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Prediction and characterisation of the human B cell response to a heterologous two-dose Ebola vaccine.

Ebola virus disease (EVD) outbreaks are increasing, posing significant threats to affected communities. Effective outbreak management depends on protecting frontline health workers, a key focus of EVD vaccination strategies. IgG specific to the viral glycoprotein serves as the correlate of protection for recent vaccine licensures. Using advanced cellular and transcriptomic analyses, we examined B cell responses to the Ad26.ZEBOV, MVA-BN-Filo EVD vaccine. Our findings reveal robust plasma cell and lasting B cell memory responses post-vaccination. Machine-learning models trained on blood gene expression predicted antibody response magnitude. Notably, we identified a unique B cell receptor CDRH3 sequence post-vaccination resembling known Orthoebolavirus zairense (EBOV) glycoprotein-binding antibodies. Single-cell analyses further detailed changes in plasma cell frequency, subclass usage, and CDRH3 properties. These results highlight the predictive power of early immune responses, captured through systems immunology, in shaping vaccine-induced B cell immunity.

Reverse Shoulder Arthroplasty for Acute Trauma vs Trauma Sequalae following failed conservative management: A cohort study using data from the National Joint Registry and Hospital Episode Statistics for England.

INTRODUCTION: While the majority of proximal humerus fractures (PHFs) can be managed conservatively, for some, particularly complex 3- or 4-part fractures, management is controversial. The decision-making process can be challenging, especially in older patients when considering whether secondary surgery for failed non operative management comes with more risk than acute surgical treatment. There is limited evidence in the literature that compares the outcomes of patients having an acute reverse shoulder arthroplasty (rTSA) for trauma against those having an rTSA for trauma sequalae following failed previous conservative management. This study aims to use the National Joint Registry (NJR) and Hospital Episode Statistics (HES) for England to compare outcomes of rTSA for acute trauma against those of rTSA for trauma sequalae following failed conservative management. METHODS: NJR data from April 2012 to March 2022 was linked to HES. All patients undergoing an rTSA for acute or trauma sequalae were included. Primary outcome was revision. Secondary outcomes were non revision re-operation, mortality, medical complications within 30 & 90 days of primary procedure and length of stay. RESULTS: In the propensity matched cohorts, there were 2488 patients in the acute trauma group and 1267 patients in the trauma sequalae group. rTSA for trauma sequalae had a higher cumulative revision rate at 1,3,5,7 and 10 years and statistically significant increased risk in overall revision (HR of 2.44 (1.68-3.55 p<0.001) in comparison to acute trauma rTSA. There was no statistical difference in incidence of non-revision re-operation (p=0.17). At one year the mortality rate was 4.11% (3.38-5.00) for acute trauma and 3.07% (2.23-4.23) for trauma sequalae and this was not statistically different (HR 0.74 (0.51-1.09) p=0.13). In the acute trauma group, there was a statistically significant increase in medical complications at 30 & 90 days post procedure as well as length of stay (p<0.001). CONCLUSION: Based on this national joint registry analysis, patients are twice as likely to require a revision surgery if they undergo rTSA after conservative management has failed, compared to those who receive the procedure immediately following a proximal humerus fracture. While this may inform decision making and the consent process, given some of the limitations around registry analysis, the findings underline the importance of well-designed prospective trials in establishing the optimal timing of surgery. LEVEL OF EVIDENCE: Level III; Retrospective Cohort Comparison using Large Database; Treatment Study.

Risk of Arterial and Venous Thrombotic Events Among Patients with COVID-19: A Multi-National Collaboration of Regulatory Agencies from Canada, Europe, and United States.

PURPOSE: Few studies have examined how the absolute risk of thromboembolism with COVID-19 has evolved over time across different countries. Researchers from the European Medicines Agency, Health Canada, and the United States (US) Food and Drug Administration established a collaboration to evaluate the absolute risk of arterial (ATE) and venous thromboembolism (VTE) in the 90 days after diagnosis of COVID-19 in the ambulatory (eg, outpatient, emergency department, nursing facility) setting from seven countries across North America (Canada, US) and Europe (England, Germany, Italy, Netherlands, and Spain) within periods before and during COVID-19 vaccine availability. PATIENTS AND METHODS: We conducted cohort studies of patients initially diagnosed with COVID-19 in the ambulatory setting from the seven specified countries. Patients were followed for 90 days after COVID-19 diagnosis. The primary outcomes were ATE and VTE over 90 days from diagnosis date. We measured country-level estimates of 90-day absolute risk (with 95% confidence intervals) of ATE and VTE. RESULTS: The seven cohorts included 1,061,565 patients initially diagnosed with COVID-19 in the ambulatory setting before COVID-19 vaccines were available (through November 2020). The 90-day absolute risk of ATE during this period ranged from 0.11% (0.09-0.13%) in Canada to 1.01% (0.97-1.05%) in the US, and the 90-day absolute risk of VTE ranged from 0.23% (0.21-0.26%) in Canada to 0.84% (0.80-0.89%) in England. The seven cohorts included 3,544,062 patients with COVID-19 during vaccine availability (beginning December 2020). The 90-day absolute risk of ATE during this period ranged from 0.06% (0.06-0.07%) in England to 1.04% (1.01-1.06%) in the US, and the 90-day absolute risk of VTE ranged from 0.25% (0.24-0.26%) in England to 1.02% (0.99-1.04%) in the US. CONCLUSION: There was heterogeneity by country in 90-day absolute risk of ATE and VTE after ambulatory COVID-19 diagnosis both before and during COVID-19 vaccine availability.

Effectiveness of COVID-19 Vaccines Administered During Pregnancy in Spain and Norway

Chromatin-focused genetic and chemical screens identify BRPF1 as a targetable vulnerability in Taxol-resistant triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a particularly aggressive and frequently recurring form of breast cancer, where chemotherapy is the primary treatment approach. Unfortunately, the development of resistance to chemotherapy poses a considerable challenge, restricting the already limited therapeutic alternatives for recurrent cases. Here, we generated two Taxol-resistant TNBC cell lines with a dose-escalation method to mimic chemotherapy resistance in vitro. These cells exhibited reduced growth rates, altered morphology and evasion of apoptosis. Transcriptome analysis uncovered elevated ABCB1 expression and multidrug-resistant phenotype in these resistant cells. To comprehensively investigate the key epigenetic regulators of Taxol resistance, we conducted chromatin-focused genetic and chemical screens and pinpointed Bromodomain and PHD Finger Containing 1 (BRPF1) as a novel regulator of Taxol resistance. Knockout of BRPF1, the reader protein in the MOZ-MORF histone acetyltransferase complex, but not the other complex members, sensitized resistant cells to Taxol. In addition, BRPF1 inhibitors, PFI-4 and OF-1, in combination with Taxol significantly reduced cell viability. Transcriptome analysis upon BRPF1 loss or inhibition revealed a negative impact on ribosome biogenesis-related gene sets, resulting in a global decrease in protein translation in Taxol-resistant cells. CUT&RUN-qPCR analysis demonstrated that BRPF1 directly binds to the ABCB1 promoter, enhancing its expression toward inducing a multidrug-resistant phenotype. Conversely, knockout or inhibition of BRPF1 leads to decreased ABCB1 expression. Our findings uncover a comprehensive molecular framework, highlighting the pivotal role of epigenetic reader protein BRPF1 in Taxol resistance and providing potential avenues for therapeutic intervention in TNBC.

Incidence of post-acute COVID-19 symptoms across healthcare settings in seven countries: an international retrospective cohort study using routinely-collected data.

BACKGROUND: The World Health Organisation (WHO) has identified a range of symptomatic manifestations to aid in the clinical diagnosis of post-COVID conditions, herein referred to as post-acute COVID-19 symptoms. We conducted an international network cohort study to estimate the burden of these symptoms in North American, European, and Asian populations. METHODS: A federated analysis was conducted including 10 databases from the United Kingdom, Netherlands, Norway, Estonia, Spain, France, South Korea, and the United States, between September 1st 2020 and latest data availability (which varied from December 31st 2021 to February 28th 2023), covering primary and secondary care, nationwide registries, and claims data, all mapped to the Observational Medical Outcomes Partnership Common Data Model (OMOP CDM). We defined two cohorts for the main analyses: a SARS-CoV-2 infection cohort [positive polymerase chain reaction (PCR) or rapid lateral flow test (LFT) result or clinical COVID-19 diagnosis] and a general population cohort. Individuals with less than 365 days of prior history or 120 days of follow-up were excluded. We estimated incidence rates (IRs) of the 25 WHO-proposed post-acute COVID-19 symptoms, considering symptoms that occurred ≥90 and ≤365 days after index date, excluding individuals with the respective symptoms 180 days prior to the index event. Stratified analyses were conducted by age and sex. Incidence rate ratios (IRRs) were calculated comparing rates in the infected cohort versus the general population. Results from the different databases were combined using random-effects meta-analyses. FINDINGS: 3,019,408 individuals were included in the infection cohort. 1,585,160 of them were female and 1,434,248 of them male. 929,351,505 individuals were included in the general population group. 461,195,036 of them were female and 466,022,004 of them male. The 1-year IR of any post-acute COVID-19 symptom in the COVID-19 infection cohort varied significantly across databases, from 4.4 (95% CI 3.8-5.1) per 100 person-years to 103.9 (95% CI 103.2-104.7). The five most common symptoms were joint pain (from 1.6 (95% CI 1.3-1.9) to 14.3 (95% CI 14.1-14.6)), abdominal pain (from 0.3 (95% CI 0.1-0.5) to 9.9 (95% CI 9.7-10.1)), gastrointestinal issues (from 0.6 (95% CI 0.4-0.9) to 13.3 (95% CI 13.1-13.6)), cough (from 0.3 (95% CI 0.2-0.5) to 9.1 (95% CI 8.9-9.3)), and anxiety (from 0.8 (95% CI 0.6-1.2) to 11.4 (95% CI 11.2-11.6)); whereas muscle spasms (from 0.01 (95% CI 0.008-0.2) to 1.7 (95% CI 1.6-1.8)), pins and needles (from 0.05 (95% CI 0.03-0.0.9) to 1.5 (95% CI 1.4-1.6)), memory issues (from 0.03 (95% CI 0.02-0.06) to 0.8 (95% CI 0.7-0.8)), cognitive dysfunction (from 0.007 (95% CI 0.004-0.01) to 0.6 (95% CI 0.4-0.8)), and altered smell and/or taste (from 0.04 (95% CI 0.03-0.04) to 0.7 (95% CI 0.6-0.8)) were least common. Incidence rates of any post-acute COVID-19 symptoms generally increased with age, with certain symptoms peaking in middle-aged adults (anxiety, depressive disorders, headache, altered smell and taste) and others in pre-school children (gastrointestinal issues and cough). Females had higher incidence rates for most symptoms. Based on the random-effects model, the infected cohort had a higher incidence of any post-acute COVID-19 symptom than the general population, with a meta-analytic incidence rate ratio (meta-IRR) of 1.4 (1-2). A similar pattern was seen for all individual symptoms. The highest meta-IRRs were depressive disorder, 2.6 (1.7-3.9); anxiety, 2.3 (1.4-3.8); allergy, 2.1 (1.7-2.8) and sleep disorders, 2.1 (1.5-2.6). The meta-IRR for altered smell and/or taste was 1.9 (1.3-2.8). INTERPRETATION: Post-acute COVID-19 symptoms, as listed by the WHO, were commonly observed following COVID-19 infection. However, even after standardising research methods, there was significant heterogeneity in the incidence rates from different healthcare settings and geographical locations. This is the first international study of the epidemiology of post-acute COVID-19 symptoms using the WHO-listed symptoms. Its findings contibute to understand the epidemiology of this condition from a multinational approach. Limitations of this study include the lack of consensus of the post-acute COVID-19 definition, as well as the difficulty to capture the impact on daily life of the post-acute COVID-19 symptoms in the available datasets. FUNDING: This work has been funded by the European Health Data Evidence Network (EHDEN) through an Evidence Generation Fund Grant and by the National Institute for Health and Care Research (NIHR) Oxford Biomedical Research Centre (BRC).

Treatment of systemic lupus erythematosus: Analysis of treatment patterns in adult and paediatric patients across four European countries.

OBJECTIVE: Multiple treatment options are recommended for Systemic Lupus Erythematosus (SLE) by clinical guidelines. This study aimed to explore SLE treatment patterns as there is limited real-world data of SLE medication utilisation, especially in childhood-onset SLE (cSLE). METHODS: We conducted a longitudinal cohort study using five routinely collected healthcare databases from four European countries (United Kingdom, France, Germany, and Spain). We described the characteristics of adult and paediatric patients at time of SLE diagnosis. We calculated the percentage of patients commencing SLE treatments in the first month and year after diagnosis, reported number of prescriptions, starting dose, cumulative dose, and duration of each treatment, and characterised the line of therapy. RESULTS: We characterised 11,255 patients with a first diagnosis of SLE and included 5718 in our medication utilisation analyses. The majority of adult SLE patients were female (range 80-88 %), with median age of 49 to 54 years at diagnosis. In the paediatric cohort (n = 378), 66-83 % of SLE patients were female, with median age of 12 to 16 years at diagnosis. Hydroxychloroquine and glucocorticoids were common first-line treatments in both adults and children, with second-line treatments including mycophenolate mofetil and methotrexate. Few cases of monoclonal antibody use were seen in either cohort. Initial glucocorticoid dosing in paediatric patients was often higher than in adults. CONCLUSION: Treatment choices for adult SLE patients across four European countries were in line with recent therapeutic consensus guidelines. High glucocorticoid prescriptions in paediatric patients suggests the need for steroid-sparing treatment alternatives and paediatric specific guidelines.

P035 Patient facing pharmacist reduces length of stay for paediatric short stay patients

AimTo reduce the average length of stay (LoS) of paediatric inpatients requiring discharge medication (TTO’s) on the short stay pathway (Comet).MethodsA paediatric multi-disciplinary team (MDT) used the model for improvement to identify stakeholders and key drivers for change. The Comet patient journey was mapped from A&E to discharge. Plan-Do-Study-Act (PDSA) cycles were used to reduce LoS, targeting the addition of a paediatric pharmacist to the morning ward round and use of over- label packs to facilitate nurse-led discharge for simple TTO’s required within 2 hours. Data was collected over a two week period in summer; PDSA 1 baseline data, one week prior to change; PDSA 2, one week after implementation. Baseline measurements included time taken to write, screen and dispense TTO and the average LoS. Data was collected via the electronic prescribing system (Lastword). Patients eligible for the Comet pathway were included for analysis. Results were analysed using Microsoft Excel. Ethics approval was not required for this study.ResultsPDSA one; 15 patients admitted onto the Comet pathway. 67% patients were admitted outside working hours. Six patients needed TTOs, 33% were written out of hours and all dispensed by pharmacy. Average time to writing TTO 14.6 hours (16minutes-44hhours); time to pharmacist clinical screen 19.4 hours (6 minutes – 21 hours); average time for pharmacy to dispense TTO after screening 2 hours (69–203 minutes); average LoS for all Comet patients 17.6 hours (8–44) and 26 hours (14–44) for those needing TTO’s. Post implementation 12 patients were eligible for the Comet pathway. 83% patients were admitted outside of hours. Six patients needed TTO’s, 16% were written out of hours and 33% were dispensed by the nursing team. Average time to writing TTO increased to 20.2 hours (14–26), average time to pharmacist clinical screen was reduced to 10 minutes (1–98) and average time for pharmacy to dispense TTO reduced to 57 minutes (47–74). Average LoS for Comet patients was similar to PDSA 1 at 17.7 hours (3–27) but reduced to 20.8 h0urs (5–27) for those needing TTO’s.ConclusionIncreasing patient-facing time of pharmacists to improve outcomes is recommended by the Carter report.(1)Pressures in emergency-care to free up beds for patients means we need to look for creative solutions. (2) This study found the addition of a paediatric pharmacist to the ward round increased efficiency of writing, screening and dispensing TTO’s - dramatically reducing time to screening TTO’s; and the average LoS by 5 hours. The pharmacist was aware of Comet discharges at the time of decision to discharge and was on hand to resolve medication related issues. New doctors in August could explain the increased time to writing TTO’s in the second week. Promotion of nurse-led discharge via over-label packs reduced the number of TTO’s sent to pharmacy. Limitations include2 weeks of data over summer were analysed and non-paediatric hospital activity would impact pharmacy dispensing time. Future work will test how pharmacist transcribing TTO’s on the ward round affect Los and to review pharmacist clinical interventions to assess impact on outcomes.ReferencesDepartment of Health. Carter report: Unwarranted variation: A review of operational productivity and performance in English NHS acute hospitals. 5thFebruary 2016.Royal College of Paediatrics and Child Health. Standards for Short-Stay Paediatric Assessment Units (SSPAU). March 2017.

The impact of insect herbivory on biogeochemical cycling in broadleaved forests varies with temperature.

Herbivorous insects alter biogeochemical cycling within forests, but the magnitude of these impacts, their global variation, and drivers of this variation remain poorly understood. To address this knowledge gap and help improve biogeochemical models, we established a global network of 74 plots within 40 mature, undisturbed broadleaved forests. We analyzed freshly senesced and green leaves for carbon, nitrogen, phosphorus and silica concentrations, foliar production and herbivory, and stand-level nutrient fluxes. We show more nutrient release by insect herbivores at non-outbreak levels in tropical forests than temperate and boreal forests, that these fluxes increase strongly with mean annual temperature, and that they exceed atmospheric deposition inputs in some localities. Thus, background levels of insect herbivory are sufficiently large to both alter ecosystem element cycling and influence terrestrial carbon cycling. Further, climate can affect interactions between natural populations of plants and herbivores with important consequences for global biogeochemical cycles across broadleaved forests.

Damage to tropical forests caused by cyclones is driven by wind speed but mediated by topographical exposure and tree characteristics.

Each year, an average of 45 tropical cyclones affect coastal areas and potentially impact forests. The proportion of the most intense cyclones has increased over the past four decades and is predicted to continue to do so. Yet, it remains uncertain how topographical exposure and tree characteristics can mediate the damage caused by increasing wind speed. Here, we compiled empirical data on the damage caused by 11 cyclones occurring over the past 40 years, from 74 forest plots representing tropical regions worldwide, encompassing field data for 22,176 trees and 815 species. We reconstructed the wind structure of those tropical cyclones to estimate the maximum sustained wind speed (MSW) and wind direction at the studied plots. Then, we used a causal inference framework combined with Bayesian generalised linear mixed models to understand and quantify the causal effects of MSW, topographical exposure to wind (EXP), tree size (DBH) and species wood density (ρ) on the proportion of damaged trees at the community level, and on the probability of snapping or uprooting at the tree level. The probability of snapping or uprooting at the tree level and, hence, the proportion of damaged trees at the community level, increased with increasing MSW, and with increasing EXP accentuating the damaging effects of cyclones, in particular at higher wind speeds. Higher ρ decreased the probability of snapping and to a lesser extent of uprooting. Larger trees tended to have lower probabilities of snapping but increased probabilities of uprooting. Importantly, the effect of ρ decreasing the probabilities of snapping was more marked for smaller than larger trees and was further accentuated at higher MSW. Our work emphasises how local topography, tree size and species wood density together mediate cyclone damage to tropical forests, facilitating better predictions of the impacts of such disturbances in an increasingly windier world.

Climate and forest properties explain wildfire impact on microbial community and nutrient mobilization in boreal soil

The boreal landscape stores an estimated 40% of the earth's carbon (C) found in terrestrial vegetation and soils, with a large portion collected in thick organic soil layers. These ground stores are subject to substantial removals due to the centurial return of wildfire, which has strong impacts on the soil microbial community and nutrient cycling, which in turn can control ecosystem recovery patterns and process rates, such as C turnover. Currently, predictive knowledge used in assessing fire impacts is largely focused on ecosystems that experience only superficial burning and few robust observations exist regarding the effect that smoldering combustion in deeper active soil layers has on post-fire soil activity. This study provided a highly replicated and regionally extensive survey of wildfire impact on microbial community structure (using fatty acid biomarkers) and nutrient cycling (using in situ ionic resin capsules) across broad gradients of climate, forest properties and fire conditions within 50 separate burn scars and 50 additional matched unburnt boreal forest soils. The results suggest a strong metabolic shift in burnt soils due to heat impact on their structure and a decoupling from aboveground processes, releasing ecosystem N limitation and increasing mobilization of N, P, K, and S as excess in conjunction with an altered, C-starved microbial community structure and reduced root uptake due to vegetation mortality. An additional observed climatic control over burnt soil properties has implications for altered boreal forest function in future climate and fire regimes deserving of further attention.

Mineral Soils Are an Important Intermediate Storage Pool of Black Carbon in Fennoscandian Boreal Forests.

Approximately 40% of earth's carbon (C) stored in land vegetation and soil is within the boreal region. This large C pool is subjected to substantial removals and transformations during periodic wildfire. Fire-altered C, commonly known as pyrogenic carbon (PyC), plays a significant role in forest ecosystem functioning and composes a considerable fraction of C transport to limnic and oceanic sediments. While PyC stores are beginning to be quantified globally, knowledge is lacking regarding the drivers of their production and transport across ecosystems. This study used the chemo-thermal oxidation at 375°C (CTO-375) method to isolate a particularly refractory subset of PyC compounds, here called black carbon (BC), finding an average increase of 11.6 g BC m-2 at 1 year postfire in 50 separate wildfires occurring in Sweden during 2018. These increases could not be linked to proposed drivers, however BC storage in 50 additional nearby unburnt soils related strongly to soil mass while its proportion of the larger C pool related negatively to soil C:N. Fire approximately doubled BC stocks in the mineral layer but had no significant effect on BC in the organic layer where it was likely produced. Suppressed decomposition rates and low heating during fire in mineral subsoil relative to upper layers suggests potential removals of the doubled mineral layer BC are more likely transported out of the soil system than degraded in situ. Therefore, mineral soils are suggested to be an important storage pool for BC that can buffer short-term (production in fire) and long-term (cross-ecosystem transport) BC cycling.

Refined Treatment Response Criteria for Indolent Systemic Mastocytosis Proposed by the ECNM-AIM Consortium.

Indolent systemic mastocytosis (ISM) has a favorable prognosis and normal life expectancy. However, many patients suffer from mast cell (MC) mediator-related symptoms, which significantly affect quality of life (QoL). Cutaneous, gastrointestinal, and neurological complaints, musculoskeletal pain, and the presence of skin lesions, anaphylaxis, and osteoporosis are the main symptoms and signs in ISM and must be assessed in all patients before and during treatment. Validated mastocytosis-specific patient-reported outcome measures (PROMs) should be used for this purpose. Serum tryptase and KIT D816V allele burden are recommended as secondary outcome parameters, noting that they do not reflect the severity of signs, symptoms, and related QoL impairment, but indirectly express MC burden. Changes from baseline of 90%, 60%, and 30% indicate complete response >90%, major response 60% to 90%, partial response 30% to 60%, and no response <30% to treatment. To conclude, we recommend the use of PROMs as primary outcome parameters to define treatment response in patients with ISM in clinical trials and in everyday clinical practice.

Proposed European Competence Network on Mastocytosis-American Initiative in Mast Cell Diseases (ECNM-AIM) Response Criteria in Advanced Systemic Mastocytosis.

Advanced systemic mastocytosis (AdvSM) is characterized by the presence of KIT D816V and other somatic mutations (eg, in SRSF2, ASXL1, and RUNX1) in 95% and 60% to 70% of patients, respectively. The biological and clinical consequences of AdvSM include multilineage involvement (eg, associated hematologic neoplasm) in 60% to 80% of patients, variable infiltration and damage (C-findings) of predominantly bone marrow and visceral organs through affected mast cell (MC) and non-MC lineages, and elevated levels of serum tryptase. Recently, the treatment landscape has substantially changed with the introduction of the multikinase/KIT inhibitor midostaurin and the selective KIT D816V inhibitor avapritinib. In this review, we discuss the evolution of AdvSM response criteria that have been developed to better capture clinical benefit (eg, improved responses and progression-free and overall survival). We propose refined response criteria from European Competence Network on Mastocytosis and American Initiative in Mast Cell Diseases investigators that use a tiered approach to segregate the effects of histopathologic (eg, bone marrow MC burden, tryptase), molecular (eg, KIT D816V variant allele frequency), clinical (eg, C-findings), and symptom response on long-term outcomes. These response criteria require evaluation in future prospective clinical trials of selective KIT inhibitors and other novel agents.

Global Classification of Mast Cell Activation Disorders: An ICD-10-CM-Adjusted Proposal of the ECNM-AIM Consortium.

Mast cell activation (MCA) is common and occurs in a number of pathologic conditions, including IgE-dependent and independent allergic reactions, atopic disorders, autoimmune processes, and mastocytosis. In a subset of patients, no underlying disease and no known trigger of MCA are found. When the symptoms are severe, systemic, and recurrent, and accompanied by a diagnostic increase in the serum tryptase level or other mast cell mediators, an MCA syndrome (MCAS) may be diagnosed. In these patients, the symptoms typically respond to drugs suppressing MCA, mediator production in mast cells, or mediator effects. In each case, diagnostic consensus criteria must be fulfilled to diagnose MCAS. In other patients, MCA may be local, less severe, or less acute, or may be suspected but not confirmed, so that the diagnostic criteria of MCAS are not fulfilled. In these patients, it may be difficult to prove MCA, for example, by measuring multiple mast cell mediators or basophil activation, the latter as a surrogate of IgE-dependent hypersensitivity. However, validated diagnostic criteria for implicating suspected MCA behind such conditions are lacking, even if some of these conditions have recently been assigned to an International Classification of Diseases-10-Clinical Modification code (ICD-10-CM). In this article, we discuss diagnostic features and criteria and propose a ICD-10-CM-adjusted classification for disorders associated with MCA, herein referred to as MCA disorders (MCADs), with special emphasis on the delineation between confirmed MCAS, MCAD not fulfilling MCAS criteria, and suspected MCAD that is not present. In addition, we discuss the discrimination between overt MCAD and predisposing conditions, such as atopic states, mastocytosis, and hereditary alpha tryptasemia.

Updated Diagnostic Criteria and Classification of Mast Cell Disorders: A Consensus Proposal.

Mastocytosis is a hematologic neoplasm characterized by expansion and focal accumulation of neoplastic mast cells (MC) in diverse organs, including the skin, bone marrow (BM), spleen, liver, and gastrointestinal tract. The World Health Organization classification divides the disease into prognostically distinct variants of cutaneous mastocytosis (CM) and systemic mastocytosis (SM). Although this classification remains valid, recent developments in the field and the advent of new diagnostic and prognostic parameters created a need to update and refine definitions and diagnostic criteria in MC neoplasms. In addition, MC activation syndromes (MCAS) and genetic features predisposing to SM and MCAS have been identified. To discuss these developments and refinements in the classification, we organized a Working Conference comprised of experts from Europe and the United States in August 2020. This article reports on outcomes from this conference. Of particular note, we propose adjustments in the classification of CM and SM, refinements in diagnostic criteria of SM variants, including smoldering SM and BM mastocytosis (BMM), and updated criteria for MCAS and other conditions involving MC. CD30 expression in MC now qualifies as a minor SM criterion, and BMM is now defined by SM criteria, absence of skin lesions and absence of B- and C-findings. A basal serum tryptase level exceeding 20 ng/mL remains a minor SM criterion, with recognition that hereditary alpha-tryptasemia and various myeloid neoplasms may also cause elevations in tryptase. Our updated proposal will support diagnostic evaluations and prognostication in daily practice and the conduct of clinical trials in MC disorders.

Psychological distress and trauma in doctors providing frontline care during the COVID-19 pandemic in the United Kingdom and Ireland: a prospective longitudinal survey cohort study.

OBJECTIVES: The psychological impact of the COVID-19 pandemic on doctors is a significant concern. Due to the emergence of multiple pandemic waves, longitudinal data on the impact of COVID-19 are vital to ensure an adequate psychological care response. The primary aim was to assess the prevalence and degree of psychological distress and trauma in frontline doctors during the acceleration, peak and deceleration of the COVID-19 first wave. Personal and professional factors associated with psychological distress are also reported. DESIGN: A prospective online three-part longitudinal survey. SETTING: Acute hospitals in the UK and Ireland. PARTICIPANTS: Frontline doctors working in emergency medicine, anaesthetics and intensive care medicine during the first wave of the COVID-19 pandemic in March 2020. PRIMARY OUTCOME MEASURES: Psychological distress and trauma measured using the General Health Questionnaire-12 and the Impact of Events-Revised. RESULTS: The initial acceleration survey distributed across networks generated a sample of 5440 doctors. Peak and deceleration response rates from the original sample were 71.6% (n=3896) and 56.6% (n=3079), respectively. Prevalence of psychological distress was 44.7% (n=1334) during the acceleration, 36.9% (n=1098) at peak and 31.5% (n=918) at the deceleration phase. The prevalence of trauma was 23.7% (n=647) at peak and 17.7% (n=484) at deceleration. The prevalence of probable post-traumatic stress disorder was 12.6% (n=343) at peak and 10.1% (n=276) at deceleration. Worry of family infection due to clinical work was the factor most strongly associated with both distress (R2=0.06) and trauma (R2=0.10). CONCLUSION: Findings reflect a pattern of elevated distress at acceleration and peak, with some natural recovery. It is essential that policymakers seek to prevent future adverse effects through (a) provision of vital equipment to mitigate physical and psychological harm, (b) increased awareness and recognition of signs of psychological distress and (c) the development of clear pathways to effective psychological care. TRIAL REGISTRATION NUMBER: ISRCTN10666798.

Psychological distress during the acceleration phase of the COVID-19 pandemic: a survey of doctors practising in emergency medicine, anaesthesia and intensive care medicine in the UK and Ireland.

OBJECTIVE: To quantify psychological distress experienced by emergency, anaesthetic and intensive care doctors during the acceleration phase of COVID-19 in the UK and Ireland. METHODS: Initial cross-sectional electronic survey distributed during acceleration phase of the first pandemic wave of COVID-19 in the UK and Ireland (UK: 18 March 2020-26 March 2020 and Ireland: 25 March 2020-2 April 2020). Surveys were distributed via established specialty research networks, within a three-part longitudinal study. Participants were doctors working in emergency, anaesthetic and intensive medicine during the first pandemic wave of COVID-19 in acute hospitals across the UK and Ireland. Primary outcome measures were the General Health Questionnaire-12 (GHQ-12). Additional questions examined personal and professional characteristics, experiences of COVID-19 to date, risk to self and others and self-reported perceptions of health and well-being. RESULTS: 5440 responses were obtained, 54.3% (n=2955) from emergency medicine and 36.9% (n=2005) from anaesthetics. All levels of doctor seniority were represented. For the primary outcome of GHQ-12 score, 44.2% (n=2405) of respondents scored >3, meeting the criteria for psychological distress. 57.3% (n=3045) had never previously provided clinical care during an infectious disease outbreak but over half of respondents felt somewhat prepared (48.6%, n=2653) or very prepared (7.6%, n=416) to provide clinical care to patients with COVID-19. However, 81.1% (n=4414) either agreed (31.1%, n=2709) or strongly agreed (31.1%, n=1705) that their personal health was at risk due to their clinical role. CONCLUSIONS: Findings indicate that during the acceleration phase of the COVID-19 pandemic, almost half of frontline doctors working in acute care reported psychological distress as measured by the GHQ-12. Findings from this study should inform strategies to optimise preparedness and explore modifiable factors associated with increased psychological distress in the short and long term. TRIAL REGISTRATION NUMBER: ISRCTN10666798.

The linkages between photosynthesis, productivity, growth and biomass in lowland Amazonian forests.

Understanding the relationship between photosynthesis, net primary productivity and growth in forest ecosystems is key to understanding how these ecosystems will respond to global anthropogenic change, yet the linkages among these components are rarely explored in detail. We provide the first comprehensive description of the productivity, respiration and carbon allocation of contrasting lowland Amazonian forests spanning gradients in seasonal water deficit and soil fertility. Using the largest data set assembled to date, ten sites in three countries all studied with a standardized methodology, we find that (i) gross primary productivity (GPP) has a simple relationship with seasonal water deficit, but that (ii) site-to-site variations in GPP have little power in explaining site-to-site spatial variations in net primary productivity (NPP) or growth because of concomitant changes in carbon use efficiency (CUE), and conversely, the woody growth rate of a tropical forest is a very poor proxy for its productivity. Moreover, (iii) spatial patterns of biomass are much more driven by patterns of residence times (i.e. tree mortality rates) than by spatial variation in productivity or tree growth. Current theory and models of tropical forest carbon cycling under projected scenarios of global atmospheric change can benefit from advancing beyond a focus on GPP. By improving our understanding of poorly understood processes such as CUE, NPP allocation and biomass turnover times, we can provide more complete and mechanistic approaches to linking climate and tropical forest carbon cycling.

Removal of retained bullets from the hip joint in civilian gunshot injuries

Background Removal of bullets retained within joints is indicated to prevent mechanical blockade, third body wear and resultant arthritis, plus lead arthropathy and rarely, systemic lead poisoning. We aimed to report on the largest series of removal of bullets from the hip joint using open surgical techniques. Methods This is a retrospective cohort study of all patients who presented to a single Level 1 trauma unit with civilian gunshot injuries that had breached the hip joint between 1 January 2009 and 31 December 2022. Results We identified 117 adult patients who met our inclusion criteria. Of these patients, 72 had bullets retained within the hip joint area. Forty-six patients underwent bullet removal using the following techniques: hip arthrotomy (n = 19), surgical hip dislocation (n = 18), direct removal without capsulotomy (tractotomy) (n = 5), removal at site of fracture fixation/replacement (n = 3), posterior wall osteotomy (n = 1). No patients underwent hip arthroscopy. In 26 patients we did not remove bullets for the following reasons: the final location was extra-capsular embedded in the soft tissues (n = 17); a clinical decision to not remove the bullet due to the patient’s clinical condition not allowing for further surgery (n = 8); and patient refusal (n = 1). Conclusion With adequate preoperative imaging and surgical planning, removal of retained bullets from the hip joint can be achieved using open surgical techniques without the need for hip arthroscopy. This is particularly important in clinical settings where hip arthroscopy is not readily available.