak humoral responses (Week 6), geometric means of total antibody titers were 1096 (95% CI 1013, 1186) from the FD group and 877 (95% CI 804, 956) from the LF group, achieving the primary endpoint of non-inferiority of MVA-BN FD compared to MVA-BN LF. At peak cellular responses (Week 2), geometric means of T cell spot forming units were 449 (95% CI 341, 590) from the FD group and 316 (95% CI 234, 427) from the LF group. Both formulations of MVA-BN were well tolerated, with similar unsolicited AEs and solicited systemic reactions in both groups but slightly more local reactions in the FD group. No vaccine-related serious adverse events (SAEs) or vaccine-related AE of special interest were reported. The FD formulation of MVA-BN was shown to be equivalent to MVA-BN LF.

Objective Lifestyle intervention can produce clinically significant weight loss and reduced disease risk/severity for many individuals with overweight/obesity. Dietary lapses, instances of non-adherence to the recommended dietary goal(s) in lifestyle intervention, are associated with less weight loss and higher energy intake. There are distinct “types” of dietary lapse (e.g., eating an off-plan food, eating a larger portion), and behavioral, psychosocial, and contextual mechanisms may differ across dietary lapse types. Some lapse types also appear to impact weight more than others. Elucidating clear lapse types thus has potential for understanding and improving adherence to lifestyle intervention. Methods This 18-month observational cohort study will use real-time digital assessment tools within a multi-level factor analysis framework to uncover “lapse phenotypes” and understand their impact on clinical outcomes. Adults with overweight/obesity ( n = 150) will participate in a 12-month online lifestyle intervention and 6-month weight loss maintenance period. Participants will complete 14-day lapse phenotyping assessment periods at baseline, 3, 6, 12, and 18 months in which smartphone surveys, wearable devices, and geolocation will assess dietary lapses and relevant phenotyping characteristics. Energy intake (via 24-h dietary recall) and weight will be collected at each assessment period. Results This trial is ongoing; data collection began on 31 October 2022 and is scheduled to complete by February 2027. Conclusion Results will inform novel precision tools to improve dietary adherence in lifestyle intervention, and support updated theoretical models of adherence behavior. Additionally, these phenotyping methods can likely be leveraged to better understand non-adherence to other health behavior interventions. Trial Registration This study was prospectively registered https://clinicaltrials.gov/study/NCT05562427

Abstract Various erythropoietic abnormalities are highly prevalent among patients with pulmonary arterial hypertension (PAH) and associated with worse disease severity. Given the poorly understood yet important roles of dysregulated erythropoiesis and iron metabolism in PAH, we sought to further characterize the hematologic and iron profiles in PAH and their relationship to PAH severity. We recruited 67 patients with PAH and 13 healthy controls. Hemodynamics attained within 1 year of blood sample collection were available for 36 patients. Multiple hematologic, iron, and inflammatory parameters were evaluated for their association with hemodynamics. The subset with hemodynamic data consisted of 29 females (81%). The most common etiologies were idiopathic PAH (47%) and connective tissue disease‐related PAH (33%). 19 (53%) had functional class 3 or 4 symptomatology, and 12 (33%) were on triple pulmonary vasodilator therapy. Immature reticulocyte fraction (IRF) had significant positive correlations with mean pulmonary artery (PA) pressure (mPAP) (0.59, p

Abstract Background Functional somatic syndromes (FSSs), defined as chronic physical symptoms with no identifiable organic cause, may impact results after hip and knee arthroplasty. The purpose of this study was to perform a systematic review assessing the relationship between FSSs and clinical outcomes after primary total hip arthroplasty (THA), total knee arthroplasty (TKA), and unicompartmental knee arthroplasty (UKA). Methods The PubMed and Web of Science databases were queried from January 1955 through December 2021 for studies investigating the impact of at least one FSS (fibromyalgia, irritable bowel syndrome (IBS), chronic headaches, and chronic low back pain) on outcomes after primary THA/TKA/UKA. Outcomes of interest included patient-reported outcome measures (PROMs), postoperative opioid use, complications, revisions, and costs of care. Results There were twenty-eight studies, including 768,909 patients, of which 378,384 had an FSS. Five studies reported preoperative PROMs prior to THA/TKA, all of which showed worse PROMs among patients with at least 1 FSS diagnosis. Thirteen studies reported postoperative PROMs after THA/TKA, all of which demonstrated worse PROMs among patients with at least 1 FSS diagnosis. Patients with FSS diagnoses were more likely to continue using opioids at 3, 6, and 12 months following TKA, THA, and UKA. Medical and surgical complications, as well as revision rates, were higher among patients with FSSs. Conclusion Patients with FSSs have inferior PROMs and are at increased risk for prolonged postoperative opioid use, medical and surgical complications, and revision after hip and knee arthroplasty. Improved understanding of the factors influencing the success of hip and knee arthroplasty is critical. Future studies should address the biopsychosocial determinants of health that can impact outcomes after total joint arthroplasty.

Abstract Background In low- and middle-income countries countries, millions of deaths occur annually from household air pollution (HAP), pulmonary tuberculosis (PTB), and HIV-infection. However, it is unknown whether HAP influences PTB risk among people living with HIV-infection. Methods We conducted a case-control study among 1,277 HIV-infected adults in Bukavu, eastern Democratic Republic of Congo (February 2018 – March 2019). Cases had current or recent (3h/day and ≥2 times/day and ≥5 days/week were more likely to have PTB (aOR 1·36; 95%CI 1·06-1·75) than those spending less time in the kitchen. Time-weighted average 24h personal CO exposure was related dose-dependently with the likelihood of having PTB, with aOR 4·64 (95%CI 1·1-20·7) for the highest quintile [12·3-76·2 ppm] compared to the lowest quintile [0·1-1·9 ppm]. Conclusion Time spent cooking and personal CO exposure were independently associated with increased risk of PTB among people living with HIV. Considering the high burden of TB-HIV coinfection in the region, effective interventions are required to decrease HAP exposure caused by cooking with biomass among people living with HIV, especially women.

Organ preservation in heart transplantation is key to preventing primary graft dysfunction, the most common cause of early graft loss. Historically, the standard of care was preservation on ice, with no monitoring ability and problems with even temperature distribution. Recently, the SherpaPak, an Food & Drug Administration-approved transport device, has emerged as a solution to these 2 issues, allowing for even temperature distribution, no organ contact with ice, and continuous monitoring during transport. This method of transport falls under static cold preservation, but may allow for longer ischemic times beyond the recommended 4-hour limit. Here, we report a case of heart transplantation using the SherpaPak transport device for a distance of almost 3000 miles and total ischemic time over 7 hours—the longest yet reported for a donor heart transported using the SherpaPak system. The patient had excellent functional outcomes with no evidence of primary graft dysfunction. This case suggests that, with careful donor and recipient selection, SherpaPak may potentially be used for longer distances and ischemic times than initially recommended, as a safe and cheaper alternative to ex-vivo perfusion devices.

Abstract Rhizobia diversity in the rhizosphere is one of the key promoters of biological nitrogen fixation between host legumes and microsymbionts, although related complex interaction may depend on various factors. This research was intended to assess the abundance of indigenous rhizobia isolates under various soil conditions, as well as their effectiveness to nodulate legumes such as soybeans. Factors such as soil properties and legume species influence the volume and symbiotic effectiveness of native rhizobia to nodulate crop legumes. To investigate the abundance of rhizobia isolates, legume crops were uprooted to obtain nodules for most probable number (MPN) determination of rhizobia isolates, and soybean (Glycine max.) was used to verify the presence of suitable and efficient rhizobia strains for nitrogen fixation. Soil samples were obtained from the holes out of which nodules were collected, and the laboratory analysis included pH, Mg, K, available P, organic C, Ca, and N to establish the correlation between the soil status and number of rhizobia isolates' cells. Significant variations (p‐value

BackgroundRecipients of Vascularized Composite Allotransplants require effective immunosuppressive therapy to prevent graft rejection. This systematic review summarizes the current body of literature on immunosuppressive regimens used in face and hand transplants while summarizing their outcome in terms of rejection, renal failure, and infections.MethodsA systematic search of electronic databases was conducted to identify relevant studies from 1998 until July 1st, 2023. We included all studies that discussed immunosuppressive strategies in face and hand transplant recipients according to PRISMA.ResultsThe standard triple maintenance therapy was mostly adjusted due to nephrotoxicity or high incidence of rejection. The most common alternative treatments utilized were sirolimus (25/91; 27.5%) or everolimus (9/91; 9.9%) following hand- and photophoresis (7/45; 15.6%), sirolimus (5/45; 11.1%) or belatacept (1/45; 2.2%) following face transplantation. Episodes of rejection were reported in 60 (65.9%) of hand- and 33 (73%) of face transplant patients respectively. Graft loss of 12 (13.2%) hand and 4 (8.9%) face transplants was reported. Clinical CMV infection was observed in 6 (6.6%) hand and 7 (15.5%) face transplant recipients.ConclusionsBased on the herein presented data, facial grafts exhibited a heightened incidence of rejection episodes and CMV infections. Facial mucosa adds complexity to the immunological graft composition highlighting the need of individualized immunosuppressive regimens and further research.

Abstract Objective The aim was to develop and test a novel screen of adult ADHD, with a specific focus on clinical use. We designed a series of three studies to accomplish this aim. Method Study One (n = 155) and Study Two (n = 591) collected data via surveys to conduct exploratory and confirmatory factor analyses, respectively. Study Three analyzed the scale’s psychometrics in a clinical sample (n = 151). Results Study One and Study Two identified a 10-item scale with a two-factor structure. Study Three found good discriminant validity, sensitivity = 80.0%, specificity = 80.2%, and convergent validity with both the Brown Executive Function/Attention Scales, r (131) = .76, p

Abstract Introduction Carers of people with mental illness may face distinct challenges, including navigating fragmented health and social services during discharge from mental health hospitals. Currently, limited examples of interventions that support carers of people with mental illness in improving patient safety during transitions of care exist. We aimed to identify problems and solutions to inform future carer‐led discharge interventions, which is imperative for ensuring patient safety and the well‐being of carers. Methods The nominal group technique was used which combines both qualitative and quantitative data collection methods in four distinct phases: (1) problem identification, (2) solution generation, (3) decision making and (4) prioritisation. The aim was to combine expertise from different stakeholder groups (patients, carers and academics with expertise in primary/secondary care, social care or public health) to identify problems and generate solutions. Results Twenty‐eight participants generated potential solutions that were grouped into four themes. The most acceptable solution for each was as follows: (1) ‘Carer Involvement and Improving Carer Experience’ a dedicated family liaison worker, (2) ‘Patient Wellness and Education’ adapting and implementing existing approaches to help implement the patient care plan, (3) ‘Carer Wellness and Education’ peer/social support interventions for carers and (4) ‘Policy and System Improvements’ understanding the co‐ordination of care. Conclusion The stakeholder group concurred that the transition from mental health hospitals to the community is a distressing period, where patients and carers are particularly vulnerable to safety and well‐being risks. We identified numerous feasible/acceptable solutions to enable carers to improve patient safety and maintain their own mental wellbeing. Patient and Public Contribution Patient and public contributors were represented in the workshop and the focus of the workshop was to identify the problems they faced and co‐design potential solutions. Patient and public contributors were involved in the funding application and study design.

A comparison of the accuracy of intraocular lens (IOL) power calculation formulae, including SRK/T, HofferQ, Holladay 1, Haigis, MM, Barrett Universal II (BUII), Emmetropia Verifying Optical (EVO), and AS-OCT ray tracing, was performed. One hundred eyes implanted with either the Rayone EMV RAO200E (Rayner Intraocular Lenses Limited, Worthing, UK) or the Artis Symbiose (Cristalens Industrie, Lannion, France) IOL were included. Biometry was obtained using IOLMaster 700 (Carl Zeiss Meditec AG, Jena, Germany) and MS-39 AS-OCT (CSO, Firenze, Italy). Mean (MAE) and median (MedAE) absolute errors and percentage of eyes within ±0.25D, ±0.50D, ±0.75D, and ±1.00D of the target were compared, with ±0.75D considered a key metric. The highest percentage within ±0.75D was found with MM (96%) followed by the Haigis (94%) for the enhanced monofocal IOL. SRK/T (94%) had the highest percentage within ±0.75D, followed by Holladay 1, MM, BUII, and ray tracing (all 90%) for the multifocal IOL. No statistically significant difference in MAE was found with both IOLs. EVO showed the lowest MAE for the enhanced monofocal and ray tracing for the multifocal IOL. EVO and ray tracing showed the lowest MedAE for the two respective IOLs. A similar performance with high accuracy across formulae was found. MM and ray tracing appear to have similar accuracy to the well-established formulae and displayed a high percentage of eyes within ±0.75D.

This study investigates the application of an eNose (electrochemical sensory array) device as a rapid and cost-effective screening tool to detect increasingly prevalent counterfeit electronic cigarettes, and those to which potentially hazardous excipients such as vitamin E acetate (VEA) have been added, without the need to generate and test the aerosol such products are intended to emit. A portable, in-field screening tool would also allow government officials to swiftly identify adulterated electronic cigarette e-liquids containing illicit flavorings such as menthol. Our approach involved developing canonical discriminant analysis (CDA) models to differentiate formulation components, including e-liquid bases and nicotine, which the eNose accurately identified. Additionally, models were created using e-liquid bases adulterated with menthol and VEA. The eNose and CDA model correctly identified menthol-containing e-liquids in all instances but were only able to identify VEA in 66.6% of cases. To demonstrate the applicability of this model to a commercial product, a Virginia Tobacco JUUL product was adulterated with menthol and VEA. A CDA model was constructed and, when tested against the prediction set, it was able to identify samples adulterated with menthol 91.6% of the time and those containing VEA in 75% of attempts. To test the ability of this approach to distinguish commercial e-liquid brands, a model using six commercial products was generated and tested against randomized samples on the same day as model creation. The CDA model had a cross-validation of 91.7%. When randomized samples were presented to the model on different days, cross-validation fell to 41.7%, suggesting that interday variability was problematic. However, a subsequently developed support vector machine (SVM) identification algorithm was deployed, increasing the cross-validation to 84.7%. A prediction set was challenged against this model, yielding an accuracy of 94.4%. Altered Elf Bar and Hyde IQ formulations were used to simulate counterfeit products, and in all cases, the brand identification model did not classify these samples as their reference product. This study demonstrates the eNose’s capability to distinguish between various odors emitted from e-liquids, highlighting its potential to identify counterfeit and adulterated products in the field without the need to generate and test the aerosol emitted from an electronic cigarette.

Abstract Introduction GINA guidelines recommend increasing the dose of inhaled corticosteroids (ICS) as a step-up option for patients with inadequately controlled asthma at GINA step 4 [inadequately controlled asthma on medium-dose ICS/long-acting beta-2 agonist (LABA)]. The aim of this study was to compare the efficacy and safety of long-acting muscarinic antagonists (LAMA) add-on to medium-dose ICS/LABA in patients at GINA 2022 step 4. Methods This post hoc analysis of the IRIDIUM study evaluated the change from baseline in trough forced expiratory volume (FEV1 ) in patients receiving medium-dose MF/IND/GLY versus high-dose MF/IND and high-dose FLU/SAL at Week 26. Other outcomes included improvement in lung functions [peak expiratory flow (PEF), forced vital capacity (FVC), forced expiratory flow between 25% and 75% of the FVC (FEF)25–75%)], asthma control [Asthma Control Questionnaire (ACQ-7)], responder analysis (≥ 0.5 unit improvement in ACQ-7), and reduction in asthma exacerbations at Weeks 26 and 52. Results A total of 1930 patients were included in this analysis. Medium-dose MF/IND/GLY improved trough FEV1 versus high-dose MF/IND (Δ 41 mL; 95% CI – 7–90) and high-dose FLU/SAL (Δ 88 mL; 95% CI 39–137) at Week 26 which were sustained until Week 52. Exacerbation rates were 16% lower with medium-dose MF/IND/GLY versus high-dose MF/IND for all (mild, moderate, and severe) exacerbations and 21–30% lower versus high-dose FLU/SAL for all (mild, moderate, and severe), moderate or severe, and severe exacerbations over 52 weeks. Further improvements in other lung functions were observed with medium-dose MF/IND/GLY. No new safety signals were identified. Conclusion Medium-dose MF/IND/GLY improved lung function and reduced asthma exacerbations compared to high-dose ICS/LABA and may be an undervalued option in patients at GINA 2022 step 4. Trial Registration ClinicalTrials.gov Identifier: NCT02571777.

Abstract Background Mental illness and medication safety are key priorities for healthcare systems around the world. Despite most patients with mental illness being treated exclusively in primary care, our understanding of medication safety challenges in this setting is fragmented. Method Six electronic databases were searched between January 2000-January 2023. Google Scholar and reference lists of relevant/included studies were also screened for studies. Included studies reported data on epidemiology, aetiology, or interventions related to medication safety for patients with mental illness in primary care. Medication safety challenges were defined using the drug-related problems (DRPs) categorisation. Results Seventy-nine studies were included with 77 (97.5%) reporting on epidemiology, 25 (31.6%) on aetiology, and 18 (22.8%) evaluated an intervention. Studies most commonly (33/79, 41.8%) originated from the United States of America (USA) with the most investigated DRP being non-adherence (62/79, 78.5%). General practice was the most common study setting (31/79, 39.2%) and patients with depression were a common focus (48/79, 60.8%). Aetiological data was presented as either causal (15/25, 60.0%) or as risk factors (10/25, 40.0%). Prescriber-related risk factors/causes were reported in 8/25 (32.0%) studies and patient-related risk factors/causes in 23/25 (92.0%) studies. Interventions to improve adherence rates (11/18, 61.1%) were the most evaluated. Specialist pharmacists provided the majority of interventions (10/18, 55.6%) with eight of these studies involving a medication review/monitoring service. All 18 interventions reported positive improvements on some medication safety outcomes but 6/18 reported little difference between groups for certain medication safety measures. Conclusion Patients with mental illness are at risk of a variety of DRPs in primary care. However, to date, available research exploring DRPs has focused attention on non-adherence and potential prescribing safety issues in older patients with dementia. Our findings highlight the need for further research on the causes of preventable medication incidents and targeted interventions to improve medication safety for patients with mental illness in primary care.

Abstract Introduction Stakeholder engagement remains scarce in basic brain research. However, it can greatly improve the relevance of investigations and accelerate the translation of study findings to policy. The Lifebrain consortium investigated risk and protective factors influencing brain health using cognition, lifestyle and imaging data from European cohorts. Stakeholder activities of Lifebrain—organized in a separate work package—included organizing stakeholder events, investigating public perceptions of brain health and dissemination. Here, we describe the experiences of researchers and stakeholders regarding stakeholder engagement in the Lifebrain project. Methods Stakeholder engagement in Lifebrain was evaluated through surveys among researchers and stakeholders and stakeholders' feedback at stakeholder events through evaluation forms. Survey data were analysed using a simple content analysis approach, and results from evaluation forms were summarized after reviewing the frequency of responses. Results Consortium researchers and stakeholders experienced the engagement activities as meaningful and relevant. Researchers highlighted that it made the research and research processes more visible and contributed to new networks, optimized data collection on brain health perceptions and the production of papers and provided insights into stakeholder views. Stakeholders found research activities conducted in the stakeholder engagement work package to be within their field of interest and research results relevant to their work. Researchers identified barriers to stakeholder engagement, including lack of time, difficulties in identifying relevant stakeholders, and challenges in communicating complex scientific issues in lay language and maintaining relationships with stakeholders over time. Stakeholders identified barriers such as lack of budget, limited resources in their organization, time constraints and insufficient communication between researchers and stakeholders. Conclusion Stakeholder engagement in basic brain research can greatly benefit researchers and stakeholders alike. Its success is conditional on dedicated human and financial resources, clear communication, transparent mutual expectations and clear roles and responsibilities. Public Contribution Patient organizations, research networks, policymakers and members of the general public were involved in engagement and research activities throughout the project duration.

BackgroundThe path of rehabilitation of an eye after open globe injury (OGI) may require multiple additional secondary surgeries after the initial repair. Although much has been studied regarding the outcomes of secondary surgeries after open globe repair, it can be challenging to understand the possible implications of the surgical rehabilitative process. This retrospective study considers the benefits of the required additional secondary surgeries for a consecutive series of OGI patients.MethodsOGI patients who had at least one additional surgery after the initial open globe repair (OGR) were studied retrospectively. Additional inclusion criteria included: follow up of at least 12 months since the initial injury and at least 3 months since their most recent surgery, and no additional planned interventions. Preoperative visual acuity was compared to final visual acuity. Additionally, the odds of achieving ambulatory vision (≥20/800) and reading vision (≥20/40) were calculated after each indicated consecutive surgery.ResultsA cohort of 74 eyes from 73 patients met our inclusion criteria. These patients underwent a mean of two additional surgeries. The mean logMAR VA improved from 2.3 (HM) at presentation to 1.4 (20/150), or a 9-line Snellen equivalent improvement. Upon reaching their final visit status, 50% of patients had achieved ambulatory vision and 30% of patients had achieved reading vision. The odds of achieving ambulatory vision after completion of all the rehabilitative surgical process compared to the vision prior to the secondary rehabilitative surgery were higher (OR: 19.1, 95% CI: 7.9 – 30.4, p = 0.0008) as were the odds of achieving reading vision (OR: 4.6, 95% CI: 0.2 – 9.0, p = 0.04). With subsequent second, third, and fourth additional surgeries, the odds of achieving either ambulatory or reading vision at the final visit compared to their preoperative visual acuities were not significant (p > 0.05) but the visual acuity continued to trend toward visual improvement.ConclusionApproximately 50% of individuals who required additional surgery at UMN achieved ambulatory vision and 30% achieved reading vision. The odds of visual improvement through the surgical rehabilitative process were very high, with the greatest gains generally achieved after the first surgery.

In our recent paper on the clinical pharmacology of tafenoquine (Watson et al., 2022), we used all available individual patient pharmacometric data from the tafenoquine pre-registration clinical efficacy trials to characterise the determinants of anti-relapse efficacy in tropical vivax malaria. We concluded that the currently recommended dose of tafenoquine (300 mg in adults, average dose of 5 mg/kg) is insufficient for cure in all adults, and a 50% increase to 450 mg (7.5 mg/kg) would halve the risk of vivax recurrence by four months. We recommended that clinical trials of higher doses should be carried out to assess their safety and tolerability. Sharma and colleagues at the pharmaceutical company GSK defend the currently recommended adult dose of 300 mg as the optimum balance between radical curative efficacy and haemolytic toxicity (Sharma et al., 2024). We contend that the relative haemolytic risks of the 300 mg and 450 mg doses have not been sufficiently well characterised to justify this opinion. In contrast, we provided evidence that the currently recommended 300 mg dose results in sub-maximal efficacy, and that prospective clinical trials of higher doses are warranted to assess their risks and benefits.

Water droplets containing the SARS-CoV-2 virus, responsible for coronavirus 2019 transmission, were introduced into a controlled-temperature and -humidity chamber. The SARS-CoV-2 virus with green fluorescent protein tag in droplets was used to infect Caco-2 cells, with viability assessed through flow cytometry and microscopic counting. Whereas temperature fluctuations within typical indoor ranges (20°C–30°C) had minimal impact, we observed a notable decrease in infection rate as the surrounding air’s relative humidity increased. By investigating humidity levels between 20% and 70%, we identified a threshold of ≥40% relative humidity as most effective in diminishing SARS-CoV-2 infectivity. We also found that damage of the viral proteins under high relative humidity may be responsible for the decrease in their activity. This outcome supports previous research demonstrating a rise in the concentration of reactive oxygen species within water droplets with elevated relative humidity.

The observation of neutron stars enables the otherwise impossible study of fundamental physical processes. The timing of binary radio pulsars is particularly powerful, as it enables precise characterization of their (three-dimensional) positions and orbits. PSR J0437–4715 is an important millisecond pulsar for timing array experiments and is also a primary target for the Neutron Star Interior Composition Explorer (NICER). The main aim of the NICER mission is to constrain the neutron star equation of state by inferring the compactness ( M _p / R ) of the star. Direct measurements of the mass M _p from pulsar timing therefore substantially improve constraints on the radius R and the equation of state. Here we use observations spanning 26 yr from Murriyang, the 64 m Parkes radio telescope, to improve the timing model for this pulsar. Among the new precise measurements are the pulsar mass M _p = 1.418 ± 0.044 M _⊙ , distance D = 156.96 ± 0.11 pc, and orbital inclination angle i = 137.°506 ± 0.°016, which can be used to inform the X-ray pulse profile models inferred from NICER observations. We demonstrate that these results are consistent between multiple data sets from the Parkes Pulsar Timing Array (PPTA), each modeled with different noise assumptions. Using the longest available PPTA data set, we measure an apparent second derivative of the pulsar spin frequency and discuss how this can be explained either by kinematic effects due to the proper motion and radial velocity of the pulsar or excess low-frequency noise such as a gravitational-wave background.

The COVID pandemic placed a spotlight on alcohol use and the hardships of working within the food and beverage industry, with millions left jobless. Following previous studies that have found elevated rates of alcohol problems among bartenders and servers, here we studied the alcohol use of bartenders and servers who were employed during COVID. From February 12-June 16, 2021, in the midst of the U.S. COVID national emergency declaration, survey data from 1,010 employed bartender and servers were analyzed to quantify rates of excessive or hazardous drinking along with regression predictors of alcohol use as assessed by the 10-item Alcohol Use Disorders Identification Test (AUDIT). Findings indicate that more than 2 out of 5 (44%) people surveyed reported moderate or high rates of alcohol problem severity (i.e., AUDIT scores of 8 or higher)-a rate 4 to 6 times that of the heavy alcohol use rate reported pre- or mid-pandemic by adults within and outside the industry. Person-level factors (gender, substance use, mood) along with the drinking habits of one's core social group were significantly associated with alcohol use. Bartenders and servers reported surprisingly high rates of alcohol problem severity and experienced risk factors for hazardous drinking at multiple ecological levels. Being a highly vulnerable and understudied population, more studies on bartenders and servers are needed to assess and manage the true toll of alcohol consumption for industry employees.

In the northeast U.S., resource managers commonly apply 7-day, 10-year (7Q10) low flow estimates for protecting aquatic species in streams. In this paper, the efficacy of process-based hydrologic models is evaluated for estimating 7Q10s compared to the United States Geological Survey's (USGS) widely applied web-application StreamStats, which uses traditional statistical regression equations for estimating extreme flows. To generate the process-based estimates, the USGS's National Hydrologic Modeling (NHM-PRMS) framework (which relies on traditional rainfall-runoff modeling) is applied with 36 years of forcings from the Daymet climate dataset to a representative sample of ninety-four unimpaired gages in the Northeast and Mid-Atlantic U.S. The rainfall-runoff models are calibrated to the measured streamflow at each gage using the recommended NHM-PRMS calibration procedure and evaluated using Kling-Gupta Efficiency (KGE) for daily streamflow estimation. To evaluate the 7Q10 estimates made by the rainfall-runoff models compared to StreamStats, a multitude of error metrics are applied, including median relative bias (cfs/cfs), Root Mean Square Error (RMSE) (cfs), Relative RMSE (RRMSE) (cfs/cfs), and Unit-Area RMSE (UA-RMSE) (cfs/mi2). The calibrated rainfall-runoff models display both improved daily streamflow estimation (median KGE improving from 0.30 to 0.52) and 7Q10 estimation (smaller median relative bias, RMSE, RRMSE, and UA-RMSE, especially for basins larger than 100 mi2). The success of calibration is extended to ungaged locations using the machine learning algorithm Fuzzy C-Means (FCM) clustering, finding that traditional K-Means clustering (FCM clustering with no fuzzification factor) is the preferred method for model regionalization based on (1) Silhouette Analysis, (2) daily streamflow KGE, and (3) 7Q10 error metrics. The optimal rainfall-runoff models created with clustering show improvement for daily streamflow estimation (a median KGE of 0.48, only slightly below that of the calibrated models at 0.52); however, these models display similar error metrics for 7Q10 estimation compared to the uncalibrated models, neither of which provide improved error compared to the statistical estimates. Results suggest that the rainfall-runoff models calibrated to measured streamflow data provide the best 7Q10 estimation in terms of all error metrics except median relative bias, but for all models applicable to ungaged locations, the statistical estimates from StreamStats display the lowest error metrics in every category.

BackgroundIt is estimated that 237 million medication errors occur in England each year with a significant number occurring in the community. Our understanding of the causes of preventable medication errors and adverse drug events (ADE) affecting patients with mental illness is limited in this setting. Better understanding of the factors that contribute to errors can support the development of theory-driven improvement interventions.MethodsRemote qualitative semi-structured interviews with 26 community-based healthcare professionals in England and Wales were undertaken between June–November 2022. Recruitment was undertaken using purposive sampling via professional networks. Interviews were guided by the critical incident technique and analysed using the framework method. Any data that involved speculation was not included in the analysis. Independent analysis was carried out by the research team to extract themes guided by the London Protocol.ResultsA total of 43 medication errors and 12 preventable ADEs were discussed, with two ADEs having an unknown error origin. Prescribing errors were discussed most commonly (n = 24), followed by monitoring errors (n = 8). Six contributory factor themes were identified: the individual (staff); the work environment; the teams/interfaces; the organisation and management; the patient; and the task and technology. The individual (staff) factors were involved in just over 80% of all errors discussed. Participants reported a lack of knowledge regarding psychotropic medication and mental illnesses which accompanied diffusion of responsibility. There were difficulties with team communication, particularly across care interfaces, such as ambiguity/brevity of information being communicated and uncertainty concerning roles which created confusion amongst staff. Unique patient social/behavioural contributory factors were identified such as presenting with challenging behaviour and complex lifestyles, which caused difficulties attending appointments as well as affecting overall clinical management.ConclusionThese findings highlight that the causes of errors are multifactorial with some unique to this patient group. Key areas to target for improvement include the education/training of healthcare professionals regarding neuropharmacology/mental illnesses and enhancing communication across care interfaces. Future research should explore patient perspectives regarding this topic to help develop a holistic picture. These findings can be used to guide future intervention research to ameliorate medication safety challenges for this patient group.

Abstract Understanding how plants grow is critical for agriculture and fundamental for illuminating principles of multicellular development. Here, we apply desorption electrospray ionization mass spectrometry imaging (DESI-MSI) to the chemical mapping of the developing maize root. This technique reveals a range of small molecule distribution patterns across the gradient of stem cell differentiation in the root. To understand the developmental logic of these patterns, we examine tricarboxylic acid (TCA) cycle metabolites. In both Arabidopsis and maize, we find evidence that elements of the TCA cycle are enriched in developmentally opposing regions. We find that these metabolites, particularly succinate, aconitate, citrate, and α-ketoglutarate, control root development in diverse and distinct ways. Critically, the developmental effects of certain TCA metabolites on stem cell behavior do not correlate with changes in ATP production. These results present insights into development and suggest practical means for controlling plant growth.

Abstract Background Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multisystem illness characterized by substantial reduction in function accompanied by profound unexplained fatigue not significantly relieved by rest, post-exertional malaise, and other symptoms. Reduced natural killer (NK) cell count and cytotoxicity has been investigated as a biomarker for ME/CFS, but few clinical laboratories offer the test and multi-site verification studies have not been conducted. Methods We determined NK cell counts and cytotoxicity in 174 (65%) ME/CFS, 86 (32%) healthy control (HC) and 10 (3.7%) participants with other fatigue associated conditions (ill control [IC]) from the Multi-Site Clinical Assessment of ME/CFS (MCAM) study using an assay validated for samples shipped overnight instead of testing on day of venipuncture. Results We found a large variation in percent cytotoxicity [mean and (IQR) for ME/CFS and HC respectively, 34.1% (IQR 22.4–44.3%) and 33.6% (IQR 22.9–43.7%)] and no statistically significant differences between patients with ME/CFS and HC (p-value = 0.79). Analysis stratified on illness domain measured with standardized questionnaires did not identify an association of NK cytotoxicity with domain scores. Among all participants, NK cytotoxicity was not associated with survey results of physical and mental well-being, or health factors such as history of infection, obesity, smoking, and co-morbid conditions. Conclusion These results indicate this assay is not ready for clinical implementation and studies are needed to further explore immune parameters that may be involved in the pathophysiology of ME/CFS.

Imprint Desorption Electrospray Ionization Mass Spectrometry Imaging (IDESI-MSI) has proven to be a robust and reliable tool for chemically imaging biological samples such as fungi, animal tissues, and plants, but the choice of the imprint substrate is crucial. It must effectively transfer maximum amounts of species from the sample while preserving the original spatial distribution of detected molecules. In this study, we explored the potential of utilizing an oil-absorbing film, known for its soft nature and excellent lipophilicity, as an imprint substrate for IDESI-MSI on biological samples. To assess the transfer efficiency of the amounts of molecules and molecular patterns, we conducted experiments using mouse brain tissue. The result shows that more than 90% of the analytes can be transferred to the oil-absorbing film from the original tissue. A comparison of IDESI-MSI results between the oil-absorbing film and the original tissue demonstrates the material’s capability to transfer most molecules from the original tissue and retain images of different analytes with high spatial fidelity. We extended our investigation to plant imaging, where we applied IDESI-MSI to a cross-section of okra. The oil-absorbing film exhibited promise in this context as well. These findings suggest that IDESI-MSI utilizing the oil-absorbing film holds potential across various research fields, including biological metabolism, chemistry, and clinical research, making this technique widely applicable.

Abstract INTRODUCTION We evaluated the accuracy of remote and in‐person digital tests to distinguish between older adults with and without AD pathological change and used the Montreal Cognitive Assessment (MoCA) as a comparison test. METHODS Participants were 69 cognitively normal older adults with known beta‐amyloid (Aβ) PET status. Participants completed smartphone‐based assessments 3×/day for 8 days, followed by TabCAT tasks, DCTclock™, and MoCA at an in‐person study visit. We calculated the area under the curve (AUC) to compare task accuracies to distinguish Aβ status. RESULTS Average performance on the episodic memory (Prices) smartphone task showed the highest accuracy (AUC = 0.77) to distinguish Aβ status. On in‐person measures, accuracy to distinguish Aβ status was greatest for the TabCAT Favorites task (AUC = 0.76), relative to the DCTclockTM (AUC = 0.73) and MoCA (AUC = 0.74). DISCUSSION Although further validation is needed, our results suggest that several digital assessments may be suitable for more widespread cognitive screening application.

Reduced activity of the enzymes encoded by PHGDH, PSAT1, and PSPH causes a set of ultrarare, autosomal recessive diseases known as serine biosynthesis defects. These diseases present in a broad phenotypic spectrum: at the severe end is Neu-Laxova syndrome, in the intermediate range are infantile serine biosynthesis defects with severe neurological manifestations and growth deficiency, and at the mild end is childhood disease with intellectual disability. However, L-serine supplementation, especially if started early, can ameliorate and in some cases even prevent symptoms. Therefore, knowledge of pathogenic variants can improve clinical outcomes. Here, we use a yeast-based assay to individually measure the functional impact of 1,914 SNV-accessible amino acid substitutions in PSAT. Results of our assay agree well with clinical interpretations and protein structure-function relationships, supporting the inclusion of our data as functional evidence as part of the ACMG variant interpretation guidelines. We use existing ClinVar variants, disease alleles reported in the literature and variants present as homozygotes in the primAD database to define assay ranges that could aid clinical variant interpretation for up to 98% of the tested variants. In addition to measuring the functional impact of individual variants in yeast haploid cells, we also assay pairwise combinations of PSAT1 alleles that recapitulate human genotypes, including compound heterozygotes, in yeast diploids. Results from our diploid assay successfully distinguish the genotypes of affected individuals from those of healthy carriers and agree well with disease severity. Finally, we present a linear model that uses individual allele measurements to predict the biallelic function of ~1.8 million allele combinations corresponding to potential human genotypes. Taken together, our work provides an example of how large-scale functional assays in model systems can be powerfully applied to the study of ultrarare diseases.

Prospermatogonia (ProSpg) link the embryonic development of male primordial germ cells to the healthy establishment of postnatal spermatogonia and spermatogonial stem cells. While these spermatogenic precursor cells undergo the characteristic transitions of cycling and quiescence, the transcriptional events underlying these developmental hallmarks remain unknown. Here, we investigated the expression and function of TBP-associated factor 4b (Taf4b) in the timely development of quiescent mouse ProSpg using an integration of gene expression profiling and chromatin mapping. We find that Taf4b mRNA expression is elevated during the transition of mitotic-to-quiescent ProSpg and Taf4b-deficient ProSpg are delayed in their entry into quiescence. Gene ontology, protein network analysis, and chromatin mapping demonstrate that TAF4b is a direct and indirect regulator of chromatin and cell cycle-related gene expression programs during ProSpg quiescence. Further validation of these cell cycle mRNA changes due to the loss of TAF4b was accomplished via immunostaining for proliferating cell nuclear antigen (PCNA). Together, these data indicate that TAF4b is a key transcriptional regulator of the chromatin and quiescent state of the developing mammalian spermatogenic precursor lineage.

With increasing global focus on planetary boundaries, food safety and quality, the presence of per- and polyfluoroalkyl substances (PFAS) in the food chain presents a challenge for the sustainable production and supply of quality assured food. Consumption of food is the primary PFAS exposure route for the general population. At contaminated sites, PFAS have been reported in a range of agricultural commodities including cattle. Consumer exposure assessments are complicated by the lack of validated modelling approaches to estimate PFAS bioaccumulation in cattle. Previous studies have shown that PFAS bioaccumulation in livestock is influenced by environmental, spatial and temporal factors that necessitate a dynamic modelling approach.This work presents an integrated exposure and population toxicokinetic (PopTK) model for cattle that estimates serum and tissue concentrations of PFAS over time. Daily exposures were estimated from intakes of water, pasture, and soil, and considered animal growth, seasonal variability (pasture moisture content and temperature) and variable PFAS concentrations across paddocks. Modelled serum and tissue estimates were validated against monitoring data from Australian and Swedish cattle farms. The models were also used to develop and test practical management options for reducing PFAS exposure and to prioritise remediation for farms. Model outputs for exposure management scenarios (testing cattle rotation and targeted supplementation of feed and water) showed potential for marked reductions in consumer exposures from cattle produce.

This article contains the data on the Length-weight relationship (LWR) parameters play a crucial role in fisheries management, particularly in fish stock monitoring methods like fish visual census, where biomass estimation relies on the measurement of individual fish lengths in situ. Localized LWR parameters provide more accurate assessments of local fish stocks due to the influence of environmental conditions, which vary across different locations. In this study, we present the LWR parameters for 161 species belonging to 60 genera and 21 families of commercially important coral reef-associated fishes found in the waters surrounding the Tawi-Tawi islands in Southern Philippines. Among the families with at least 10 species recorded were the Serranidae or groupers (24 species), Lutjanidae or snappers (17 species), Nemipteridae or coral breams (14 species), Acanthuridae or surgeonfishes (12 species), Carangidae or jacks (12 species), Scaridae or parrotfishes (12 species), and Siganidae or rabbitfishes (10 species). Approximately 30% or 48 species exhibited a negative allometric growth pattern (b < 3), indicating that these species tend to become more slender as they increase in length. Conversely, around 14% or 23 species displayed a positive growth type (b > 3), where the fish becomes heavier as they increase in length. The majority of the species, accounting for 56% or 90 species, demonstrated an isometric growth pattern (b = 3), where the growth rate for weight and length is proportional. The LWR analysis yielded a coefficient of determination (r2) with an average value of 0.9553, indicating highly significant relationships between length and weight for all species studied (P

Abstract Since the early 2010s, synthetic opioids have significantly contributed to overall opioid-related overdose mortalities. For point of reference, of the 68,630 opioid-related deaths recorded in 2020, 56,516 involved synthetic opioids. During much of this period, fentanyl has been the most commonly used synthetic opioid. This time when fentanyl was the most popular opioid has been called the “third wave” of the opioid crisis, partly because it led to a sharp rise in deaths from overdoses. Other synthetic opioids, such as carfentanil, protonitazene, and isotonitazene, have also become more widely diverted for nonmedical used. Carfentanil is an even more potent fentanyl derivative that was initially used in the mid-1980s as a general anesthetic for large animals such as elephants. Related to its strong affinity for mu opioid receptors, carfentanil is still utilized in medicine and science today as a radiotracer for positron emission tomography imaging. Protonitazene and isotonitazene belong to a novel class of synthetic opioids called benzimidazoles that were manufactured in the 1950s as novel analgesics. These agents have come under recent scrutiny as designer synthetic opioids becoming more prevalent. However, to date, there is incomplete data regarding the prevalence of synthetic opioids, as traditional toxicology screenings may not be sensitive to detect these compounds at such low doses post-mortem, particularly when blood is drawn from the periphery instead of central tissues such as the brain, lung, or heart. This narrative review aims to highlight the clinical challenges presented by these new synthetic opioids.

The pathogenesis of primary glenohumeral arthritis (GHOA) is mediated by a complex interaction between osseous anatomy and the surrounding soft tissues. Recently, there has been growing interest in characterizing the association between the anterior shoulder joint capsule and primary GHOA because of the potential for targeted treatment interventions. Emerging evidence has shown substantial synovitis, fibrosis, and mixed inflammatory cell infiltrate in the anterior capsule of osteoarthritic shoulders. In addition, increased thickening of the anterior shoulder joint capsule has been associated with greater posterior glenoid wear and humeral head subluxation. While these findings suggest that anterior capsular disease may play a causative role in the etiology and progression of eccentric GHOA, further studies are needed to support this association. The purpose of this article is to review the pathogenesis of primary GHOA, contextualize current hypotheses regarding the role of the anterior capsule in the disease process, and provide directions for future research.

Total hip and knee replacement are effective operations for the management of end-stage arthritis. There are increasing numbers of these operations being performed, and the rate of increase is anticipated to continue into the future (1, 2, 3, 4). There is also a substantial rise in the lifetime risk of a person receiving a total hip or knee replacement and this has been shown in several countries (5, 6, 7, 8). There are a large number of joint replacement prostheses on the market available for use and not all perform the same. Many have no published outcomes. Joint replacement registries provide an appropriate way to monitor the real-world outcomes of these procedures and can provide comparative data on the rates of revision for specific prostheses. Revisions are generally defined in joint registries as a removal or exchange of a prosthesis or part thereof and provide an unambiguous record of a problem with the joint replacement. There are many factors that affect revision rates. Non-device-related issues may include patient factors, surgical technique, surgeon experience and volume of cases. Device-related factors may contribute to the variation in the rates of revision with individual prostheses.

Abstract Cardiovascular ageing contributes to cognitive impairment. However, the unique and synergistic contributions of multiple cardiovascular factors to cognitive function remain unclear because they are often condensed into a single composite score or examined in isolation. We hypothesized that vascular risk factors, electrocardiographic features and blood pressure indices reveal multiple latent vascular factors, with independent contributions to cognition. In a population-based deep-phenotyping study (n = 708, age 18–88), path analysis revealed three latent vascular factors dissociating the autonomic nervous system response from two components of blood pressure. These three factors made unique and additive contributions to the variability in crystallized and fluid intelligence. The discrepancy in fluid relative to crystallized intelligence, indicative of cognitive decline, was associated with a latent vascular factor predominantly expressing pulse pressure. This suggests that higher pulse pressure is associated with cognitive decline from expected performance. The effect was stronger in older adults. Controlling pulse pressure may help to preserve cognition, particularly in older adults. Our findings highlight the need to better understand the multifactorial nature of vascular aging.

Abstract Background Without aggressive treatment, pulmonary arterial hypertension (PAH) has a 5-year mortality of approximately 40%. A patient’s response to vasodilators at diagnosis impacts the therapeutic options and prognosis. We hypothesized that analyzing perfusion images acquired before and during vasodilation could identify characteristic differences between PAH and control subjects. Methods We studied 5 controls and 4 subjects with PAH using HRCT and 13NN PET imaging of pulmonary perfusion and ventilation. The total spatial heterogeneity of perfusion (CV2 Qtotal) and its components in the vertical (CV2 Qvgrad) and cranio-caudal (CV2 Qzgrad) directions, and the residual heterogeneity (CV2 Qr), were assessed at baseline and while breathing oxygen and nitric oxide (O2 + iNO). The length scale spectrum of CV2 Qr was determined from 10 to 110 mm, and the response of regional perfusion to O2 + iNO was calculated as the mean of absolute differences. Vertical gradients in perfusion (Qvgrad) were derived from perfusion images, and ventilation-perfusion distributions from images of 13NN washout kinetics. Results O2 + iNO significantly enhanced perfusion distribution differences between PAH and controls, allowing differentiation of PAH subjects from controls. During O2 + iNO, CV2 Qvgrad was significantly higher in controls than in PAH (0.08 (0.055–0.10) vs. 6.7 × 10–3 (2 × 10–4–0.02), p

Background: Total hip arthroplasty (THA) is an effective treatment for symptomatic hip osteoarthritis. The aim of this study was to determine the revision outcome of commercially available navigation technologies. Methods: Data from the Australian Orthopaedic Association National Joint Replacement Registry from January 2016 to December 2020 included all primary THA procedures performed for osteoarthritis. Procedures using the Intellijoint HIP navigation system were identified and compared to procedures using “other” computer navigation systems and to nonnavigated procedures. The cumulative percent revision (CPR) was compared between the 3 groups using Kaplan-Meier estimates of survivorship and hazard ratios from Cox proportional hazards models, adjusted for age and gender. Results: There were 1911 procedures that used the Intellijoint system, 4081 used “other” computer navigation systems, and 160,661 were nonnavigated procedures. The all-cause 2-year CPR rate for the Intellijoint system was 1.8% (95% confidence interval [CI], 1.2-2.6), compared to 2.2% (95% CI, 1.8-2.8) for other navigated cases and 2.2% (95% CI, 2.1-2.3) for nonnavigated cases. A prosthesis analysis identified the Paragon/Acetabular Shell THAs combined with the Intellijoint system to have a higher (3.4%) rate of revision than nonnavigated THAs (hazard ratio = 2.00 [95% CI, 1.01-4.00], P = .048). When this combination was excluded, the Intellijoint group demonstrated a 2-year CPR of 1.3%. There was no statistical difference in the CPR between the 3 groups before or after excluding the Paragon/Acetabular Shell system. Conclusions: The preliminary data presented demonstrate no statistical difference in all-cause revision rates when comparing the Intellijoint system with “other” navigation systems and “nonnavigated” approaches for primary THAs. Level of evidence: III (National registry analysis).

Background and purpose: Antibiotic-loaded bone cement (ALBC) and systemic antibiotic prophylaxis (SAP) have been used to reduce periprosthetic joint infection (PJI) rates. We investigated the use of ALBC and SAP in primary total knee arthroplasty (TKA). Patients and methods: This observational study is based on 2,971,357 primary TKAs reported in 2010–2020 to national/regional joint arthroplasty registries in Australia, Denmark, Finland, Germany, Italy, the Netherlands, New Zealand, Norway, Romania, South Africa, Sweden, Switzerland, the UK, and the USA. Aggregate-level data on trends and types of bone cement, antibiotic agents, and doses and duration of SAP used was extracted from participating registries. Results: ALBC was used in 77% of the TKAs with variation ranging from 100% in Norway to 31% in the USA. Palacos R+G was the most common (62%) ALBC type used. The primary antibiotic used in ALBC was gentamicin (94%). Use of ALBC in combination with SAP was common practice (77%). Cefazolin was the most common (32%) SAP agent. The doses and duration of SAP used varied from one single preoperative dosage as standard practice in Bolzano, Italy (98%) to 1-day 4 doses in Norway (83% of the 40,709 TKAs reported to the Norwegian arthroplasty register). Conclusion: The proportion of ALBC usage in primary TKA varies internationally, with gentamicin being the most common antibiotic. ALBC in combination with SAP was common practice, with cefazolin the most common SAP agent. The type of ALBC and type, dose, and duration of SAP varied among participating countries.