Microclots, as defined by amyloid-fibrinogen aggregates, predict risks of disseminated intravascular coagulation and mortality.

ABSTRACT: Microclots have been associated with various conditions, including postacute sequelae of severe acute respiratory syndrome coronavirus 2 infection. They have been postulated to be amyloid-fibrin(ogen) aggregates, but their role as a prognostic biomarker remains unclear. To examine their possible clinical utility, blood samples were collected for the first 96 hours from critically ill patients (n = 104) admitted to the intensive care unit (ICU). Detection was by staining platelet-poor plasma samples with thioflavin T and visualized by fluorescent microscopy. Image J software was trained to identify and quantify microclots, which were detected in 44 patients (42.3%) on ICU admission but not in the remaining 60 (57.7%) or the 20 healthy controls (0.0%). Microclots on admission to ICU were associated with a primary diagnosis of sepsis (microclots present in sepsis, 23/44 [52.3%] vs microclots absent in sepsis, 19/60 [31.7%]; P = .044). Multicolor immunofluorescence demonstrated that microclots consisted of amyloid-fibrinogen aggregates, which was supported by proteomic analysis. Patients with either a high number or larger-sized microclots had a higher likelihood of developing disseminated intravascular coagulation (odds ratio [OR], 51.4; 95% confidence interval [CI], 6.3-6721.1; P < .001) and had an increased probability of 28-day mortality (OR, 5.3; 95% CI, 2.0-15.6; P < .001). This study concludes that microclots, as defined by amyloid-fibrin(ogen) aggregates, are potentially useful in identifying sepsis and predicting adverse coagulopathic and clinical outcomes.

Low Iodine Nutrition Knowledge in Chinese Breastfeeding Women despite Adequate Iodine Status.

There has been a scarcity of evidence about iodine nutrition knowledge among women during pregnancy and lactation. The aim of this study was to determine women's iodine knowledge and the relationship between knowledge and iodine status during pregnancy and lactation. Women were recruited from a hospital in the western part of China in the third trimester of pregnancy and followed until the end of the first week of lactation. The women's iodine status was measured by their urinary iodine concentration (UIC) and an iodine-specific, validated food frequency questionnaire (FFQ). Iodine nutrition knowledge was assessed using an iodine nutrition knowledge questionnaire. A total of 200 women (mean age of 29.0 ± 4.2 years) completed the whole study. The majority of the women did not consume enough iodine during both pregnancy and lactation (231.89 vs. 237.26 µg/day). The overall mean iodine knowledge scores in our sample of women during pregnancy and lactation were 4.77 and 4.87, indicating low iodine knowledge. The use of iodized salt and a higher education level were significantly associated with an increased iodine knowledge score. In conclusion, this study reported poor iodine nutrition knowledge in women, highlighting a public health concern. Therefore, the iodine knowledge of women should be improved, possibly via maternal health campaigns to avoid the consequences of iodine deficiency disorders in newborns.

Autophagy prevents graft failure during murine graft-versus-host disease.

ABSTRACT: Autophagy is an intracellular survival process that has established roles in the long-term survival and function of hematopoietic stem cells (HSC). We investigated the contribution of autophagy to HSC fitness during allogeneic transplantation and graft-versus-host disease (GVHD). We demonstrate in vitro that both tumor necrosis factor and IL-1ß, major components of GVHD cytokine storm, synergistically promote autophagy in both HSC and their more mature hematopoietic progenitor cells (HPC). In vivo we demonstrate that autophagy is increased in donor HSC and HPC during GVHD. Competitive transplant experiments demonstrated that autophagy-deficient cells display reduced capacity to reconstitute the hematopoietic system compared to wild-type counterparts. In a major histocompatibility complex-mismatched model of GVHD and associated cytokine dysregulation, we demonstrate that autophagy-deficient HSC and progenitors fail to establish durable hematopoiesis, leading to primary graft failure and universal transplant related mortality. Using several different models, we confirm that autophagy activity is increased in early progenitor and HSC populations in the presence of T-cell-derived inflammatory cytokines and that these HSC populations require autophagy to survive. Thus, autophagy serves as a key survival mechanism in HSC and progenitor populations after allogeneic stem cell transplant and may represent a therapeutic target to prevent graft failure during GVHD.

The use of breast milk iodine concentration in the first week of lactation as a biomarker of iodine status in breast-feeding women.

Breast milk iodine concentration (BMIC) is a promising indicator of iodine status in lactating women. However, there are limited data on its usefulness to reflect maternal iodine deficiency. Therefore, the aim of our study was to assess iodine concentration in breast milk and urine samples in exclusively breast-feeding women. Eligible pregnant women undergoing routine antenatal care in a large hospital in Shaanxi Province, China, were followed up from the third trimester of pregnancy until the first week of lactation. Urine samples (20 ml) were collected during pregnancy and lactation. Iodine concentration in samples was measured based on Sandell-Kolthoff reaction. Breast milk samples (5 ml) were provided during lactation. A receiver operating curve (ROC) was constructed to determine the diagnostic performance of BMIC. An iodine-specific FFQ was completed twice during pregnancy and lactation. A total of 200 women completed the study. The overall median BMIC was 89 µg/l, indicating iodine sufficiency (i.e. BMIC reference range between 60 and 465 µg/l). Women reported similar median urinary iodine concentration (UIC) during pregnancy and lactation (112 and 113 µg/l, respectively), but their iodine status differed - mild-to-moderate iodine deficiency during pregnancy and iodine sufficiency during lactation. The ROC for BMIC using UIC as a reference standard was 0·755 (95 % CI: 0·644, 0·866). In conclusion, this study demonstrated that women were iodine sufficient in the first week of lactation as assessed by UIC, which was consistent with BMIC. These findings suggested that BMIC is a useful biomarker to assess iodine status in lactating women.

Imetelstat-mediated alterations in fatty acid metabolism to induce ferroptosis as a therapeutic strategy for acute myeloid leukemia.

Telomerase enables replicative immortality in most cancers including acute myeloid leukemia (AML). Imetelstat is a first-in-class telomerase inhibitor with clinical efficacy in myelofibrosis and myelodysplastic syndromes. Here, we develop an AML patient-derived xenograft resource and perform integrated genomics, transcriptomics and lipidomics analyses combined with functional genetics to identify key mediators of imetelstat efficacy. In a randomized phase II-like preclinical trial in patient-derived xenografts, imetelstat effectively diminishes AML burden and preferentially targets subgroups containing mutant NRAS and oxidative stress-associated gene expression signatures. Unbiased, genome-wide CRISPR/Cas9 editing identifies ferroptosis regulators as key mediators of imetelstat efficacy. Imetelstat promotes the formation of polyunsaturated fatty acid-containing phospholipids, causing excessive levels of lipid peroxidation and oxidative stress. Pharmacological inhibition of ferroptosis diminishes imetelstat efficacy. We leverage these mechanistic insights to develop an optimized therapeutic strategy using oxidative stress-inducing chemotherapy to sensitize patient samples to imetelstat causing substantial disease control in AML.

A randomised double-blind placebo-controlled trial of minocycline and/or omega-3 fatty acids added to treatment as usual for at risk Mental States: The NAYAB study.

BACKGROUND: Inflammatory mechanisms are thought to contribute to the onset of psychosis in persons with an at-risk mental state (ARMS). We investigated whether the anti-inflammatory properties of minocycline and omega-3 polyunsaturated fatty acids (omega-3), alone or synergistically, would prevent transition to psychosis in ARMS in a randomised, double-blind, placebo-controlled trial in Pakistan. METHODS: 10,173 help-seeking individuals aged 16-35 years were screened using the Prodromal Questionaire-16. Individuals scoring 6 and over were interviewed using the Comprehensive Assessment of At-Risk Mental States (CAARMS) to confirm ARMS. Participants (n = 326) were randomised to minocycline, omega-3, combined minocycline and omega-3 or to double placebo for 6 months. The primary outcome was transition to psychosis at 12 months. FINDINGS: Forty-five (13.8 %) participants transitioned to psychosis. The risk of transition was greater in those randomised to omega-3 alone or in combination with minocycline (17.3.%), compared to 10.4 % in those not exposed to omega-3; a risk-ratio (RR) of 1.67, 95 % CI [0.95, 2.92] p = 0.07. The RR for transitions on minocycline vs. no minocycline was 0.86, 95 % CI [0.50, 1.49] p > 0.10. In participants who did not become psychotic, CAARMS and depression symptom scores were reduced at six and twelve months (mean CAARMS difference = 1.43; 95 % CI [0.33, 1.76] p < 0.01 in those exposed to omega-3. Minocycline did not affect CAARMS or depression scores. INTERPRETATION: In keeping with other studies, omega-3 appears to have beneficial effects on ARMS and mood symptom severity but it increased transition to psychosis, which may reflect metabolic or developmental consequences of chronic poor nutrition in the population. Transition to psychosis was too rare to reveal a preventative effect of minocycline but minocycline did not improve symptom severity. ARMS symptom severity and transition to psychosis appear to have distinct pathogeneses which are differentially modulated by omega-3 supplementation. FUNDING: The study was funded by the Stanley Research Medical Institute.

Australia and New Zealand consensus position statement: use of COVID-19 therapeutics in patients with haematological malignancies.

Despite widespread vaccination rates, we are living with high transmission rates of SARS-CoV-2. Although overall hospitalisation rates are falling, the risk of serious infection remains high for patients who are immunocompromised because of haematological malignancies. In light of the ongoing pandemic and the development of multiple agents for treatment, representatives from the Haematology Society of Australia and New Zealand and infectious diseases specialists have collaborated on this consensus position statement regarding COVID-19 management in patients with haematological disorders. It is our recommendation that both patients with haematological malignancies and treating specialists be educated regarding the preventive and treatment options available and that patients continue to receive adequate vaccinations, keeping in mind the suboptimal vaccine responses that occur in haematology patients, in particular, those with B-cell malignancies and on B-cell-targeting or depleting therapy. Patients with haematological malignancies should receive treatment for COVID-19 in accordance with the severity of their symptoms, but even mild infections should prompt early treatment with antiviral agents. The issue of de-isolation following COVID-19 infection and optimal time to treatment for haematological malignancies is discussed but remains an area with evolving data. This position statement is to be used in conjunction with advice from infectious disease, respiratory and intensive care specialists, and current guidelines from the National COVID-19 Clinical Evidence Taskforce and the New Zealand Ministry of Health and Cancer Agency Te Aho o Te Kahu COVID-19 Guidelines.

Immunoproteasome function maintains oncogenic gene expression in KMT2A-complex driven leukemia.

Pharmacologic targeting of chromatin-associated protein complexes has shown significant responses in KMT2A-rearranged (KMT2A-r) acute myeloid leukemia (AML) but resistance frequently develops to single agents. This points to a need for therapeutic combinations that target multiple mechanisms. To enhance our understanding of functional dependencies in KMT2A-r AML, we have used a proteomic approach to identify the catalytic immunoproteasome subunit PSMB8 as a specific vulnerability. Genetic and pharmacologic inactivation of PSMB8 results in impaired proliferation of murine and human leukemic cells while normal hematopoietic cells remain unaffected. Disruption of immunoproteasome function drives an increase in transcription factor BASP1 which in turn represses KMT2A-fusion protein target genes. Pharmacologic targeting of PSMB8 improves efficacy of Menin-inhibitors, synergistically reduces leukemia in human xenografts and shows preserved activity against Menin-inhibitor resistance mutations. This identifies and validates a cell-intrinsic mechanism whereby selective disruption of proteostasis results in altered transcription factor abundance and repression of oncogene-specific transcriptional networks. These data demonstrate that the immunoproteasome is a relevant therapeutic target in AML and that targeting the immunoproteasome in combination with Menin-inhibition could be a novel approach for treatment of KMT2A-r AML.

Demographic, clinical and laboratory differences between paediatric acute COVID-19 and PIMS-TS-results from a single centre study in the UK.

Background: Paediatric symptomatic SARS-CoV-2 infections associate with two presentations, acute COVID-19 and paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS). Phenotypic comparisons, and reports on predictive markers for disease courses are sparse and preliminary. Methods: A chart review of COVID-19 and PIMS-TS patients (≤19 years) admitted to Alder Hey Children's NHS Foundation Trust, a tertiary centre in the North-West of England, was performed (02/2020-09/2022). Results: A total of 161 symptomatic COVID-19 and 50 PIMS-TS patients were included. Peaks in admissions of patients with PIMS-TS occurred approximately 4 weeks after those for acute COVID-19. The incidence of in-patients with PIMS-TS reduced over time, and there were no admissions after February 2022. When compared to acute COVID-19, PIMS-TS patients were older (median: 10.3 years vs. 2.03 years; p < 0.001). There were no differences in gender distribution, but minority ethnicities were over-represented among PIMS-TS patients. Regional ethnic distribution was reflected among acute COVID-19 patients (66% vs. 84.5% White Caucasian, p = 0.01). Pre-existing comorbidities were more common among acute COVID-19 patients (54.7% vs. 8%, p < 0.001). PIMS-TS patients more commonly presented with abdominal symptoms (92% vs. 50.3%), neurological symptoms (28% vs. 10.6%) and skin rashes (72% vs. 16.8%), (p ≤ 0.01) when compared with acute COVID-19, where respiratory symptoms were more common (51.6% vs. 32%, p = 0.016). PIMS-TS more frequently required intensive care admission (64% vs. 16.8%), and inotropic support (64% vs. 9.3%) (all p < 0.05). More deaths occurred among acute COVID-19 patients [0 vs. 7 (4.4%)], with 5/7 (71%) in the context of pre-existing comorbidities. When compared to acute COVID-19, PIMS-TS patients exhibited more lymphopenia and thrombocytopenia, a more pronounced acute phase reaction, and more hyponatraemia (p < 0.05). Partial least square discriminant analysis of routine laboratory parameters allowed (incomplete) separation of patients at diagnosis, and variable importance projection (VIP) scoring revealed elevated CRP and low platelets as the most discriminatory parameters. Conclusion: Admissions for PIMS-TS reduced with increasing seroconversion rates in the region. Young age and pre-existing comorbidities associate with hospital admission for acute COVID-19. While PIMS-TS may present more acutely with increased need for intensive care, acute COVID-19 had an increased risk of mortality in this cohort.

Implantation in the lower half of the uterine cavity and decreased trophoblastic thickness can predict subsequent miscarriage: a prospective cohort study.

Abstract: Embryo implantation is vital for successful conception but remains to be fully understood. Trophoblast invasion is key for implantation, with anchorage and depth of placentation determined by its extent. There is a dearth of synchronous information regarding IVF, implantation site, and trophoblastic thickness (TT). Our aim was to determine whether pregnancy implantation site and TT, had an impact on outcomes of IVF pregnancies. This prospective observational study was undertaken at a tertiary referral UK fertility unit over 14 months, collecting data on implantation site and TT from three-dimensional (3D) images of the uterus following early pregnancy scan. Of the 300 women recruited, 277 (92%) had live births, 20 (7%) miscarried, 2 (0.7%) had stillbirths, and 1 (0.3%) had a termination. Significantly more pregnancies that resulted in miscarriage (7/20, 35%) were located in the lower uterine cavity when compared to ongoing pregnancies (15/277, 5%) (P < 0.01). TT was significantly higher in ongoing pregnancies when compared with those who miscarried (7.2 mm vs 5.5 mm; P < 0.01). Implantation in the lower half of the uterine cavity and decreased TT are significantly associated with an increased rate of miscarriage. Identification of those at risk should prompt increased monitoring with the aim of supporting these pregnancies. Lay summary: Implantation of an embryo in the womb is vital for a successful pregnancy. We wanted to find out whether findings on an ultrasound scan in early pregnancy had an impact on outcomes of IVF pregnancies. Three hundred women were recruited to the study, 277 (92%) had live births and unfortunately 20 (7%) had a miscarriage, 2 (0.7%) had stillbirths, and 1 (0.3%) had a termination. Many more of the pregnancies that miscarried implanted in the lower part of the womb. The thickness of the infiltration of the pregnancy into the womb was significantly higher in the ongoing pregnancies. We concluded that implantation in the lower half of the womb and reduced infiltration of the pregnancy seen on scan are associated with an increased rate of miscarriage. We propose that when we identify those at risk, we should increase monitoring, with the aim of supporting these pregnancies.

Evaluation of a novel, multicomponent anxiety management programme for people with intellectual disability: protocol for a mixed-methods, quasi-experimental feasibility study.

INTRODUCTION: Studies have shown some benefits to single approaches to psychological therapies for the treatment of anxiety in people with intellectual disability such as modified cognitive-behavioural therapy and mindfulness. To our knowledge, no studies have used a multicomponent approach for the individual treatment of anxiety-related disorders in this population group. A co-production group of clinical experts and people with intellectual disability has created a novel multicomponent anxiety management programme (MCAMP-ID). The aims of this study are to investigate (1) the feasibility of this approach in reducing anxiety for people with a mild/moderate intellectual disability, (2) the feasibility of outcome measures and (3) the feasibility of completing a future randomised controlled trial of this programme. The data from this feasibility study will be used to inform trial design and to complete power calculation. METHODS AND ANALYSIS: Sixty people with intellectual disability will be invited to participate in the study across four intellectual disability services within one mental health trust in Northwest England. The specialist services will deliver either treatment as usual (TAU) or the novel intervention (MCAMP-ID). MCAMP-ID comprises of 10 individual sessions delivered by a member of the clinical team once a week for between 10 and 12 weeks. TAU will be based on standard treatment currently delivered to meet the person's specific needs. The outcomes of the study will be feasibility of recruitment, attrition, adherence to the programme and suitability of outcome measures. A mixed-methods approach will be used to assess outcomes. ETHICS AND DISSEMINATION: The study received approval from the Research Ethics Committee and Health Research Authority (23/EM/0044) through the Integrated Research Application System (IRAS ID: 315557) in March 2023. Participants will provide informed consent before taking part. Study findings will be presented at conferences and published within a peer-reviewed journal. TRIAL REGISTRATION NUMBER: ISRCTN16062949.

ACTivity as medicine In Oncology for Head and Neck (ACTIOHN): Protocol for a feasibility study investigating a patient-centred approach to exercise for people with head and neck cancer.

BACKGROUND AND AIM: Attempts at personalisation of exercise programmes in head and neck cancer (HaNC) have been limited. The main aim of the present study is to investigate the feasibility and acceptability of introducing a remotely delivered, fully personalised, collaborative, and flexible approach to prescribing and delivering exercise programmes into the HaNC usual care pathway. METHODS: This is a single arm, feasibility study. Seventy patients diagnosed with HaNC will be recruited from two regional HaNC centres in the United Kingdom. Patients will undertake an 8-week exercise programme designed and delivered by cancer exercise specialists. The exercise programme will start any time between the time of diagnosis and up to 8 weeks after completing treatment, depending on patient preference. The content of the exercise programme will be primarily based on patient needs, preferences, and goals, but guided by current physical activity guidelines for people with cancer. The primary outcome measure is retention to the study. Secondary quantitative outcomes are uptake to the exercise programme, different measures of exercise adherence, pre- and post-intervention assessments of fatigue (Multidimensional Fatigue Symptom Inventory-Short Form), quality of life (SF-36), physical activity levels (International Physical Activity Questionnaire-Short Form), and various components of physical fitness. The outcomes of the nested qualitative study are acceptability and feasibility of the intervention evaluated via interviews with patients, health care professionals, and the cancer exercise specialists. Intervention and participant fidelity will be determined using checklists and scrutiny of each patient's logbook and the cancer exercise specialists' meeting notes. Analysis of quantitative data will be via standard summary statistics. Qualitative data will be analysed using thematic analysis. EXPECTED RESULTS: This feasibility study will inform the design and conduct of a future randomised controlled trial. Success will be defined according to a traffic light system for identifying the appropriateness of progression to a randomised controlled trial. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number registry (ISRCTN82505455).

Cell fate determinant Llgl1 is required for propagation of acute myeloid leukemia.

Scribble complex proteins can influence cell fate decisions and self-renewal capacity of hematopoietic cells. While specific cellular functions of Scribble complex members are conserved in mammalian hematopoiesis, they appear to be highly context dependent. Using CRISPR/Cas9-based genetic screening, we have identified Scribble complex-related liabilities in AML including LLGL1. Despite its reported suppressive function in HSC self-renewal, inactivation of LLGL1 in AML confirms its relevant role for proliferative capacity and development of AML. Its function was conserved in human and murine models of AML and across various genetic backgrounds. Inactivation of LLGL1 results in loss of stemness-associated gene-expression including HoxA-genes and induces a GMP-like phenotype in the leukemia stem cell compartment. Re-expression of HoxA9 facilitates functional and phenotypic rescue. Collectively, these data establish LLGL1 as a specific dependency and putative target in AML and emphasizes its cell-type specific functions.

Bilateral globus pallidus internus (GPi) deep brain stimulation for cervical dystonia: Effects on motor and non-motor symptoms within 5 years follow.

BACKGROUND: Cervical Dystonia ("CD") is a movement disorder characterised by sustained muscle contractions in the neck, causing involuntary posturing. Deep brain stimulation ("DBS") of the globus pallidal internus (GPi) is advanced treatment for pharmaco-refractory patients. As CD is a rare disease, cohort studies are often limited to patients of heterogenous disease profile, small sample size or short follow-up. This study firstly aimed to measure the efficacy of GPi-DBS on motor and non-motor symptoms of CD. A secondary aim was to evaluate if clinical factors - such as age, disease duration and baseline disease severity - influence variability of motor outcomes. METHODS: 37 idiopathic CD patients were recruited from movement disorders clinics at The Walton NHS Foundation Trust, Liverpool, UK. Patients were assessed pre-operatively, and 1 year, 3 years and 5 years post-operatively with the following clinical scales: Toronto Western Spasmodic Torticollis Rating Scale ("TWSTRS"), Hospital Anxiety and Depression Scale and EuroQuol-5D. RESULTS: GPI-DBS significantly improved overall TWSTRS scores by 57% from baseline to 5Y FU (p < 0.001). It also significantly improved TWSTRS severity, disability, and pain sub-scores by 72%, 59% and 46% respectively. We did not find a significant improvement in mood or quality of life scores at 5 years. Similarly, clinical factors at baseline did not correlate with variability in motor outcome. CONCLUSION: We concluded that GPi-DBS is an effective treatment for motor symptoms and pain in CD. There was limited effect on mood and QoL, and no clinical predictive factors of outcome were identified.

Genome-wide transcription factor-binding maps reveal cell-specific changes in the regulatory architecture of human HSPCs.

Hematopoietic stem and progenitor cells (HSPCs) rely on a complex interplay among transcription factors (TFs) to regulate differentiation into mature blood cells. A heptad of TFs (FLI1, ERG, GATA2, RUNX1, TAL1, LYL1, LMO2) bind regulatory elements in bulk CD34+ HSPCs. However, whether specific heptad-TF combinations have distinct roles in regulating hematopoietic differentiation remains unknown. We mapped genome-wide chromatin contacts (HiC, H3K27ac, HiChIP), chromatin modifications (H3K4me3, H3K27ac, H3K27me3) and 10 TF binding profiles (heptad, PU.1, CTCF, STAG2) in HSPC subsets (stem/multipotent progenitors plus common myeloid, granulocyte macrophage, and megakaryocyte erythrocyte progenitors) and found TF occupancy and enhancer-promoter interactions varied significantly across cell types and were associated with cell-type-specific gene expression. Distinct regulatory elements were enriched with specific heptad-TF combinations, including stem-cell-specific elements with ERG, and myeloid- and erythroid-specific elements with combinations of FLI1, RUNX1, GATA2, TAL1, LYL1, and LMO2. Furthermore, heptad-occupied regions in HSPCs were subsequently bound by lineage-defining TFs, including PU.1 and GATA1, suggesting that heptad factors may prime regulatory elements for use in mature cell types. We also found that enhancers with cell-type-specific heptad occupancy shared a common grammar with respect to TF binding motifs, suggesting that combinatorial binding of TF complexes was at least partially regulated by features encoded in DNA sequence motifs. Taken together, this study comprehensively characterizes the gene regulatory landscape in rare subpopulations of human HSPCs. The accompanying data sets should serve as a valuable resource for understanding adult hematopoiesis and a framework for analyzing aberrant regulatory networks in leukemic cells.

Using technology to reduce critical deterioration (the DETECT study): a cost analysis of care costs at a tertiary children's hospital in the United Kingdom.

BACKGROUND: Electronic early warning systems have been used in adults for many years to prevent critical deterioration events (CDEs). However, implementation of similar technologies for monitoring children across the entire hospital poses additional challenges. While the concept of such technologies is promising, their cost-effectiveness is not established for use in children. In this study we investigate the potential for direct cost savings arising from the implementation of the DETECT surveillance system. METHODS: Data were collected at a tertiary children's hospital in the United Kingdom. We rely on the comparison between patients in the baseline period (March 2018 to February 2019) and patients in the post-intervention period (March 2020 to July 2021). These provided a matched cohort of 19,562 hospital admissions for each group. From these admissions, 324 and 286 CDEs were observed in the baseline and post-intervention period, respectively. Hospital reported costs and Health Related Group (HRG) National Costs were used to estimate overall expenditure associated with CDEs for both groups of patients. RESULTS: Comparing post-intervention with baseline data we found a reduction in the total number of critical care days, driven by an overall reduction in the number of CDEs, however without statistical significance. Using hospital reported costs adjusted for the Covid-19 impact, we estimate a non-significant reduction of total expenditure from £16.0 million to £14.3 million (corresponding to £1.7 million of savings - 11%). Additionally, using HRG average costs, we estimated a non-significant reduction of total expenditure from £8.2 million to £ 7.2 million (corresponding to £1.1 million of savings - 13%). DISCUSSION AND CONCLUSION: Unplanned critical care admissions for children not only impose a substantial burden on patients and families but are also costly for hospitals. Interventions aimed at reducing emergency critical care admissions can be crucial to contribute to the reduction of these episodes' costs. Even though cost reductions were identified in our sample, our results do not support the hypothesis that reducing CDEs using technology leads to a significant reduction on hospital costs. TRIAL REGISTRATION: Current Controlled Trials ISRCTN61279068, date of registration 07/06/2019, retrospectively registered.

Clinicians', patients' and carers' perspectives on borderline personality disorder in Pakistan: A mixed methods study protocol.

Borderline Personality Disorder (BPD) is a condition characterised by significant social and occupational impairment and high rates of suicide. In high income countries, mental health professionals carry negative attitudes towards patients with BPD, find it difficult to work with patients with BPD, and even avoid seeing these patients. Negative attitudes and stigma can cause patients to fear mistreatment by health care providers and create additional barriers to care. Patients' self-stigma and illness understanding BPD also affects treatment engagement and outcomes; better knowledge about mental illness predicts intentions to seek care. The perspectives of mental health clinicians and patients on BPD have not been researched in the Pakistani setting and likely differ from other settings due to economic, cultural, and health care system differences. Our study aims to understand the attitudes of mental health clinicians towards patients with BPD in Pakistan using a self-report survey. We also aim to explore explanatory models of illness in individuals with BPD and their family members/carers using a Short Explanatory Model Interview (SEMI). The results of this study are important as we know attitudes and illness understanding greatly impact care. Results of this study will help guide BPD-specific training for mental health clinicians who care for patients with BPD and help inform approaches to interventions for patients with BPD in Pakistan.

Follow up of women after obstetric anal sphincter injuries (OASI)-What is the role of anorectal testing?

AIMS: To evaluate the benefit of performing anorectal studies on all women following primary obstetric anal sphincter injury (OASI) repair over performing them on symptomatic women only. METHODS: Women who attended perineal clinic between 2007 and 2020 underwent symptom assessment and anorectal studies at 6 weeks and 6 months postpartum. Anorectal studies including endo anal ultrasound (EAUS) and anal manometry (AM) were performed. The anorectal studies of symptomatic women who were the case group, were compared with asymptomatic women who were the control group. RESULTS: A total of 1348 women were seen in the perineal clinic over 13 years. A total of 454 (33.7%) women were symptomatic. A total of 894 (66.3%) women were asymptomatic. A total of 313 (35%) asymptomatic women had two abnormal anorectal studies, 274 (31%) had abnormal AM alone, and 86 (9.6%) had abnormal EAUS alone. A total of 221 (24.7%) asymptomatic women had normal anorectal studies. CONCLUSION: Almost 70% of women were asymptomatic 6 months following primary OASI repair. Most had at least one abnormal anorectal study result. Selectively performing anorectal tests on symptomatic women would not identify asymptomatic women at risk of future faecal incontinence following further vaginal birth. Without anorectal study results, women would not receive accurate counseling about the risks of vaginal birth. Anorectal studies should be offered to all women following OASI where resources allow.