Heterogeneity of platelets and their responses.

There has been increasing recognition of heterogeneity in blood platelets and their responses, particularly in recent years, where next-generation technologies and advanced bioinformatic tools that interrogate "big data" have enabled large-scale studies of RNA and protein expression across a growing list of disease states. However, pioneering platelet biologists and clinicians were already hypothesizing upon and investigating heterogeneity in platelet (and megakaryocyte) activity and platelet metabolism and aggregation over half a century ago. Building on their foundational hypotheses, in particular Professor Marian A. Packham's pioneering work and a State of the Art lecture in her memoriam at the 2023 International Society on Thrombosis and Haemostasis Congress by Anandi Krishnan, this review outlines the key features that contribute to the heterogeneity of platelets between and within individuals. Starting with important epidemiologic factors, we move stepwise through successively smaller scales down to heterogeneity revealed by single-cell technologies in health and disease. We hope that this overview will urge future scientific and clinical studies to recognize and account for heterogeneity of platelets and aim to apply methods that capture that heterogeneity. Finally, we summarize other exciting new data presented on this topic at the 2023 International Society on Thrombosis and Haemostasis Congress.

Management of patients with germline predisposition to haematological malignancies considered for allogeneic blood and marrow transplantation: Best practice consensus guidelines from the UK Cancer Genetics Group (UKCGG), CanGene-CanVar, NHS England Genomic Laboratory Hub (GLH) Haematological Malignancies Working Group and the British Society of Blood and Marrow Transplantation and cellular therapy (BSBMTCT).

Germline predisposition to haematological cancers is increasingly being recognised. Widespread adoption of high-throughput and whole genome sequencing is identifying large numbers of causative germline mutations. Constitutional pathogenic variants in six genes (DEAD-box helicase 41 [DDX41], ETS variant transcription factor 6 [ETV6], CCAAT enhancer binding protein alpha [CEBPA], RUNX family transcription factor 1 [RUNX1], ankyrin repeat domain containing 26 [ANKRD26] and GATA binding protein 2 [GATA2]) are particularly significant in increasing the risk of haematological cancers, with variants in some of these genes also associated with non-malignant syndromic features. Allogeneic blood and marrow transplantation (BMT) is central to management in many haematological cancers. Identification of germline variants may have implications for the patient and potential family donors. Beyond selection of an appropriate haematopoietic stem cell donor there may be sensitive issues surrounding identification and counselling of hitherto asymptomatic relatives. If BMT is needed, there is frequently a clinical urgency that demands a rapid integrated multidisciplinary approach to testing and decision making involving haematologists in collaboration with Clinical and Laboratory Geneticists. Here, we present best practice consensus guidelines arrived at following a meeting convened by the UK Cancer Genetics Group (UKCGG), the Cancer Research UK (CRUK) funded CanGene-CanVar research programme (CGCV), NHS England Genomic Laboratory Hub (GLH) Haematological Oncology Malignancies Working Group and the British Society of Blood and Marrow Transplantation and Cellular Therapy (BSBMTCT).

Effectiveness of man therapy to reduce suicidal ideation and depression among working-age men: A randomized controlled trial.

OBJECTIVE: This randomized controlled trial of the online intervention, man therapy (MT), evaluated efficacy to reduce suicidal ideation (SI) and depression among working-aged men. METHOD: Five-hundred and fifty-four men enrolled and 421 completed all surveys. Control Condition men explored the Healthy Men Michigan (HMM) website and Intervention Condition men explored HMM and MT. Hypotheses included men who used MT would report decreased SI and depression over time compared to Control Condition men. RESULTS: Latent growth curve modeling revealed improvements in SI (slope = -0.23, p < 0.001, 95% CI: -0.29, -0.16) and depression (slope = -0.21, p < 0.001, 95% CI: -0.23, -0.18) over time for men in both groups; however, there was no difference in slope based on group assignment. Depression, lifetime suicide attempts, and interpersonal needs were associated with SI. Interpersonal needs and poor mental health were associated with depression. No group differences in change in risk and protective factors over time were observed. MT sub-group analyses revealed significant improvements in risk and protective factors. CONCLUSION: While a direct effect of MT versus HMM on SI or depression was not observed, men in both groups improved. Results suggest online screening might play a role in reducing SI and depression among men and there are potential benefits to MT related to mental health, social support, and treatment motivation.

Frequency, Method, Intensity, and Health Sequelae of Sexual Choking Among U.S. Undergraduate and Graduate Students.

Although sexual choking is now prevalent, little is known about how people engage in choking in terms of frequency, intensity, method, or potential health sequelae. In a campus-representative survey of undergraduate and graduate students, we aimed to: (1) describe the prevalence of ever having choked/been choked as part of sex; (2) examine the characteristics of choking one's sexual partners (e.g., age at first experience, number of partners, frequency, intensity, method); (3) examine the characteristics of having been choked during sex; and (4) assess immediate responses of having been choked including the extent to which frequency and method (e.g., hand, ligature, limb) of having been choked predicts the range of responses endorsed by participants. A total of 4254 randomly sampled students (2668 undergraduate, 1576 graduate) completed a confidential online survey during Spring 2021. The mean age of first choking/being choked was about 19, with more undergraduates than graduate students reporting first choking/being choked in adolescence. Women and transgender/gender non-binary participants were significantly more likely to have been choked than men. Participants more often reported the use of hands compared to limbs or ligature. Common responses to being choked were pleasurable sensations/euphoria (81.7%), a head rush (43.8%), feeling like they could not breathe (43.0%), difficulty swallowing (38.9%), unable to speak (37.6%), and watery eyes (37.2%). About 15% had noticed neck bruising and 3% had lost consciousness from being choked. Greater frequency and intensity of being choked was associated with reports of more physical responses as was use of limb (arm, leg) or ligature.

Toward platelet transcriptomics in cancer diagnosis, prognosis and therapy.

Widespread adoption of next-generation techniques such as RNA-sequencing (RNA-seq) has enabled research examining the transcriptome of anucleate blood platelets in health and disease, thus revealing a rich platelet transcriptomic signature that is reprogrammed in response to disease. Platelet signatures not only capture information from parent megakaryocytes and progenitor hematopoietic stem cells but also the bone marrow microenvironment, and underlying disease states. In cancer, the substantive body of research in patients with solid tumours has identified distinct signatures in 'tumour-educated platelets', reflecting influences of the tumour, stroma and vasculature on splicing, sequestration of tumour-derived RNAs, and potentially cytokine and microvesicle influences on megakaryocytes. More recently, platelet RNA expression has emerged as a highly sensitive approach to profiling chronic progressive haematologic malignancies, where the combination of large data cohorts and machine-learning algorithms enables precise feature selection and potential prognostication. Despite these advances, however, our ability to translate platelet transcriptomics toward clinical diagnostic and prognostic efforts remains limited. In this Perspective, we present a few actionable steps for our basic, translational and clinical research communities in advancing the utility of the platelet transcriptome as a highly sensitive biomarker in cancer and collectively enable efforts toward clinical translation and patient benefit.

Preceding group A streptococcus skin and throat infections are individually associated with acute rheumatic fever: evidence from New Zealand.

INTRODUCTION: Acute rheumatic fever (ARF) is usually considered a consequence of group A streptococcus (GAS) pharyngitis, with GAS skin infections not considered a major trigger. The aim was to quantify the risk of ARF following a GAS-positive skin or throat swab. METHODS: This retrospective analysis used pre-existing administrative data. Throat and skin swab data (1 866 981 swabs) from the Auckland region, New Zealand and antibiotic dispensing data were used (2010-2017). Incident ARF cases were identified using hospitalisation data (2010-2018). The risk ratio (RR) of ARF following swab collection was estimated across selected features and timeframes. Antibiotic dispensing data were linked to investigate whether this altered ARF risk following GAS detection. RESULTS: ARF risk increased following GAS detection in a throat or skin swab. Maori and Pacific Peoples had the highest ARF risk 8-90 days following a GAS-positive throat or skin swab, compared with a GAS-negative swab. During this period, the RR for Maori and Pacific Peoples following a GAS-positive throat swab was 4.8 (95% CI 3.6 to 6.4) and following a GAS-positive skin swab, the RR was 5.1 (95% CI 1.8 to 15.0). Antibiotic dispensing was not associated with a reduction in ARF risk following GAS detection in a throat swab (antibiotics not dispensed (RR: 4.1, 95% CI 2.7 to 6.2), antibiotics dispensed (RR: 4.3, 95% CI 2.5 to 7.4) or in a skin swab (antibiotics not dispensed (RR: 3.5, 95% CI 0.9 to 13.9), antibiotics dispensed (RR: 2.0, 95% CI 0.3 to 12.1). CONCLUSIONS: A GAS-positive throat or skin swab is strongly associated with subsequent ARF, particularly for Maori and Pacific Peoples. This study provides the first population-level evidence that GAS skin infection can trigger ARF.

Platelet Heterogeneity in Myeloproliferative Neoplasms.

Myeloproliferative neoplasms (MPNs) are a group of malignant disorders of the bone marrow where a dysregulated balance between proliferation and differentiation gives rise to abnormal numbers of mature blood cells. MPNs encompass a spectrum of disease entities with progressively more severe clinical features, including complications with thrombosis and hemostasis and an increased propensity for transformation to acute myeloid leukemia. There is an unmet clinical need for markers of disease progression. Our understanding of the precise mechanisms that influence pathogenesis and disease progression has been limited by access to disease-specific cells as biosources. Here, we review the landscape of MPN pathology and present blood platelets as potential candidates for disease-specific understanding. We conclude with our recent work discovering progressive platelet heterogeneity by subtype in a large clinical cohort of patients with MPN.

Descriptive analysis of group A Streptococcus in skin swabs and acute rheumatic fever, Auckland, New Zealand, 2010-2016.

BACKGROUND: Group A Streptococcus (GAS) can trigger an immune-mediated response resulting in acute rheumatic fever (ARF). Historically, ARF has been considered a consequence of preceding GAS pharyngitis, but increasing evidence suggests that GAS skin infections may be a driver. Data on the primary care burden of GAS skin infection are limited. This paper aims to describe and compare the prevalence and distribution of GAS detection in skin swabs and ARF rates in the Auckland population. METHODS: This cross-sectional study used all laboratory skin swab data from people who had a skin swab taken as a result of a consultation with a health professional in the Auckland region (2010-2016). Initial primary hospitalisations for ARF were identified and all data were linked using unique patient identifiers to patient's age, prioritised ethnicity, sex, and socio-economic status. FINDINGS: 377,410 skin swabs from 239,494 individuals were included. 12·8% of swabs were GAS positive, an annual incidence of 4·8 per 1,000 person-years. Maori and Pacific Peoples under 20 years of age had markedly higher GAS detection in skin swabs (RR 4·0; 95% CI 3·9-4·2: RR 6·8; 95% CI 6·6-7·0) and significantly higher ARF rates (RR 30·3; 95% CI 19·5-46·9: RR 69·7 95% CI 45·8-106·1) compared with European/Other ethnicities. INTERPRETATION: The observation that GAS detection was markedly higher in Maori and Pacific Peoples provides a potential explanation for the marked ethnic differences in ARF. These findings support a greater focus on addressing the burden of skin infection in NZ, including as ARF prevention. FUNDING: The first author received a training stipend from the New Zealand College of Public Health Medicine (NZCPHM) during her Masters of Public Health.

Indolent T-Cell Lymphoproliferative Disorder of the Uterine Corpus: A Case Report.

Primary lymphoproliferative disorders of the uterus are rare, with the majority being B-cell diseases or aggressive T-cell disease. We present the case of a 31-yr old in whom an Indolent T-cell lymphoproliferative disorder (iTCLPD) was identified in resection chippings for a suspected fibroid, following presentation with menorrhagia. Laboratory investigations revealed an oligoclonal T-cell infiltrate with the immunophenotype of nonactivated cytotoxic T cells, and a proliferative fraction of 10% to 15%. There was no clinical or radiologic evidence of systemic disease, and the patient remained well with no indication of relapse 1 yr from resection and diagnosis. iTCLPD of the uterine corpus has features in common with the recently described iTCLPD of the gastrointestinal tract and primary cutaneous acral CD8 T-cell lymphoma. Recognition of these parallels is important as few other cases of iTCLPD have been described, and it suggests local resection rather than systemic treatment as the best therapeutic strategy.

Perceptions of belongingness and social support attenuate PTSD symptom severity among firefighters: A multistudy investigation.

Firefighters experience high rates of posttraumatic stress disorder (PTSD). It is imperative to identify malleable factors that protect against the development of PTSD symptoms among this population. We examined whether perceptions of belongingness broadly (Study 1) and social support from supervisors, coworkers, and family/friends specifically (Study 2) are associated with lower PTSD symptom severity among firefighters. Study 1 included 840 U.S. firefighters (91.1% male); participants completed the Interpersonal Needs Questionnaire and PTSD Checklist-Civilian Version. Study 2 included 200 U.S. women firefighters exposed to a Criterion A traumatic event; participants completed the Generic Job Stress Questionnaire, Life Events Checklist for Diagnostic and Statistical Manual of Mental Disorders-5, and PTSD Checklist for Diagnostic and Statistical Manual of Mental Disorders-5. Linear regression analyses were conducted, adjusting for the number of years participants served as firefighters. Greater belongingness broadly (Study 1; b = -0.740, p < .001) as well as social support specifically (Study 2) from supervisors (b = -4.615, p < .001), coworkers (b = -4.465, p = .001), and family/friends (b = -3.206, p = .021) were associated with less severe PTSD symptoms. When all sources of social support were entered into a single model, only support from supervisors was significantly associated with lower overall PTSD symptom severity (b = -4.222, p = .004). Belongingness and social support may protect against the development of PTSD among firefighters. Supervisor social support may be particularly salubrious, suggesting that top-down mental wellness promotion within the fire service may be indicated to protect firefighters against PTSD. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Mental health service use and help-seeking among women firefighters with a career history of suicidality.

Research indicates that women firefighters may experience elevated rates of suicidal thoughts and behaviors; however, little is known about how at-risk women firefighters interface with mental health services and other support sources. This study aimed to identify rates of mental health service use and help-seeking, correlates of service use, and preferred sources of support among women firefighters with a career history of suicidality. A sample of 119 United States women firefighters reporting a history of suicide ideation, plans, and/or attempts during their firefighting careers completed a web-based survey of behavioral health. Descriptive statistics, chi-square tests, and logistic regression analyses were utilized to examine rates of help-seeking and correlates of service use. Of the sample, 73.1% reported seeking professional mental health services and 43.7% reported seeking other forms of support (e.g., support groups, hotlines) during their firefighting careers. Stigma concerns were most frequently cited as hypothetical barriers to care; however, rates of stigma concerns did not appear to be significantly higher among service users. Participants reported a preference for seeking care from a psychologist, therapist, and/or counselor. Findings indicate that the majority of women firefighters with a career history of suicidality have utilized mental health services or other sources of support during their firefighting careers. Results suggest that self-reported stigma may not serve as a significant barrier to mental health service utilization in this population. Further research is needed to examine the temporal relationship between suicidality and service use in a nationally representative sample of women firefighters. (PsycINFO Database Record

The reversal of anticoagulation in clinical practice .

Widespread use of anticoagulant drugs for treatment and -prevention of thromboembolic events means it is common to encounter patients requiring reversal of anticoagulation for management of bleeding or invasive procedures. While supportive and general measures apply for patients on all agents, recent diversification in the number of licensed agents makes an understanding of drug-specific reversal strategies essential. Recognising effects upon, and limitations of, laboratory measures of coagulation also plays an important role. An understanding of reversal strategies alone is insufficient to competently care for patients who may require anticoagulation reversal. It is also necessary to reduce the need for reversal through correct prescribing and by employing appropriate periprocedural bridging strategies for elective and semi-elective procedures. Finally, consideration of whether and when to reintroduce an anticoagulant drug following reversal is important not only to balance bleeding and thrombotic risks for individual patients but also for timely management of discharge.

Exposure to suicide and suicide bereavement among women firefighters: Associated suicidality and psychiatric symptoms.

OBJECTIVE: To examine experiences with suicide exposure and bereavement among women firefighters. METHODS: Women firefighters (N = 266, Mage  = 37.64y) completed self-report measures assessing their experiences with suicide exposure, history of suicidality, current psychiatric symptoms, and suicide risk. RESULTS: Three-fourths (74.4%) of participants reported knowing someone who had died by suicide; of these participants, 31.3% reported losing a fellow firefighter to suicide. Exposure to suicide during one's firefighting career was associated with more severe psychiatric symptoms and suicide risk. Greater impact of a suicide death was significantly associated with more severe current suicide risk, even after controlling for prior suicidality and other psychiatric symptoms. CONCLUSIONS: Women firefighters exposed to suicide during their careers may experience more severe psychiatric symptoms and increased suicide risk as compared to their counterparts without this exposure. In particular, women firefighters who are more severely impacted by a suicide loss may be at increased suicide risk.

Problematic alcohol use and suicidal ideation among firefighters: A multi-study investigation of the explanatory roles of perceived burdensomeness and thwarted belongingness.

BACKGROUND: Firefighters are at increased risk for both problematic alcohol use and suicidality. Research has found that problematic alcohol use is related to suicidality among this population; however, limited data exist regarding what might account for this association. The present two-study investigation (1) examined the association between suicidality and problematic alcohol use among two large samples of firefighters and (2) tested whether interpersonal theory of suicide constructs-perceived burdensomeness (PB) and thwarted belongingness (TB)-serve as indirect indicators of this relationship. METHODS: Participants in Study 1 were 944 U.S. firefighters (12.5% female); participants in Study 2 were 241 U.S. women firefighters. Participants completed the Interpersonal Needs Questionnaire, Alcohol Use Disorders Identification Test, and the Depressive Symptom Inventory-Suicidality Subscale (Study 1) or the Self-Injurious Thoughts and Behaviors Interview-Short Form (Study 2). Bias-corrected bootstrap indirect effects path analyses were utilized. RESULTS: In Study 1, more problematic alcohol use was significantly associated with more severe career suicidal ideation via PB but not TB. In Study 2, problematic alcohol use was associated with career suicidal ideation via both PB and TB. PB seems to account for the relationship between problematic alcohol use and career suicidal ideation among male and female firefighters. LIMITATIONS: Limitations include use of a cross-sectional design, use of retrospective measures of suicidal ideation, and our findings derived from subsamples of two existing datasets. CONCLUSIONS: Findings suggest that PB and TB may explain the relationship between problematic alcohol use and suicidal ideation, but that this effect is discrepant based on gender.

A genome-wide RNAi screen identifies MASK as a positive regulator of cytokine receptor stability.

Cytokine receptors often act via the Janus kinase and signal transducer and activator of transcription (JAK/STAT) pathway to form a signalling cascade that is essential for processes such as haematopoiesis, immune responses and tissue homeostasis. In order to transduce ligand activation, cytokine receptors must dimerise. However, mechanisms regulating their dimerisation are poorly understood. In order to better understand the processes regulating cytokine receptor levels, and their activity and dimerisation, we analysed the highly conserved JAK/STAT pathway in Drosophila, which acts via a single receptor, known as Domeless. We performed a genome-wide RNAi screen in Drosophila cells, identifying MASK as a positive regulator of Domeless dimerisation and protein levels. We show that MASK is able to regulate receptor levels and JAK/STAT signalling both in vitro and in vivo We also show that its human homologue, ANKHD1, is also able to regulate JAK/STAT signalling and the levels of a subset of pathway receptors in human cells. Taken together, our results identify MASK as a novel regulator of cytokine receptor levels, and suggest functional conservation, which may have implications for human health.This article has an associated First Person interview with the first author of the paper.

What is the evidence for a role for diet and nutrition in osteoarthritis?

As current treatment options in OA are very limited, OA patients would benefit greatly from some ability to self-manage their condition. Since diet may potentially affect OA, we reviewed the literature on the relationship between nutrition and OA risk or progression, aiming to provide guidance for clinicians. For overweight/obese patients, weight reduction, ideally incorporating exercise, is paramount. The association between metabolic syndrome, type-2 diabetes and OA risk or progression may partly explain the apparent benefit of dietary-lipid modification resulting from increased consumption of long-chain omega-3 fatty-acids from oily fish/fish oil supplements. A strong association between OA and raised serum cholesterol together with clinical effects in statin users suggests a potential benefit of reduction of cholesterol by dietary means. Patients should ensure that they meet the recommended intakes for micronutrients such as vitamin K, which has a role in bone/cartilage mineralization. Evidence for a role of vitamin D supplementation in OA is unconvincing.

HPV-negative, but not HPV-positive, oropharyngeal carcinomas induce fibroblasts to support tumour invasion through micro-environmental release of HGF and IL-6.

Human papillomavirus (HPV) infection is causally related to a subset of oropharyngeal carcinomas (OPC) and is linked to a more favourable prognosis compared to HPV-negative OPC. The mechanisms underlying this effect on prognosis are not fully understood, but interactions with the tumour microenvironment may be pivotal. Here, we investigated the role of the tumour microenvironment in HPV-positive compared to HPV-negative cancer using 2D and 3D modelling of OPC interactions with stromal fibroblasts. HPV-negative, but not HPV-positive, OPC-derived cell lines induced a rapid fibroblast secretory response that supported 2D cancer cell migration and invasion in vitro. Array profiling of this HPV-negative induced fibroblast secretome identified hepatocyte growth factor (HGF) as the principal secreted factor that promoted cancer cell migration. The interaction between HPV-negative cell lines and fibroblasts in 2D was prevented using c-Met (HGF receptor) inhibitors, which further restricted both HPV-negative and positive cell invasion in 3D co-culture models. Furthermore, we discovered a synergistic relationship between HGF and IL-6 in the support of migration that relates JAK activation to HGF responsiveness in HPV-negative lines. In summary, our data show significant differences in the interactions between HPV-positive and HPV-negative OPC cells and stromal fibroblasts. In addition, we, provide in vitro evidence to support the clinical application of c-MET inhibitors in the control of early HPV-negative OPC.

Women Firefighters and Workplace Harassment: Associated Suicidality and Mental Health Sequelae.

This cross-sectional study investigated the association between harassment, career suicidality, and psychiatric symptoms among women firefighters. Women firefighters (n = 290) completed self-report measures of experiences with harassment on the job, career suicidality, and various psychiatric symptoms. Logistic regression analyses and one-way analyses of variance were used to address study aims. Of the sample, 21.7% reported having experienced sexual harassment and 20.3% reported having been threatened or harassed in another way on their firefighting job. Sexual harassment and other threats/harassment on the job were both significantly associated with a greater likelihood of reporting career suicidal ideation, as well as reporting more severe psychiatric symptoms. Harassment and threats experienced on the job may be associated with increased suicide risk and more severe psychiatric symptoms among women firefighters. Efforts are needed to reduce the occurrence of harassment and threats within the fire service and provide support for women firefighters who have been harassed or threatened.