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Competing Interests: Disclosures None of the authors reported any disclosures.

Both the 2022 WHO HAEM5 and the International Consensus Classification of lymphoma have refined the way we now approach high-grade B-cell lymphoma (HGBL) with MYC and BCL2 and/or BCL6 rearrangements moving the previous generation of classification a step forward. The unifying biology of MYC/BCL2 tumours has been clearer and their inferior prognosis confirmed compared to those with morphological similarities but lacking the classifying cytogenetic abnormalities. FISH testing has largely become population based and we have learnt much from this. We can readily define molecular categories and apply these widely to clinical practice. Uncertainty has however been shed upon the place of double MYC/BCL6 translocations in defining a common disease group. We have enhanced knowledge of outcomes and the role of therapy intensification to overcome chemotherapy resistance. For those patients failed by initial induction chemotherapy, immunotherapy approaches, including CAR-T therapies, are improving outcomes. Novel inhibitors, targeting dysregulated oncogenic proteins are being explored at pace. The rare, but difficult, diagnostic classification HGBL (NOS) remains a diagnosis of exclusion with limited data on an optimal clinical approach. The days of talking loosely of double and triple hit lymphoma are numbered as this review synergises the current data on biology, prognosis, and therapies in HGBL., (Copyright © 2024 American Society of Hematology.)

MYC translocation occurs in 8-14% of diffuse large B-cell lymphoma (DLBCL), and may concur with BCL2 and/or BCL6 translocation, known as double-hit (DH) or triple-hit (TH). DLBCL-MYC/BCL2-DH/TH are largely germinal centre B-cell like subtype, but show variable clinical outcome, with IG::MYC fusion significantly associated with inferior survival. While DLBCL-MYC/BCL6-DH are variable in their cell-of-origin subtypes and clinical outcome. Intriguingly, only 40-50% of DLBCL with MYC translocation show high MYC protein expression (>70%). We studied 186 DLBCLs with MYC translocation including 32 MYC/BCL2/BCL6-TH, 75 MYC/BCL2-DH and 26 MYC/BCL6-DH. FISH revealed a MYC/BCL6 fusion in 59% of DLBCL-MYC/BCL2/BCL6-TH and 27% of DLBCL-MYC/BCL6-DH. Targeted NGS showed a similar mutation profile and LymphGen genetic subtype between DLBCL-MYC/BCL2/BCL6-TH and DLBCL-MYC/BCL2-DH, but variable LymphGen subtypes among DLBCL-MYC/BCL6-DH. MYC protein expression is uniformly high in DLBCL with IG::MYC, but variable in those with non-IG::MYC including MYC/BCL6-fusion. Translocation breakpoint analyses of 8 cases by TLC-based NGS showed no obvious genomic configuration that enables MYC transactivation in 3 of the 4 cases with non-IG::MYC, while a typical promoter substitution or IGH super enhancer juxtaposition in the remaining cases. The findings potentially explain variable MYC expression in DLBCL with MYC translocation, and also bear practical implications in its routine assessment., (© 2024. The Author(s).)

The advent of immunotherapy in lymphomas, beginning with Rituximab, have led to paradigm shifting treatments that are increasingly bringing a greater number of affected patients within the ambit of durable disease control and cure. Bispecific antibodies harness the properties of the immunoglobulin antibody structure to design molecules which, apart from engaging with the target tumour associated antigen, engage the host's T-cells to cause tumour cell death. Mosunetuzumab, an anti-CD20 directed bispecific antibody was the first to be approved in follicular lymphoma, this has now been followed by quick approvals of Glofitamab and Epcoritamab in diffuse large B-cell lymphomas. This article reviews contemporary data and ongoing studies evaluating the role of bispecific antibodies in indolent b-cell non Hodgkin lymphomas. This is an area of active research and presents many opportunities in advancing the treatment of indolent lymphomas and potentially forge a chemo-free treatment paradigm in this condition., Competing Interests: AD reports a relationship with the following: F Hoffmann-La Roche Ltd that includes consulting or advisory, funding grants, speaking and lecture fees, and travel reimbursement; AbbVie Ltd. that includes consulting or advisory; Genmab BV that includes consulting or advisory; AstraZeneca that includes consulting or advisory and funding grants; Sobi Inc that includes consulting or advisory; Incyte Corporation that includes consulting or advisory; CellCentric Limited that includes funding grants; Bristol Myers Squibb Co that includes consulting or advisory and funding grants; Gilead Sciences Kite HQ that includes consulting or advisory. VR reports a relationship with the following: AbbVie Inc that includes travel reimbursement; Cancer Research UK that includes travel reimbursement; AstraZeneca India Private Limited that includes non-financial support; Pfizer India that includes consulting or advisory; Roche Products India Pvt. Ltd that includes consulting or advisory; European Society for Medical Oncology that includes non-financial support; Intas Pharmaceuticals Ltd that includes non-financial support and travel reimbursement., (Copyright © 2024 Radhakrishnan and Davies.)

Intertidal artificial habitats are proliferating, but are generally simpler in structure and host lower biodiversity than natural rocky reefs. Eco-engineering aims to enhance the biodiversity of coastal infrastructure, often through physical structural modifications that mimic topographic properties of natural shores. Relationships between biotic assemblages and structural properties of natural and artificial reefs have been extensively studied at sampling scales of up to 1 m 2 . But evidence that quantified local structural variation has an appreciable influence on biotic assemblages, at a shore-wide scale across regional environmental gradients, is lacking. Here we addressed this knowledge gap with an observational study at 32 natural and artificial intertidal reef sites in Wales, UK. We used multivariate community analysis and permutation tests to examine associations between local physical structure, regional environmental variables and sessile biotic assemblages. A potential influence of local habitat structure on assemblage composition was evident across regional-scale environmental gradients. Compared to natural sites, artificial reefs had lower taxonomic richness, distinct and more variable assemblage composition, and different physical structure. After removing the effect of habitat (natural or artificial), canonical correspondence analysis showed that environmental variables (wave exposure, sea surface temperature and salinity variation), along with two metrics of physical structure (standard deviation in log-transformed detrended roughness and skewness of surface verticality, both at 0.5 m scale), explained 40 % of the variation in assemblage composition among sites. The two structural metrics independently explained 14.5 % of the variation. Associations identified between individual taxa and environmental variables indicated that sites with a higher proportion of horizontal surfaces hosted more canopy macroalgae, which in turn support other algae and invertebrates. Our findings provide evidence to inform scaling-up of structural eco-engineering interventions from experimental contexts to enhance the biodiversity of coastal infrastructure across regional extents., 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 © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Dietary practices of masters athletes (MAs) may promote healthy ageing; however, they are poorly understood. The aims of this systematic review were to synthesise the literature on the dietary intakes of MAs and undertake comparisons between younger (35-50 years) and older (>50 years) MAs and the general population. A search was conducted across seven databases to identify relevant publications for screening and data extraction. Averages for energy intake (EI), macronutrients, and micronutrients were compared with data from the 2011-2012 Australian Health Survey (general population). Twenty-six studies ( n = 2819) were included. Energy intake was higher for older (8908 kJ/d versus 7792 kJ/d) but not younger MAs (9073 kJ/d versus 8872 kJ/d) versus the general population. Younger versus older male MAs had higher energy and macronutrient intakes. Energy intake for older was comparable to younger female MAs (7819 kJ/d versus 7485 kJ/d), but older had higher protein, lower carbohydrate, and higher micronutrient intakes. Micronutrient intake was higher in MAs than the general population. Similar EIs for older MAs and younger general population may indicate potential for a higher-quality diet. Younger female MAs may restrict or misreport EI, requiring further investigation. There is a need for more comprehensive assessments of dietary intake in MAs to ascertain diet quality in relation to health.

Predictive models can improve the efficiency of wildlife management by guiding actions at the local, landscape and regional scales. In recent decades, a vast range of modelling techniques have been developed to predict species distributions and patterns of population spread. However, data limitations often constrain the precision and biological realism of models, which make them less useful for supporting decision-making. Complex models can also be challenging to evaluate, and the results are often difficult to interpret for wildlife management practitioners. There is therefore a need to develop techniques that are appropriately robust, but also accessible to a range of end users. We developed a hybrid species distribution model that utilises commonly available presence-only distribution data and minimal demographic information to predict the spread of roe deer ( Capreolus caprelous ) in Great Britain. We take a novel approach to representing the environment in the model by constraining the size of habitat patches to the home-range area of an individual. Population dynamics are then simplified to a set of generic rules describing patch occupancy. The model is constructed and evaluated using data from a populated region (England and Scotland) and applied to predict regional-scale patterns of spread in a novel region (Wales). It is used to forecast the relative timing of colonisation events and identify important areas for targeted surveillance and management. The study demonstrates the utility of presence-only data for predicting the spread of animal species and describes a method of reducing model complexity while retaining important environmental detail and biological realism. Our modelling approach provides a much-needed opportunity for users without specialist expertise in computer coding to leverage limited data and make robust, easily interpretable predictions of spread to inform proactive population management., Competing Interests: The authors declare that no competing interests exist., (© 2023 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)

Coral reefs are iconic ecosystems that support diverse, productive communities in both shallow and deep waters. However, our incomplete knowledge of cold-water coral (CWC) niche space limits our understanding of their distribution and precludes a complete accounting of the ecosystem services they provide. Here, we present the results of recent surveys of the CWC mound province on the Blake Plateau off the U.S. east coast, an area of intense human activity including fisheries and naval operations, and potentially energy and mineral extraction. At one site, CWC mounds are arranged in lines that total over 150 km in length, making this one of the largest reef complexes discovered in the deep ocean. This site experiences rapid and extreme shifts in temperature between 4.3 and 10.7 °C, and currents approaching 1 m s -1 . Carbon is transported to depth by mesopelagic micronekton and nutrient cycling on the reef results in some of the highest nitrate concentrations recorded in the region. Predictive models reveal expanded areas of highly suitable habitat that currently remain unexplored. Multidisciplinary exploration of this new site has expanded understanding of the cold-water coral niche, improved our accounting of the ecosystem services of the reef habitat, and emphasizes the importance of properly managing these systems., (© 2023. The Author(s).)

Abstract: Traumatic peripheral nerve injuries are at high risk of neuropathic pain for which novel effective therapies are urgently needed. Preclinical models of neuropathic pain typically involve irreversible ligation and/or nerve transection (neurotmesis). However, translation of findings to the clinic has so far been unsuccessful, raising questions on injury model validity and clinically relevance. Traumatic nerve injuries seen in the clinic commonly result in axonotmesis (ie, crush), yet the neuropathic phenotype of "painful" nerve crush injuries remains poorly understood. We report the neuropathology and sensory symptoms of a focal nerve crush injury using custom-modified hemostats resulting in either complete ("full") or incomplete ("partial") axonotmesis in adult mice. Assays of thermal and mechanically evoked pain-like behavior were paralleled by transmission electron microscopy, immunohistochemistry, and anatomical tracing of the peripheral nerve. In both crush models, motor function was equally affected early after injury; by contrast, partial crush of the nerve resulted in the early return of pinprick sensitivity, followed by a transient thermal and chronic tactile hypersensitivity of the affected hind paw, which was not observed after a full crush injury. The partially crushed nerve was characterized by the sparing of small-diameter myelinated axons and intraepidermal nerve fibers, fewer dorsal root ganglia expressing the injury marker activating transcription factor 3, and lower serum levels of neurofilament light chain. By day 30, axons showed signs of reduced myelin thickness. In summary, the escape of small-diameter axons from Wallerian degeneration is likely a determinant of chronic pain pathophysiology distinct from the general response to complete nerve injury., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

Rationale & Objective: PRESERVE seeks to provide new knowledge to inform shared decision-making regarding blood pressure (BP) management for pediatric chronic kidney disease (CKD). PRESERVE will compare the effectiveness of alternative strategies for monitoring and treating hypertension on preserving kidney function; expand the National Patient-Centered Clinical Research Network (PCORnet) common data model by adding pediatric- and kidney-specific variables and linking electronic health record data to other kidney disease databases; and assess the lived experiences of patients related to BP management., Study Design: Multicenter retrospective cohort study (clinical outcomes) and cross-sectional study (patient-reported outcomes [PROs])., Setting & Participants: PRESERVE will include approximately 20,000 children between January 2009-December 2022 with mild-moderate CKD from 15 health care institutions that participate in 6 PCORnet Clinical Research Networks (PEDSnet, STAR, GPC, PaTH, CAPRiCORN, and OneFlorida+). The inclusion criteria were ≥1 nephrologist visit and ≥2 estimated glomerular filtration rate (eGFR) values in the range of 30 to <90 mL/min/1.73 m 2 separated by ≥90 days without an intervening value ≥90 mL/min/1.73 m 2 and no prior dialysis or kidney transplant., Exposures: BP measurements (clinic-based and 24-hour ambulatory BP); urine protein; and antihypertensive treatment by therapeutic class., Outcomes: The primary outcome is a composite event of a 50% reduction in eGFR, eGFR of <15 mL/min/1.73 m 2 , long-term dialysis or kidney transplant. Secondary outcomes include change in eGFR, adverse events, and PROs., Analytical Approach: Longitudinal models for dichotomous (proportional hazards or accelerated failure time) and continuous (generalized linear mixed models) clinical outcomes; multivariable linear regression for PROs. We will evaluate heterogeneity of treatment effect by CKD etiology and degree of proteinuria and will examine variation in hypertension management and outcomes based on socio-demographics., Limitations: Causal inference limited by observational analyses., Conclusions: PRESERVE will leverage the PCORnet infrastructure to conduct large-scale observational studies that address BP management knowledge gaps for pediatric CKD, focusing on outcomes that are meaningful to patients., Plain-Language Summary: Hypertension is a major modifiable contributor to loss of kidney function in chronic kidney disease (CKD). The purpose of PRESERVE is to provide evidence to inform shared decision-making regarding blood pressure management for children with CKD. PRESERVE is a consortium of 16 health care institutions in PCORnet, the National Patient-Centered Clinical Research Network, and includes electronic health record data for >19,000 children with CKD. PRESERVE will (1) expand the PCORnet infrastructure for research in pediatric CKD by adding kidney-specific variables and linking electronic health record data to other kidney disease databases; (2) compare the effectiveness of alternative strategies for monitoring and treating hypertension on preserving kidney function; and (3) assess the lived experiences of patients and caregivers related to blood pressure management., (© 2023 Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc.)

Novel disease-modifying treatments for neuropathic pain are urgently required. The cellular immune response to nerve injury represents a promising target for therapeutic development. Recently, the role of natural killer (NK) cells in both CNS and PNS disease has been the subject of growing interest. In this opinion article, we set out the case for NK cell-based intervention as a promising avenue for development in the management of neuropathic pain. We explore the potential cellular and molecular targets of NK cells in the PNS by contrasting with their reported functional roles in CNS diseases, and we suggest strategies for using the beneficial functions of NK cells and immune-based therapeutics in the context of neuropathic pain., Competing Interests: Declaration of interests H.W.K., A.J.D., and S.B.O. are named inventors on a patent for the use of immune cells in the treatment of nerve injury. S.W. has no interests to declare., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. The REMoDL-B phase III adaptive trial compared rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) versus R-CHOP + bortezomib (RB-CHOP) in patients with diffuse large B-cell lymphoma (DLBCL), stratified by molecular subtype. Primary analysis at a median follow-up of 30 months found no effect of bortezomib on progression-free survival (PFS) or overall survival (OS). Retrospective analysis using a gene expression-based classifier identified a molecular high-grade (MHG) group with worse outcomes. We present an updated analysis for patients successfully classified by the gene expression profile (GEP). Eligible patients were age older than 18 years with untreated DLBCL, fit enough for full-dose chemotherapy, and with adequate biopsies for GEP. Of 1,077 patients registered, 801 were identified with Activated B-Cell (ABC), Germinal Center B-cell, or MHG lymphoma. At a median follow-up of 64 months, there was no overall benefit of bortezomib on PFS or OS (5-year PFS hazard ratio [HR], 0.81; P = .085; OS HR, 0.86; P = .32). However, improved PFS and OS were seen in ABC lymphomas after RB-CHOP: 5-year OS 67% with R-CHOP versus 80% with RB-CHOP (HR, 0.58; 95% CI, 0.35 to 0.95; P = .032). Five-year PFS was higher in MHG lymphomas: 29% versus 55% (HR, 0.46; 95% CI, 0.26 to 0.84). Patients with ABC and MHG DLBCL may benefit from the addition of bortezomib to R-CHOP in initial therapy.

The dinosaur-bird transition involved several anatomical, biomechanical, and physiological modifications of the theropod bauplan. Non-avian maniraptoran theropods, such as Troodon , are key to better understand changes in thermophysiology and reproduction occurring during this transition. Here, we applied dual clumped isotope (Δ 47 and Δ 48 ) thermometry, a technique that resolves mineralization temperature and other nonthermal information recorded in carbonates, to eggshells from Troodon , modern reptiles, and modern birds. Troodon eggshells show variable temperatures, namely 42 and 29 ± 2 °C, supporting the hypothesis of an endothermic thermophysiology with a heterothermic strategy for this extinct taxon. Dual clumped isotope data also reveal physiological differences in the reproductive systems between Troodon , reptiles, and birds. Troodon and modern reptiles mineralize their eggshells indistinguishable from dual clumped isotope equilibrium, while birds precipitate eggshells characterized by a positive disequilibrium offset in Δ 48 . Analyses of inorganic calcites suggest that the observed disequilibrium pattern in birds is linked to an amorphous calcium carbonate (ACC) precursor, a carbonate phase known to accelerate eggshell formation in birds. Lack of disequilibrium patterns in reptile and Troodon eggshells implies these vertebrates had not acquired the fast, ACC-based eggshell calcification process characteristic of birds. Observation that Troodon retained a slow reptile-like calcification suggests that it possessed two functional ovaries and was limited in the number of eggs it could produce; thus its large clutches would have been laid by several females. Dual clumped isotope analysis of eggshells of extinct vertebrates sheds light on physiological information otherwise inaccessible in the fossil record.

Membranous glomerulonephritis (MGN) is a common cause of nephrotic syndrome in adults, mediated by glomerular antibody deposition to an increasing number of newly recognised antigens. Previous case reports have suggested an association between patients with anti-contactin-1 (CNTN1)-mediated neuropathies and MGN. In an observational study we investigated the pathobiology and extent of this potential cause of MGN by examining the association of antibodies against CNTN1 with the clinical features of a cohort of 468 patients with suspected immune-mediated neuropathies, 295 with idiopathic MGN, and 256 controls. Neuronal and glomerular binding of patient IgG, serum CNTN1 antibody and protein levels, as well as immune-complex deposition were determined. We identified 15 patients with immune-mediated neuropathy and concurrent nephrotic syndrome (biopsy proven MGN in 12/12), and 4 patients with isolated MGN from an idiopathic MGN cohort, all seropositive for IgG4 CNTN1 antibodies. CNTN1-containing immune complexes were found in the renal glomeruli of patients with CNTN1 antibodies, but not in control kidneys. CNTN1 peptides were identified in glomeruli by mass spectroscopy. CNTN1 seropositive patients were largely resistant to first-line neuropathy treatments but achieved a good outcome with escalation therapies. Neurological and renal function improved in parallel with suppressed antibody titres. The reason for isolated MGN without clinical neuropathy is unclear. We show that CNTN1, found in peripheral nerves and kidney glomeruli, is a common target for autoantibody-mediated pathology and may account for between 1 and 2% of idiopathic MGN cases. Greater awareness of this cross-system syndrome should facilitate earlier diagnosis and more timely use of effective treatment., Competing Interests: SR runs a not-for-profit diagnostic testing service for nodal/paranodal antibodies. All other authors have declared that no competing interests exist. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Fehmi 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.)

Distributional shifts in species ranges provide critical evidence of ecological responses to climate change. Assessments of climate-driven changes typically focus on broad-scale range shifts (e.g. poleward or upward), with ecological consequences at regional and local scales commonly overlooked. While these changes are informative for species presenting continuous geographic ranges, many species have discontinuous distributions-both natural (e.g. mountain or coastal species) or human-induced (e.g. species inhabiting fragmented landscapes)-where within-range changes can be significant. Here, we use an ecosystem engineer species (Sabellaria alveolata) with a naturally fragmented distribution as a case study to assess climate-driven changes in within-range occupancy across its entire global distribution. To this end, we applied landscape ecology metrics to outputs from species distribution modelling (SDM) in a novel unified framework. SDM predicted a 27.5% overall increase in the area of potentially suitable habitat under RCP 4.5 by 2050, which taken in isolation would have led to the classification of the species as a climate change winner. SDM further revealed that the latitudinal range is predicted to shrink because of decreased habitat suitability in the equatorward part of the range, not compensated by a poleward expansion. The use of landscape ecology metrics provided additional insights by identifying regions that are predicted to become increasingly fragmented in the future, potentially increasing extirpation risk by jeopardising metapopulation dynamics. This increased range fragmentation could have dramatic consequences for ecosystem structure and functioning. Importantly, the proposed framework-which brings together SDM and landscape metrics-can be widely used to study currently overlooked climate-driven changes in species internal range structure, without requiring detailed empirical knowledge of the modelled species. This approach represents an important advancement beyond predictive envelope approaches and could reveal itself as paramount for managers whose spatial scale of action usually ranges from local to regional., (© 2022 John Wiley & Sons Ltd.)

Background: Children with glomerular disease have unique risk factors for compromised bone health. Studies addressing skeletal complications in this population are lacking., Methods: This retrospective cohort study utilized data from PEDSnet, a national network of pediatric health systems with standardized electronic health record data for more than 6.5 million patients from 2009 to 2021. Incidence rates (per 10,000 person-years) of fracture, slipped capital femoral epiphysis (SCFE), and avascular necrosis/osteonecrosis (AVN) in 4598 children and young adults with glomerular disease were compared with those among 553,624 general pediatric patients using Poisson regression analysis. The glomerular disease cohort was identified using a published computable phenotype. Inclusion criteria for the general pediatric cohort were two or more primary care visits 1 year or more apart between 1 and 21 years of age, one visit or more every 18 months if followed >3 years, and no chronic progressive conditions defined by the Pediatric Medical Complexity Algorithm. Fracture, SCFE, and AVN were identified using SNOMED-CT diagnosis codes; fracture required an associated x-ray or splinting/casting procedure within 48 hours., Results: We found a higher risk of fracture for the glomerular disease cohort compared with the general pediatric cohort in girls only (incidence rate ratio [IRR], 1.6; 95% CI, 1.3 to 1.9). Hip/femur and vertebral fracture risk were increased in the glomerular disease cohort: adjusted IRR was 2.2 (95% CI, 1.3 to 3.7) and 5 (95% CI, 3.2 to 7.6), respectively. For SCFE, the adjusted IRR was 3.4 (95% CI, 1.9 to 5.9). For AVN, the adjusted IRR was 56.2 (95% CI, 40.7 to 77.5)., Conclusions: Children and young adults with glomerular disease have significantly higher burden of skeletal complications than the general pediatric population., (Copyright © 2022 by the American Society of Nephrology.)

Background and Objectives: Recent outbreaks of Zika virus (ZIKV) in South and Central America have highlighted significant neurologic side effects. Concurrence with the inflammatory neuropathy Guillain-Barré syndrome (GBS) is observed in 1:4,000 ZIKV cases. Whether the neurologic symptoms of ZIKV infection are immune mediated is unclear. We used rodent and human live cellular models to screen for anti-peripheral nerve reactive IgG and IgM autoantibodies in the sera of patients with ZIKV with and without GBS., Methods: In this study, 52 patients with ZIKV-GBS were compared with 134 ZIKV-infected patients without GBS and 91 non-ZIKV controls. Positive sera were taken forward for target identification by immunoprecipitation and mass spectrometry, and candidate antigens were validated by ELISA and cell-based assays. Autoantibody reactions against glycolipid antigens were also screened on an array., Results: Overall, IgG antibody reactivities to rat Schwann cells (SCs) (6.5%) and myelinated cocultures (9.6%) were significantly higher, albeit infrequent, in the ZIKV-GBS group compared with all controls. IgM antibody immunoreactivity to dorsal root ganglia neurones (32.3%) and SCs (19.4%) was more frequently observed in the ZIKV-GBS group compared with other controls, whereas IgM reactivity to cocultures was as common in ZIKV and non-ZIKV sera. Strong axonal-binding ZIKV-GBS serum IgG antibodies from 1 patient were confirmed to react with neurofascin 155 and 186. Serum from a ZIKV-infected patient without GBS displayed strong myelin-binding and putative antilipid antigen reaction characteristics. There was, however, no significant association of ZIKV-GBS with any known antiglycolipid antibodies., Discussion: Autoantibody responses in ZIKV-GBS target heterogeneous peripheral nerve antigens suggesting heterogeneity of the humoral immune response despite a common prodromal infection., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

The coronavirus, COVID-19 pandemic spread across the globe in 2020, with an initial high case mortality in those requiring intensive care treatment due to serious complication. A vaccine programme was quickly developed and currently the UK is one of highest double vaccinated and boosted countries in the world. Despite tremendous efforts by the UK, new cases of COVID-19 are still occurring, due to viral mutation. A major problem associated with COVID-19 is the large a-symptomatic spread within the population. Little investigation into the a-symptomatic population has been carried out and therefore we pose that the residual effects of a-symptomatic infection is still largely unknown. Prior to mass vaccination, a multi-phased single cohort study of IgM and IgG COVID-19 antibody prevalence and the associated haemostatic changes were assessed in a Welsh cohort of 739 participants, at three time points. Positive antibody participants with age and gender matched negative antibody controls were assessed at 0, 3 and 6 months. Antibody positive females appeared to have lower antibody responses in comparison to their a-symptomatic male counterparts. Despite this initial testing showed a unique significant increase in TRAP-6-induced platelet aggregation, prothrombin time (PT) and clot initiation time. Despite coagulation parameters beginning to return to normal at 3 months, significant decreases are observed in both haemoglobin and haematocrit levels. The production of extracellular vesicles (EV) was also determined in this study. Although the overall number of EV does not change throughout the study, at the initial 0 months' time point a significant increase in the percentage of circulating pro-coagulant platelet derived EV is seen, which does not appear to be related to the extent of platelet activation in the subject. We conclude that early, but reversible changes in haemostatic pathways within the a-symptomatic, female, antibody positive COVID-19 individuals are present. These changes may be key in identifying a period of pro-coagulative risk for a-symptomatic female patients., (Crown Copyright © 2022. Published by Elsevier Ltd. All rights reserved.)

Introduction Exacerbations of chronic obstructive pulmonary disease (COPD) are a frequent reason for hospital admission and a major cause of morbidity and mortality. A useful biomarker or indicator of disease severity at the time of presentation could help guide treatment and identify those with poor prognosis who need early aggressive intervention. We hypothesized that patients who present to the hospital with COPD exacerbations who are found to have elevated procalcitonin (PCT) levels will have worse outcomes such as longer admissions, increased intensive care unit (ICU) utilization, and more frequent readmissions than those with normal levels, regardless of presence or absence of infiltrate on initial chest X-ray (CXR). Methods We conducted a retrospective chart review of patients admitted to our facility with a respiratory complaint and a diagnosis of COPD to examine the relation between PCT and disease severity. A total of 156 unique encounters were reviewed, with 87 included in the final data set. Data was collected on baseline medical conditions as well as clinical status at the time of presentation. Primary endpoints included the need for overnight ICU admission, hospital length of stay greater than seven days, and repeat visit within 30 days of discharge. Secondary endpoints included the need for intubation at the time of admission, in-hospital mortality or discharge to hospice, and ICU length of stay. Results Patients with elevated PCT levels (>0.25ng/mL) had a significantly increased likelihood of a need for ICU admission (odds ratio 3.18) and hospital length of stay greater than seven days (odds ratio 3.38). There was no statistically significant difference in the Emergency Department readmission rate or any of the secondary outcomes. Conclusions Our data suggests that PCT may be a useful early biomarker for patients with COPD presenting with an acute respiratory illness., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Davies et al.)

Importance: Treatment of ST-segment elevation myocardial infarction (STEMI) in rural settings involves thrombolysis followed by transfer to a percutaneous coronary intervention-capable hospital. The first step is accurate diagnosis via electrocardiography (ECG), but one-third of all STEMI incidents go unrecognized and hence untreated., Objective: To reduce missed diagnoses of STEMI., Design, Setting, and Participants: This cluster randomized clinical trial included 29 hospital emergency departments (EDs) in rural Australia with no emergency medicine specialists, which were randomized to usual care vs automatically triggered diagnostic support from the tertiary referral hospital (management of rural acute coronary syndromes [MORACS] intervention). Patients presenting with symptoms compatible with acute coronary syndromes (ACS) were eligible for inclusion. The study was conducted from December 2018 to April 2020. Data were analyzed in August 2021., Intervention: Triage of a patient with symptoms compatible with ACS triggered an automated notification to the tertiary hospital coronary care unit. The ECG and point-of-care troponin results were reviewed remotely and a phone call was made to the treating physician in the rural hospital to assist with diagnosis and initiation of treatment., Main Outcomes and Measures: The proportion of patients with missed STEMI diagnoses., Results: A total of 6249 patients were included in the study (mean [SD] age, 63.6 [12.2] years; 48% female). Of 7474 ED presentations with suspected ACS, STEMI accounted for 77 (2.0%) in usual care hospitals and 46 (1.3%) in MORACS hospitals. Missed diagnosis of STEMI occurred in 27 of 77 presentations (35%) in usual care hospitals and 0 of 46 (0%) in MORACS hospitals (P < .001). Of eligible patients, 48 of 75 (64%) in the usual care group and 36 of 36 (100%) in the MORACS group received primary reperfusion (P < .001). In the usual care group, 12-month mortality was 10.3% (n = 8) vs 6.5% (n = 3) in the MORACS group (relative risk, 0.64; 95% CI, 0.18-2.23). Patients with missed STEMI diagnoses had a mortality of 25.9% (n = 7) compared with 2.0% (n = 1) for those with accurately diagnosed STEMI (relative risk, 13.2; 95% CI, 1.71-102.00; P = .001). Overall, there were 6 patients who did not have STEMI as a final diagnosis; 5 had takotsubo cardiomyopathy and 1 had pericarditis. There was no difference between groups in the rate of alternative final diagnosis., Conclusion and Relevance: The findings indicate that MORACS diagnostic support service reduced the proportion of missed STEMI and improved the rates of primary reperfusion therapy. Accurate diagnosis of STEMI was associated with lower mortality., Trial Registration: anzctr.org.au Identifier: ACTRN12619000533190.

Purpose: Globally, private and public organisations invest ever increasing amounts of money, time and effort to develop leadership capabilities in current and future leaders. Whilst such investment results in benefits for some, the full value of developmental strategies on offer is not always realised. Challenges inhibiting achievement of full value include struggling to identify learning programs that best fit with the organisational structure, culture, mission and vision and difficulties in maximising engagement of personnel at multiple levels of the management structure., Design/methodology/approach: The purpose of this study is to introduce a pathway for health services to develop and embed simulation-based educational strategies that provide targeted learning for leaders and teams. Aligning this approach to leadership development through presentation of case studies in which the model has been applied illustrates the pathway for application in the health-care sector., Findings: The findings of the approach to leadership development are presented through the presentation of a case study illustrating application of the ADELIS model to simulation-based learning., Practical Implications: The ADELIS model, outlined in this study, provides a guide for creating customised and flexible learning designs that apply simulation-based learning, enabling organisations to develop and provide leadership training for individuals, units and teams that is appropriately fit for purpose., Originality/value: The key contribution to health-care leadership development offered in this study is the rationale for using simulation-based learning accompanied by a model and pathway for creating such a pedagogical approach, which embraces the reality of workplace circumstances., (© Emerald Publishing Limited.)

Background: Weight control programs for children monitor BMI changes using BMI z-scores that adjust BMI for the sex and age of the child. It is, however, uncertain if BMIz is the best metric for assessing BMI change., Objective: To identify which of 6 BMI metrics is optimal for assessing change. We considered a metric to be optimal if its short-term variability was consistent across the entire BMI distribution., Subjects: 285 643 2- to 17-year-olds with BMI measured 3 times over a 10- to 14-month period., Methods: We summarized each metric's variability using the within-child standard deviation., Results: Most metrics' initial or mean value correlated with short-term variability (|r| ~ 0.3 to 0.5). The metric for which the within-child variability was largely independent (r = 0.13) of the metric's initial or mean value was the percentage of the 50th expressed on a log scale. However, changes in this metric between the first and last visits were highly (r ≥ 0.97) correlated with changes in %95th and %50th., Conclusions: Log %50 was the metric for which the short-term variability was largely independent of a child's BMI. Changes in log %50th, %95th, and %50th are strongly correlated., (© 2022 World Obesity Federation. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

Patients with hematological malignancies are at increased risk of severe COVID-19 outcomes due to compromised immune responses, but the insights of these studies have been compromised due to intrinsic limitations in study design. Here we present the PROSECO prospective observational study ( NCT04858568 ) on 457 patients with lymphoma that received two or three COVID-19 vaccine doses. We show undetectable humoral responses following two vaccine doses in 52% of patients undergoing active anticancer treatment. Moreover, 60% of patients on anti-CD20 therapy had undetectable antibodies following full vaccination within 12 months of receiving their anticancer therapy. However, 70% of individuals with indolent B-cell lymphoma displayed improved antibody responses following booster vaccination. Notably, 63% of all patients displayed antigen-specific T-cell responses, which increased after a third dose irrespective of their cancer treatment status. Our results emphasize the urgency of careful monitoring of COVID-19-specific immune responses to guide vaccination schemes in these vulnerable populations., (© 2022. The Author(s).)

Plastic pollution and climate change have commonly been treated as two separate issues and sometimes are even seen as competing. Here we present an alternative view that these two issues are fundamentally linked. Primarily, we explore how plastic contributes to greenhouse gas (GHG) emissions from the beginning to the end of its life cycle. Secondly, we show that more extreme weather and floods associated with climate change, will exacerbate the spread of plastic in the natural environment. Finally, both issues occur throughout the marine environment, and we show that ecosystems and species can be particularly vulnerable to both, such as coral reefs that face disease spread through plastic pollution and climate-driven increased global bleaching events. A Web of Science search showed climate change and plastic pollution studies in the ocean are often siloed, with only 0.4% of the articles examining both stressors simultaneously. We also identified a lack of regional and industry-specific life cycle analysis data for comparisons in relative GHG contributions by materials and products. Overall, we suggest that rather than debate over the relative importance of climate change or marine plastic pollution, a more productive course would be to determine the linking factors between the two and identify solutions to combat both crises., 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 © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Cell-to-cell interactions between the immune and nervous systems are increasingly recognized for their importance in health and disease. Assessment of cellular neuro-immune interactions can be aided by co-culture of two (or more) cells in an in vitro model system that preserves the morphology of neuronal cells. Here we describe methods to investigate the cytotoxic effector functions of natural killer cells on sensory neurons isolated from syngeneic embryonic and adult mice. We present methods for the morphological analysis of axon fragmentation (pruning) and dynamic cell function via live confocal calcium imaging. These techniques can easily be adapted to study interactions between other combinations of immune cell subsets and neuronal populations., (© 2022. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: This study compared the importance of age at adiposity rebound versus childhood BMI to subsequent BMI levels in a longitudinal analysis., Methods: From the electronic health records of 4.35 million children, a total of 12,228 children were selected who were examined at least once each year between ages 2 and 7 years and reexamined after age 14 years. The minimum number of examinations per child was six. Each child's rebound age was estimated using locally weighted regression (lowess), a smoothing technique., Results: Children who had a rebound age < 3 years were, on average, 7 kg/m 2 heavier after age 14 years than were children with a rebound age ≥ 7 years. However, BMI after age 14 years was more strongly associated with BMI at the rebound than with rebound age (r = 0.57 vs. -0.44). Furthermore, a child's BMI at age 3 years provided more information on BMI after age 14 years than did rebound age. In addition, rebound age provided no information on subsequent BMI if a child's BMI at age 6 years was known., Conclusions: Although rebound age is related to BMI after age 14 years, a child's BMI at age 3 years provides more information and is easier to obtain., (© 2021 The Obesity Society (TOS). This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

A complex interplay of biotic and abiotic factors underpins the distribution of species and operates across different levels of biological organization and life history stages. Understanding ecosystem engineer reproductive traits is critical for comprehending and managing the biodiversity-rich habitats they create. Little is known about how the reproduction of the reef-forming worm, Sabellaria alveolata, varies across environmental gradients. By integrating broad-scale environmental data with in-situ physiological data in the form of biochemical traits, we identified and ranked the drivers of intraspecific reproductive trait variability (ITV). ITV was highest in locations with variable environmental conditions, subjected to fluctuating temperature and hydrodynamic conditions. Our trait selection pointed to poleward sites being the most physiologically stressful, with low numbers of irregularly shaped eggs suggesting potentially reduced reproductive success. Centre-range individuals allocated the most energy to reproduction, with the highest number of intermediate-sized eggs, whilst equatorward sites were the least physiologically stressful, thus confirming the warm-adapted nature of our model organism. Variation in total egg diameter and relative fecundity were influenced by a combination of environmental conditions, which changed depending on the trait and sampling period. An integrated approach involving biochemical and reproductive traits is essential for understanding macro-scale patterns in the face of anthropogenic-induced climate change across environmental and latitudinal gradients., (© 2021. The Author(s).)