Prolonged Caffeine Therapy for Preterm Infants

Approximately 13 million newborns were preterm (born before 37 weeks of gestation) across all member states of the World Health Organization in 2020. In 2023, the US preterm birth rate was 10.4%. Nearly all preterm infants require specialized in-hospital care to support their immature respiratory, cardiovascular, central nervous, digestive, and immune function. The length of the initial hospital stay depends on the duration of gestation, the medical condition at birth, and the development of complications such as infections or chronic lung disease. The main determinant of discharge readiness is the infant’s physiological maturity, defined as adequate control of breathing, respiratory stability, full oral feeding with appropriate weight gain, and good temperature control in a crib. In addition, the preparedness of the family and the suitability of the home environment should be confirmed. Most very preterm infants (those born between 28 and

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When Empathy, and Healing, Are Elusive

As studies suggest empathy in medicine continues to decline, mirroring the trend seen in other societal realms, poetry remains an important medium for questioning why, and reclaiming it. In the poem “20 Marlboro Reds,” smoking, both a communal bonding ritual and noisome health risk, becomes a complex metaphor for our vexed attempts to connect with others. The desire to belong and the harmful effects of smoking are simultaneously evoked when the speaker first experiences nausea after trying cigars offered by a friend. Colloquial, almost irreverent language belies the speaker’s nagging aloneness: as the stanzas wryly move through his adolescence and young adulthood, two “black cigarillos” at parties (accompanied by “thick liquor,” another fraught social lubricant) seem a jaunty rallying cry for teenage rebelliousness; and later, smoking marijuana because “a girl wanted me to” and finding “nothing happened” suggests that genuine human connection remains elusive. The irony in the search for shared feeling deepens when eventually, we infer, the speaker becomes a physician and a patient with metastatic lung cancer is craving a cigarette, so the speaker offers to fetch some. With roles reversed and the speaker and would-be healer now supplying the cigarettes, long-sought empathy is never really kindled, as the request is forgotten and instead they watch a wholesome television show together. Any facile notion of empathy is critiqued, however, as in the final lines, the speaker ruefully smokes the cigarettes himself after the patient dies, ever alone in his frustrated quest, “while I contemplated what/was killing me.”

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Clinically directed initiation versus routine use of amoxicillin-clavulanate and the risk of local complications among patients with haemotoxic snakebite envenomation treated at a teaching hospital in southern India: a randomised, non-inferiority trial

Objective
Amoxicillin-clavulanate is commonly used to prevent infections following snakebites despite the lack of clinical evidence. We aimed to demonstrate that clinically directed initiation of amoxicillin-clavulanate would be non-inferior to routine use in this setting.

Design
Open-label, randomised, non-inferiority trial with blinded adjudication of endpoints.

Setting
Emergency department of a teaching hospital in southern India.

Participants
Adults with local swelling following snakebites within 24 hours of bite.

Interventions
In the routine use strategy, intravenous followed by oral amoxicillin-clavulanate was administered for at least 5 days. In the clinically directed strategy, the antibiotic was only initiated for clinical failures.

Primary and secondary outcome measures
Primary outcomes were protocol-defined clinical failure and total antibiotic consumption. Non-inferiority margin was prespecified as 10%. Secondary outcomes were the length of hospital stay, total antivenom consumption, new-onset organ failure, bleeding requiring transfusion, death/need for surgical intervention and drug-related adverse events.

Results
The trial was prematurely stopped due to the COVID-19 situation after randomising 66 patients—34 to clinically directed initiation and 32 to routine use arms. Russell’s viper was the most common (21 (32%)) biting snake species identified; 52 (79%) patients had evidence of haemotoxic envenomation at baseline, and 24 (36%) patients developed AKI. There were 10 clinical failures—six in the clinically directed initiation arm and four in the routine use arm. The difference in clinical failure between the two arms was 5.2% (–12.0%–21.7%; p=0.291); the upper bound of the CI exceeded the prespecified non-inferiority margin. Total antibiotic consumption, expressed in DDDs, was significantly lower in the clinically directed initiation arm (0 (0–1) vs 5.31 (4.67–6.17); p

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Nonculprit Vulnerable Plaques and Prognosis in Myocardial Infarction With Versus Without ST-Segment Elevation: A PROSPECT II Substudy

Circulation, Volume 151, Issue 25, Page 1767-1779, June 24, 2025. BACKGROUND:Clinical guidelines recommend different revascularization strategies for nonculprit lesions in patients with ST-segment–elevation myocardial infarction (STEMI) versus non-STEMI (NSTEMI). Whether the prevalence of untreated high-risk vulnerable plaques differs in STEMI and NSTEMI and affects their outcomes is unknown.METHODS:In PROSPECT II (Providing Regional Observations to Study Predictors of Events in the Coronary Tree II), a multicenter, prospective natural history study, patients with recent myocardial infarction underwent 3-vessel coronary angiography with coregistered near-infrared spectroscopy and intravascular ultrasound after successful percutaneous coronary intervention of obstructive lesions from 2014 through 2017. Two-feature high-risk plaques were defined as those with both plaque burden ≥70% and maximum lipid core burden index over any 4-mm segment ≥324.7. The primary end point was major adverse cardiovascular events arising from untreated nonculprit lesions during a median 3.7-year follow-up.RESULTS:Of 898 patients, 199 (22.2%) with 849 nonculprit lesions had STEMI and 699 (77.8%) with 2784 nonculprit lesions had NSTEMI. By intravascular ultrasound, the median nonculprit lesion length was 17.4 mm (interquartile range, 16.3–18.5) in STEMI and 17.7 mm (interquartile range, 17.1–18.4) in NSTEMI (P=0.63), and the median minimal lumen area was 5.5 mm2(interquartile range, 5.3–5.7 mm2) in STEMI and 5.5 mm2(interquartile range, 5.3–5.6 mm2) in NSTEMI (P=0.99). At the lesion level, the prevalence of 2-feature high-risk nonobstructive nonculprit plaques was slightly higher in patients with STEMI than in patients with NSTEMI (12.8% versus 10.1%;P=0.03). At the patient level, however, the prevalence of 2-feature high-risk plaques was similar in STEMI versus NSTEMI (38.8% versus 32.7%;P=0.11). The prevalence of patients with 1 or more lesions meeting at least 1 high-risk plaque criterion was also similar (plaque burden ≥70%, 63.3% versus 57.8% [P=0.16]; maximum lipid core burden index over any 4-mm segment ≥324.7, 63.3% versus 57.6% [P=0.15]). The 4-year rates of nonculprit lesion–related major adverse cardiovascular events were similar in STEMI versus NSTEMI (8.6% versus 7.8%; hazard ratio, 1.02 [95% CI, 0.57–1.81];P=0.95), as were the rates of all major adverse cardiovascular events (14.2% versus 13.0%; hazard ratio, 1.06 [95% CI, 0.68–1.64];P=0.80).CONCLUSIONS:In the PROSPECT II study, the per-patient prevalence of high-risk vulnerable plaques was comparable in STEMI versus NSTEMI, as was the overall long-term incidence of nonculprit lesion–related and all major adverse cardiovascular events. These results support a similar revascularization strategy for nonculprit lesions in patients with STEMI or NSTEMI after culprit lesion management.REGISTRATION:URL:https://www.clinicaltrials.gov; Unique identifier: NCT02171065.

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Associations of sleep characteristics with all-cause, cardiovascular and non-cardiovascular mortality among rural Chinese older adults: a cohort study

Study objectives
The longitudinal associations of sleep timing and time in bed (TIB) with all-cause, cardiovascular and non-cardiovascular mortality are unclear in Chinese rural populations.

Methods
This population-based cohort study included 2468 participants who were aged ≥60 years and residing in rural communities in western Shandong Province. Sleep timing and TIB were assessed using standard questionnaires at baseline in 2014. Mid-sleep time was defined as the halfway point between the bedtime and wake-up time. Vital status until December 2022 and causes of death for all participants were ascertained via death registry plus interviews with informants (eg, family members or village doctors). Data were analysed using restricted cubic splines (RCS) and Cox proportional-hazards models.

Results
During the mean follow-up of 7.36 (SD 2.03) years, 657 participants died. The RCS analysis showed non-linear relationships of sleep duration and mid-sleep time at baseline with all-cause and cardiovascular mortality. Specifically, when baseline sleep characteristics were categorised into tertiles, the multivariable-adjusted HR for all-cause mortality was higher for long sleep duration ( >8 vs 7–8 hours; HR 1.27; 95% CI 1.06 to 1.53), long TIB ( >9 vs

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Parenting Acceptance and Commitment Therapy Online (PACT Online) for parents of children diagnosed with or with increased likelihood of neurodevelopmental disability: study protocol of a randomised controlled trial

Introduction
Approximately 1 in 13 Australian children have a neurodevelopmental disability. This project aims to assess the effectiveness and implementation of an online parenting support programme, Parenting Acceptance and Commitment Therapy (PACT) Online, for parents of children with neurodevelopmental disabilities for improving the parent–child relationship and parent and child outcomes.

Methods and analysis
This hybrid type 1 randomised controlled trial will focus on evaluating intervention effectiveness and understanding the context for implementation. The primary outcome is observed emotional availability within parent–child interactions assessed at postintervention (12 weeks postbaseline) with additional measurement at follow-up (6 months postbaseline). Secondary outcomes include (1) parent-reported emotional availability, (2) parental mindfulness, (3) parent mental health, (4) psychological flexibility, (5) adjustment to child’s disability, (6) health behaviour and (7) regulatory abilities as well as child outcomes of (1) mental health, (2) adaptive behaviour and (3) regulatory abilities. Evaluation of implementation will include an economic evaluation of costs and consequences, and an implementation analysis grounded in the consolidated framework for implementation research with a focus on contextual factors influencing implementation.

Ethics and dissemination
Ethical approval has been obtained from the University of Queensland Human Research Ethics Committee (023/HE000040). Dissemination of study outcomes will occur through the appropriate scientific channels. Long-term implementation will be grounded within the implementation analysis and occur in partnership with the partner organisations and consumer engagement panel. This will include releasing the PACT Online intervention as a massive open online course on the edX platform if support for intervention effectiveness and implementation is found.

Trial registration number
ACTRN12623000612617; this trial has been registered with the Australian New Zealand Clinical Trials Registry.

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Medicines support and social prescribing to address patient priorities in multimorbidity (MIDAS): protocol for a definitive, multi-arm, cluster randomised, controlled trial in Irish general practice

Background
There is increasing awareness of the impact of living with multiple long-term conditions (referred to as multimorbidity) on patients and health systems. Managing multimorbidity remains a challenge for primary care providers; necessitating tailored interventions that are both clinically and cost effective. In the Irish health system, two pilot trials have demonstrated promising results for patients living with multimorbidity. The first, MultimorbiditY COllaborative Medication Review And DEcision making (MyComrade), involved pharmacists supporting the management of polypharmacy, and the second, Link MultiMorbidity (LinkMM), involved link workers delivering social prescribing. This definitive trial aims to evaluate the clinical and cost effectiveness of both these interventions, as well as conduct a process evaluation.

Methods
This is a pragmatic, multi-arm, definitive, cluster randomised controlled trial in Irish general practices. The trial will include three arms: (1) MyComrade; (2) LinkMM and (3) usual care, acting as an efficient shared control arm for both interventions. For this trial, 672 patients will be recruited from 48 general practices. The eligibility criteria for the patients will be: (1) over 18 years of age; (2) has two or more chronic conditions; (3) taking 10 or more regular medicines and (4) attending their general practice team for chronic disease management. Outcome data will be collected for all participants, across all trial arms at baseline and 6 months. Primary outcomes include the number of medicines (reflecting the MyComrade intervention) and patient capability (reflecting the LinkMM intervention). Secondary outcomes include proportions and types of potentially inappropriate medications, patient experience of care, patient activation, self-rated health, health-related quality of life, mortality and healthcare utilisation. Quantitative and qualitative data will be collected to inform the process evaluation. Additionally, an economic evaluation will be conducted to evaluate the cost-effectiveness of both interventions compared with the control arm.

Ethics and dissemination
The trial protocol was approved by the Irish College of General Practice (ICGP) Ethical Review Board (ref: ICGP_Rec_2023_016). A formal knowledge dissemination plan has been developed for the trial, which includes peer-reviewed publications, conference presentations and reports to healthcare professionals, commissioners and policymakers.

Trial registration number
ISRCTN11585238.

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Informing family physician payment reform in Canada: protocol for a cross-provincial, multimethod study

Background
Amid growing concerns about primary care accessibility and the need to support longitudinal, community-based models of care, Canadian provinces have implemented major reforms to how family physicians are paid. These models share objectives of making longitudinal, community-based family practice more attractive and, to some degree, addressing long-standing disparities in pay between family medicine and other specialties. These new remuneration models require robust evaluation to guide improvements, future investments and planning.

Methods and analysis
We will conduct a multimethod study to explore physician perceptions and outcomes of these new models. First, we will complete semi-structured interviews with family physicians in British Columbia, Manitoba and Nova Scotia (provinces where a new blended compensation model has been introduced). Interviews will explore family physicians’ motivations for moving onto the blended compensation model; how the model has impacted their practice, administrative burden, visit length, capacity, changes to care coordination; and other areas of interest. Second, using provincial and national administrative datasets, we will assess the impact of these payment reforms on service volume, attachment/enrolment, continuity of care, and costs.

Ethics and dissemination
We have obtained cross-jurisdictional ethics approvals from Research Ethics British Columbia for the qualitative components and Nova Scotia Health for the quantitative components of this research. Harmonised ethics approvals have been obtained from additional institutions across all study regions. We will create summaries of findings of provincial and cross-provincial analyses and share them with relevant policymakers, physician associations and study participants. Our dissemination will also include traditional publications such as peer-reviewed articles, commentaries/editorials, and academic conferences.

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Effects of microgravity on neuromuscular control of the spine: a protocol for a systematic review and meta-analysis

Introduction
As spaceflight missions become more frequent and prolonged, the effects of microgravity on the musculoskeletal system represent a critical concern for astronauts’ health given their increased risk of spinal pain and injury. A better understanding of the adaptations induced by microgravity on neuromuscular control of the spine is essential to guide the development of effective countermeasures. Thus, this systematic review will aim to investigate the effects of microgravity on the neuromuscular control of the spine.

Methods and analysis
This protocol has been developed following the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols. MEDLINE, EMBASE, CINAHL, Web of Science, PubMed, grey literature and specialised space research resources will be searched from inception up to December 31, 2024. Screening processes, data extraction and risk of bias assessment will be conducted by two independent reviewers. Studies investigating the acute and long-term effects of microgravity on neuromuscular control of the spine will be included. Studies investigating spaceflight conditions or other protocols simulating microgravity, such as parabolic flights, dry immersion and long-term bed rest, will be considered eligible. Non-randomised studies of intervention with before-and-after design will represent the main studies of interest, and their risk of bias will be evaluated with the Risk Of Bias In Non-randomised Studies-of Interventions tool. Random-effect meta-analyses will be conducted for quantitative synthesis when clinical and methodological consistency is ensured. The certainty of evidence will be evaluated using the Grading of Recommendations, Assessment, Development and Evaluation guidelines.

Ethics and dissemination
As this systematic review is based on previously published studies, no ethical approval is required. The findings will be disseminated through publication in an international peer-reviewed journal and presented at conferences. All data relevant to the study will be included in the article or uploaded as supplementary information.

PROSPERO registration number
CRD42024608544.

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Protocol for the economic evaluation of individualised (early) patient-directed rehabilitation versus standard rehabilitation after surgical repair of the rotator cuff of the shoulder (RaCeR 2)

Introduction
RaCeR 2 is a pragmatic multicentre, open-label, randomised controlled trial, with full economic evaluation. The primary aim is to assess whether individualised (early) patient-directed rehabilitation (EPDR) results in less shoulder pain and disability at 12 weeks postrandomisation following surgical repair of full-thickness tears of the rotator cuff of the shoulder compared with the current standard (delayed) rehabilitation. This paper provides the protocol for the RaCeR 2 health economic evaluation.

Methods and analysis
The health economic analysis of RaCeR 2 is made up of three phases: (1) development of an initial state-transition model structure, (2) within-trial cost consequence analysis and (3) long-term model-based cost-effectiveness analysis (CEA) from the National Health Service and Personal Social Service perspective in England. Descriptive statistics (eg, mean, standard deviation, 95% confidence intervals and minimum and maximum values) will be reported for within-trial resource use, costs and health-related quality of life (HRQoL). Health state-specific costs and HRQoL will be estimated using regression model approaches and used to inform a state-transition simulation model designed to quantify the long-term costs and quality-adjusted life years (QALYs) experienced by patients over the model’s time horizon. Where appropriate, final CEA model results will be reported as cost per QALY gained for individualised EPDR versus standard (delayed) rehabilitation. Model assumptions and overall parameter uncertainty will be tested using probabilistic sensitivity analysis and scenario analyses. All regression analyses will be adjusted for baseline participant demographic and symptomatic characteristics.

Ethics and dissemination
A favourable ethical review was granted by London-Stanmore Research Ethics Committee (23/LO/0195) on 13 April 2023. Findings will be disseminated in peer-reviewed journals, at scientific conferences, and via the study website.

Trial registration number
ISRCTN11499185

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