Epidemiology and excess mortality of antimicrobial resistance in bacteraemias among cancer patients: a cohort study using routinely collected health data from regional hospital trusts in Oxford and Oslo, 2008-2018

Objectives
We investigated the epidemiology and impact on mortality of antimicrobial resistance (AMR) in cancer patients with bacteraemia at Oxford University Hospitals (OxUH), UK, and Oslo University Hospital (OsUH), Norway, during 2008–2018.

Design
Historical cohort study.

Setting
Regional hospital trusts with multiple sites in OxUH and OsUH.

Methods
Patients with cancer and blood cultures positive for one of six pathogen groups during a hospital stay within 3 years following their first cancer diagnosis were followed for 30 days after their first bacteraemia episode. We determined the number of cases and the proportion of infections with an AMR phenotype. Excess mortality and the population-attributable fraction (PAF) due to AMR were estimated by contrasting observed mortality at the end of follow-up with an estimated counterfactual scenario where AMR was absent from all bacteraemias, using inverse probability weighting.

Main outcome measure
30-day all-cause mortality following the first bacteraemia episode.

Main exposure measure
A resistant phenotype of the causative pathogen.

Results
The study included 1929 patients at OxUH and 1640 patients at OsUH. The highest resistance proportions were found for vancomycin resistance in enterococci (85/314, 27.1%) and carbapenem-resistance in Pseudomonas aeruginosa (63/260, 24.2%) at OxUH, and third-generation cephalosporin resistance in Escherichia coli (62/743, 8.3%) and Klebsiella pneumoniae (14/223, 6.3%) at OsUH. Observed mortality for all infections was 26.4% at OxUH, with an estimated counterfactual mortality without AMR of 24.7%, yielding an excess mortality of 1.7% (95% CI: 0.8 to 2.5%). The PAF was 6.3% (95% CI: 2.9 to 9.6%), meaning an estimated 32 of 509 deaths could be attributed to AMR. Limited events at OsUH precluded a similar estimate.

Conclusions
Despite estimating modest excess mortality, the mortality attributable to resistance in these two high-income, low-prevalence settings highlights the potential for escalation if global resistance trends continue to worsen.

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Protocol for a prospective cohort study to determine the multimodal biomarkers of delirium and new dementia after acute illness in older adults: ORCHARD-PS

Introduction
Delirium is common in the older hospital population and is often precipitated by acute illness. Delirium is associated with poor outcomes including subsequent cognitive decline and dementia and may therefore be a modifiable risk factor for dementia. However, the mechanisms underpinning the delirium–dementia relationship and the role of coexisting acute illness factors remain uncertain. Current biomarker studies of delirium have limitations including lack of detailed delirium characterisation with few studies on neurodegenerative or neuroimaging biomarkers especially in the acute setting. The Oxford and Reading Cognitive Health After Recovery from acute illness and Delirium—Prospective Study (ORCHARD-PS) aims to elucidate the pathophysiology of delirium and subsequent cognitive decline after acute illness in older adults, through acquisition of multimodal biomarkers for deep phenotyping of delirium and acute illness, and follow-up for incident dementia.

Methods and analysis
ORCHARD-PS is a bi-centre, prospective cohort study. Consecutive eligible patients requiring acute hospital admission or assessment are identified by the relevant acute clinical care team. All patients age >65 years without advanced dementia, nursing home residence, end-stage frailty or terminal illness are eligible. Details of potential participants are communicated to the research team and written informed consent or consultee agreement is obtained. Participants are interviewed as soon as possible after admission/assessment using a structured proforma.
Data are collected on demographics, diagnosis and comorbidities, social and functional background. Delirium is assessed using the 4A’s test, Confusion Assessment Method (long-form), Observational Scale of Level of Arousal, Richmond Agitation-Sedation Scale and Memorial Delirium Assessment Scale and diagnosed using the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria. Delirium is categorised by time of onset (prevalent vs incident), dementia status, motoric subtype, severity and duration. Cognitive tests include the 10-point Abbreviated Mental Test and Montreal Cognitive Assessment. Participants are reassessed every 48–72 hours if remaining in hospital. Informant questionnaire data and interview are supplemented by hand searching of medical records and linkage to electronic patient records for nursing risk assessments, vital observations, laboratory results and International Classification of Diseases, Tenth Revision diagnostic and procedure codes.
In-person follow-up with more detailed cognitive testing and informant interview is undertaken at 3 months, and 1 and 3 years supplemented with indirect follow-up using medical records. Blood banking is performed at baseline and all follow-ups for future biomarker analyses. CT-brain and MRI-brain imaging acquired as part of standard care is obtained for quantification of brain atrophy and white matter disease/stroke supplemented by research CT-brain imaging. Outcomes include length of hospitalisation, change in care needs, institutionalisation, mortality, readmission, longitudinal changes in cognitive and functional status and incident dementia. Biomarker associations with delirium, and with incident dementia on follow-up, will be determined using logistic or Cox regression as appropriate, unadjusted and adjusted for covariates including demographics, baseline cognition, frailty, comorbidity and apolipoprotein E genotype.

Ethics and dissemination
ORCHARD-PS is approved by the South Central—Berkshire Research Ethics Committee (REC Reference: 23/SC/0199). Results will be disseminated through peer-reviewed publications and conference presentations.

Trial registration number
ISRCTN24171810.

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Low-dose versus high-dose intravenous nitroglycerin in the treatment of sympathetic crashing acute pulmonary oedema: a systematic review and meta-analysis focusing on efficacy, safety and outcomes

Objectives
Sympathetic crashing acute pulmonary oedema (SCAPE) is a menacing medical emergency and a severe form of acute heart failure that requires urgent intervention. Nitroglycerin (NTG) is commonly used in SCAPE management, but the optimal dosing remains uncertain. This meta-analysis compared the efficacy and safety of high-dose vs low-dose NTG in SCAPE patients, assessing mechanical ventilation need, symptom resolution, hospital stay and major adverse cardiovascular events (MACE).

Design
Systematic review and meta-analysis conducted per Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines, registered in Prospective Register of Systematic Reviews (CRD42024527486).

Data sources
A comprehensive search in PubMed, Europe PMC and ScienceDirect up to November 2024. Reference lists of included studies were also reviewed.

Eligibility criteria
Randomised controlled trials (RCTs) and observational studies comparing high-dose NTG (≥100 mcg/min) with low-dose NTG (

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Behavioural activation for low mood and anxiety in male frontline NHS workers (BALM): a pre-post intervention study

Objectives
To evaluate the impact and acceptability of a tailored, gender-responsive behavioural activation (BA) intervention for improving depression and anxiety in male National Health Service (NHS) frontline workers.

Design
Pre-post intervention study.

Setting
Three NHS organisations in the North of England.

Participants
45 men aged ≥18 years working in a frontline NHS role scoring in the subclinical range (5–14) on the Patient Health Questionnaire-9 (PHQ-9) (depression) and/or the Generalised Anxiety Disorder-7 (GAD-7) (anxiety) at baseline.

Interventions
A tailored BA treatment programme consisting of up to eight telephone support sessions over a period of 4–6 weeks, accompanied by a BA self-help manual.

Main outcome measures
Self-reported symptom severity of depression, assessed by PHQ-9, and anxiety, assessed by GAD-7, at baseline and 4 and 6 months. Acceptability from the perspectives of male study participants and coaches who delivered the intervention was assessed in a nested qualitative study using the theoretical framework of acceptability (TFA).

Results
PHQ-9 and GAD-7 scores decreased from baseline to 4 months on both the PHQ-9 and GAD-7. While scores increased from 4 months to 6 months, the 6-month scores remained below those of the baseline scores. Acceptability of the intervention was high across all constructs of the TFA. The practical and action-oriented strategies of the intervention, and the confidential, flexible, convenient mode of delivery, worked to support men’s engagement with the intervention.

Conclusions
Delivery of a tailored, gender-responsive BA intervention was appealing to, and beneficial for, men working in frontline NHS roles with less severe depression and anxiety. The BALM intervention offers promise as a tailored workplace mental health programme that is aligned with men’s needs and preferences and can help overcome a reticence to engage with mental health support in NHS staff and beyond.

Trial registration number
ISRCTN48636092.

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Clinical effect of ePRO-based symptom monitoring and management on improving survival outcomes in patients with advanced cancer: a single-centre, prospective, randomised controlled trial protocol

Introduction
Symptom management is crucial in cancer care, yet patient symptoms are often overlooked in routine care. There is some evidence that electronic symptom monitoring and management can improve patients’ physical function, symptom control, quality of life and survival outcomes. However, the evidence of the impact on survival outcomes in patients with advanced cancer is still limited and debated. This study aims to conduct a prospective randomised controlled trial by a professional symptom management team to monitor and manage symptoms in advanced cancer patients via an electronic information systems for patient-reported outcomes (ePRO) system (WeChat mini-program) and to verify its effectiveness on improving overall survival.

Methods and analysis
This is a single-centre, prospective, open-labelled, randomised, parallel-controlled clinical trial targeting patients with advanced cancer. We plan to recruit 940 patients using a stratified block randomisation method based on different tumour types. The control group will receive a symptom management self-care manual (both electronic and paper versions). Similarly, the intervention group will receive the same manual and education while also received symptom management by the hospital’s specialised symptom management team through the ePRO system. The primary outcome is comparison of overall survival between groups at the 24-month follow-up. Secondary outcomes will include quality of life, psychological status and incidence of adverse events.

Ethics and dissemination
The study protocol and related documents received approval from the Ethics Committee of Peking University Cancer Hospital (IRB) in December 2023 (2023YJZ99). Ethical approval will be obtained before implementing any major study revisions in the future. The results of this study will be disseminated through academic seminars, peer-reviewed publications and academic conferences.

Trial registration number
ChiCTR2400081247.

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Association between anti-Müllerian hormone levels during pregnancy and pregnancy outcomes in infertile patients undergoing in vitro fertilisation/intracytoplasmic sperm injection: protocol for a multicentre prospective cohort study

Introduction
Polycystic ovary syndrome (PCOS), recognised as the predominant aetiological factor in ovulatory dysfunction-related infertility, accounts for approximately 70% of anovulatory infertility cases. Patients with PCOS have significantly higher anti-Müllerian hormone (AMH) levels than their counterparts undergoing in vitro fertilisation (IVF) for non-PCOS indications (eg, male/tubal factors). Several studies have suggested that a high AMH level is associated with adverse pregnancy outcomes in IVF, particularly preterm delivery. However, most of these studies are retrospective studies, and their results are inconsistent. The majority of AMH measurements are conducted before pregnancy; however, AMH levels fluctuate dynamically during pregnancy. There is a pressing need for a well-structured prospective study to definitively establish whether high AMH levels during pregnancy are associated with IVF/intracytoplasmic sperm injection (ICSI) pregnancy outcomes in PCOS patients.

Methods and analysis
This prospective cohort study will be conducted at four reproductive medicine centres. The plan is to enrol 1,320 PCOS patients and 1320 non-PCOS women who undergo IVF/ICSI and achieve singleton clinical pregnancies. Serum samples will be collected at about 6 weeks of gestation to measure the serum AMH level. Follow-up visits will be conducted at 12, 28 and 37 weeks of gestation, delivery and 6 weeks after delivery to obtain information about pregnancy outcomes and complications. The primary outcome is preterm delivery.

Ethics and dissemination
The study was approved by the Medical Research Ethics Committee of Peking University Third Hospital (M2022618). Informed consent will be obtained from all patients. The results of this clinical study will be presented at scientific conferences and submitted to a peer-reviewed journal.

Trial registration number
ChiCTR2300068554.

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Non-randomised prospective clinical trial to improve follow-up adherence, survivorship knowledge and late effects documentation at a childhood cancer clinic in Western Kenya: a study protocol

Introduction
International survivorship guideline consortia have developed strategies to prevent, detect and manage late effects of childhood cancer survivors. However, recommendations do not adequately reflect the everyday reality of paediatric oncology care in low- and middle-income countries. In this study protocol, a survivorship intervention programme, comprising an educational component and a follow-up component, is described. The Educational Programme aims to improve follow-up adherence of childhood cancer survivors through increasing survivorship knowledge of caregivers. The Follow-up Programme aims to map late effects by implementing a follow-up form at the outpatient clinic to be used by trained healthcare providers.

Methods and analysis
This non-randomised prospective clinical trial will be performed at a referral hospital in Western Kenya. 100 caregivers of children diagnosed with cancer, who will complete treatment within 2 months, will be enrolled and followed for 24 months after completion of treatment. A caregiver control group receiving usual care will be recruited, and sequentially, caregivers will be included in an intervention group to attend an educational group session where they receive educational materials (video, booklet and Survivorship Card). Primary study outcome will be survivors’ follow-up adherence. Survivors will be considered lost to follow-up after they miss a scheduled appointment and do not revisit the clinic for more than 6 months. Mixed models regression analyses will be performed to determine intervention effects on follow-up adherence and on caregiver survivorship knowledge uptake. Additionally, healthcare providers will be trained on follow-up care, whereafter a form will be introduced at the outpatient clinic to document late effects in paediatric survivors attending the clinic for the period of a year. Secondary outcomes will be late effects prevalence as documented in the follow-up form and caregiver and healthcare provider survivorship knowledge uptake. Implementation measures (reach, potential effectiveness, adoption, satisfaction and maintenance) will be evaluated for both programmes.

Ethics and dissemination
The Institutional Research and Ethics Committee has approved the study protocol. Findings will also be shared with governmental and non-governmental organisations that support children with cancer in Kenya to inform their target audiences and guide their policy development.
Lessons learnt from this study could inform healthcare providers and policy makers on how to shape survivorship programmes in the Kenyan context and possibly implement similar programmes in other centres in Sub-Saharan Africa.

Trial registration number
NCT06680687.

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Effectiveness of the BioFire FilmArray for the rapid detection of bloodstream infection in haematological patients with febrile neutropenia (the ONFIRE study): study protocol of a prospective, multicentre observational study at three reference university hospitals in Spain

Introduction
Bloodstream infection (BSI) due to multidrug-resistant Gram-negative bacilli is a serious global health problem that has a profound impact on severely immunosuppressed neutropenic haematological patients. Prompt institution of appropriate antimicrobial therapy is crucial for improving outcomes in these patients, and in an era of multidrug resistance, antimicrobial stewardship programmes are mandatory. Blood cultures, the current gold standard for the diagnosis of BSI, present two main drawbacks: the prolonged time to results and their low sensitivity, especially if the patient has received antimicrobial treatment before blood extraction. The aim of this study is to determine whether a molecular technique, the BioFire FilmArray Blood Culture Identification 2 (BCID2) panel, achieves higher sensitivity and specificity than conventional blood cultures for the microbiological diagnosis of BSI in haematological patients with febrile neutropenia.

Methods and analysis
This multicentre, prospective, observational study will be conducted at three reference university hospitals in Spain. The population will comprise haematological patients scheduled to undergo diagnostic blood cultures as standard care for the microbiological diagnosis of the febrile neutropenia episode. The BioFire FilmArray panel will be performed in patients with positive blood cultures at the time of blood culture positivity and in patients with negative blood cultures at 48 hours of incubation. The primary endpoint will be the sensitivity and specificity of the BioFire FilmArray BCID2 panel compared with conventional blood cultures. The secondary endpoints will be this same comparison in the subgroup of patients with recent (

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Strategic multimodal intervention in at-risk elderly Indians for prevention of dementia (SMRUTHI INDIA): a cohort multiple randomised controlled trial (cmRCT) protocol

Introduction
Treating modifiable risk factors of dementia may prevent or delay dementia cases by up to 40%. The ‘Strategic Multimodal Intervention in at-risk Elderly Indians for Prevention of Dementia (SMRUTHI INDIA)’ study will be conducted to establish a trial-ready cohort of elderly Indians who are at high risk of developing dementia.

Methods and analysis
The main aim of the study is to create and study a cohort of individuals at high risk of dementia in rural India, where we can do multiple intervention trials. The study uses the ‘Cohort Multiple Randomised Controlled Trial’ (cmRCT) design, which combines a cohort study with in-built provisions to do multiple randomised controlled trials. A large rural cohort of size 10 000 (four zones of India, through established Indian Council of Medical Research – Model Rural Health Research Units) will be followed systematically with yearly neuropsychological evaluation for 5 years (the current funding supports first 3000 participants). The study also proposes to design a multimodal ‘care bundle’ for the prevention of dementia, which is culturally tailored and context-specific to the Indian population. This intervention will undergo testing for feasibility in the hospital setting at the central coordinating site through a pilot randomised controlled trial (6 months, 30 participants). In parallel, the care bundle will be culturally and linguistically adapted and pilot-tested in 20 participants in each zone. The final curated care bundle (first intervention that is planned) will then be tested for efficacy in phase 2 of the SMRUTHI INDIA cmRCT cohort.

Ethics and dissemination
The study has received ethical clearance at the central coordinating site and at each of the four clinical sites by the Institute Research Committee of each site. The outcomes of the study will be disseminated to various target audiences, including research participants, general public, scientific community and policy makers through national and international conferences and events, social media, various community engagement activities and publication in peer-reviewed journals.

Trial registration number
The study protocol is registered in the Clinical Trial Registry of India (CTRI/2024/01/061172).

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Development of a large Danish single-centre retro- and prospective transgender cohort using a web-based platform: a study protocol of a transgender cohort study

Introduction
Referrals for gender-affirming healthcare services have surged in recent decades, presumably driven by increased visibility, acceptance and reduced barriers to care. Despite these advances, transgender and gender-diverse individuals continue to face significant mental health challenges, including elevated rates of anxiety, depression as well as high prevalence of autistic traits. Gender-affirming hormonal treatment (GAHT) has been suggested to improve mental health and quality of life (QoL) among transgender individuals; however, the short- and long-term treatment effects of GAHT are not yet fully understood. Therefore, this study aims to establish a comprehensive cohort of transgender individuals at the Centre for Gender Identity (CGI), Aalborg University Hospital, Denmark, to enhance understanding and treatment outcomes.

Methods and analysis
The Transgender Cohort (TraCK) will recruit participants from February 14, 2024, with recruitment occurring continuously alongside yearly follow-up. This single-centre cohort study will include both retrospective and prospective data collection. Transgender individuals referred to CGI will be invited to participate in the study via the Danish digital mail system called e-Boks. Participants must provide informed consent and complete a baseline questionnaire. Data will be collected from self-reported questionnaires and medical records across multiple specialists. Self-reported questionnaires include WHO-Quality of Life BREF, Eating Disorders Examination Questionnaire, Autism Spectrum Quotient, Transgender Congruence Scale, and Gender Minority Stress and Resilience Measure. Medical records will provide information on demographics, mental health, physical health, and gender-affirming treatment details. Data will be managed using REDCap, ensuring compliance with GDPR and the National Data Protection Act.

Ethics and dissemination
While recognising the potential privacy risks associated with data collection, the study considers these outweighed by the benefits of advancing knowledge on gender diversity and the impacts of gender-affirming care. The North Jutland Region Ethics Committee reviewed the project, determining no formal approval was needed, but it was registered and approved (no. F2024-012) by the North Jutland Region. Findings will be disseminated through peer-reviewed journals, conferences, and accessible reports for participants.

Registration details
This study is registered with the North Jutland Region (no. F2024-012). Recruitment and data collection began on February 14, 2024, and will continue alongside yearly follow-up. Keywords Transgender individuals, transgender and gender-diverse, transgender cohort, transgender health, transgender research, cohort study, gender-affirming care.

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Factors Associated With Early Reocclusion in Recanalized Intracranial Atherosclerotic Occlusion: ANGEL-REBOOT Insights

Stroke, Ahead of Print. BACKGROUND:Early reocclusion following successful recanalization through mechanical thrombectomy is linked to poor clinical outcomes in patients with stroke with intracranial atherosclerotic occlusion (ICAS-O). However, the factors influencing early reocclusion remain inadequately understood. This study is a post hoc analysis of 24-hour reocclusion in patients with successfully recanalized ICAS-O from a multicenter trial.METHODS:Patients with successfully recanalized ICAS-O were selected from the ANGEL-REBOOT trial (Randomized Study of Bailout Intracranial Angioplasty Following Thrombectomy for Acute Large Vessel Occlusion). Reocclusion was defined as a 24-hour arterial occlusive lesion score of 0 to 1, determined by magnetic resonance or computed tomography angiography. Possible factors associated with early reocclusion were screened through univariable analysis, and then, multivariable logistic regression was used to identify independent factors associated with early reocclusion.RESULTS:Among the 348 patients in the ANGEL-REBOOT trial, 21 could not be diagnosed with ICAS-O, 14 failed recanalization by the end of the procedure, and 14 had no follow-up angiography data. Finally, a total of 299 subjects were included, with a median age of 63 (interquartile range, 55–69) years, and 77 of 299 (25.75%) were females. The 24-hour reocclusion rate was 9.7% (29/299). Through backward elimination, 3 independent factors remained in the final multivariable logistic regression model. Specifically, puncture-to-recanalization time (per hour increase: odds ratio, 1.80 [95% CI, 1.31–2.47]) was positively associated with reocclusion, while general anesthesia (odds ratio, 0.25 [95% CI, 0.10–0.65]) and a postprocedural expanded Thrombolysis in Cerebral Infarction score of 2c-3 (odds ratio, 0.35 [95% CI, 0.14–0.85]) were negatively associated with reocclusion. Compared with patients without reocclusion, those with reocclusion had significantly greater 90-day modified Rankin Scale scores (median 4 versus 1, Mann-WhitneyUtest;P

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Economic burden of hypertension in Iran: a prevalence-based cost of illness study

Objectives
Hypertension is one of the silent diseases and is the major cause of many chronic conditions. The treatment services for hypertension and its cardiovascular complications impose high costs on society and the health system. However, in LMCs, there is not enough evidence-based information about the costs of high blood pressure. This study aims to assess the economic burden of hypertension in Iran in 2020.

Design
A prevalence-based cost of illness study.

Setting
Data on hypertension and selected diseases, including their prevalence, incidence, mortality risk and death counts, were sourced from literature reviews, the Global Burden of Disease (GDP) and the Non-Communicable Diseases Research Centre. Cost estimates were derived from health insurance data, surveys, research studies and treatment protocols. Additional data, such as population, employment rates, household activity rates, wage rates and GDP per capita, were obtained from the Statistical Centre of Iran and the World Bank.

Participants and methods
A prevalence-based cost of illness study was used to estimate the economic burden of hypertension. The focus was on the most significant diseases associated with high blood pressure, including coronary heart disease, ischaemic stroke, haemorrhagic stroke and the direct costs of hypertension. Subsequently, the total number of patients was multiplied by the average cost per patient for each disease. To calculate the average cost, inpatient and outpatient, direct non-medical and indirect costs of diseases were estimated and multiplied by a population-attributed fraction of high blood pressure. Direct costs (hospitalisation and outpatient costs and direct non-medical costs) of hypertension were calculated using the bottom-up approach, and the human capital approach was used to calculate indirect costs.

Results
According to the results of the study, the total economic burden of hypertension was $ purchasing power parity (PPP) 12 848.22 million, of which the share of direct medical, non-medical and indirect costs of hypertension were $ PPP 7245.13 million (56.4%), $ PPP 1173.42 million (9.1%) and $ PPP 4429.68 million (34.5%), respectively. The total economic burden of high blood pressure was equal to 23% of the total economic burden of four chronic diseases.

Conclusion
The economic burden of high blood pressure in the country is very high and significant, and it was equivalent to about 1% of the country’s gross domestic product in 2020, which shows the necessity of preventive interventions.

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