Risk Difference Research Articles

The association between myasthenia gravis and risk of fracture: a systematic review and meta-analysis.

Patients with myasthenia gravis (MG), because of their muscle weakness and exposure to corticosteroids treatment, are generally considered to be at increased risk for osteoporosis or fracture. However, clinical evidence of this issue is lacking. In this review, we systematically searched databases, including Cochrane Library, PubMed, Embase, and Airiti library from inception to the end of November 2023 for cohort studies that compared participants with MG and participants without MG for incidence of osteoporosis or fracture. We used the Newcastle-Ottawa Scale for quality assessment. In total, we included 3 studies with 34,865 participants. The pooled meta-analysis using the random effect model demonstrated no significant difference in risk of fracture in the MG group (odds ratio = 1.52; 95% confidence interval = 0.74 to 3.12; I2 = 93%; between-study variance [τ2] = 0.32) compared with that for the non-MG group. Due to limited studies, we could not perform a quantitative analysis for risk of osteoporosis. In conclusion, we found no robust evidence to support the proposition that patients with MG are at higher risk for fracture than general comparators. The explanations and underlying mechanisms of this finding remain unclear, we therefore conclude that additional studies are warranted.

Geographic and psychosocial correlates of homelessness or unstable housing among USveterans in the Midwest.

The purpose of this study was to explore (1) the prevalence of physical and mental health conditions among veterans stratified by homelessness and unstable housing (HUH) in several Midwestern states, and (2) the correlation between HUH and sociodemographic, military, financial, risky behavior, health, and geographical characteristics. The study cohort consisted of 7260 HUH veterans and stably housed veterans in 2018-2022 in Veterans Integrated Service Network (VISN) 23. A multivariate logistic regression analysis was performed which revealed the strongest associations with HUH were any incarceration experience (adjusted odds ratio [AOR] = 0.21) and rural location (AOR = 0.33). Frontier and remote location scores (AOR = 1.23) were associated with increased risk of HUH among veterans. Our results suggest potential differences in risk for HUH among veterans living in rural versus frontier and remote locations, which may be important to consider to provide care to the many veterans in these areas.

Transcatheter Aortic Valve Implantation in Low-Risk Tricuspid or Bicuspid Aortic Stenosis: The NOTION-2 Trial.

Transcatheter aortic valve implantation (TAVI) has become the first choice to treat older patients with severe symptomatic aortic stenosis (AS). This study aimed to compare TAVI with surgery in low-risk patients ≤ 75 years of age, including both tricuspid and bicuspid AS. The NOTION-2 trial enrolled and 1:1 randomized low-risk patients aged ≤ 75 years with severe symptomatic AS to TAVI or surgery. The primary endpoint was a composite of all-cause mortality, stroke or rehospitalization (related to the procedure, valve or heart failure) at 12 months. A total of 370 patients were enrolled with a mean age of 71.1 years and a median Society of Thoracic Surgeons risk score of 1.1%. A total of 100 patients had bicuspid AS. The 1-year incidence of the primary endpoint was 10.2% in the TAVI group and 7.1% in the surgery group (absolute risk difference 3.1%; 95% confidence interval [CI], -2.7% to 8.8%; hazard ratio (HR) 1.4, 95% CI: 0.7 to 2.9; p=0.3). Patients with TAVI, when compared to surgery, had lower risk of major bleeding and new-onset atrial fibrillation and higher risk of non-disabling stroke, permanent pacemaker implantation and moderate-or-greater paravalvular regurgitation. The risk of the primary composite endpoint was 8.7% and 8.3% in patients with tricuspid AS (HR 1.0, 95% CI: 0.5 to 2.3) and 14.3% and 3.9% in patients with bicuspid AS (HR 3.8, 95% CI: 0.8 to 18.5) treated with TAVI or surgery, respectively (P for interaction=0.1). Among low-risk patients aged ≤ 75 years with severe symptomatic AS, the rate of the composite of death, stroke, or rehospitalization at one year was similar between TAVI and surgery. TAVI outcomes in young bicuspid AS patients warrant caution and should be further investigated. (NOTION-2, ClinicalTrials.gov, NCT02825134).

Bleeding Risk in Patients Receiving Omega-3 Polyunsaturated Fatty Acids: A Systematic Review and Meta-Analysis of Randomized Clinical Trials.

There is a potential concern about increased bleeding risk in patients receiving omega-3 polyunsaturated fatty acids (PUFAs). The aims of this study-level meta-analysis were to determine the risk of bleeding and to assess whether this relationship is linked to the received dose of omega-3 PUFAs or the background use of antiplatelet treatment. Electronic databases were searched through May 2023 to identify randomized clinical trials of patients receiving omega-3 PUFAs. Overall bleeding events, including fatal and central nervous system events, were identified and compared with those of a control group. A total of 120 643 patients from 11 randomized clinical trials were included. There was no difference in the pooled meta-analytic events of bleeding among patients receiving omega-3 PUFAs and those in the control group (rate ratio [RR], 1.09 [95% CI, 0.91-1.31]; P=0.34). Likewise, the incidence of hemorrhagic stroke, intracranial bleeding, and gastrointestinal bleeding were similar. A prespecified analysis was performed in patients receiving high-dose purified eicosapentaenoic acid (EPA), which demonstrated a 50% increase in the relative risk of bleeding but only a modest increase in the absolute risk of bleeding (0.6%) when compared with placebo. Bleeding risk was associated with the dose of EPA (risk difference, 0.24 [95% CI, 0.05-0.43]; P=0.02) but not the background use of antiplatelet therapy (risk difference, -0.01 [95% CI, -0.02 to 0]; P=0.056). Omega-3 PUFAs were not associated with increased bleeding risk. Patients receiving high-dose purified EPA may incur additional bleeding risk, although its clinical significance is very modest.

The cementless taper wedge vs. fit-and-fill stem in primary total hip arthroplasty: risk of stem-related complication differs across Dorr types.

The choice between a cementless taper wedge stem and a fit-and-fill stem in total Hip arthroplasty (THA) for various proximal femoral morphological types has not been thoroughly evaluated. This study aimed to compare the risk of stem-related complications between these two stem types in Dorr type A, B, and C femurs. From January 2015 through April 2021, we retrospectively reviewed 1995 cementless THA procedures. We stratified all procedures into three groups: Dorr type A (N = 360, 18.0%), B (N = 1489, 74.7%) and C (N = 146, 7.3%). The primary outcome domain was stem-related complications, including stem subsidence ≥ 3mm, intraoperative fracture, periprosthetic fracture and aseptic stem loosening. We performed multivariate regression analysis to compare the risk of stem-related complication between the two stem types. Other factors included age, sex, body mass index, diagnosis, age-adjusted Charlson comorbidity index, stem alignment and canal fill ratio. The incidence of stem-related complications in the taper wedge and fit-and-fill stem groups was 4.4% (N = 15) and 6.5% (N = 107), respectively. Fit-and-fill stems showed an increased risk of stem-related complications (aOR: 9.903, 95% CI: 1.567-62.597) only in Dorr type C femurs. No significant difference in risk was observed in Dorr type A and B femurs. Furthermore, the canal fill ratio at the lesser trochanter, 2cm and 7cm below the lesser trochanter, did not exhibit an association with stem-related complications in any Dorr type. Concerning the risk of stem-related complications, the taper wedge stem was a better choice in Dorr type C femurs. However, there was no difference in risk between the taper wedge stem and fit-and-fill stem in Dorr type A and B femurs.

Feedback Loop Failure Modes in Medical Diagnosis: How Biases Can Emerge and Be Reinforced.

Medical diagnosis in practice connects to research through continuous feedback loops: Studies of diagnosed cases shape our understanding of disease, which shapes future diagnostic practice. Without accounting for an imperfect and complex diagnostic process in which some cases are more likely to be diagnosed correctly (or diagnosed at all), the feedback loop can inadvertently exacerbate future diagnostic errors and biases. A feedback loop failure occurs if misleading evidence about disease etiology encourages systematic errors that self-perpetuate, compromising future diagnoses and patient care. This article defines scenarios for feedback loop failure in medical diagnosis. Through simulated cases, we characterize how disease incidence, presentation, and risk factors can be misunderstood when observational data are summarized naive to biases arising from diagnostic error. A fourth simulation extends to a progressive disease. When severe cases of a disease are diagnosed more readily, less severe cases go undiagnosed, increasingly leading to underestimation of the prevalence and heterogeneity of the disease presentation. Observed differences in incidence and symptoms between demographic groups may be driven by differences in risk, presentation, the diagnostic process itself, or a combination of these. We suggested how perceptions about risk factors and representativeness may drive the likelihood of diagnosis. Differing diagnosis rates between patient groups can feed back to increasingly greater diagnostic errors and disparities in the timing of diagnosis and treatment. A feedback loop between past data and future medical practice may seem obviously beneficial. However, under plausible scenarios, poorly implemented feedback loops can degrade care. Direct summaries from observational data based on diagnosed individuals may be misleading, especially concerning those symptoms and risk factors that influence the diagnostic process itself. Current evidence about a disease can (and should) influence the diagnostic process. A feedback loop failure may occur if biased "evidence" encourages diagnostic errors, leading to future errors in the evidence base.When diagnostic accuracy varies for mild versus severe cases or between demographic groups, incorrect conclusions about disease prevalence and presentation will result without specifically accounting for such variability.Use of demographic characteristics in the diagnostic process should be done with careful justification, in particular avoiding potential cognitive biases and overcorrection.

Modifiable lifestyle factors and lifetime risk of atrial fibrillation: longitudinal data from the Korea NHIS-HealS and UK Biobank cohorts

BackgroundThe reason for higher incidence of atrial fibrillation (AF) in Europe compared with East Asia is unclear. We aimed to investigate the association between modifiable lifestyle factors and lifetime risk of AF in Europe and East Asia, along with race/ethnic similarities and disparities.Methods1:1 propensity score matched pairs of 242,763 East Asians and 242,763 White Europeans without AF were analyzed. Modifiable lifestyle factors considered were blood pressure, body mass index, cigarette smoking, diabetes, alcohol consumption, and physical activity, categorized as non-adverse or adverse levels. Lifetime risk of AF was estimated from the index age of 45 years to the attained age of 85 years, accounting for the competing risk of death.ResultsThe overall lifetime risk of AF was higher in White Europeans than East Asians (20.9% vs 15.4%, p < 0.001). The lifetime risk of AF was similar between the two races in individuals with non-adverse lifestyle factor profiles (13.4% vs 12.9%, p = 0.575), whereas it was higher in White Europeans with adverse lifestyle factor profiles (22.1% vs 15.8%, p < 0.001). The difference in the lifetime risk of AF between the two races increased as the burden of adverse lifestyle factors worsened (1 adverse lifestyle factor; 4.3% to ≥ 3 adverse lifestyle factors; 11.2%). Compared with East Asians, the relative risk of AF in White Europeans was 23% and 62% higher for one (hazard ratio [HR] 1.23, 95% confidence interval [CI] 1.16–1.29) and ≥ 3 adverse lifestyle factors (HR 1.62, 95% CI 1.51–1.75), respectively.ConclusionsThe overall higher lifetime risk of AF in White Europeans compared with East Asians might be attributable to adverse lifestyle factors. Adherence to healthy lifestyle factors was associated with the lifetime risk of AF of about 1 in 8 regardless of race/ethnicity.

Real-World Risk of Severe Cytopenias in Multiple Myeloma Patients Sequentially Treated with Immunomodulatory Drugs.

Most multiple myeloma (MM) patients experience cytopenias, likely driven by both disease and treatment-related factors. Immunomodulatory agents (IMiDs), which form the backbone of most anti-myeloma regimens, are known to cause higher grade cytopenias. In this context, the impact of sequential IMiD treatments on cytopenia risk is unknown. We evaluated the cumulative risks of severe cytopenias following second line of therapy (LOT) initiation in 5573 MM patients in the Flatiron Health database. Patients for whom both LOTs 1 and 2 contained IMiDs were considered "sequentially exposed"; those for whom neither contained IMiDs were "never exposed." For the neutropenia outcome, compared to the never exposed, the sequentially exposed had the highest 1-year risk (risk difference [RD] 12%), followed by those only recently exposed during LOT 2 (RD 8%), then by those with only past exposure during LOT 1 (RD 5%). A similar pattern was observed for leukopenia, but no meaningful differences were observed for anemia or thrombocytopenia. The associations between sequential exposure, versus never, with neutropenia and leukopenia were even stronger among those with a recent cytopenia history. Results suggest that sequential exposure to IMiDs is a risk factor for higher grade cytopenias. These findings have profound clinical implications in choosing newer LOTs with potential risks of cytopenia.

Antithrombotic Treatment and Clinical Outcomes After Intracerebral Hemorrhage: A Retrospective Cohort Study from the Swedish Stroke Register.

A rapid shift has occurred from vitamin K antagonists toward direct oral anticoagulants, which have a lower risk of intracerebral hemorrhage (ICH). However, effects on clinical outcomes after ICH are understudied. We aimed to describe the prevalence of antithrombotic drugs and to study the prognosis among prestroke functionally independent Swedish patients with ICH. We identified all patients diagnosed with nontraumatic ICH in 2017 to 2021 from the Swedish Stroke Register (n=13 155) and assessed death and functional outcome at 3 months after ICH in prestroke functionally independent patients (n=10 014). Functional outcome was estimated among 3-month survivors on the basis of self-reported activities of daily living scores. Risks of outcomes were estimated using Poisson regression. In 13 155 patients, 14.5% used direct oral anticoagulant, 10.1% vitamin K antagonists, and 21.6% antiplatelets at ICH onset. Among 10 014 pre-stroke activities of daily living-independent patients, oral anticoagulants and antiplatelets were associated with increased mortality risk (adjusted risk ratio, 1.27 [95% CI, 1.13-1.43]; P<0.001; and adjusted risk ratio, 1.23 [95% CI, 1.13-1.34]; P<0.001 respectively). Mortality risk did not statistically differ between antiplatelets and oral anticoagulants nor between direct oral anticoagulant and vitamin K antagonists. Among 5126 patients with nonmissing functional outcome (69.1% of survivors), antiplatelets (adjusted risk ratio, 1.06 [95% CI, 0.99-1.13]; P=0.100) and oral anticoagulants (adjusted risk ratio, 1.01 [95% CI, 0.92-1.12]; P=0.768) were not statistically significantly associated with functional dependence. There was no statistically significant difference in mortality risk between direct oral anticoagulant and vitamin K antagonists in prestroke functionally independent patients (unadjusted for oral anticoagulant class indication). Furthermore, mortality risk in antiplatelet and oral anticoagulant users might differ less than previously suggested.

Ponatinib vs Imatinib in Frontline Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia

In newly diagnosed Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL), disease progression due to acquired resistance to first- or second-generation BCR::ABL1 tyrosine kinase inhibitors is common. Ponatinib inhibits BCR::ABL1 and all single-mutation variants, including T315I. To compare frontline ponatinib vs imatinib in adults with newly diagnosed Ph+ ALL. Global registrational, phase 3, open-label trial in adults aged 18 years or older with newly diagnosed Ph+ ALL. From January 2019 to May 2022, eligible patients at 77 sites were randomized 2:1 to ponatinib (30 mg/d) or imatinib (600 mg/d) with reduced-intensity chemotherapy, followed by single-agent ponatinib or imatinib after the cycle 20 phase of the trial. The last date of follow-up for this analysis was August 12, 2022. Patients received ponatinib, 30 mg/d, or imatinib, 600 mg/d, with reduced-intensity chemotherapy, followed by single-agent ponatinib or imatinib after cycle 20. The ponatinib dose was reduced to 15 mg on achievement of minimal residual disease-(MRD) negative complete remission. The primary end point of this interim analysis was MRD-negative complete remission (≤0.01% BCR::ABL1 [MR4] centrally assessed by reverse transcriptase-quantitative polymerase chain reaction), with complete remission maintained for at least 4 weeks at the end of cycle 3. The key secondary end point was event-free survival. Of 245 patients randomized (median age, 54 years; 133 [54.3%] female), 232 (ponatinib, n = 154; imatinib, n = 78) who had p190 or p210 dominant isoforms verified by the central laboratory were analyzed for the primary end point. The MRD-negative complete remission rate (primary end point) was significantly higher with ponatinib (34.4% [53/154]) vs imatinib (16.7% [13/78]) (risk difference, 0.18 [95% CI, 0.06-0.29]; P = .002). At the data cutoff, event-free survival had not met the prespecified number of events. Median event-free survival was not reached in the ponatinib group and was 29 months in the imatinib group. The most common adverse events were similar between treatment groups. Arterial occlusive events were infrequent and comparable between groups (ponatinib, 2.5%; imatinib, 1.2%). Ponatinib demonstrated a superior rate of MRD-negative complete remission at the end of induction vs imatinib when combined with reduced-intensity chemotherapy in adults with newly diagnosed Ph+ ALL. The safety profile of ponatinib was comparable with imatinib. ClinicalTrials.gov Identifier: NCT03589326.

Gender-based differences in clinical profile, management and mortality in cardiogenic shock. Prognostic accuracy of CardShock vs IABP Score, the Shock-CAT study

Abstract Funding Acknowledgements None. Background Mortality in cardiogenic shock (CS) remains very high. Gender could influence in aetiology, management, outcomes and risk stratification predictors. Purpose The aim is to analyse differences in clinical profile, management, in-hospital prognosis and mortality risk in CS patients depending on sex and compare the prognostic accuracy of CardShock and IABP scores between sexes in a Mediterranean cohort. Method Shock-CAT study was a multicentre, prospective, observational study conducted between December 2018 and December 2019 in eight public University hospitals in Spain, including CS patients of different aetiologies. Data on clinical presentation, biomarkers, management, including mechanical cardiac/circulatory support (MCS) were analysed comparing women and men. Cardshock and IABP score have been compared to assess 90-days mortality risk between sexes. Results A total of 382 CS patients (p) were included: women 24.9% (n=95 p) and men 75.1% (n=287p). Women were older than men (68.9 vs 64.1 years, P=0.004). CS due to acute coronary syndrome (ACS) was more frequent in men (66.6% vs 43.2%), and myocarditis (1.7 vs 6.3%), stress cardiomyopathy (0.3% vs 8.4%) and severe aortic stenosis (2.4% vs 6.3%) were more prevalent in women, all p&amp;lt;0.001. Cardiac arrest was more prevalent in men than women (38.4% vs 25.3%, p=0.020). MCS was implanted in 35.3% of patients, without gender differences (men 36.6%, women 31.6%, p=0.376). Even though there was a non-significant trend to lower use in women of IABP (31.1% vs 26.5%), Impella (13.5% vs 7.4%) or ECMO (10.4% vs 7.4%). Risk scores were similar between sexes: Cardshock (men:4.32 vs 4.40 women, p=0.674) and IABP score (men: 2.31 vs 2.04 women, p=0.190). There were no differences between men and women in in-hospital mortality (32.4% vs 34.7%, p=0.675) or 6-months mortality (41.5% vs 40%, p=0.989). Receiver-operating characteristic curves demonstrated that IABP shock score had superior prognostic power for predicting 90-days mortality when compared with Cardshock score in men (area under the curve -AUC- 0.72 vs 0.64) respectively, p=0.009, although both scores were similar in women (AUC 0.70 vs 0.72, p=0.635), Figures 1-2. Conclusions Women with CS were older than men and had less ACS and cardiac arrest at admission. There is a non-significant lower use of mechanical assistance devices in women, although in-hospital or 6-months mortality were similar in both sexes. IABP score provided better 90-days mortality risk prediction than CardShock score in men, but both scores were similar in women with cardiogenic shock.Men ROC Curves 90-days MortalityWomen ROC Curves 90-days Mortality

The Comparison of Lifestyles, Mental Risks, and Physical Indices among Individuals with Ultra-High Risk of Psychosis, Patients with Schizophrenia, and the General Public

(1) Background: Early interventions may effectively reduce the risk of mental disorders in individuals with ultra-high risk. Specifying the health needs of individuals with ultra-high risk is crucial before the implementation of successful early intervention. This study aimed to explore the differences in lifestyles, mental risks, and physical indices among individuals with ultra-high risk, patients with schizophrenia, and healthy subjects. (2) Methods: A cross-section design applying seven questionnaires with physical examinations for 144 participants aged 13–45 years old was conducted in this study. The questionnaires included one about personal data, four on mental risks, and two for lifestyles. (3) Results: The individuals with ultra-high risk scored similarly in many dimensions as the patients with schizophrenia, but they displayed lower positive symptoms, lower negative symptoms, lower prodromal symptoms, higher interpersonal deficits, lower nutrition intake, and higher levels of exercise than the patients with schizophrenia. Female individuals with ultra-high risk had lower self-esteem, higher positive symptoms, lower nutrition intake, and higher exercise levels than male ones. (4) Conclusions: The study pinpointed specific health needs with interpersonal deficits, nutrition intake, and physical activity for the individuals with ultra-high risk. Future interventions targeted on improving social function, dietary pattern, and exercise will be beneficial.

Impact of clinical frailty scale on short and long term outcome in patients with acute coronary syndrome

Abstract Funding Acknowledgements None. Background As recently outlined in the European Society of Cardiology (ESC) guidelines on acute coronary syndrome (ACS), scarce data still exits about the prognostic role of frailty to guide clinical decision-making for patients with ACS. Purpose To assess the potential predictive value of frailty both for short, and long term all-cause mortality, in a contemporary ACS population. Methods All consecutive admissions due to ACS, from 01/01/2019 to 31/12/2021, were retrospectively reviewed from an internal database of a tertiary cardiac center in Salerno (Italy). Logistic and Cox proportional regression analysis were performed in order to assess the contribution of frailty on 30-days and long term mortality. Frailty was assessed using the Clinical Frailty Scale (CFS) and patients were classified as non frail (CFS 1-4), and frail (CFS 5-9). Both logistic and Cox regression analysis were adjusted for age, gender, GRACE risk score, comorbidity burden, defined by the Charlson comorbidity score (CCS), and all other relevant covariates associated with outcomes of interest in the univariate analysis. In order to estimate the survival rates during the follow-up, a Kaplan Meyer analysis was carried out and differences between the CFS groups were assessed using the log-rank test. Robustness of the results were assessed through an internal validation procedure with bootstrapping. All statistical analyses were performed using SPSS software version 25.0 (SPPS Inc., Chicago, Illinois) and R version 4.0.5 (R Foundation for Statistical Computing, Vienna, Austria). A p-value of less than 0.05 was considered significant. Results 1366 patients were identified. The median age was 68 (58-77). Of these patients, 1087 (79,6%) were classified as non-frail (CFS 1-4), and 279 (20,4%) as frail (CFS 5-9). 120 (8,8%) and 140 (11,2%) deaths occurred, respectively, during the first 30 days from admission, and during long term follow-up (median follow-up time: 15 months; IQR: 10-24). After multivariate regression analysis the CFS was associated with both short and long-term mortality (OR: 1,6, 95% CI: 1,34-1,91; p&amp;lt;0,001 and HR: 1,37, 95% CI: 1,18-1,58; p&amp;lt;0,001, Fig. 1). Patients with CFS ≥ 5 showed significant higher mortality rate during long term follow-up (p&amp;lt;0.001; Fig.2). Conclusions The CFS is a strong predictor of both short and long-term mortality in patients affected by ACS also after comprehensive adjustment for baseline differences in other risk factors.Fig. 2

NRN1 epistasis with BDNF and CACNA1C: mediation effects on symptom severity through neuroanatomical changes in schizophrenia.

The expression of Neuritin-1 (NRN1), a neurotrophic factor crucial for neurodevelopment and synaptic plasticity, is enhanced by the Brain Derived Neurotrophic Factor (BDNF). Although the receptor of NRN1 remains unclear, it is suggested that NRN1's activation of the insulin receptor (IR) pathway promotes the transcription of the calcium voltage-gated channel subunit alpha1 C (CACNA1C). These three genes have been independently associated with schizophrenia (SZ)risk, symptomatology, and brain differences. However, research on how they synergistically modulate these phenotypes is scarce. We aimed to study whether the genetic epistasis between these genes affects the risk and clinical presentation of the disorder via its effect on brain structure. First, we tested the epistatic effect of NRN1 and BDNF or CACNA1C on (i) the risk for SZ, (ii) clinical symptoms severity and functionality (onset, PANSS, CGI and GAF), and (iii) brain cortical structure (thickness, surface area and volume measures estimated using FreeSurfer) in a sample of 86 SZ patients and 89 healthy subjects. Second, we explored whether those brain clusters influenced by epistatic effects mediate the clinical profiles. Although we did not find a direct epistatic impact on the risk, our data unveiled significant effects on the disorder's clinical presentation. Specifically, the NRN1-rs10484320 x BDNF-rs6265 interplay influenced PANSS general psychopathology, and the NRN1-rs4960155 x CACNA1C-rs1006737 interaction affected GAF scores. Moreover, several interactions between NRN1 SNPs and BDNF-rs6265 significantly influenced the surface area and cortical volume of the frontal, parietal, and temporal brain regions within patients. The NRN1-rs10484320 x BDNF-rs6265 epistasis in the left lateral orbitofrontal cortex fully mediated the effect on PANSS general psychopathology. Our study not only adds clinical significance to the well-described molecular relationship between NRN1 and BDNF but also underscores the utility of deconstructing SZ into biologically validated brain-imaging markers to explore their mediation role in the path from genetics to complex clinical manifestation.

Multisystemic inflammatory syndrome in children and the BNT162b2 vaccine: a nationwide cohort study.

This research demonstrates that vaccinating children and adolescents against COVID-19 has reduced the risk of MIS-C during the study period. • Most of the published literature regarding vaccine effectiveness is based on case-control studies, which are limited due to small sample sizes and the inability to fully estimate the risk of MIS-C among vaccinated and unvaccinated children and adolescents. • The known underestimation of COVID-19 diagnosis among children and adolescents is challenging, as they often have few to no symptoms. • Significant risk difference was found in favor of the vaccinated group, even after including extreme assumptions regarding the underdiagnosed COVID-19 rate. • During this nationwide study period, it was found that vaccinating children and adolescents reduced the risk of MIS-C and its complications.

Association Between Periprosthetic Joint Infection and Mortality Following Primary Total Hip Arthroplasty

Background: Periprosthetic joint infection (PJI) remains a dreaded and unpredictable complication after total hip arthroplasty (THA). In addition to causing substantial morbidity, PJI may contribute to long-term mortality risk. Our objective was to determine the long-term mortality risk associated with PJI following THA. Methods: This population-based, retrospective cohort study included adult patients (≥18 years old) in Ontario, Canada, who underwent their first primary elective THA for arthritis between April 1, 2002, and March 31, 2021. The primary outcome was death within 10 years after the index THA. Mortality was compared between propensity-score-matched groups (PJI within 1 year after surgery versus no PJI within 1 year after surgery) with use of survival analyses. Patients who died within 1 year after surgery were excluded to avoid immortal time bias. Results: A total of 175,432 patients (95,883 [54.7%] women) with a mean age (and standard deviation) of 67 ± 11.4 years underwent primary THA during the study period. Of these, 868 patients (0.49%) underwent surgery for a PJI of the replaced joint within 1 year after the index procedure. After matching, patients with a PJI within the first year had a significantly higher 10-year mortality rate than their counterparts (11.4% [94 of 827 patients] versus 2.2% [18 of 827 patients]; absolute risk difference, 9.19% [95% confidence interval (CI), 6.81% to 11.6%]; hazard ratio, 5.49 [95% CI, 3.32 to 9.09]). Conclusions: PJI within 1 year after surgery is associated with over a fivefold increased risk of mortality within 10 years. The findings of this study underscore the importance of prioritizing efforts related to the prevention, diagnosis, and treatment of PJIs. Level of Evidence: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Real-world effectiveness of CDK4/6 inhibitors on patients with HR+/HER2– advanced breast cancer in South Korea, focusing on underrepresented patients

Objective We assessed the real-world effectiveness of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors as first-line treatments in postmenopausal patients with HR+/HER2− advanced breast cancer, focusing on younger (<45 years) and older (>78 years) populations not considered in clinical trials. Methods We analyzed nationwide claims data from the Health Insurance Review and Assessment Service between November 2016 and February 2021. In this retrospective cohort study, patients using CDK4/6 inhibitors and aromatase inhibitors were selected and grouped by age as follows: 45–78 years (trial-enrolled), <45 years (younger), and >78 years (older). We estimated the median real-world progression-free survival (rwPFS) and overall survival (OS) using the Kaplan-Meier method. We conducted Cox regression analysis using a sub-distribution hazard model to evaluate risk factors (age, history of prior systemic treatment, presence of metastasis, comorbidity index, and type of provider) and estimated hazard ratios (HR). Results Among the 2,830 patients who received CDK4/6 inhibitors as first-line therapy, we identified 358 (12.65%) younger and 148 (5.23%) older underrepresented patients. The younger patient group (50.84%) had the highest rate of prior systemic therapy, followed by the trial-enrolled (25.39%) and older patient groups (8.11%). The median rwPFS was shorter in the older group (19.30 months) than those in the younger and the trial-enrolled age groups (30.33 and 34.53 months, respectively; p = .002). The HR of older age for death was 1.59 (95% confidence interval (CI) = 1.24–2.03). For rwPFS, the HR of prior systemic therapy was 1.19 (95% CI = 1.04–1.37). Conclusions The younger age group, which was underrepresented in the trial, did not show a significant difference in risk compared with the enrolled age group. However, the older age group, which was also underrepresented in the trial, faces a risk of mortality but not progression. Patients who fall outside the specified age groups for the clinical trial can still expect the same level of effectiveness in terms of progression.

Initiative to deprescribe high-risk drugs for older adults presenting to the emergency department after falls.

Over 35 million falls occur in older adults annually and are associated with increased emergency department (ED) revisits and 1-year mortality. Despite associations between medications and falls, the prevalence of fall risk-increasing drugs remains high. Our objective was to implement an ED-based medication reconciliation for patients presenting after falls and determine whether an intervention targeting high-risk medications was related to decreased future falls. This was an observational prospective cohort study at a single site in the United States. Adults 65 years and older presenting to the ED after falls had a pharmacist review their medicines. Pharmacists made recommendations to taper, stop, or discuss medications with the primary clinician. At 3, 6, and 12 months, we recorded the number of fall-related return ED visits and determined if recommended medication changes had been implemented. We compared the rate of return visits of patients who had followed the medication change recommendations and those who received recommendations but had no change in their medications using chi-square tests. A total of 577 patients (mean age 81 years, 63.6% female) were enrolled of 1509 potentially eligible patients. High-risk medications were identified in 310 patients (53.7%) who received medication recommendations. High-risk medications were associated with repeat fall-related visits at 12 months (risk difference 8.1% [95% confidence interval 0.97-15.0]). A total of 134 (43%) patients on high-risk medications had evidence of medication modification. At 12 months, there was no statistically significant difference in return fall visits between patients who had modifications to medications compared with those who had not implemented changes (p = 0.551). Our findings identified opportunities for medication optimization in over half of emergency visits for falls and demonstrated that medication counseling in the ED is feasible. However, evaluation of the effect on future falls was limited.

Racial and Ethnic Differences in Mortality and Functional Outcomes Following Aneurysmal Subarachnoid Hemorrhage.

Ischemic and hemorrhagic stroke incidence tends to be higher among minority racial and ethnic groups. The effect of race and ethnicity following an aneurysmal subarachnoid hemorrhage (aSAH) remains poorly understood. Thus, we aimed to explore the association between race and ethnicity and aSAH outcomes. Single-center retrospective review of patients with aSAH from January 2009 to March 2023. Primary outcome was in-hospital mortality. Secondary outcomes included delayed cerebral ischemia, cerebral infarction, radiographic and symptomatic vasospasm, pulmonary complications, epileptic seizures, external ventricular drain placement, and modified Rankin Scale score at discharge and 3-month follow-up. Associations between race and ethnicity and outcomes were assessed using binary and ordinal regression models, with multivariable models adjusted for significant covariates. A total of 1325 patients with subarachnoid hemorrhage presented to our center. Among them, 443 cases were excluded, and data from 882 patients with radiographically confirmed aSAH were analyzed. Distribution by race and ethnicity was 40.8% (n=360) White, 31.4% (n=277) Hispanic, 22.1% (n=195) Black, and 5.7% (n=50) Asian. Based on Hunt-Hess and modified Fisher grade, aSAH severity was similar among groups (P=0.269 and P=0.469, respectively). In-hospital mortality rates were highest for Asian (14.0%) and Hispanic (11.2%) patients; however, after adjusting for patient sex, age, health insurance, smoking history, alcohol and substance abuse, and aneurysm treatment, the overall likelihood was comparable to White patients. Hispanic patients had higher risks of developing cerebral infarction (adjusted odds ratio, 2.17 [1.20-3.91]) and symptomatic vasospasm (adjusted odds ratio, 1.64 [1.05-2.56]) than White patients and significantly worse discharge modified Rankin Scale scores (adjusted odds ratio, 1.44 [1.05-1.99]). Non-White patients also demonstrated a lower likelihood of 0 to 2 discharge modified Rankin Scale scores (adjusted odds ratio, 0.71 [0.50-0.98]). No significant interactions between race and ethnicity and age or sex were found for in-hospital mortality and functional outcomes. Our study identified significant differences in cerebral infarction and symptomatic vasospasm risk between Hispanic and White patients following aSAH. A higher likelihood of worse functional outcomes at discharge was found among non-White patients. These findings emphasize the need to better understand predisposing risk factors that may influence aSAH outcomes. Efforts toward risk stratification and patient-centered management should be pursued.

Cardiovascular and bone health outcomes in older people with subclinical hypothyroidism treated with levothyroxine: a systematic review and meta-analysis

BackgroundThyroid dysfunction is common in older people, with females at higher risk. Evidence suggests that thyroid-stimulating hormone (TSH) levels naturally increase with age. However, as uniform serum TSH reference ranges are applied across the adult lifespan, subclinical hypothyroidism (SCH) diagnosis is more likely in older people, with some individuals also being commenced treatment with levothyroxine (LT4). It is unclear whether LT4 treatment in older people with SCH is associated with adverse cardiovascular or bone health outcomes.MethodsA systematic review and meta-analysis were performed to synthesise previous studies evaluating cardiovascular and bone health outcomes in older people with SCH, comparing LT4 treatment with no treatment. PubMed, Embase, Cochrane Library, MEDLINE, and Web of Science databases were searched from inception until March 13, 2023, and studies that evaluated cardiovascular and bone health events in people with SCH over 50 years old were selected.ResultsSix articles that recruited 3853 participants were found, ranging from 185 to 1642 participants, with the proportion of females ranging from 45 to 80%. The paucity of data resulted in analysis for those aged over 65 years only. Additionally, a study with 12,212 participants aged 18 years and older was identified; however, only data relevant to patients aged 65 years and older were considered for inclusion in the systematic review. Of these 7 studies, 4 assessed cardiovascular outcomes, 1 assessed bone health outcomes, and 2 assessed both. A meta-analysis of cardiovascular outcomes revealed a pooled hazard ratio of 0.89 (95% CI 0.71–1.12), indicating no significant difference in cardiovascular risk between older individuals with SCH treated with LT4 compared to those without treatment. Due to overlapping sub-studies, meta-analysis for bone health outcomes was not possible.ConclusionsThis systematic review and meta-analysis found no significant association between LT4 use and cardiovascular and bone health outcomes in SCH participants over 65 years.Systematic review registrationPROSPERO CRD42022308006