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Sphingosine-1-phosphate (S1P) receptor (S1PR) agonists, such as fingolimod (FTY720), alleviate nociception in preclinical pain models by either activation (agonism) or inhibition (functional antagonism) of S1PR type-1 (S1PR1). However, the dose-dependence and temporal relationship between reversal of nociception and modulation of S1PR1 signaling has not been systematically investigated. This study examined the relationship between FTY720-induced antinociception and S1PR1 adaptation using a sciatic nerve chronic constriction injury (CCI) model of neuropathic pain in male and female C57Bl/6J mice. Daily injections of FTY720 for 14 days dose-dependently reversed CCI-induced mechanical allodynia without tolerance development, and concomitantly resulted in a dose-dependent reduction of G-protein activation by the S1PR1-selective agonist SEW2871 in the lumbar spinal cord and brain. These findings indicate FTY720-induced desensitization of S1PR1 signaling coincides with its anti-allodynic effects. Consistent with this finding, a single injection of FTY720 reversed mechanical allodynia while concomitantly producing partial desensitization of S1PR1-stimulated G-protein activation in the CNS. However, mechanical allodynia returned 24-hr post injection, despite S1PR1 desensitization at that time, demonstrating a dissociation between these measures. Furthermore, CCI surgery led to elevations of sphingolipid metabolites, including S1P, which were unaffected by daily FTY720 administration, suggesting FTY720 reversed mechanical allodynia by targeting S1PR1 rather than sphingolipid metabolism. Supporting this hypothesis, acute administration of the S1PR1-selective agonist CYM-5442 mimicked the anti-allodynic effect of FTY720. In contrast, the S1PR1-selective antagonist NIBR-0213 prevented the anti-allodynic effect of FTY720, but NIBR-0213 given alone did not affect nociception. These results indicate that FTY720 alleviates CCI-induced allodynia through a mechanism distinct from functional antagonism., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

A paradigm shift in drug development is the discovery of small molecules that harness the ubiquitin-proteasomal pathway to eliminate pathogenic proteins. Here we provide a modality for targeted protein degradation in lysosomes. We exploit an endogenous lysosomal pathway whereby protein arginine methyltransferases (PRMTs) initiate substrate degradation via arginine methylation. We developed a heterobifunctional small molecule, methylarginine targeting chimera (MrTAC), that recruits PRMT1 to a target protein for induced degradation in lysosomes. MrTAC compounds degraded substrates across cell lines, timescales and doses. MrTAC degradation required target protein methylation for subsequent lysosomal delivery via microautophagy. A library of MrTAC molecules exemplified the generality of MrTAC to degrade known targets and neo-substrates-glycogen synthase kinase 3β, MYC, bromodomain-containing protein 4 and histone deacetylase 6. MrTAC selectively degraded target proteins and drove biological loss-of-function phenotypes in survival, transcription and proliferation. Collectively, MrTAC demonstrates the utility of endogenous lysosomal proteolysis in the generation of a new class of small molecule degraders., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

The evolution of SARS-CoV-2 has led to the emergence of numerous variants of concern (VOCs), marked by changes in the viral spike glycoprotein, the primary target for neutralising antibody (nAb) responses. Emerging VOCs, particularly omicron sub-lineages, show resistance to nAbs induced by prior infection or vaccination. The precise spike protein changes contributing to this resistance remain unclear in infectious cell culture systems. In the present study, a large panel of infectious SARS-CoV-2 mutant viruses, each with spike protein changes found in VOCs, including omicron JN.1 and its derivatives KP.2 and KP.3, was generated using a reverse genetic system. The susceptibility of these viruses to antibody neutralisation was measured using plasma from convalescent and vaccinated individuals. Synergistic roles of combined substitutions in the spike receptor binding domain (RBD) were observed in neutralisation resistance. However, recombinant viruses with the entire spike protein from a specific VOC showed enhanced resistance, indicating that changes outside the RBD are also significant. In silico analyses of spike antibody epitopes suggested that changes in neutralisation could be due to altered antibody binding affinities. Assessing ACE2 usage for entry through anti-ACE2 antibody blocking and ACE2 siRNA revealed that omicron BA.2.86 and JN.1 mutant viruses were less dependent on ACE2 for entry. However, surface plasmon resonance analysis showed increased affinity for ACE2 for both BA.2.86 and JN.1 compared to the ancestral spike. This detailed analysis of specific changes in the SARS-CoV-2 spike enhances understanding of coronavirus evolution, particularly regarding neutralising antibody evasion and ACE2 entry receptor dependence.

Background: Women with Sjögren's Disease are more likely to experience pregnancy complications compared to their counterparts without the disease. Attention to detail and familiarity with the most recent research and guidelines in this field are required to achieve optimal maternal and fetal outcomes. Such complications include pregnancy induced hypertension, fetal growth restriction, thromboembolic events, and preterm delivery. Among the most life-threatening sequela of maternal Sjogren's Disease is fetal autoimmune congenital heart block (ACHB), which has high potential to cause intrauterine fetal death, neonatal mortality, developmental delay, and other long-term pediatric complications. Currently, surveillance with weekly echocardiograms and obstetric sonograms in the second trimester are recommended to screen for ACHB with the goal of early detection and intervention before progression from first- or second- of heart block to complete heart block., Objective: We describe a case of maternal Sjogren's Disease, which prompted us to raise questions regarding the optimal frequency of obtaining fetal echocardiograms, and the ideal management in case a prolonged PR interval was to be found. We use this case to provide a springboard for discussion on updated antenatal management strategies for ACHB prevention., Methods: To conduct this analysis, we searched PubMed for articles published over the last 10 years, with attention focused on articles written since 2016. Additionally, updated guidelines by other specialties such as Rheumatology, Cardiology and Pediatrics on this issue were reviewed., Results: Thorough search of the literature yielded several meta-analyses concurring that the mothers with Sjogren's Disease had increased rates of premature birth, pregnancy induced hypertension, increased risks of delivering infants with intrauterine growth restriction (IUGR), with the most life-threatening risk being that of congenital heart block. Literature supporting prophylactic hydroxychloroquine and the use of steroids to reverse or halt the progression of congenital heart block at the time of diagnoses appeared at the forefront of search results., Conclusion: Pregnant women with SS have an increased risk for complications such as intrauterine growth restriction, thromboembolic events, pregnancy-induced hypertension, preterm delivery, and cesarean delivery and should prioritize obtaining pre- or peri-conceptional counseling. In women with anti SSA/SSB antibodies, a medication regimen should be considered with the object of decreasing the concentration of these antibodies, and hence decrease the risks of ACHB. Current literature supports the inclusion of hydroxychloroquine for this purpose, even prior to conception. Although the most recent studies recommend against prophylactic use of steroids, their potential to prevent progression to complete block should be weighed against their potential negative effects. Short and long-term treatment with corticosteroids has been associated with increased maternal risk of infection, weight gain, osteonecrosis, hypertension and bone mineral density disorders. Intrauterine growth restriction, oligohydramnios, and adrenal suppression have been among the fetal risks associated with steroids while improved infant survival or decreased need for pacing have not been demonstrated. Management of these pregnancies is complex and should include a multidisciplinary approach involving a maternal-fetal medicine sub-specialist, a rheumatologist, a pediatrician, a neonatologist, and the patient herself with her family in a model of shared decision-making.

Objectives: To evaluate junior resident self-assessments and utilization of effective coaching principles by chief resident coaches in a resident peer surgical coaching program., Design: All residents underwent the Surgical Coaching for Operative Performance Enhancement (SCOPE) coaching curriculum. Junior residents ("coachees") were paired with chief resident coaches. A case was selected for coaching. The coaching structure was: 1) junior resident preoperative goal setting, 2) unscrubbed, intraoperative case observation by the coach, 3) postoperative coaching debrief. Debriefs were recorded to determine frequency of junior resident self-assessment and use of the effective coaching principles (goal setting, collaborative analysis, constructive feedback, action planning). Deductive thematic analysis was conducted., Setting: A general surgery residency at a single, large academic medical center., Participants: 16 junior resident (PGY1-3) coachees and 6 chief resident (PGY5) coaches., Results: There were 18 recorded coaching debrief sessions that lasted an average of 12.65 minutes (range 4-31 minutes). All debrief sessions included self-assessments by the junior resident coachees. There were numerous examples of the 4 effective coaching principles with all debriefs including use of at least 3. The most commonly used were collaborative analysis and constructive feedback. For technical skills, these highlighted body positioning, needle angles, and dissection techniques, including instrument choice, laparoscopic instrument technique, and use of electrocautery. Collaborative analysis of nontechnical skills emphasized communication with the attending surgeon, specifically operative decision-making and advocating for resident autonomy. Nontechnical constructive feedback addressed strategies the coaches themselves used for managing stress, interacting with attendings, and excelling in the operating room., Conclusions: Self-assessments and use of effective coaching principles were frequent throughout peer coaching debriefs. Collaborative analysis and constructive feedback were employed to promote operative technical and nontechnical skill development. Within a peer coaching program, residents are able to employ high level teaching and coaching techniques to encourage operative performance enhancement., (Copyright © 2024 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

Since the development of consensus-recommended indicators for pediatric malnutrition in 2014, screening and diagnosis of pediatric malnutrition have improved, but the indicators are not always used; malnutrition continues to be underdiagnosed in some community and healthcare settings. In particular, mid-upper arm circumference (MUAC) is underused as a screening indicator for pediatric malnutrition, despite its unique advantages and usefulness in several clinical situations. In December 2022, a scientific roundtable was held to bring together several experts in pediatric malnutrition. One of the goals of the scientific roundtable was to discuss the clinical use of anthropometric measures as screening tools for pediatric malnutrition status, with a focus on the use of MUAC. This article arose from that event and is intended as an educational tool to aid clinicians in implementing MUAC measurements. In addition to describing the use of MUAC as a screening tool, the article discusses several clinical situations in which MUAC is especially useful. Additionally, the article reviews practical aspects of measuring and interpreting MUAC values, provides links to additional educational resources, and briefly reviews areas in which further research is needed regarding the use of MUAC for screening of nutrition status in children., (© 2024 The Author(s). Nutrition in Clinical Practice published by Wiley Periodicals LLC on behalf of American Society for Parenteral and Enteral Nutrition.)

A total of 1019 samples collected on 726 Spanish swine farms suffering from outbreaks of respiratory disease were screened for influenza A viruses (IAVs) using a RT-qPCR method. A subset of positive samples was further analyzed using a subtype-specific RT-qPCR method (n: 142) and Sanger sequencing (n: 64). A total of 19.4% samples from 23% farms tested positive, with infection being most common in suckling (53.6%) and weaning pigs (30.2%). Viruses belonging to four HA subtypes (H1av, H1hu, H1pdm, H3) were detected, with subtypes H1avN2, H1huN2 and H1avN1 accounting for over half of the specimens. An optimized protocol with newly designed primers allowed the detection of H3 viruses in a significant number of samples (21%). A comparison of antigenic positions revealed that circulating strains exhibited mutations with vaccine strains in a significant percentage of amino acid residues, both in the NA protein (27.8-43.3%) and particularly in the HA protein (51-75.3%)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Lay Abstract: Timely identification of autism spectrum conditions is a necessity to enable children to receive the most benefit from early interventions. Emerging technological advancements provide avenues for detecting subtle, early indicators of autism from routinely collected health information. This study tested a model that provides a likelihood score for autism diagnosis from baby wellness visit records collected during the first 2 years of life. It included records of 591,989 non-autistic children and 12,846 children with autism. The model identified two-thirds of the autism spectrum condition group (boys 63% and girls 66%). Sex-specific models had several predictive features in common. These included language development, fine motor skills, and social milestones from visits at 12-24 months, mother's age, and lower initial growth but higher last growth measurements. Parental concerns about development or hearing impairment were other predictors. The models differed in other growth measurements and birth parameters. These models can support the detection of early signs of autism in girls and boys by using information routinely recorded during the first 2 years of life., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: Estimated glomerular filtration rate (eGFR) and urine albumin/creatinine ratio (ACR) are insensitive biomarkers for early detection of hypertension-mediated organ damage (HMOD). In this nationwide cross-sectional study, we assessed potential biomarkers for early HMOD in healthy persons and patients with hypertension. We hypothesised that plasma levels of biomarkers: (1) are different between healthy controls and patients with hypertension, (2): can classify patients with hypertension according to the degree of hypertension severity., Design and Methods: Patients with hypertension prescribed ≥2 antihypertensive agents were selected from a multicentre study. Healthy controls were selected from an ongoing study of living kidney donor candidates. Uncontrolled hypertension was defined as systolic daytime ambulatory blood pressure ≥135 mmHg. Kidney HMOD was defined by ACR > 3.0 mg/mmol or eGFR < 60 mL/min/1.73 m 2 . Patients with hypertension were categorised into three groups: (1) controlled hypertension; (2) uncontrolled hypertension without kidney HMOD; (3) uncontrolled hypertension with kidney HMOD. Fifteen biomarkers were analysed using a Luminex bead-based immunoassay, and nine fell within the specified analytical range., Results: Plasma levels of Interleukin 1 receptor antagonist (IL-1RA), neutrophil gelatinase-associated lipocalin (NGAL) and uromodulin were significantly different between healthy controls ( n  = 39) and patients with hypertension ( n  = 176). In regression models, with controlled hypertension ( n  = 55) as the reference category, none of the biomarkers were associated with uncontrolled hypertension without ( n  = 59) and with ( n  = 62) kidney HMOD. In models adjusted for cardiovascular risk factors and eGFR, osteopontin (OPN) was associated with uncontrolled hypertension without kidney HMOD (odds ratio (OR) 1.77 (1.05-2.98), p  = 0.03), and regulated upon activation normal T-cell expressed and secreted (RANTES) with uncontrolled hypertension with kidney HMOD (OR 0.57 (0.34-0.95), p  = 0.03)., Conclusions: None of the biomarkers could differentiate our hypertension groups when established risk factors were considered. Plasma OPN may identify patients with uncontrolled hypertension at risk for kidney HMOD.

Biological age is a construct that seeks to evaluate the biological wear and tear process of the organism that cannot be observed by chronological age. We estimate individuals' biological age based on biomarkers from multiple systems and validate it through its association with mortality from natural causes. Biological age was estimated in 12,109 participants (6621 women and 5488 men) from the first visit of the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) who had valid data for the biomarkers used in the analyses. Biological age was estimated using the Klemera and Doubal method. The difference between chronological age and biological age (Δage) was computed. Cox proportional hazard models stratified by sex were used to assess whether Δage was associated with mortality risk after a median follow-up of 9.1 years. The accuracy of the models was estimated by the area under the curve (AUC). Δage had equal mean for men and women, with greater variability for men. Cox models showed that every 1-year increase in Δage was associated with increased mortality in men (HR (95% CI) 1.21; 1.17-1.25) and women (HR (95% CI) 1.24; 1.15-1.34), independently of chronological age. Results of the AUC demonstrated that the predictive power of models that only included chronological age (AUC chronological age = 0.7396) or Δage (AUC Δage = 0.6842) was lower than those that included both, chronological age and Δage (AUC chronological age + Δage = 0.802), in men. This difference was not observed in women. We demonstrate that biological age is strongly related to mortality in both genders and is a valid predictor of death in Brazilian adults, especially among men., (© 2024. The Author(s), under exclusive licence to American Aging Association.)

Objective: To establish an image acquisition and post-processing workflow for the determination of the proton density fat fraction (PDFF) in calf muscle tissue at 7 T., Materials and Methods: Echo times (TEs) of the applied vendor-provided multi-echo gradient echo sequence were optimized based on simulations of the effective number of signal averages (NSA*). The resulting parameters were validated by measurements in phantom and in healthy calf muscle tissue (n = 12). Additionally, methods to reduce phase errors arising at 7 T were evaluated. Finally, PDFF values measured at 7 T in calf muscle tissue of healthy subjects (n = 9) and patients with fatty replacement of muscle tissue (n = 3) were compared to 3 T results., Results: Simulations, phantom and in vivo measurements showed the importance of using optimized TEs for the fat-water separation at 7 T. Fat-water swaps could be mitigated using a phase demodulation with an additional B 0 map, or by shifting the TEs to longer values. Muscular PDFF values measured at 7 T were comparable to measurements at 3 T in both healthy subjects and patients with increased fatty replacement., Conclusion: PDFF determination in calf muscle tissue is feasible at 7 T using a chemical shift-based approach with optimized acquisition and post-processing parameters., Competing Interests: Declarations. Conflict of interest: This work was supported by the German Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung [BMBF]) under the project Molecular Assessment of Signatures Characterizing the Remission of Arthritis (MASCARA, No. 01EC1903A) and by the German Research Foundation (DFG) under the project MR biosignatures at UHF (500888779 / RU5534). Gast L started employment at Siemens Healthineers AG (Erlangen, Germany), and Zeiger P at Bechtle GmbH (Nürnberg, Germany) during drafting of the manuscript. The authors have no further relevant financial or non-financial interests to disclose. Ethical standards: All measurements involving human participants have been approved by the local ethics committee in accordance with the principles of the 1964 Helsinki declaration and its later amendments. All participants gave written informed consent prior to their examination., (© 2024. The Author(s).)

Regenerative approaches towards neuronal loss following traumatic brain or spinal cord injury have long been considered a dogma in neuroscience and remain a cutting-edge area of research. This is reflected in a large disparity between the number of studies investigating primary and secondary injury as therapeutic targets in spinal cord and traumatic brain injuries. Significant advances in biotechnology may have the potential to reshape the current state-of-the-art and bring focus to primary injury neurotrauma research. Recent studies using neural-glial factor/antigen 2 (NG2) cells indicate that they may differentiate into neurons even in the developed brain. As these cells show great potential to play a regenerative role, studies have been conducted to test various manipulations in neurotrauma models aimed at eliciting a neurogenic response from them. In the present study, we systematically reviewed the experimental protocols and findings described in the scientific literature, which were peer-reviewed original research articles (1) describing preclinical experimental studies, (2) investigating NG2 cells, (3) associated with neurogenesis and neurotrauma, and (4) in vitro and/or in vivo, available in PubMed/MEDLINE, Web of Science or SCOPUS, from 1998 to 2022. Here, we have reviewed a total of 1504 papers, and summarized findings that ultimately suggest that NG2 cells possess an inducible neurogenic potential in animal models and in vitro. We also discriminate findings of NG2 neurogenesis promoted by different pharmacological and genetic approaches over functional and biochemical outcomes of traumatic brain injury and spinal cord injury models, and provide mounting evidence for the potential benefits of manipulated NG2 cell ex vivo transplantation in primary injury treatment. These findings indicate the feasibility of NG2 cell neurogenesis strategies and add new players in the development of therapeutic alternatives for neurotrauma., (Copyright © 2024 Copyright: © 2024 Neural Regeneration Research.)

Objective: To examine the relationship between the penetration (or reach) of a national program aiming to integrate mental health clinicians into all primary care clinics (PC-MHI) and rates of guideline-concordant follow-up and treatment among clinic patients newly identified with depression in the Veterans Health Administration (VA)., Data Sources/study Setting: 15,155 screen-positive patients 607,730 patients with 2-item Patient Health Questionnaire scores in 82 primary care clinics, 2015-2019., Study Design: In this retrospective cohort study, we used established depression care quality measures to assess primary care patients who (a) newly screened positive (score ≥3) and (b) were identified with depression by clinicians via diagnosis and/or medication (n = 15,155; 15,650 patient-years). Timely follow-up included ≥3 mental health, ≥3 psychotherapy, or ≥3 primary care visits for depression. Minimally appropriate treatment included ≥4 mental health visits, ≥3 psychotherapy, or ≥60 days of medication. In multivariate regressions, we examined whether higher rates of PC-MHI penetration in clinic (proportion of total primary care patients in a clinic who saw any PC-MHI clinician) were associated with greater depression care quality among cohort patients, adjusting for year, healthcare system, and patient and clinic characteristics., Data Collection/extraction Methods: Electronic health record data from 82 VA clinics across three states., Principal Findings: A median of 9% of all primary care patients were seen by any PC-MHI clinician annually. In fully adjusted models, greater PC-MHI penetration was associated with timely depression follow-up within 84 days (∆P = 0.5; SE = 0.1; p < 0.001) and 180 days (∆P = 0.3; SE = 0.1; p = 0.01) of a positive depression screen. Completion of at least minimal treatment within 12 months was high (77%), on average, and not associated with PC-MHI penetration., Conclusions: Greater PC-MHI program penetration was associated with early depression treatment engagement at 84-/180-days among clinic patients newly identified with depression, with no effect on already high rates of completion of minimally sufficient treatment within the year., (Published 2024. This article is a U.S. Government work and is in the public domain in the USA. Health Services Research published by Wiley Periodicals LLC on behalf of Health Research and Educational Trust.)

Background: According to data from the USA, the incidence of incidentally discovered pulmonary nodules is 5.8 per 1000 person-years for women and 5.2 per 1000 person-years for men. Their management as recommended in the pertinent guidelines can substantially improve clinical outcomes. More than 95% of all pulmonary nodules revealed by computed tomography (CT) are benign, but many cases are not managed in conformity with the guidelines. In this article, we summarize the appropriate clinical approach and provide an overview of the pertinent diagnostic studies and when they should be performed., Methods: This review is based on relevant publications retrieved by a selective search in PubMed. The authors examined English-language recommendations issued since 2010 for the management of pulmonary nodules, supplemented by comments from the German lung cancer guideline., Results: In general, the risk that an incidentally discovered pulmonary nodule is malignant is low but rises markedly with increasing size and the presence of risk factors. When such a nodule is detected, the further recommendation, depending on size, is either for follow-up examinations with chest CT or else for an extended evaluation with positron emission tomography-CT and biopsy for histology. The diagnostic evaluation should include consideration of any earlier imaging studies that may be available as an indication of possible growth over time. Single nodules measuring less than 6 mm, in patients with few or no risk factors, do not require any follow-up. Lung cancer is diagnosed in just under 10% of patients with a nodule measuring more than 8 mm., Conclusion: The recommendations of the guidelines for the management of incidentally discovered pulmonary nodules are intended to prevent both over- and undertreatment. If a tumor is suspected, further care should be provided by an interdisciplinary team.

Preschool anxiety is highly prevalent and well known to predict risk for future psychopathology. The present study explores whether a diagnosis of an anxiety disorder in preschool interacts with (a) social skills and (b) cognitive ability to longitudinally predict psychopathology, two well-known protective factors, among a sample of 207 children measured at preschool (Mage = 4.34 years) and early childhood (Mage = 6.61 years). To assess social skills and cognitive ability, we utilized the Social Skills Rating Scale and the Differential Abilities Scale, respectively. To assess psychopathology, we utilized the parent report of the Preschool Age Psychiatric Assessment. Hierarchical linear regression models revealed significant interactions between both social skills and cognitive ability with preschool anxiety. We observed that social skills protected against emergent psychopathology for both children with and without anxiety, although this association was stronger for children with preschool anxiety. Contrastingly, cognitive ability served as a protective factor against future psychopathology primarily among children without preschool anxiety. Results from this study identify targets for future intervention and inform our understanding of how preschool anxiety, a common disorder among young children, shapes future psychopathology risk in childhood.

We report on the synthesis of Mg 0.6 Mn 0.7 Co 0.7 Ni 0.6 Cu 0.4 TeO 6 , which is isostructural with multiferroic Mn 3 TeO 6 (space group R 3 ¯ ). Study of its magnetic properties indicates establishment of the long-range antiferromagnetic order at 16.3 K, slightly lower than that of pure Mn 3 TeO 6 . The tiny hysteresis of magnetization loop along with specific heat data implies the presence of ferromagnetic magnons at low temperatures. Dielectric measurements reveal sequence of well-defined steps in the real part of permittivity and peaks in the imaginary parts of permittivity at 30, 92, and 212 K attributable to the highly diffused structural changes, which are characteristic to relaxor ferroelectrics. It is shown that usual interpretation of this structure type as corundum-related is not accurate: the hexagonal oxygen packing is not close and is not double-layered. Therefore, Mn 3 TeO 6 represents a very special structure type.

Numerous areas of the Semipalatinsk Test Site (STS) were subjected to radioactive contamination, including tritium. The tritium content in plants was determined in free water (TFWT) and in the organic component (OBT). It has been established that the OBT content in plants for the "Sary-Uzen" site between combat boreholes ranges from <7-125 Bq/kg and the background OBT content is 21.5 Bq/kg. The maximum OBT values in plants have been recorded in the vicinity of boreholes and range from 7.1 (near the borehole numbered 106) to 200,000 Bq/kg (near the borehole numbered 101). Overall, the tritium content in the vegetation cover at the "Sary-Uzen" site is negligible and does not pose a threat. Isolated cases of tritium content in drinking water exceeding the intervention level have been identified in plants in the "Lazurit" area, as well as near combat boreholes numbered 125 and 101., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To identify the COVID-19 impact on well-being/mental health, coping strategies and risk factors in adolescent worldwide., Method: Anonymous online multi-national/language survey in the general population (representative/weighted non-representative samples, 14-17years), measuring change in well-being (WHO-5/range=0-100) and psychopathology (validated composite P-score/range=0-100), WHO-5 <50 and <29, pre- versus during COVID-19 pandemic (26/04/2020-26/06/2022). Coping strategies, nine a-priori defined individual/cumulative risk factors were measured. χ 2 , penalized cubic splines, linear regression, and correlation analyses were conducted., Results: Analyzing 8,115 of 8,762 initiated surveys (representative=75.1%), the pre-pandemic WHO-5 and P-score remained stable during the study (excluding relevant recall bias/drift), but worsened intra-pandemic by 5.55±17.13 (standard deviation) and 6.74±16.06 points, respectively (effect size d=0.27 and d=0.28). The proportion of adolescents with WHO-5 scores suggesting depression screening (<50) and major depression (<29) increased from 9% to 17% and 2% to 6%. WHO-5 worsened (descending magnitude, with cumulative effect) in adolescents with a mental or physical disorder, female gender, and with school closure. Results were similar for P-score, with the exception of school closure (not significant) and living in a low-income country, as well as not living in a large city (significant). Changes were significantly but minimally related to COVID-19 deaths/restrictions, returning to near-pre-pandemic values after >2 years. The three most subjectively effective coping strategies were internet use, exercise/walking, and social contacts., Conclusion: Overall, well-being/mental health worsened (small effect sizes) during early stages of COVID-19, especially in vulnerable subpopulations. Identified at-risk groups, association with pandemic-related measures, and coping strategies can inform individual behaviours and global public health strategies., (Copyright © 2024. Published by Elsevier Inc.)

This paper describes an iridium-catalyzed allylation of ring-fused pyrazolones that proceeds with excellent regio-, diastereo- and enantio-selectivities. The approach exploits unactivated, racemic allylic alcohols as a source of allyl building blocks. Asymmetric syntheses of a series of biologically relevant, chiral pyrazolones highlight the utility of the methodology. The use of Cu(OTf) 2 as a co-catalyst greatly enhances the regioselectivity of the reaction and permits selective syntheses of branched allylation products.

Feedback on cognitive workload may reduce decision-making mistakes. Machine learning-based models can produce feedback from physiological data such as electroencephalography (EEG) and electrocardiography (ECG). Supervised machine learning requires large training data sets that are (1) relevant and decontaminated and (2) carefully labeled for accurate approximation, a costly and tedious procedure. Commercial over-the-counter devices are low-cost resolutions for the real-time collection of physiological modalities. However, they produce significant artifacts when employed outside of laboratory settings, compromising machine learning accuracies. Additionally, the physiological modalities that most successfully machine-approximate cognitive workload in everyday settings are unknown. To address these challenges, a first-ever hybrid implementation of feature selection and self-supervised machine learning techniques is introduced. This model is employed on data collected outside controlled laboratory settings to (1) identify relevant physiological modalities to machine approximate six levels of cognitive-physical workloads from a seven-modality repository and (2) postulate limited labeling experiments and machine approximate mental-physical workloads using self-supervised learning techniques., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Context.—: Genomic reports are primarily organized in a narrative and unstructured format with variations in content and format. Regulatory requirements and professional guidelines for genetic test reporting exist but provide little guidance for effective communication of information., Objective.—: To assess clinical genomic reporting practices across 5 disciplines within molecular diagnostics, including germline, somatic solid tumors, somatic hematologic malignancies, pharmacogenomics, and prenatal cell-free DNA screening., Design.—: Reporting practices were assessed by using a structured review of clinical genomic reports from multiple laboratories in 5 molecular disciplines spanning different practice settings. Report content was reviewed by the presence/absence of from 27 to 44 elements, including 23 elements required by the College of American Pathologists and/or the Clinical Laboratory Improvement Amendments of 1988 (CLIA). If present, the element's location on the report was recorded., Results.—: A total of 69 genomics reports from 31 laboratories were reviewed. Overall, the reports were compliant with regulatory requirements but showed variability in both format and content. Six of 7 required reporting elements (per CLIA, 42 CFR [Code of Federal Regulations] 493.1291) were included in 90% of the reports. However, these elements were often located in different report sections. Only patient demographics were always found in a specific report section (header)., Conclusions.—: These results show that reports are overall compliant with regulatory requirements, despite some reporting elements being less consistently reported. The lack of consistent presentation of the data elements presents an opportunity to improve the communication of molecular testing results to clinicians and patients., (© 2024 College of American Pathologists.)

Background: Nanocarriers have been proposed as a solution for drug-resistant epilepsy., Methods: A systematic review of animal and in vitro studies was conducted to evaluate the efficacy, toxicity, and biological properties of nanocarriers. Searches were performed in PubMed/Medline and Scopus from March 2023 to March 2024., Results: Eighteen studies were identified: 2 in vitro, 9 in vivo, and 7 combined. While epilepsy models and seizure control assessments were consistent, there was variability in evaluating the potential toxicity of nanocarriers. Only one study did not show a reduction in brain inflammation, seizures, and cell loss. Nanocarrier toxicity was evaluated just in six studies, all of which indicated low toxicity both in vitro and in vivo., Conclusions: Nanocarriers with antiseizure drugs manage seizures, inflammation, oxidative stress, and behavior impairment in drug-resistant epilepsy. Furthermore, nanocarriers are a safe option for delivering antiseizure drugs, though more research is needed to confirm these findings., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Introduction: Radiological investigations for epiphora often use techniques involving ionising radiation and may require invasive canalicular cannulation. Magnetic resonance dacryocystography (MRDCG) has been explored but is currently not widely utilised in clinical imaging departments. The aim of this technical report is to describe the optimisation of a non-invasive MRDCG technique using a continuous gadolinium drip to assess the anatomy and real-time functionality of the nasolacrimal drainage system (NLDS)., Methods: A protocol was developed on a 1.5 Tesla (1.5 T) magnetic resonance imaging (MRI) scanner using a 32-channel head coil. Coronal and axial T2-weighted sequences demonstrated the anatomy of the NLDS region. An automated slow drip infusion of gadolinium contrast media, diluted with saline (1:100), was delivered simultaneously to both eyes during a two-dimensional (2D) dynamic acquisition. Post-instillation, a three-dimensional (3D) T1-weighted sequence confirmed the presence or absence of contrast media in the NLDS., Results: Clear visualisation of the anatomy and real-time contrast flow through the NLDS were achieved in 85 % of cases., Conclusion: This non-invasive MRDCG technique can provide both anatomical and functional evaluation of the NLDS in under 30 minutes. Further work is needed to compare MRDCG findings to more established methods such as DCG and DSG., Competing Interests: Conflict of interest statement The authors have no conflicts of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Surgical site infections (SSIs) are a major driver of morbidity after combined liver and colorectal surgery for metastatic colorectal cancer. Available literature is inadequate to characterize risk factors and benchmarks for quality improvement., Methods: Consecutive cases of simultaneous liver and colorectal surgery for colorectal adenocarcinoma from November 2013 through September 2022 were reviewed for SSIs per National Surgical Quality Improvement Program (NSQIP) and National Healthcare Safety Network (NHSN) criteria. Univariable and multivariable logistic regression evaluated associations with NSQIP 30-day organ-space SSIs., Results: In 580 procedures, the rate of 30-day organ-space SSIs was 16% (n = 94) using NSQIP criteria and 11% (n = 64) using NHSN criteria; 4% (n = 24) had incisional SSIs by both criteria. Most organ-space SSIs were perihepatic, and a minority were associated with bile (26%) or anastomotic (15%) leak. Independent risk factors for organ-space SSIs included major liver resection, upper abdominal (compared with lower abdominal/pelvic) colorectal procedure, and ostomy reversal. Organ-space SSI rates increased over time by approximately 16% per calendar year (p = 0.02) despite a declining rate of major liver resection; incisional SSI rates remained low. Overall, major morbidity was 22%, with 7-day median length of stay (interquartile range 6-9) and 0.3% 90-day mortality., Conclusion: Organ-space SSIs are a significant driver of postoperative morbidity in simultaneous liver and colorectal resections for metastatic colorectal adenocarcinoma. Our findings confirm simultaneous resection remains safe and interventions to mitigate the risk of perihepatic organ-space SSIs in high-risk patients are warranted., Competing Interests: Disclosure. Lauren E. Schleimer, Lynn Hakki, Kenneth Seier, Susan K. Seo, Nina Cohen, Shauna Usiak, Tiffany Romero, Mini Kamboj, Crisanta Ilagan, Lily V. Saadat, Remo Alessandris, Kevin C. Soares, Maria Widmar, Iris H. Wei, Emmanouil P. Pappou, Philip B. Paty, Garrett M. Nash, William R. Jarnagin, Mithat Gonen, T. Peter Kingham, and Michael I. D’Angelica have no conflicts of interest to disclose. Jeffrey Drebin reports employment and leadership at American Regent (spouse), and stock and other ownership interests in Alnylam, Arrowhead Pharmaceuticals, and Ions Pharmaceuticals. Alice C. Wei reports consulting fees from Histosonics and institutional research funding from Ipsen. J. Joshua Smith reports travel support for fellow education from Intuitive Surgical (19/20 August 2015), serving as a clinical advisor for Guardant Health (19/20 March 2019) and Foundation Medicine (5 April 2022), serving as a consultant and speaker for Johnson & Johnson (8–10 May 2022), and serving as a clinical advisor and consultant for GlaxoSmithKline (2023). Julio Garcia-Aguilar reports consulting for Ethicon and Intuitive Surgical. Martin R. Weiser reports consulting for PrecisCa and intellectual property rights for UpToDate., (© 2024. Society of Surgical Oncology.)

Background: The role of stereotactic body radiation therapy (SBRT) in the management of advanced EGFR/ALK/ROS1-driven non-small cell lung carcinoma (NSCLC) remains undefined. In EGFR-mutant NSCLC, 50-60% of recurrences on first-line tyrosine kinase inhibitor (TKI) occur in originally involved sites and may lead to subsequent distant failures (DF). We sought to determine whether consolidative SBRT to residual sites reduces DF., Patients and Methods: This is a single-arm, phase II trial of SBRT to residual sites of disease in patients with metastatic oncogene-driven NSCLC with stable or responding disease to TKI within 12 months of treatment start. The primary endpoint was DF frequency at 12 months after SBRT., Results: Median follow-up was 57.1 months. The trial enrolled 27 of 30 planned patients between 2015 - 2021, stopping early due to slow accrual. Most (n = 22) had EGFR driver mutations. The majority (59.5%) were treated with later-generation TKIs. Median time from TKI start to SBRT was 6.4 months. Twenty-five patients (92.6%) received SBRT to the residual lung primary only. The 12-month DF rate was 19% (95% CI, 7-36%). Median PFS from SBRT was 15.0 months (95% CI, 8.6-46.7). Two-year LF rate of irradiated sites was 11% (95% CI, 3-27%). Two-year and median OS were 88% (95% CI, 68-96%) and 59.6 months (95% CI, 42.3-NR), respectively. There were no grade ≥3 adverse events related to SBRT., Conclusions: In patients treated with first-line TKIs, consolidative SBRT was associated with improvement in distant disease control compared with historical controls, supporting ongoing randomized trials., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: To prospectively assess the effect of endometriosis and uterine fibroids on the long term risk of premature mortality (younger than 70 years)., Design: Prospective cohort study SETTING: The Nurses' Health Study II, United States (1989-2019)., Participants: 110 091 women aged 25-42 years in 1989 without a history of hysterectomy before endometriosis or fibroids diagnosis, cardiovascular diseases, or cancer., Main Outcome Measures: Hazard ratios (estimated by Cox proportional hazards models) for total and cause specific premature mortality according to laparoscopically confirmed endometriosis or ultrasound or hysterectomy confirmed uterine fibroids reported in biennial questionnaires., Results: 4356 premature deaths were recorded during 2 994 354 person years of follow-up (27.2 years per person), including 1459 from cancer, 304 from cardiovascular diseases, and 90 from respiratory diseases. The crude incidence of all cause premature mortality for women with and without laparoscopically confirmed endometriosis was 2.01 and 1.40 per 1000 person years, respectively. In age adjusted models, laparoscopically confirmed endometriosis was associated with a hazard ratio of 1.19 (95% confidence interval 1.09 to 1.30) for premature death; these models were strengthened after also adjusting for potential confounders including behavioral factors (1.31, 1.20 to 1.44). Cause specific mortality analyses showed that the association was largely driven by mortality from senility and ill-defined diseases (1.80, 1.19 to 2.73), non-malignant respiratory diseases (1.95, 1.11 to 3.41), diseases of the nervous system and sense organs (2.50, 1.40 to 4.44), and malignant neoplasm of gynecological organs (2.76, 1.79 to 4.26). Ultrasound or hysterectomy confirmed uterine fibroids were not associated with all cause premature mortality (1.03, 0.95 to 1.11), but were associated with a greater risk of mortality from malignant neoplasm of gynecological organs (2.32, 1.59 to 3.40) in cause specific mortality analyses. The risk of mortality caused by cardiovascular and respiratory diseases varied according to joint categories of endometriosis and uterine fibroids, with an increased risk of all cause premature mortality among women reporting both endometriosis and uterine fibroids., Conclusion: Women with a history of endometriosis and uterine fibroids might have an increased long term risk of premature mortality extending beyond their reproductive lifespan. These conditions were also associated with an increased risk of death due to gynecological cancers. Endometriosis was associated with a greater risk of non-cancer mortality. These findings highlight the importance for primary care providers to consider these gynecological disorders in their assessment of women's health., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and have declared: support from National Natural Science Foundation of China and the National Institutes of Health for the submitted work. No financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Academic Burnout (ABO) is prevalent among medical students and is characterized by mental and physical exhaustion, cynicism, and a sense of inadequacy. Informal Peer-Assisted Learning (IPAL) is recognized as an effective strategy to enhance student wellness and mitigate ABO by fostering collaborative learning and support without direct faculty oversight. This study evaluates the effectiveness of IPAL in reducing ABO, focusing on the mediation of the observed variables and its impact on student well-being., Methods: This study extends previous research using Structural Equation Modeling (SEM) to include mediation analysis of the observed variables within the latent constructs of Cynicism (CY) and Inadequacy (IN) that are thought to influence the relationship between IPAL and ABO. Data were sourced from a validated Student Burnout Inventory (SBI-8) across a sample of medical students with varied IPAL engagement levels. Our approach used General Linear Model (GLM) mediation models to explore both direct and indirect effects of IPAL on ABO., Results: The indirect effect of IPAL on ABO is mediated through specific observed variables, including CY2 "loss of interest in academic work" (β = -0.092, CI, -0.174/-0.011, p = 0.027), IN1 "feeling of inadequacy" (β = -0.062, CI, -0.12/-0.005, p = 0.035), and IN2 "reduced academic expectations" (β = -0.042, CI, -0.079/-0.007, p = 0.025). The total effect of IPAL on ABO was significant (β = 0.170 CI, -0.326/-0.010, p = 0.034), the total indirect effect was significant (β = -0.197, CI, -0.338/-0.055, p = 0.006)., Conclusions: IPAL effectively addresses critical aspects of burnout, specifically through reducing feelings of cynicism and inadequacy among medical students. These results provide a valuable framework in designing targeted interventions to reduce ABO., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

In mammals, early embryonic gastrulation process is high energy demanding. Previous studies showed that, unlike endoderm and mesoderm cells, neuroectoderm differentiated from human embryonic stem cells relied on aerobic glycolysis as the major energy metabolic process, which generates lactate as the final product. Here we explored the function of intracellular lactate during neuroectoderm differentiation. Our results revealed that the intracellular lactate level was elevated in neuroectoderm and exogenous lactate could further promote hESCs differentiation towards neuroectoderm. Changing intracellular lactate levels by sodium lactate or LDHA inhibitors had no obvious effect on BMP or WNT/β-catenin signaling during neuroectoderm differentiation. Notably, histone lactylation, especially H3K18 lactylation was significant upregulated during this process. We further performed CUT&Tag experiments and the results showed that H3K18la is highly enriched at gene promoter regions. By analyzing data from CUT&Tag and RNA-seq experiments, we further identified that four genes, including PAX6, were transcriptionally upregulated by lactate during neuroectoderm differentiation. A H3K18la modification site at PAX6 promoter was verified and exogenous lactate could also rescue the level of PAX6 after shPAX6 inhibition., Competing Interests: Declarations Ethical approval Not applicable. Consent to participate Not applicable. Consent to publish Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: People hospitalised for coronavirus disease 2019 (COVID-19) have elevated incidence of diabetes. However, it is unclear whether this is due to shared risk factors, confounding or stress hyperglycaemia in response to acute illness., Methods: We analysed a multicentre prospective cohort study (PHOSP-COVID) of people ≥18 years discharged from NHS hospitals across the United Kingdom following COVID-19. Individuals were included if they attended at least one research visit with a HbA1c measurement within 14 months of discharge and had no history of diabetes at baseline. The primary outcome was new onset diabetes (any type), as defined by a first glycated haemoglobin (HbA1c) measurement ≥6.5% (≥48 mmol/mol). Follow-up was censored at the last HbA1c measurement. Age-standardised incidence rates and incidence rate ratios (adjusted for age, sex, ethnicity, length of hospital stay, body mass index, smoking, physical activity, deprivation, hypertension, hyperlipidaemia/hypercholesterolaemia, intensive therapy unit admission, invasive mechanical ventilation, corticosteroid use and C-reactive protein score) were calculated using Poisson regression. Incidence rates were compared with the control groups of published clinical trials in the United Kingdom by applying the same inclusion and exclusion criteria, where possible., Results: Incidence of diabetes was 91.4 per 1000 person-years and was higher in South Asian (incidence rate ratios [IRR] = 3.60; 1.77, 7.32; p < 0.001) and Black ethnic groups (IRR = 2.36; 1.07, 5.21; p = 0.03) compared with White ethnic groups. When restricted to similar characteristics, the incidence rates were similar to those in UK clinical trials data., Conclusion: Diabetes incidence following hospitalisation for COVID-19 is high, but it remains uncertain whether it is disproportionately higher than pre-pandemic levels., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

This clinical study aimed to assess the effectiveness and safety of Vuong Hoat (VH) natural health supplement for reducing the negative impact of low back pain, improving the quality of life, and enhancing functional activities in patients with lumbar degenerative disc disease (LDD). The open-label, randomized, controlled clinical trial involved 60 patients suffering from low back pain caused by LDD. The participants were randomly assigned to either a study group (SG) comprising 30 subjects or a control group (CG) comprising 30 subjects. Patients in the CG received treatment with electro-acupuncture, while those in the SG were administered VH in conjunction with the same electro-acupuncture protocol for 28 days. The clinical progression and tolerability of both groups were compared based on seven objective measurements: visual analog scale index, Schober test, fingertip-to-floor distance, spinal flexion, spinal extension, spinal tilt, and spinal rotation. After 14 days of treatment, the SG showed a significant improvement in overall outcomes compared to the CG. Specifically, 43.3% of SG patients achieved very good results, 53.3% had good results, and 3.4% had moderate results, whereas corresponding figures for the CG were 6.7%, 76.7%, and 16.6%, respectively ( P < .05). After 28 days of treatment, both groups demonstrated a shift toward very good results, with the SG continuing to show better outcomes than the CG ( P < .05). In the SG, the very good results increased to 76.7%, good results decreased to 20%, and moderate results were 3.3%. On the other hand, the CG had 46.7% very good results, 43.3% good results, and 10% moderate results. Notably, no side effects were reported from the VH treatments during the study. The findings of this study indicate that VH health supplement is a safe and effective approach for managing low back pain and limited spinal movement in patients with LDD.

Industrial pollution is a major driver of ecosystem degradation, but it can also act as a driver of contemporary evolution. As a result of intense mining activity during the Industrial Revolution, several rivers across the southwest of England are polluted with high concentrations of metals. Despite the documented negative impacts of ongoing metal pollution, brown trout (Salmo trutta L.) survive and thrive in many of these metal-impacted rivers. We used population genomics, transcriptomics, and metal burdens to investigate the genomic and transcriptomic signatures of potential metal tolerance. RADseq analysis of six populations (originating from three metal-impacted and three control rivers) revealed strong genetic substructuring between impacted and control populations. We identified selection signatures at 122 loci, including genes related to metal homeostasis and oxidative stress. Trout sampled from metal-impacted rivers exhibited significantly higher tissue concentrations of cadmium, copper, nickel and zinc, which remained elevated after 11 days in metal-free water. After depuration, we used RNAseq to quantify gene expression differences between metal-impacted and control trout, identifying 2042 differentially expressed genes (DEGs) in the gill, and 311 DEGs in the liver. Transcriptomic signatures in the gill were enriched for genes involved in ion transport processes, metal homeostasis, oxidative stress, hypoxia, and response to xenobiotics. Our findings reveal shared genomic and transcriptomic pathways involved in detoxification, oxidative stress responses and ion regulation. Overall, our results demonstrate the diverse effects of metal pollution in shaping both neutral and adaptive genetic variation, whilst also highlighting the potential role of constitutive gene expression in promoting metal tolerance., (© 2024 The Author(s). Molecular Ecology published by John Wiley & Sons Ltd.)

A bimetallic core-shell-shell nanorods structure with gap-embedded Raman reporter 5,5'-dithio-bis-(2-nitrobenzoic acid) (DTNB) was developed and applied as a SERS-active nanotag in surface-enhanced Raman scattering lateral flow immunoassay (SERS-LFIA) of the insecticide fipronil. Due to the strong SERS signal of the Au DTNB @Ag DTNB @AgNRods, fipronil is detected with extremely low detection limit of 4.6 pg/mL. To the best of our knowledge, the proposed technique is the first SERS-LFIA of fipronil, proven to be effective in the selective determination of the target analyte and capable of detecting fipronil in a matrix of food samples (cucumber and apple juice) with recoveries of 97.0-117.0%. Moreover, the applied functionalization of the SERS nanotag with anti-species antibodies has provided a versatile immunoprobe that could improve performance of different LFIAs., Competing Interests: Declarations Conflict of interest The authors have no relevant financial or non-financial interests to disclose.The authors have no conflicts of interest to declare that are relevant to the content of this article.All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.The authors have no financial or proprietary interests in any material discussed in this article., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Background: The global incidence of thyroid cancer has increased over the past several decades. While this increase is partially due to increased detection, environmental pollutants have also emerged as a possible contributing factor. Our goal was to perform a systematic review to assess the relationship between environmental air pollution and thyroid cancer. Methods: Systematic literature search was performed using PubMed, EMBASE, Cochrane Library, Web of Science, and Scopus databases for original articles published prior to March 2024, investigating outdoor air pollution and thyroid cancer/nodules (PROSPERO CRD42024517624). Inclusion criteria included quantitative reporting of pollutant levels and effect size. Specific pollutants included ozone (O 3 ), particulate matter less than 2.5 (PM 2.5 ) or 10 microns in diameter (PM 10 ), sulfur dioxide (SO 2 ), nitric oxides (NO x ), carbon monoxide (CO), and polyaromatic hydrocarbons (PAHs). Study design, sample size, pollution assessment method, covariates, and strength/direction of associations between pollutants and thyroid cancer/nodule detection were extracted, and descriptive synthesis was utilized to summarize pertinent findings. Risk of bias was assessed using the National Heart, Lung, and Blood Institute quality assessment tool. Results: Of 1294 identified studies, 11 met inclusion criteria. Over 6 million patients from diverse regions were represented across studies. Pollutants studied included O 3 in 5 studies; PM 2.5 , PM 10 , SO 2 , and NO x in 3 studies; unspecified PM and CO in 2 studies; and PAHs in 1 study. Primary outcome was thyroid cancer diagnosis among 9 studies and thyroid nodule detection in 2. All studies examining NO x and O 3 reported increased risks ranging from 1.03 to 1.5-fold and 1.1 to 1.3-fold, respectively. Both studies assessing PM 2.5 reported 1.18 to 1.23-fold increased odds of thyroid cancer diagnosis, and the magnitude of association increased with increasing duration or concentration of PM 2.5 Inconsistent results were observed for levels of CO, PM 10 , and SO 2 . Conclusion: While an emerging body of literature suggests a potential association between air pollution and thyroid cancer, the quality of evidence is limited by study design constraints, variability in exposure assessment, and inconsistent adjustment for potential confounding factors. The heterogeneity in study designs and methodologies present challenges in interpreting results, underscoring the need for standardized approaches in future research.

Introduction: In recent decades, centralization of health care has resulted in a number of obstetric unit closures. While studies support better infant outcomes in larger facilities, few have investigated maternal outcomes. We investigated obstetric unit closures over time and whether obstetric volume is associated with onset of labor, postpartum hemorrhage (PPH) and obstetric anal sphincter injury (OASIS)., Material and Methods: All births registered in Sweden between 1992 and 2019 (Medical Birth Register, N = 2 931 140), linked with data on sociodemographic characteristics and maternal/infant diagnoses, were used to describe obstetric unit closures. After excluding congenital malformations, obstetric volume was categorized (low: 0-1999, medium: 2000-3999, high: ≥4000 births per year). Restricting to 2004 onwards (after most closures), the association between volume and onset of labor (spontaneous as reference) was estimated. Restricting to spontaneous, full-term (≥37 weeks gestation) cephalic births, we then investigated the association between volume and PPH and, after excluding planned cesarean sections, OASIS. Odds ratios from multilevel (logistic) models clustered by hospital were estimated., Results: The 20 dissolved obstetric units (1992-2019) had relatively stable volume until their closure. Compared to the average, women birthing in the highest volume hospitals were older (31.3 years vs. 30.4) and a higher proportion had >12 years of education (57 vs. 51%). Compared to high-volume hospitals, there was no significant difference in labor starting by elective cesarean section or induction, rather than spontaneously, among low (OR 0.88, 95% CI: 0.73-1.06) and medium (OR 0.84, 95% CI 0.71-1.01) volume hospitals. There were lower odds of PPH among low (OR 0.72, 95% CI 0.63-0.85) and medium (OR 0.83, 95% CI 0.72-0.97) volume hospitals. No significant association was found between obstetric volume and OASIS (low: OR 0.98, 95% CI 0.82-1.18; medium: OR 0.90, 95% CI 0.77-1.05)., Conclusions: There was not a strong relationship between obstetric volume and maternal outcomes. Reduced odds of PPH for women birthing in smaller units may be due to triaging high-risk pregnancies to larger hospitals. While there was no significant association between obstetric volume and onset of labor or OASIS, other important factors related to closures, such as workload and overcrowding, should be investigated., (© 2024 The Author(s). Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

A family of Pd 2 L 4 cages prepared from ligands based on an axially chiral diamino-[1,1'-biazulene] motif (serving as a unique azulene-based surrogate of the ubiquitous BINOL moiety) is reported. We show that preparing a cage starting from the racemate of a shorter bis-monodentate ligand derivative, equipped with pyridine donor groups, leads to integrative ("social") chiral self-sorting, exclusively yielding the meso-trans product, but only in a selection of solvents. This phenomenon is driven by individual solvent molecules acting as hydrogen bonding tethers between the amino groups of neighboring ligands, thereby locking the final coordination cage in a single isomeric form. The experimental (solvent-dependent NMR, single-crystal X-ray diffraction) observations of this cooperative interaction could be explained by computational analyses only when explicit solvation was considered. Furthermore, we prepared a larger chiral ligand with isoquinoline donors, which, unlike the first one, does not undergo social self-sorting from its racemic mixture, further highlighting the importance of solvents bridging short distances between the amino groups. Homochiral cages formed from this larger ligand, however, furnish a cavity that can bind anionic and neutral metal complexes such as [Pt(CN) 6 ] 2- and Cr(CO) 6 and discriminate between the two enantiomers of chiral guest camphor sulfonate.

As global temperatures rise, improving crop yields will require enhancing the thermotolerance of crops. One approach for improving thermotolerance is using bioengineering to increase the thermostability of enzymes catalysing essential biological processes. Photorespiration is an essential recycling process in plants that is integral to photosynthesis and crop growth. The enzymes of photorespiration are targets for enhancing plant thermotolerance as this pathway limits carbon fixation at elevated temperatures. We explored the effects of temperature on the activity of the photorespiratory enzyme glycerate kinase (GLYK) from various organisms and the homologue from the thermophilic alga Cyanidioschyzon merolae was more thermotolerant than those from mesophilic plants, including Arabidopsis thaliana. To understand enzyme features underlying the thermotolerance of C. merolae GLYK (CmGLYK), we performed molecular dynamics simulations using AlphaFold-predicted structures, which revealed greater movement of loop regions of mesophilic plant GLYKs at higher temperatures compared to CmGLYK. Based on these simulations, hybrid proteins were produced and analysed. These hybrid enzymes contained loop regions from CmGLYK replacing the most mobile corresponding loops of AtGLYK. Two of these hybrid enzymes had enhanced thermostability, with melting temperatures increased by 6 °C. One hybrid with three grafted loops maintained higher activity at elevated temperatures. Whilst this hybrid enzyme exhibited enhanced thermostability and a similar K m for ATP compared to AtGLYK, its K m for glycerate increased threefold. This study demonstrates that molecular dynamics simulation-guided structure-based recombination offers a promising strategy for enhancing the thermostability of other plant enzymes with possible application to increasing the thermotolerance of plants under warming climates., (© 2024 The Author(s). Plant Biotechnology Journal published by Society for Experimental Biology and The Association of Applied Biologists and John Wiley & Sons Ltd.)

Colorectal cancer (CRC) is a common cancer in Ireland. Of all CRCs, 2-4% are attributable to Lynch Syndrome (LS), the most common CRC predisposition syndrome. LS is caused by constitutional pathogenic variants (PVs) affecting mismatch repair (MMR) genes with resultant MMR protein deficiency (dMMR). Screening of all CRCs with MMR immunohistochemistry (IHC) testing is advocated to increase the detection of LS. However, successful implementation requires appropriate downstream management. In Ireland the traditional pathway involves referral to cancer genetics services to assess eligibility for genetic testing. Cancer genetics services in Ireland face many challenges in providing uniform access to timely healthcare with current wait times for assessment in excess of 1 year. An increasingly adopted pathway is that of mainstreaming, whereby genetic testing is managed locally by a multidisciplinary team member. Our institution therefore implemented an Advanced Nurse Practitioner (ANP)-led service with responsibility for the LS Diagnostic Pathway and mainstream genetic testing. Data was extracted from a prospectively maintained database of all newly diagnosed CRC patients discussed at our institutions CRC multidisciplinary meeting (MDM) between January 1st, 2023, and May 31st, 2024. MMR IHC testing was performed in 97.9% of the 385 patients diagnosed with CRC. The median time from histological confirmation of CRC to the availability of the MMR IHC report was 6 days. All 51 patients (100%) who required sequential tumor testing underwent BRAF V600 ± MLH1 promoter methylation testing. Additionally, 100% of the 14 patients eligible for mainstream genetic testing were referred to the ANP-led genetics service. The median time from the initial MDM discussion to the initiation of genetic testing was 69 days, while the median time from testing to the availability of results was 19 days. Patients received their results within a median of 21 days. MMR IHC testing increases the detection of LS through identification of dMMR tumours. Successful downstream delivery of clinical services, however, requires appropriate subsequent management, in a resource-limited environment. Our institutional experience demonstrates the feasibility, efficiency, and effectiveness of an ANP-led mainstreaming model of care for hereditary colorectal cancer., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Aging is a complex process associated with multimorbidity. Hypertension, one of widespread states, is among main causes of age-related alterations in behavior, emotionality and sociability. We studied the effects of long-term isolated housing on anxiety, depressive-like and social behavior as well as changes in the adrenocortical and sympathetic systems in the aging normotensive Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR). Ten-month-old male rats of both strains were subjected to 90-day isolated or group housing. Surprisingly, social isolation induced only mild effect on anxiety without influencing other affective-related behaviors. No effects of isolated housing on sociability or social novelty preferences were revealed. Despite the adrenal gland hypertrophy in the SHRs, corticosterone levels remained stable within the period of isolation but the expression of nuclear glucocorticoid receptor (Nr3c1) mRNA in the adrenals was lower in the SHR as compared to WKY rats. Pre-existing hypertension, associated with SHR genotype, did not significantly contribute to the effects of social isolation. The data suggest that the aged WKY and SHR rats are relatively resilient to chronic social stress associated with isolated housing., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: Although prior studies of tuberculosis-preventive treatment (TPT) for pregnant people with human immunodeficiency virus (PPWH) report conflicting adverse pregnancy outcome (APO) risks, international guidelines recommend TPT for PPWH., Methods: We used a microsimulation model to evaluate 5 TPT strategies among PPWH receiving antiretroviral therapy in South Africa: No TPT; 6 months of isoniazid (6H) or 3 months of isoniazid-rifapentine (3HP) during pregnancy (Immediate 6H or Immediate 3HP) or post partum (Deferred 6H or Deferred 3HP). The primary outcomes were maternal, fetal/infant, and combined deaths from causes potentially influenced by TPT (maternal tuberculosis, maternal hepatotoxicity, stillbirth, low birth weight [LBW], and infant tuberculosis). Tuberculosis during pregnancy confers 250% and 81% higher modeled risks of stillbirth and LBW, respectively. In lower-risk or higher-risk scenarios, immediate TPT confers 38% lower or 92% higher risks of stillbirth and 16% lower or 35% higher risks of LBW., Results: Immediate TPT would minimize deaths among PPWH. When TPT confers higher stillbirth and LBW risks, immediate TPT would produce the most combined maternal and fetal/infant deaths, even with low maternal CD4 cell count and high tuberculosis incidence. If immediate TPT yields a <4% or <20% increase in stillbirth or LBW, immediate TPT would produce fewer combined deaths than deferred TPT (sensitivity analysis range, <2%-22% and <11%-120%, respectively)., Conclusions: If APO risks are below identifiable thresholds, TPT during pregnancy could decrease combined maternal and fetal/infant deaths. Given uncertainty around isoniazid's risks, and the low threshold at which APO risks could outweigh benefits from tuberculosis deaths averted, studies of newer TPT regimens among PPWH are warranted to inform guidelines., Competing Interests: Potential conflicts of interest . E. K. discloses prior funding from ViiV Healthcare for an unrelated project. S. M. L. reports royalties from UpToDate for articles on tuberculosis infection in pregnancy. All other authors declare no conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

The hydrate of a neutral iron(III) complex based on the pyruvic acid thiosemicarbazone ligand [Fe III (Hthpy)(thpy)]·H 2 O (1) was synthesized and characterized using FT-IR spectroscopy, powder and single-crystal X-ray diffraction, dc magnetic measurements, EPR and 57 Fe Mössbauer spectroscopy. The crystal structure of 1 was determined for the first time. Two distinct chelating ligands Hthpy - and thpy 2- coordinate the Fe(III) ion to form the FeN 2 O 2 S 2 octahedron which shows a low spin geometry at 150-350 K. The crystal packing contains infinite chains of the Fe(III) complexes as well as water molecules located in cavities. Along the chain, π-π interacting pairs of the Fe complexes are linked by H-bonding. According to the dc magnetic measurements, the complete abrupt spin-crossover with half-transition temperature T 1/2 = 340 K and a hysteresis loop of 45 K occurs in the temperature range of 300-363 K. Based on the X-ray structure of 1, the Bleaney-Bowers equation for the isolated dimer model was used to approximate the temperature dependence of the magnetic susceptibility in the range of 2-50 K. The defined intradimer exchange constant J exp = -0.498(1) K corresponds to a weak antiferromagnetic exchange between the iron(III) magnetic centers. DFT calculations of H- and π-π bonded fragments of the crystal structure of 1 in the HS and LS states were carried out. Moreover, BS-DFT calculations confirm the presence of antiferromagnetic exchange J calc = -0.92 K in the π-π bonded pairs of the ferric complexes and show the exchange pathway between Fe(III) ions by the calculated spin density distribution.

In order to evaluate mercury (Hg) accumulation patterns in Southern Ocean penguins, we measured Hg concentrations and carbon (δ 13 C) and nitrogen (δ 15 N) stable isotope ratios in body feathers of adult Adélie (Pygoscelis adeliae), gentoo (Pygoscelis papua), and chinstrap (Pygoscelis antarctica) penguins living near Anvers Island, West Antarctic Peninsula (WAP) collected in the 2010/2011 austral summer. With these and data from Pygoscelis and other penguin genera (Eudyptes and Aptenodytes) throughout the Southern Ocean, we modelled Hg variation using δ 13 C and δ 15 N values. Mean concentrations of Hg in feathers of Adélie (0.09 ± 0.05 μg g -1 ) and gentoo (0.16 ± 0.08 μg g -1 ) penguins from Anvers Island were among the lowest ever reported for the Southern Ocean. However, Hg concentrations in chinstrap penguins (0.80 ± 0.20 μg g -1 ), which undertake relatively broad longitudinal winter migrations north of expanding sea ice, were significantly higher (P < 0.001) than those in gentoo or Adélie penguins. δ 13 C and δ 15 N values for feathers from all three Anvers Island populations were also the lowest among those previously reported for Southern Ocean penguins foraging within Antarctic and subantarctic waters. These observations, along with size distributions of WAP krill, suggest foraging during non-breeding seasons as a primary contributor to higher Hg accumulation in chinstraps relative to other sympatric Pygoscelis along the WAP. δ 13 C values for all Southern Ocean penguin populations, alone best explained feather Hg concentrations among possible generalized linear models (GLMs) for populations grouped by either breeding site (AICc = 36.9, w i  = 0.0590) or Antarctic Frontal Zone (AICc = 36.9, w i  = 0.0537). Although Hg feather concentrations can vary locally by species, there was an insignificant species-level effect (w i  < 0.001) across the full latitudinal range examined. Therefore, feeding ecology at breeding locations, as tracked by δ 13 C, control Hg accumulation in penguin populations across the Southern Ocean., Competing Interests: Declaration of competing interest The authors declare no competing financial interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Musculoskeletal simulations are a useful tool for improving our understanding of the human body. However, the physiological validity of predicted kinematics and forces is highly dependent upon the correct calibration of muscle parameters and the structural integrity of a model's internal skeletal structure. In this study, we show how ill-tuned muscle parameters and unphysiological deformations of a model's skeletal structure can be detected by using muscle elements as sensors with which modelling and parameterization inconsistencies can be identified through muscle and tendon strain injury assessment. To illustrate our approach, two modelling issues were recreated. First, a model repositioning simulation using the THUMS AM50 occupant model version 5.03 was performed to show how internal model deformations can occur during a change of model posture. Second, the muscle material parameters of the OpenSim gait2354 model were varied to illustrate how unphysiological muscle forces can arise if material parameters are inadequately calibrated. The simulations were assessed for muscle and tendon strain injuries using previously published injury criteria and a newly developed method to determine tendon strain injury threshold values. Muscle strain injuries in the left and right musculus pronator teres were detected during the model repositioning. This straining was caused by an unphysiologically large gap (12.92 mm) that had formed in the elbow joint. Similarly, muscle and tendon strain injuries were detected in the modified right-hand musculus gastrocnemius medialis of the gait2354 model where an unphysiological reduction of the tendon slack length introduced large pre-strain of the muscle-tendon unit. The results of this work show that the proposed method can quantify the internal distortion behaviour of musculoskeletal human body models and the plausibility of Hill-type muscle parameter choice via strain injury assessment. Furthermore, we highlight possible actions to avoid the presented issues and inconsistencies in literature data concerning the material characteristics of human tendons., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Nölle et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Human induced pluripotent stem cells (hiPSCs) have great potential to be used as alternatives to embryonic stem cells (hESCs) in regenerative medicine and disease modelling. In this study, we characterise the proteomes of multiple hiPSC and hESC lines derived from independent donors and find that while they express a near-identical set of proteins, they show consistent quantitative differences in the abundance of a subset of proteins. hiPSCs have increased total protein content, while maintaining a comparable cell cycle profile to hESCs, with increased abundance of cytoplasmic and mitochondrial proteins required to sustain high growth rates, including nutrient transporters and metabolic proteins. Prominent changes detected in proteins involved in mitochondrial metabolism correlated with enhanced mitochondrial potential, shown using high-resolution respirometry. hiPSCs also produced higher levels of secreted proteins, including growth factors and proteins involved in the inhibition of the immune system. The data indicate that reprogramming of fibroblasts to hiPSCs produces important differences in cytoplasmic and mitochondrial proteins compared to hESCs, with consequences affecting growth and metabolism. This study improves our understanding of the molecular differences between hiPSCs and hESCs, with implications for potential risks and benefits for their use in future disease modelling and therapeutic applications., Competing Interests: AB, LS, LD, AP, FS, EH, CE, HJ, HY, GF, DC No competing interests declared, EG Now works for Boehringer Ingelheim Pharma GmbH & Co KG, MP Board member of Tartan Cell Technologies Ltd, JS Board member of Tartan Cell Technologies Ltd and Glencoe Software Ltd, AL Board member of Tartan Cell Technologies Ltd and Platinum Informatics Ltd, (© 2024, Brenes et al.)