Systematic review of multivariable prognostic models for outcomes at least 30 days after hip fracture finds 18 mortality models but no nonmortality models warranting validation.

OBJECTIVES: Prognostic models have the potential to aid clinical decision-making after hip fracture. This systematic review aimed to identify, critically appraise, and summarize multivariable prediction models for mortality or other long-term recovery outcomes occurring at least 30 days after hip fracture. STUDY DESIGN AND SETTING: MEDLINE, Embase, Scopus, Web of Science, and CINAHL databases were searched up to May 2023. Studies were included that aimed to develop multivariable models to make predictions for individuals at least 30 days after hip fracture. Risk of bias (ROB) was dual-assessed using the Prediction model Risk Of Bias ASsessment Tool. Study and model details were extracted and summarized. RESULTS: From 5571 records, 80 eligible studies were identified. They predicted mortality in n = 55 studies/81 models and nonmortality outcomes (mobility, function, residence, medical, and surgical complications) in n = 30 studies/45 models. Most (n = 46; 58%) studies were published since 2020. A quarter of studies (n = 19; 24%) reported using 'machine-learning methods', while the remainder used logistic regression (n = 54; 68%) and other statistical methods (n = 11; 14%) to build models. Overall, 15 studies (19%) presented 18 low ROB models, all predicting mortality. Common concerns were sample size, missing data handling, inadequate internal validation, and calibration assessment. Many studies with nonmortality outcomes (n = 11; 37%) had clear data complexities that were not correctly modeled. CONCLUSION: This review has comprehensively summarized and appraised multivariable prediction models for long-term outcomes after hip fracture. Only 15 studies of 55 predicting mortality were rated as low ROB, warranting further development of their models. All studies predicting nonmortality outcomes were high or unclear ROB. Careful consideration is required for both the methods used and justification for developing further nonmortality prediction models for this clinical population.

Long-term colchicine for the prevention of vascular recurrent events in non-cardioembolic stroke (CONVINCE): a randomised controlled trial.

BACKGROUND: Anti-inflammatory therapy with long-term colchicine prevented vascular recurrence in coronary disease. Unlike coronary disease, which is typically caused by atherosclerosis, ischaemic stroke is caused by diverse mechanisms including atherosclerosis and small vessel disease or is frequently due to an unknown cause. We aimed to investigate the hypothesis that long-term colchicine would reduce recurrent events after ischaemic stroke. METHODS: We did a randomised, parallel-group, open-label, blinded endpoint assessed trial comparing long-term colchicine (0·5 mg orally per day) plus guideline-based usual care with usual care only. Hospital-based patients with non-severe, non-cardioembolic ischaemic stroke or high-risk transient ischaemic attack were eligible. The primary endpoint was a composite of first fatal or non-fatal recurrent ischaemic stroke, myocardial infarction, cardiac arrest, or hospitalisation (defined as an admission to an inpatient unit or a visit to an emergency department that resulted in at least a 24 h stay [or a change in calendar date if the hospital admission or discharge times were not available]) for unstable angina. The p value for significance was 0·048 to adjust for two prespecified interim analyses conducted by the data monitoring committee, for which the steering committee and trial investigators remained blinded. The trial was registered at ClinicalTrials.gov (NCT02898610) and is completed. FINDINGS: 3154 patients were randomly assigned between Dec 19, 2016, and Nov 21, 2022, with the last follow-up on Jan 31, 2024. The trial finished before the anticipated number of outcomes was accrued (367 outcomes planned) due to budget constraints attributable to the COVID-19 pandemic. Ten patients withdrew consent for analysis of their data, leaving 3144 patients in the intention-to-treat analysis: 1569 (colchicine and usual care) and 1575 (usual care alone). A primary endpoint occurred in 338 patients, 153 (9·8%) of 1569 patients allocated to colchicine and usual care and 185 (11·7%) of 1575 patients allocated to usual care alone (incidence rates 3·32 vs 3·92 per 100 person-years, hazard ratio 0·84; 95% CI 0·68-1·05, p=0·12). Although no between-group difference in C-reactive protein (CRP) was observed at baseline, patients treated with colchicine had lower CRP at 28 days and at 1, 2, and 3 years (p<0·05 for all timepoints). The rates of serious adverse events were similar in both groups. INTERPRETATION: Although no statistically significant benefit was observed on the primary intention-to-treat analysis, the findings provide new evidence supporting the rationale for anti-inflammatory therapy in further randomised trials. FUNDING: Health Research Board Ireland, Deutsche Forschungsgemeinschaft (German Research Foundation), and Fonds Wetenschappelijk Onderzoek Vlaanderen (Research Foundation Flanders), Belgium.

Perspectives of People with Stroke, Caregivers and Healthcare Professionals on an Adaptive mHealth Intervention for Physical Activity in the Prevention of Secondary Stroke: A Qualitative Study.

Introduction: Engaging in regular physical activity (PA) is associated with lower mortality following stroke, and PA reduces the chance of recurrent stroke. Despite recent guidelines to optimise PA following stroke, people with stroke are known to be less active than their age-matched counterparts. Given the heterogenous nature of stroke, adaptive PA interventions are recommended for people with stroke. Empirical data is lacking on adaptive PA or behavioural change interventions following stroke. Suggested strategies in the prevention of stroke recommend the use of mobile health (mHealth) interventions in the primary prevention of stroke. A structured stakeholder consultation process is key to successful implementation of complex interventions. This paper reports the findings of our consultation process to inform the development of an adaptive mHealth PA. Methods: We used a qualitative study design to explore the perspectives of key stakeholders on the development of an adaptive PA intervention delivered via mHealth post-stroke. Healthcare workers, carers and people with stroke participated in semi-structured one-to-one or focus group interviews. A reflexive thematic analysis was undertaken on transcribed interviews; key themes and sub-themes were developed using coding and summarised by two researchers, then reviewed by the full research team. Results: Twenty-eight stakeholders were interviewed and three main themes were identified; Key feature of a mHealth intervention, delivering a mHealth intervention, Challenges to development and use. There was widespread agreement across stakeholder groups that an adaptive mHealth PA intervention following stroke would be beneficial to people with stroke, following discharge from acute care. Conclusion: Our consultation supports the development of an adaptive PA programme that addresses specific impairments that can hinder exercise participation after stroke.

Irish Amyotrophic Lateral Sclerosis Incidence: Age, Period, and Cohort Effects Using a Partial Least Squares Regression Model.

BACKGROUND AND OBJECTIVES: To investigate the underlying reasons for variability in the incidence rate of amyotrophic lateral sclerosis (ALS) within the Irish population between the years 1996 and 2021. METHODS: The Irish ALS register was used to calculate the incidence and to subsequently extract age at diagnosis (age), year of diagnosis (period), and date of birth (cohort) for all incident patients within the study period (n = 2,771). An age-period-cohort (APC) model using partial least squares regression was constructed to examine each component separately and their respective contribution to the incidence while minimizing the well-known identifiability problem of APC effects. A dummy regression model consisting of 5 periods, 19 cohorts, and 16 age groups was used to examine nonlinear relationships within the data over time. The CIs for each of these were estimated using the jackknife method. RESULTS: The nonlinear model achieved R2 of 99.43% with 2-component extraction. Age variation was evident with those in the ages 65-79 years contributing significantly to the incidence (ßmax = 0.0746, SE = 0.000410, CI 0.00665-0.00826). However, those aged 25-60 years contributed significantly less (ßmin = -0.00393, SE = 0.000291, CI -0.00454 to -0.00340). Each successive period showed an increase in the regression model coefficient suggesting an increasing incidence over time, independent of the other factors examined-an increase of ß from -0.00489 (SE = 0.000264, CI -0.00541 to -0.00437) to 0.00973 (SE = 0.000418, CI 0.0105-0.00891). A cohort effect was demonstrated showing that the contribution of those born between 1927 and 1951 contributed to a significantly greater degree than the other birth cohorts (ßmax = 0.00577, SE = 0.000432, CI 0.00493-0.00662). DISCUSSION: Using the Irish population-based ALS Register, robust age, period, and cohort effects can be identified. The age effect may be accounted for by demographic shifts within the population. Changes in disease categorization, competing risks of death, and improved surveillance may account for period effects. The cohort effect may reflect lifestyle and environmental factors associated with the challenging economic circumstances in Ireland between 1927 and 1951. Age-period-cohort studies can help to account for changes in disease incidence and prevalence, providing additional insights into likely demographic and environmental factors that influence population-based disease risk.

Investigating incidence of and factors associated with SARS-CoV-2 infection over a nine-month period in a highly-vaccinated healthcare worker cohort.

BACKGROUND: Healthcare workers (HCWs) are at increased risk of SARS-CoV-2 infection. This risk persists despite the implementation of mitigating factors, including vaccination. The ongoing impact of incident SARS-CoV-2 infection and symptomatic COVID-19 disease in vaccinated healthcare workers is poorly understood. AIM: We aimed to describe the epidemiology of incident SARS-CoV-2 infections, as well as investigating the serological, clinical and demographic factors associated with developing infection. DESIGN: This was a multi-centre prospective longitudinal study followed a HCW cohort over a nine-month period. METHODS: Spike and nucleocapsid SARS-CoV-2 antibodies were measured at enrolment. Vaccination status, demographics, and medical history were collated. Incident infection over the study period was recorded. Multivariable regression models investigated factors associated with nucleocapsid antibody status, incident infection, and symptomatic infection. RESULTS: 1,260 participants took part, of whom n = 1,006 were anti-nucleocapsid antibody positive. Negative anti-nucleocapsid antibody was associated with older age and having a known SARS-CoV-2 acquisition risk. There were n = 274 (22%) incident infections, with n = 225 (87%) diagnosed using antigen tests. Incident infections were associated with lower anti-nucleocapsid titres, increased time since previous SARS-CoV-2 infection, and having a known acquisition risk, but were not associated with vaccination status. CONCLUSIONS: This study demonstrates a high rate of incident SARS-CoV-2 infection amongst healthcare workers, despite broad vaccine coverage. There is a shift in diagnostics, from PCR to antigen testing. We identify at-risk groups for incident infection, and these should continue be targeted as part of risk reduction campaigns. Vaccination status and prior infection status alone are not surrogates for protection.

Plasma fibrinogen and risk of vascular recurrence after ischaemic stroke: An individual participant and summary-level data meta-analysis of 11 prospective studies.

INTRODUCTION: Inflammation is an emerging target for secondary prevention after stroke and randomised trials of anti-inflammatory therapies are ongoing. Fibrinogen, a putative pro-inflammatory marker, is associated with first stroke, but its association with major adverse cardiovascular events (MACE) after stroke is unclear. MATERIALS AND METHODS: We did a systematic review investigating the association between fibrinogen and post-stroke vascular recurrence. Authors were invited to provide individual-participant data (IPD) and where available we did within-study multivariable analyses with adjustment for cardiovascular risk factors and medications. Adjusted summary-level data was extracted from published reports from studies that did not provide IPD. We pooled risk ratios (RR) by random-effects meta-analysis by comparing supra-median with sub-median fibrinogen levels and performed pre-specified subgroup analysis according to timing of phlebotomy after the index event. RESULTS: Eleven studies were included (14,002 patients, 42,800 follow-up years), of which seven provided IPD. Fibrinogen was associated with recurrent MACE on unadjusted (RR 1.35, 95% CI 1.17-1.57, supra-median vs sub-median) and adjusted models (RR 1.21, 95% CI 1.06-1.38). Fibrinogen was associated with recurrent stroke on univariate analysis (RR 1.19, 95% CI 1.03-1.39), but not after adjustment (RR 1.11, 95% CI 0.94-1.31). The association with recurrent MACE was consistently observed in patients with post-acute (⩾14 days) fibrinogen measures (RR 1.29, 95% CI 1.16-1.45), but not in those with early phlebotomy (<14 days) (RR 0.98, 95% CI 0.82-1.18) (Pinteraction = 0.01). Similar associations were observed for recurrent stroke. DISCUSSION AND CONCLUSION: Fibrinogen was independently associated with recurrence after stroke, but the association was modified by timing of phlebotomy. Fibrinogen measurements might be useful to identify patients who are more likely to derive benefit from anti-inflammatory therapies after stroke.

Computable phenotype for real-world, data-driven retrospective identification of relapse in ANCA-associated vasculitis.

OBJECTIVE: ANCA-associated vasculitis (AAV) is a relapsing-remitting disease, resulting in incremental tissue injury. The gold-standard relapse definition (Birmingham Vasculitis Activity Score, BVAS>0) is often missing or inaccurate in registry settings, leading to errors in ascertainment of this key outcome. We sought to create a computable phenotype (CP) to automate retrospective identification of relapse using real-world data in the research setting. METHODS: We studied 536 patients with AAV and >6 months follow-up recruited to the Rare Kidney Disease registry (a national longitudinal, multicentre cohort study). We followed five steps: (1) independent encounter adjudication using primary medical records to assign the ground truth, (2) selection of data elements (DEs), (3) CP development using multilevel regression modelling, (4) internal validation and (5) development of additional models to handle missingness. Cut-points were determined by maximising the F1-score. We developed a web application for CP implementation, which outputs an individualised probability of relapse. RESULTS: Development and validation datasets comprised 1209 and 377 encounters, respectively. After classifying encounters with diagnostic histopathology as relapse, we identified five key DEs; DE1: change in ANCA level, DE2: suggestive blood/urine tests, DE3: suggestive imaging, DE4: immunosuppression status, DE5: immunosuppression change. F1-score, sensitivity and specificity were 0.85 (95% CI 0.77 to 0.92), 0.89 (95% CI 0.80 to 0.99) and 0.96 (95% CI 0.93 to 0.99), respectively. Where DE5 was missing, DE2 plus either DE1/DE3 were required to match the accuracy of BVAS. CONCLUSIONS: This CP accurately quantifies the individualised probability of relapse in AAV retrospectively, using objective, readily accessible registry data. This framework could be leveraged for other outcomes and relapsing diseases.

Adolescents with Rett syndrome at critical care pathway junctures: Examining clinicians' decision to initiate invasive long-term ventilation.

BACKGROUND: The initiation of invasive long-term ventilation (I-LTV) for an adolescent with Rett Syndrome (RTT) involves many serious bioethical considerations. In moving towards a more inclusive model of patient participation, transparency surrounding the main influencing factors around this decision is important. OBJECTIVE: We aimed to identify the main drivers influencing a clinician's decision to support initiation of I-LTV for an adolescent with RTT. METHOD: We used an anonymous online vignette-based factorial survey. The survey was distributed internationally through eight professional multi-disciplinary organisations to reach clinicians working in paediatrics. RESULTS: We analysed 504 RTT vignettes completed by 246 clinicians using mixed effect regression modelling. The main three significant influencing factors identified were: parental agreement with the decision to support initiation, the family's support network, and proximity to a tertiary care centre. Additional comments from participants focused on family support, and the importance of on-going communication with the family. CONCLUSION: As the rights of those with disabilities improve and participation of adolescents in decision-making becomes more established, effective communications with the family around goals of care and particular sensitivity and reflective practice around methods of consensus building will likely contribute to a positive decision-making process at this difficult time.

Identifying high-risk subgroups for self-harm in adolescents and young adults: A longitudinal latent class analysis of risk factors.

BACKGROUND: Self-harm is a major public health concern in young people and is governed by a complex interaction of different risk factors. While many studies have identified these risk factors, less is known about how they tend to co-occur together. METHODS: A latent class analysis was conducted using risk factors for self-harm from two waves at ages 13 and 17 from the Growing Up in Ireland (GUI) study their associations with self-harm were examined longitudinally at ages 17 and 20, respectively. RESULTS: At age 13, there was a 'peer problems' group with higher probabilities of bullying, being unpopular and internalising problems and a 'school and substance use problems' group with higher probabilities of substance use, truancy or excessive absence from school and violence. Both of these two groups had over a two-fold risk of self-harm at age 17 in comparison to the low risk factor group. At age 17, there was a group with depression that was diagnosed by a medical professional with the highest relative risk (RR:13.9 (95 % CI 10.2-19.0)) of self-harm at age 20. Two other groups with undiagnosed depression had high probabilities of being bullied, and either high or low probabilities of substance use that had a 9.4 (95 % CI 6.8-13.1) and 7.4 (95 % CI 5.5-10.0) relative risk of self-harm at age 20, respectively. CONCLUSIONS: Identifying hidden sub-groups using risk factors for self-harm in young people can inform potential public health interventions by clinicians and other professionals who work with young people.

C-Reactive Protein, Interleukin-6, and Vascular Recurrence According to Stroke Subtype: An Individual Participant Data Meta-Analysis

BACKGROUND AND OBJECTIVES: Anti-inflammatory therapies reduce major adverse cardiovascular events (MACE) in coronary artery disease but remain unproven after stroke. Establishing the subtype-specific association between inflammatory markers and recurrence risk is essential for optimal selection of patients in randomized trials (RCTs) of anti-inflammatory therapies for secondary stroke prevention. METHODS: Using individual participant data (IPD) identified from a systematic review, we analyzed the association between high-sensitivity C-reactive protein, interleukin-6 (IL-6), and vascular recurrence after ischemic stroke or transient ischemic attack. The prespecified coprimary end points were (1) any recurrent MACE (first major coronary event, recurrent stroke, or vascular death) and (2) any recurrent stroke (ischemic, hemorrhagic, or unspecified) after sample measurement. Analyses were performed stratified by stroke mechanism, per quarter and per biomarker unit increase after loge transformation. We then did study-level meta-analysis with comparable published studies not providing IPD. Preferred Reporting Items for Systematic Review and Meta-Analyses IPD guidelines were followed. RESULTS: IPD was obtained from 10 studies (8,420 patients). After adjustment for vascular risk factors and statins/antithrombotic therapy, IL-6 was associated with recurrent MACE in stroke caused by large artery atherosclerosis (LAA) (risk ratio [RR] 2.30, 95% CI 1.21-4.36, p = 0.01), stroke of undetermined cause (UND) (RR 1.78, 1.19-2.66, p = 0.005), and small vessel occlusion (SVO) (RR 1.71, 0.99-2.96, p = 0.053) (quarter 4 [Q4] vs quarter 1 [Q1]). No association was observed for stroke due to cardioembolism or other determined cause. Similar results were seen for recurrent stroke and when analyzed per loge unit increase for MACE (LAA, RR 1.26 [1.06-1.50], p = 0.009; SVO, RR 1.22 [1.01-1.47], p = 0.04; UND, RR 1.18 [1.04-1.34], p = 0.01). High-sensitivity CRP was associated with recurrent MACE in UND stroke only (Q4 vs Q1 RR 1.45 [1.04-2.03], p = 0.03). Findings were consistent on study-level meta-analysis of the IPD results with 2 other comparable studies (20,136 patients). DISCUSSION: Our data provide new evidence for the selection of patients in future RCTs of anti-inflammatory therapy in stroke due to large artery atherosclerosis, small vessel occlusion, and undetermined etiology according to inflammatory marker profile.

Sequential multiple assignment randomised trial to develop an adaptive mobile health intervention to increase physical activity in people poststroke in the community setting in Ireland: TAPAS trial protocol.

INTRODUCTION: Stroke is the second-leading cause of death and disability globally. Participation in physical activity (PA) is a cornerstone of secondary prevention in stroke care. Given the heterogeneous nature of stroke, PA interventions that are adaptive to individual performance are recommended. Mobile health (mHealth) has been identified as a potential approach to supporting PA poststroke. To this end, we aim to use a Sequential Multiple Assignment Randomised Trial (SMART) design to develop an adaptive, user-informed mHealth intervention to improve PA poststroke. METHODS AND ANALYSIS: The components included in the 12-week intervention are based on empirical evidence and behavioural change theory and will include treatments to increase participation in Structured Exercise and Lifestyle or a combination of both. 117 participants will be randomly assigned to one of the two treatment components. At 6 weeks postinitial randomisation, participants will be classified as responders or non-responders based on participants' change in step count. Non-responders to the initial treatment will be randomly assigned to a different treatment allocation. The primary outcome will be PA (steps/day), feasibility and secondary clinical and cost outcomes will also be included. A SMART design will be used to evaluate the optimum adaptive PA intervention among community-dwelling, ambulatory people poststroke. ETHICS AND DISSEMINATION: Ethical approval has been granted by the Health Service Executive Mid-Western Ethics Committee (REC Ref: 026/2022). The findings will be submitted for publication and presented at relevant national and international academic conferences TRIALS REGISTRATION NUMBER: NCT05606770.

Risk and protective factors for self-harm in adolescents and young adults: An umbrella review of systematic reviews.

We conducted an umbrella review to synthesise the evidence from systematic reviews and meta-analyses that examined the risk and protective factors for self-harm in young people. We searched six different databases and used the AMSTAR-2 checklist for quality assessment. The importance of each risk and protective factor was determined based on (1) the number of times it was identified by general reviews examining any risk or protective factor, and (2) the effect sizes from meta-analyses. There were 61 systematic reviews included in this review. The most frequently identified risk factors for self-harm in young people included childhood abuse, depression/anxiety, bullying, trauma, psychiatric illnesses, substance use/abuse, parental divorce, poor family relationships, lack of friends, and exposure to self-harm behaviour in others. The risk factors with the strongest evidence for an association with self-harm were behavioural disorders, personality disorders and depression or anxiety. There was a dearth of systematic reviews examining protective factors but good family/friend relationships were most frequently identified. There was also evidence to show that non-suicidal and suicidal self-harm shared many of the same risk factors. Clinicians and other professionals who work with young people should be particularly cognisant of the psychiatric and adverse life event risk factors as well as the substance use, education-related and individual-level (e.g. being LGB) risk factors for self-harm. Knowledge of risk factors for self-harm can potentially be used to inform the design and implementation of prevention measures and further research is needed on the protective factors for self-harm.

The factorial survey as an approach to investigate clinical decision-making: examining influences on a clinician's decision to initiate life-sustaining clinical technology for a child with spinal muscular atrophy type 1.

Background: Spinal Muscular Atrophy (SMA) type 1 is a debilitating condition with a poor prognosis, though therapeutic advances are promising. Long-term ventilation is a common management strategy as respiratory function deteriorates. Without consensus on best practice respiratory management, the decision to initiate invasive LTV (I-LTV) for this group of young children involves many ethical considerations. Understanding the main influencing factors on a clinician's likelihood to initiative I-LTV for a child with chronic critical illness is important to maintain transparency and trust with the family during this challenging time. Methods: A factorial survey was used to identify the factors that influence a clinician to support initiation of I-LTV for children with SMA type 1. Factorial survey content was based on literature and evidence-based practice and the content was subject to extensive pretesting and pilot testing. An anonymous survey was disseminated (Oct 2021-Jan 2022), via eight international professional organisations, to clinicians with experience caring for children at the time of initiation of I-LTV. Results: 251 participants answered 514 vignettes on SMA type 1. The greatest influencing factor on clinician's likelihood to initiate I-LTV was parental agreement with the need to initiate I-LTV. Additional qualitative comments from participants support this finding. Clinicians also highlighted the important role of innovative therapies as well as the availability of supports for families when considering initiation however these findings were context based. Conclusions: The factorial survey approach provides a valuable way of identifying influencers on decision-making in sensitive situations. The findings demonstrate the acceptance of the centrality of parental influence in decisions on care delivery. Effective communication with the child's family is key to ensuring shared understanding and agreement of goals of care. More international research is needed on the long-term effects of novel treatments, as well as impact on quality of life and influence of geographical location, to inform decision-making.

Point of care detection of SARS-CoV-2 antibodies and neutralisation capacity-lateral flow immunoassay evaluation compared to commercial assay to inform potential role in therapeutic and surveillance practices.

Introduction: As the COVID-19 pandemic moves towards endemic status, testing strategies are being de-escalated. A rapid and effective point of care test (POCT) assessment of SARS-CoV-2 immune responses can inform clinical decision-making and epidemiological monitoring of the disease. This cross-sectional seroprevalence study of anti-SARS-CoV-2 antibodies in Irish healthcare workers assessed how rapid anti-SARS-CoV-2 antibody testing can be compared to a standard laboratory assay, discusses its effectiveness in neutralisation assessment and its uses into the future of the pandemic. Methods: A point of care lateral flow immunoassay (LFA) detecting anti-SARS-CoV-2 spike (S)-receptor binding domain (RBD) neutralising antibodies (Healgen SARS-CoV-2 neutralising Antibody Rapid Test Cassette) was compared to the Roche Elecsys/-S anti-SARS-CoV-2 antibody assays and an in vitro surrogate neutralisation assay. A correlation between anti-spike (S), anti-nucleocapsid (N) titres, and in vitro neutralisation was also assessed. Results: 1,777 serology samples were tested using Roche Elecsys/-S anti-SARS-CoV-2 assays to detect total anti-N/S antibodies. 1,562 samples were tested using the POC LFA (including 50 negative controls), and 90 samples were tested using an in vitro ACE2-RBD binding inhibition surrogate neutralisation assay. The POCT demonstrated 97.7% sensitivity, 100% specificity, a positive predictive value (PPV) of 100%, and a negative predictive value (NPV) of 61% in comparison to the commercial assay. Anti-S antibody titres determined by the Roche assay stratified by the POC LFA result groups demonstrated statistically significant differences between the "Positive" and "Negative" LFA groups (p < 0.0001) and the "Weak Positive" and "Positive" LFA groups (p < 0.0001). No statistically significant difference in ACE2-RBD binding inhibition was demonstrated when stratified by the LFA POC results. A positive, statistically significant correlation was demonstrated between the in vitro pseudo-neutralisation assay results and anti-S antibody titres (rho 0.423, p < 0.001) and anti-N antibody titres (rho = 0.55, p < 0.0001). Conclusion: High sensitivity, specificity, and PPV were demonstrated for the POC LFA for the detection of anti-S-RBD antibodies in comparison to the commercial assay. The LFA was not a reliable determinant of the neutralisation capacity of identified antibodies. POC LFA are useful tools in sero-epidemiology settings, pandemic preparedness and may act as supportive tools in treatment decisions through the rapid identification of anti-Spike antibodies.

Impact of serum sodium concentrations, and effect modifiers on mortality in the Irish Health System.

BACKGROUND: Abnormalities of serum sodium are associated with increased mortality risk in hospitalised patients, but it is unclear whether, and to what extent other factors influence this relationship. We investigated the impact of dysnatraemia on total and cause-specific mortality in the Irish health system while exploring the concurrent impact of age, kidney function and designated clinical work-based settings. METHODS: A retrospective cohort study of 32,666 participants was conducted using data from the National Kidney Disease Surveillance System. Hyponatraemia was defined as < 135 mmol/L and hypernatraemia as > 145 mmol/L with normal range 135-145 mmol/L. Multivariable Cox proportional hazards regression was used to estimate hazard ratios (HR's) and 95% Confidence Intervals (CIs) while penalised spline models further examined patterns of risk. RESULTS: There were 5,114 deaths (15.7%) over a median follow up of 5.5 years. Dysnatraemia was present in 8.5% of patients overall. In multivariable analysis, both baseline and time-dependent serum sodium concentrations exhibited a U-shaped association with mortality. Hyponatremia was significantly associated with increased risk for cardiovascular [HR 1.38 (1.18-1.61)], malignant [HR: 2.49 (2.23-2.78)] and non-cardiovascular/non-malignant causes of death [1.36 (1.17-1.58)], while hypernatremia was significantly associated with cardiovascular [HR: 2.16 (1.58-2.96)] and non-cardiovascular/ non-malignant deaths respectively [HR: 3.60 (2.87-4.52)]. The sodium-mortality relationship was significantly influenced by age, level of kidney function and the clinical setting at baseline (P < 0.001). For hyponatraemia, relative mortality risks were significantly higher for younger patients (interaction term P < 0.001), for patients with better kidney function, and for patients attending general practice [HR 2.70 (2.15-3.36)] than other clinical settings. For hypernatraemia, age and kidney function remained significant effect modifiers, with patients attending outpatient departments experiencing the greatest risk [HR 9.84 (4.88-18.62)] than patients who attended other clinical locations. Optimal serum sodium thresholds for mortality varied by level of kidney function with a flattening of mortality curve observed for patients with poorer kidney function. CONCLUSION: Serum sodium concentrations outside the standard normal range adversly impact mortality and are associated with specific causes of death. The thresholds at which these risks appear to vary by age, level of kidney function, and are modified in specific clinical settings within the health system.

A Comparison of Relative-Efficacy Estimate(S) Derived From Both Matching-Adjusted Indirect Comparisons and Standard Anchored Indirect Treatment Comparisons: A Review of Matching-Adjusted Indirect Comparisons.

OBJECTIVES: We present an empirical comparison of relative-efficacy estimate(s) from matching-adjusted indirect comparisons (MAICs) with estimates from corresponding standard anchored indirect treatment comparisons. METHODS: A total of 80 comparisons were identified from 17 publications through a systematic rapid review. A standardized metric that used reported relative treatment efficacy estimates and their associated uncertainty was used to compare the methods across different treatment indications and outcome measures. RESULTS: On aggregate, MAICs presented for connected networks tended to report a more favorable relative-efficacy estimate for the treatment for which individual-level patient data were available relative to the reported indirect treatment comparison estimate. CONCLUSIONS: Although we recognize the importance of MAIC and other population adjustment methods in certain situations, we recommend that results from these analyses are interpreted with caution. Researchers and analysts should carefully consider if MAICs are appropriate where presented and whether MAICs would have added value where omitted.

Economic evaluation of a collaborative model of pharmaceutical care in an Irish hospital: cost-utility analysis.

Background: A complex, collaborative pharmaceutical care intervention including medication review and reconciliation demonstrated a statistically significant reduction in the prevalence of discharge medication error and improved quality of prescribing for hospitalised adults.  This study sought to assess the cost-effectiveness of this intervention. Methods: A cost-utility analysis was undertaken using a decision-analytic framework. The evaluation was undertaken from the Health Service Executive's perspective, the payer for primary and secondary care settings. Direct costs associated with managing hypothetical harm consequent to intercepted discharge medication error and consequences in terms of quality-adjusted life years loss were key input parameters. Analysis was structured within a decision tree model in Microsoft Excel® populated with consequences as utilities, estimated costs using macro- and micro-costing approaches, and event probabilities generated from the original study. Incremental analysis, one-way and probabilistic sensitivity analyses were performed. Results: The results of analysis for the base-care demonstrated that the intervention dominated standard care with an incremental cost-effectiveness ratio of -€36,537.24/quality-adjusted life year, indicating that the intervention is less costly and more effective. The one-way and probabilistic sensitivity analyses both demonstrated that the intervention dominated standard care. The model was relatively robust to variation in input parameters through one-way sensitivity analysis. The cost of discharge medication error and effect parameters relating to standard care were most sensitive to change. Discussion: The analysis demonstrated the cost-effectiveness of a complex pharmaceutical intervention which will support decision-making regarding implementation. This is the first cost-utility analysis of a complex, collaborative pharmaceutical care intervention, adding to the scant evidence-base in the field.

Physical activity for depression among the chronically Ill: Results from older diabetics in the Irish longitudinal study on ageing.

Among chronically-ill older adults, the benefits of moderate-to-vigorous physical activity (MVPA) are established. Comorbid depressive symptoms and Major Depression are prevalent among the chronically-ill, but how different doses of MVPA may protect against depression remains understudied. Thus, using 10 years of data from The Irish Longitudinal Study on Ageing, we quantified longitudinal associations between MVPA doses and depressive symptoms and Major Depression among chronically-ill older adults living with type 2 diabetes (T2DM). Continuous MVPA (MET.min.week-1), three dose and five dose MVPA categories were examined. Depressive symptoms and Major Depression were measured using the center for Epidemiological Studies Depression and the Composite International Diagnostic Interview for Major Depressive Episode. Negative binomial regression and logistic models, adjusted for covariates, quantified associations across time. Among the 2,262 participants, those adhering to the WHO guidelines of 600-<1,200 MET.min.week-1 had 28% lower odds of Major Depression compared to those not achieving the guidelines (OR: 0.72; 95%CI: 0.53-0.98). For depressive symptoms, a higher MVPA dose was required with a 13% (IRR: 0.87; 95%CI: 0.82-0.93) lower rate of symptoms among those exceeding recommendations (1200-<2,400 MET.min.week-1). Interventions should focus on enhancing achievability of and compliance with these MVPA doses among the chronically-ill, including T2DM, to protect against depression.

C-Reactive Protein, Interleukin-6, and Vascular Recurrence After Stroke: An Individual Participant Data Meta-Analysis.

BACKGROUND: Anti-inflammatory therapies reduce recurrent vascular events in coronary disease. Existing studies have reported highly conflicting findings for the association of blood inflammatory markers with vascular recurrence after stroke leading to uncertainty about the potential of anti-inflammatory therapies after stroke and no consensus about the utility of measurement of inflammatory markers in current guidelines. METHODS: We investigated the association between hsCRP (high-sensitivity C-reactive protein), IL-6 (interluekin-6), and recurrent major adverse cardiovascular events (MACE), and stroke from individual participant data from 8420 patients with ischemic stroke/transient ischemic attack from 10 prospective studies. We did within-study multivariable regression analyses and then combined adjusted risk ratio (RR) by random-effects meta-analysis. RESULTS: During 18 920 person-years of follow-up, 1407 (16.7% [95% CI, 15.9-17.5]) patients had MACE and 1191 (14.1% [95% CI, 13.4-14.9]) patients had recurrent stroke. On bivariate analysis, baseline IL-6 was associated with MACE (RR, 1.26 [95% CI, 1.10-1.43]) and recurrent stroke (RR, 1.18 [95% CI, 1.05-1.32]), per unit increase logeIL-6. Similar associations were observed for hsCRP (MACE RR, 1.19 [95% CI, 1.09-1.29]; recurrent stroke RR, 1.12 [95% CI, 1.04-1.21], per unit increase logehsCRP). After adjustment for vascular risk factors and treatment, independent associations remained with MACE (IL-6, RR, 1.12 [95% CI, 1.04-1.21]; hsCRP, RR, 1.09 [95% CI, 1.04-1.15]) and recurrent stroke (IL-6, RR, 1.09 [95% CI, 1.00-1.19]; hsCRP, RR, 1.05 [95% CI, 1.00-1.11]). Comparing the top with the bottom quarters (Q4 versus Q1), IL-6 (RR, 1.35 [95% CI, 1.09-1.67]) and hsCRP (RR, 1.31 [95% CI, 1.07-1.61]) were associated with MACE after adjustment. Similar results were observed for recurrent stroke for IL-6 (RR, 1.33 [95% CI, 1.08-1.65]) but not hsCRP (RR, 1.16 [95% CI, 0.93-1.43]). CONCLUSIONS: Blood markers of inflammation were independently associated with vascular recurrence after stroke, strengthening the rationale for randomized trials of anti-inflammatory therapies for secondary prevention after ischemic stroke/TIA.

Guidance on the use of complex systems models for economic evaluations of public health interventions.

To help health economic modelers respond to demands for greater use of complex systems models in public health. To propose identifiable features of such models and support researchers to plan public health modeling projects using these models. A working group of experts in complex systems modeling and economic evaluation was brought together to develop and jointly write guidance for the use of complex systems models for health economic analysis. The content of workshops was informed by a scoping review. A public health complex systems model for economic evaluation is defined as a quantitative, dynamic, non-linear model that incorporates feedback and interactions among model elements, in order to capture emergent outcomes and estimate health, economic and potentially other consequences to inform public policies. The guidance covers: when complex systems modeling is needed; principles for designing a complex systems model; and how to choose an appropriate modeling technique. This paper provides a definition to identify and characterize complex systems models for economic evaluations and proposes guidance on key aspects of the process for health economics analysis. This document will support the development of complex systems models, with impact on public health systems policy and decision making.