Effect of Empagliflozin with or without the Addition of Evolocumab on HDL Subspecies in Individuals with Type 2 Diabetes Mellitus: A Post Hoc Analysis of the EXCEED-BHS3 Trial.

Evolocumab and empagliflozin yield a modest rise in plasma high-density lipoprotein cholesterol (HDL-C) through unknown mechanisms. This study aims to assess the effect of evolocumab plus empagliflozin vs. empagliflozin alone on HDL subspecies isolated from individuals with type 2 diabetes mellitus (T2D). This post hoc prespecified analysis of the EXCEED-BHS3 trial compared the effects of a 16-week therapy with empagliflozin (E) alone or in combination with evolocumab (EE) on the lipid profile and cholesterol content in HDL subspecies in individuals with T2D divided equally into two groups of 55 patients. Both treatments modestly increased HDL-C. The cholesterol content in HDL subspecies 2a (7.3%), 3a (7.2%) and 3c (15%) increased from baseline in the E group, while the EE group presented an increase from baseline in 3a (9.3%), 3b (16%) and 3c (25%). The increase in HDL 3b and 3c was higher in the EE group when compared to the E group (p < 0.05). No significant interactive association was observed between changes in hematocrit and HDL-C levels after treatment. Over a 16-week period, empagliflozin with or without the addition of evolocumab led to a modest but significant increase in HDL-C. The rise in smaller-sized HDL particles was heterogeneous amongst the treatment combinations.

Vitamin B5 supports MYC oncogenic metabolism and tumor progression in breast cancer.

Tumors are intrinsically heterogeneous and it is well established that this directs their evolution, hinders their classification and frustrates therapy1-3. Consequently, spatially resolved omics-level analyses are gaining traction4-9. Despite considerable therapeutic interest, tumor metabolism has been lagging behind this development and there is a paucity of data regarding its spatial organization. To address this shortcoming, we set out to study the local metabolic effects of the oncogene c-MYC, a pleiotropic transcription factor that accumulates with tumor progression and influences metabolism10,11. Through correlative mass spectrometry imaging, we show that pantothenic acid (vitamin B5) associates with MYC-high areas within both human and murine mammary tumors, where its conversion to coenzyme A fuels Krebs cycle activity. Mechanistically, we show that this is accomplished by MYC-mediated upregulation of its multivitamin transporter SLC5A6. Notably, we show that SLC5A6 over-expression alone can induce increased cell growth and a shift toward biosynthesis, whereas conversely, dietary restriction of pantothenic acid leads to a reversal of many MYC-mediated metabolic changes and results in hampered tumor growth. Our work thus establishes the availability of vitamins and cofactors as a potential bottleneck in tumor progression, which can be exploited therapeutically. Overall, we show that a spatial understanding of local metabolism facilitates the identification of clinically relevant, tractable metabolic targets.

Establishing national clinical diagnostic reference levels and achievable doses for CT examinations in Brazil: A prospective study.

PURPOSE: Diagnostic reference levels (DRL) and achievable doses (AD) are important tools for radiation dose optimization. Therefore, a prospective study was performed which aimed to establish a multi-parametric, clinical indication based - DRL(DRLCI) and clinical indication - AD (ADCI) for adult CT in Brazil. METHODS: The prospective study included 4787 patients (50 ± 18 years old; male:female 2041:2746) at 13 Brazilian sites that have been submitted to head, paranasal sinus, cervical spine, chest, or abdomen-pelvis CT between January and October 2021 for 13 clinical indications. The sites provided the following information: patient age, gender, weight, height, body mass index[BMI], clinical indications, scanner information(vendor, model, detector configuration), scan parameters (number of scan phases, kV, mA, pitch) and dose-related quantities (CT dose index volume- CTDIvol, dose length product- DLP). Median(AD) and 75th(DRL) percentile CTDIvol and DLP values were estimated for each body region and clinical indications. Non-normal data were analyzed with the Kruskal-Wallis test. RESULTS: In majority of Brazilian sites, body region and clinical indications based DRLs were at or lower than the corresponding DRLs in the US and higher than Europe. Although radiation doses varied significantly for patients in different body mass index groups (p < 0.001), within each body region, there were no differences in radiation doses for different clinical indications (p > 0.1). Radiation doses for 7/13 clinical indications were higher using iterative reconstruction technique than for the filtered back projection. CONCLUSIONS: There was substantial variation in Brazil DRLCI across different institutions with higher doses compared to the European standards. There was also a lack of clinical indication-based protocol and dose optimization based on different clinical indications for the same body region.

Comparative effectiveness and cost-effectiveness of cardioprotective glucose-lowering therapies for type 2 diabetes in Brazil: a Bayesian network model.

BACKGROUND: The escalating prevalence of type 2 diabetes (T2DM) poses an unparalleled economic catastrophe to developing countries. Cardiovascular diseases remain the primary source of costs among individuals with T2DM, incurring expenses for medications, hospitalizations, and surgical interventions. Compelling evidence suggests that the risk of cardiovascular outcomes can be reduced by three classes of glucose-lowering therapies (GLT), including SGLT2i, GLP-1A, and pioglitazone. However, an evidence-based and cost-effective protocol is still unavailable for many countries. The objective of the current study is to compare the effectiveness and cost-effectiveness of GLT in individuals with T2DM in Brazil. METHODS: We employed Bayesian Networks to calculate the incremental cost-effectiveness ratios (ICER), expressed in international dollars (Int$) per disease-adjusted life years [DALYs] averted. To determine the effectiveness of GLT, we conducted a systematic review with network meta-analysis (NMA) to provide insights for our model. Additionally, we obtained cardiovascular outcome incidence data from two real-world cohorts comprising 851 and 1337 patients in primary and secondary prevention, respectively. Our cost analysis took into account the perspective of the Brazilian public health system, and all values were converted to Int$. RESULTS: In the NMA, SGLT2i [HR: 0.81 (95% CI 0.69-0.96)], GLP-1A [HR: 0.79 (95% CI 0.67-0.94)], and pioglitazone [HR: 0.73 (95% CI 0.59-0.91)] demonstrated reduced relative risks of non-fatal cardiovascular events. In the context of primary prevention, pioglitazone yielded 0.2339 DALYs averted, with an ICER of Int$7,082 (95% CI 4,521-10,770) per DALY averted when compared to standard care. SGLT2i and GLP-1A also increased effectiveness, resulting in 0.261 and 0.259 DALYs averted, respectively, but with higher ICERs of Int$12,061 (95% CI: 7,227-18,121) and Int$29,119 (95% CI: 23,811-35,367) per DALY averted. In the secondary prevention scenario, all three classes of treatments were deemed cost-effective at a maximum willingness-to-pay threshold of Int$26,700. Notably, pioglitazone consistently exhibited the highest probability of being cost-effective in both scenarios. CONCLUSIONS: In Brazil, pioglitazone presented a higher probability of being cost-effective both in primary and secondary prevention, followed by SGLT2i and GLP-1A. Our findings support the use of cost-effectiveness models to build optimized and hierarchical therapeutic strategy in the management of T2DM. TRIAL REGISTRATION: CRD42020194415.

Prevalence of non-communicable chronic diseases: arterial hypertension, diabetes mellitus, and associated risk factors in long-lived elderly people.

OBJECTIVE: To identify the prevalence of non-communicable chronic diseases: arterial hypertension, diabetes mellitus, and associated risk factors in long-lived elderly people from three Brazilian regions. METHODS: This is a multicenter, cross-sectional, and comparative study conducted with elderly people aged 80 years or older. RESULTS: Higher prevalence of arterial hypertension were observed among those who use polypharmacy (75.7%), among elderly people aged between 80 and 84 years (33.9%), as well as in elderly people who are overweight (78.2%). The prevalence of diabetes was 24% (RP: 0.76; 95% CI: 0.59-0.98) lower among women compared to men and 2.15 times higher among those who use five or more medications (RP: 2.15; 95% CI: 1.63-2.85). CONCLUSIONS: In our sample, polypharmacy, body weight, and gender determine the prevalence of non-communicable chronic diseases: arterial hypertension and diabetes mellitus in long-lived elderly people.

Metoprolol for prevention of bucking at orotracheal extubation: a double-blind, placebo-controlled randomised trial.

BACKGROUND: Respiratory responses to extubation can cause serious postoperative complications. Beta-blockers, such as metoprolol, can interfere with the cough pathway. However, whether metoprolol can effectively control respiratory reflexes during extubation remains unclear. The objective of this study is to evaluate the efficacy of intravenous metoprolol in attenuating respiratory responses to tracheal extubation. METHODS: Randomized, double-blinded, placebo-controlled trial. SETTING: Tertiary referral center located in Brasília, Brazil. Recruitment: June 2021 to December 2021. SAMPLE: 222 patients of both sexes with an American Society of Anesthesiologists (ASA) physical status I-III aged 18-80 years. Patients were randomly assigned to receive intravenous metoprolol 5 mg IV or placebo at the end of surgery. The primary outcome was the proportion of patients who developed bucking secondary to endotracheal tube stimulation of the tracheal mucosa during extubation. Secondary outcomes included coughing, bronchospasm, laryngospasm, Mean Blood Pressure (MAP), and Heart Rate (HR) levels. RESULTS: Two hundred and seven participants were included in the final analysis: 102 in the metoprolol group and 105 in the placebo group. Patients who received metoprolol had a significantly lower risk of bucking (43.1% vs. 64.8%, Relative Risk [RR = 0.66], 95% Confidence Interval [95% CI 0.51-0.87], p = 0.003). In the metoprolol group, 6 (5.9%) patients had moderate/severe coughing compared with 33 (31.4%) in the placebo group (RR = 0.19; 95% CI 0.08-0.43, p < 0.001). CONCLUSION: Metoprolol reduced the risk of bucking at extubation in patients undergoing general anesthesia compared to placebo.

Compared efficacy of rituximab, abatacept, and tocilizumab in patients with rheumatoid arthritis refractory to methotrexate or TNF inhibitors agents: a systematic review and network meta-analysis.

BACKGROUND: Our aim was to compare the efficacy of rituximab, tocilizumab, and abatacept in individuals with rheumatoid arthritis (RA) refractory to treatments with MTX or TNFi agents. METHODS: We searched 6 databases until January 2023 for phase 2-4 RCTs evaluating patients with RA refractory to MTX or TNFi therapy treated with rituximab, abatacept, and tocilizumab (intervention arm) compared to controls. Study data were independently assessed by two investigators. The primary outcome was considered as achieving ACR70 response. RESULTS: The meta-analysis included 19 RCTs, with 7,835 patients and a mean study duration of 1.2 years. Hazard ratios for achieving an ACR70 response at six months were not different among the bDMARDs, however, we found high heterogeneity. Three factors showing a critical imbalance among the bDMARD classes were identified: baseline HAQ score, study duration, and frequency of TNFi treatment in control arm. Multivariate meta-regression adjusted to these three factors were conducted for the relative risk (RR) for ACR70. Thus, heterogeneity was attenuated (I2 = 24%) and the explanatory power of the model increased (R2 = 85%). In this model, rituximab did not modify the chance of achieving an ACR70 response compared to abatacept (RR = 1.773, 95%CI 0.113-10.21, p = 0.765). In contrast, abatacept was associated with RR = 2.217 (95%CI 1.554-3.161, p < 0.001) for ACR70 compared to tocilizumab. CONCLUSION: We found high heterogeneity among studies comparing rituximab, abatacept, and tocilizumab. On multivariate metaregressions, if the conditions of the RCTs were similar, we estimate that abatacept could increase the chance of reaching an ACR70 response by 2.2-fold compared to tocilizumab.

USP15-USP7 Axis and UBE2T Differential Expression May Predict Pathogenesis and Poor Prognosis in De Novo Myelodysplastic Neoplasm.

The aim of this study was to evaluate the expression of USP7, USP15, UBE2O, and UBE2T genes in Myelodysplastic neoplasm (MDS) to identify possible targets of ubiquitination and deubiquitination in MDS pathobiology. To achieve this, eight datasets from the Gene Expression Omnibus (GEO) database were integrated, and the expression relationship of these genes was analyzed in 1092 MDS patients and healthy controls. Our results showed that UBE2O, UBE2T, and USP7 were upregulated in MDS patients compared with healthy individuals, but only in mononucleated cells collected from bone marrow samples (p < 0.001). In contrast, only the USP15 gene showed a downregulated expression compared with healthy individuals (p = 0.03). Additionally, the upregulation of UBE2T expression was identified in MDS patients with chromosomal abnormalities compared with patients with normal karyotypes (p = 0.0321), and the downregulation of UBE2T expression was associated with MDS hypoplastic patients (p = 0.033). Finally, the USP7 and USP15 genes were strongly correlated with MDS (r = 0.82; r2 = 0.67; p < 0.0001). These findings suggest that the differential expression of the USP15-USP7 axis and UBE2T may play an important role in controlling genomic instability and the chromosomal abnormalities that are a striking characteristic of MDS.

Structure of the d-Cycloserine-Resistant Variant D322N of Alanine Racemase from Mycobacterium tuberculosis.

Alanine racemase (Alr) is a pyridoxal 5'-phosphate-dependent enzyme that catalyzes the racemization of l-alanine to d-alanine. Alr is one of the two targets of the broad-spectrum antibiotic d-cycloserine (DCS), a structural analogue of d-alanine. Despite being an essential component of regimens used to treat multi- and extensively drug-resistant tuberculosis for almost seven decades, resistance to DCS has not been observed in patients. We previously demonstrated that DCS evades resistance due to an ultralow rate of emergence of mutations. Yet, we identified a single polymorphism (converting Asp322 to Asn) in the alr gene, which arose in 8 out of 11 independent variants identified and that confers resistance. Here, we present the crystal structure of the Alr variant D322N in both the free and DCS-inactivated forms and the characterization of its DCS inactivation mechanism by UV-visible and fluorescence spectroscopy. Comparison of these results with those obtained with wild-type Alr reveals the structural basis of the 240-fold reduced inhibition observed in Alr D322N.

Evaluation of the effectiveness of the FOCUS ADHD App in monitoring adults with attention-deficit/hyperactivity disorder.

BACKGROUND: The current investigation assessed a) the performance of the FOCUS ADHD mobile health application (App) in increasing pharmacological treatment adherence and improving patients' knowledge of attention-deficit/hyperactivity disorder (ADHD) and b) the impact of implementing a financial incentive for using the App (i.e., a discount on medication). METHODS: In a randomized, blind, parallel-group clinical trial, 73 adults diagnosed with ADHD were allocated into three groups for 3 months: a) Pharmacological treatment as usual (TAU); b) TAU and the App (App Group); and c) TAU and the App + a commercial discount on the purchase of medication prescribed for ADHD treatment (App + Discount Group). RESULTS: There was no significant difference in mean treatment adherence between groups, assessed as a medication possession ratio (MPR). However, the App + Discount Group exhibited greater medication intake registrations compared with the App Group during the initial phase of the trial. The financial discount also produced a 100% App adoption rate. App use did not increase ADHD knowledge, though knowledge scores were high at baseline. The usability and quality of the App were rated favorably. CONCLUSIONS: The FOCUS ADHD App achieved a high adoption rate and positive evaluations by users. Use of the App did not increase adherence to treatment as measured by MPR, but, for App users, the addition of a financial incentive to use the App produced an increase in treatment adherence in terms of medication intake registrations. The present results offer encouraging data for combining incentives with mobile digital health solutions to positively impact treatment adherence in ADHD.

CD4+ T cell memory is impaired by species-specific cytotoxic differentiation, but not by TCF-1 loss.

CD4+ T cells are typically considered as 'helper' or 'regulatory' populations that support and orchestrate the responses of other lymphocytes. However, they can also develop potent granzyme (Gzm)-mediated cytotoxic activity and CD4+ cytotoxic T cells (CTLs) have been amply documented both in humans and in mice, particularly in the context of human chronic infection and cancer. Despite the established description of CD4+ CTLs, as well as of the critical cytotoxic activity they exert against MHC class II-expressing targets, their developmental and memory maintenance requirements remain elusive. This is at least in part owing to the lack of a murine experimental system where CD4+ CTLs are stably induced. Here, we show that viral and bacterial vectors encoding the same epitope induce distinct CD4+ CTL responses in challenged mice, all of which are nevertheless transient in nature and lack recall properties. Consistent with prior reports, CD4+ CTL differentiation is accompanied by loss of TCF-1 expression, a transcription factor considered essential for memory T cell survival. Using genetic ablation of Tcf7, which encodes TCF-1, at the time of CD4+ T cell activation, we further show that, contrary to observations in CD8+ T cells, continued expression of TCF-1 is not required for CD4+ T cell memory survival. Whilst Tcf7-deficient CD4+ T cells persisted normally following retroviral infection, the CD4+ CTL subset still declined, precluding conclusive determination of the requirement for TCF-1 for murine CD4+ CTL survival. Using xenotransplantation of human CD4+ T cells into murine recipients, we demonstrate that human CD4+ CTLs develop and persist in the same experimental conditions where murine CD4+ CTLs fail to persist. These observations uncover a species-specific defect in murine CD4+ CTL persistence with implications for their use as a model system.

The effectiveness of COVID-19 vaccines against severe cases and deaths in Brazil from 2021 to 2022: a registry-based study.

Background: Brazil started the COVID-19 mass vaccination in January 2021 with CoronaVac and ChAdOx1, followed by BNT162b2 and Ad26.COV2.S vaccines. By the end of 2021, more than 317 million vaccine doses were administered in the adult population. This study aimed at estimating the effectiveness of the primary series of COVID-19 vaccination and booster shots in protecting against severe cases and deaths in Brazil during the first year of vaccination. Methods: A cohort dataset of over 158 million vaccination and severe cases records linked from official national registries was analyzed via a mixed-effects Poisson model, adjusted for age, state of residence, time after immunization, and calendar time to estimate the absolute vaccine effectiveness of the primary series of vaccination and the relative effectiveness of the booster. The method permitted analysis of effectiveness against hospitalizations and deaths, including in the periods of variant dominance. Findings: Vaccine effectiveness against severe cases and deaths remained over 25% and 50%, respectively, after 19 weeks from primary vaccination of BNT162b2, ChAdOx1, or CoronaVac vaccines. The boosters conferred greater protection than the primary series of vaccination, with heterologous boosters providing marginally greater protection than homologous. The effectiveness against hospitalization during the Omicron dominance in the 60+ years old population started at 61.7% (95% CI, 26.1-86.2) for ChAdOx1, 95.6% (95% CI, 82.4-99.9) for CoronaVac, and 72.3% (95% CI, 51.4-87.4) for the BNT162b2 vaccine. Interpretation: This study provides real-world evidence of the effectiveness of COVID-19 vaccination in Brazil, including during the Omicron wave, demonstrating protection even after waning effectiveness. Comparisons of the effectiveness among different vaccines require caution due to potential bias effects related to age groups, periods in the pandemic, and eventual behavioural changes. Funding: Fundação Oswaldo Cruz (FIOCRUZ), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundação de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ), Pan American Health Organization (PAHO), Departamento de Ciência e Tecnologia da Secretaria de Ciência, Tecnologia, Inovação e Insumos Estratégicos em Saúde do Ministério da Saúde do Brasil (DECIT/SCTIE/MS).

Metabolomic profiling reveals bacterial metabolic adaptation strategies and new metabolites.

How has metabolomics helped our understanding of infectious diseases? With the threat of antimicrobial resistance to human health around the world, metabolomics has emerged as a powerful tool to comprehensively characterize metabolic pathways to identify new drug targets. However, its output is constrained to known metabolites and their metabolic pathways. Recent advances in instrumentation, methodologies, and computational mass spectrometry have accelerated the use of metabolomics to understand pathogen-host metabolic interactions. This short review discusses a selection of recent publications using metabolomics in infectious/bacterial diseases. These studies unravel the links between metabolic adaptations to environments and host metabolic responses. Moreover, they highlight the importance of enzyme function and metabolite characterization in identifying new drug targets and biomarkers, as well as precision medicine in monitoring therapeutics and diagnosing diseases.

Structural and thermodynamic properties of quasi-2D Mo(1-x)Wx(S, Se, Te)2monolayer alloys: a statistical first principle study.

In this work, we report anab initiostudy of the structural and thermodynamic properties of two-dimensional transition-metal dichalcogenides (2D-TMDC) alloys, Mo(1-x)Wx(S, Se, Te)2, using the cluster expansion framework to compute the Helmholtz free energy of alloys as a function of alloy composition and temperature, in the framework of the generalized quasi-chemical approximation. We consider alloying only on the metal sublayer. Our results indicate a weak dependence of the structural properties (lattice constants, nearest-neighbor bond lengths, and layer width) on the alloy composition (i.e. concentrations of W and Mo atoms), in line with the very similar values of the atomic radii of Mo and W atoms. A stronger dependence on the chalcogen is obtained, a trend that reflects the larger variations in atomic radii among the three chalcogen species. As a function of composition, the structural parameters we examined show similar trends, with negligible bowing (i.e. deviations from a Vegard's law interpolation between end compounds), for the three alloys. Moreover, already at 300 K the behavior of these structural features as a function of composition is very similar to that of the standard-regular-solution (SRS) high-temperature limit. In contrast, the electronic band gaps of the the three alloys as a function of composition show small but significant bowing, as high as -1% to -2% near thex= 0.5 alloy composition. Similarly to the structural features, the band gaps attain the high-temperature SRS limit already at 300 K. Regarding thermodynamic properties, we obtain negative values of the internal energy of mixing for the three alloys over the full range of compositions. Therefore, the theoretical alloying phase diagram for the three alloys is featureless, with stability of a fully-mixed alloy at all temperatures and compositions, with no miscibility gap (hence no bimodal nor spinodal decomposition lines). The thermodynamic potentials (mixing internal energy, mixing entropy, and mixing free energy) reach the high-temperature limit at ∼1000 K, the temperature range of synthesis of 2D-TMDC alloys. These trends of structural and electronic properties of the 2D-TMDC alloys are due to the very similar atomic radii and the nearly identical coordination chemistry of Mo and W. Our results are in agreement with experimental work on the alloying of Mo and W atoms, for samples of Mo(1-x)WxS2monolayer alloys, that found that the random mixed alloy is the thermodynamically stable state for this alloy, with no segregation or phase separation.

Phenotypic changes in low-density lipoprotein particles as markers of adverse clinical outcomes in COVID-19.

BACKGROUND AND AIMS: Low-density lipoprotein (LDL) plasma concentration decline is a biomarker for acute inflammatory diseases, including coronavirus disease-2019 (COVID-19). Phenotypic changes in LDL during COVID-19 may be equally related to adverse clinical outcomes. METHODS: Individuals hospitalized due to COVID-19 (n = 40) were enrolled. Blood samples were collected on days 0, 2, 4, 6, and 30 (D0, D2, D4, D6, and D30). Oxidized LDL (ox-LDL), and lipoprotein-associated phospholipase A2 (Lp-PLA2) activity were measured. In a consecutive series of cases (n = 13), LDL was isolated by gradient ultracentrifugation from D0 and D6 and was quantified by lipidomic analysis. Association between clinical outcomes and LDL phenotypic changes was investigated. RESULTS: In the first 30 days, 42.5% of participants died due to Covid-19. The serum ox-LDL increased from D0 to D6 (p < 0.005) and decreased at D30. Moreover, individuals who had an ox-LDL increase from D0 to D6 to over the 90th percentile died. The plasma Lp-PLA2 activity also increased progressively from D0 to D30 (p < 0.005), and the change from D0 to D6 in Lp-PLA2 and ox-LDL were positively correlated (r = 0.65, p < 0.0001). An exploratory untargeted lipidomic analysis uncovered 308 individual lipids in isolated LDL particles. Paired-test analysis from D0 and D6 revealed higher concentrations of 32 lipid species during disease progression, mainly represented by lysophosphatidyl choline and phosphatidylinositol. In addition, 69 lipid species were exclusively modulated in the LDL particles from non-survivors as compared to survivors. CONCLUSIONS: Phenotypic changes in LDL particles are associated with disease progression and adverse clinical outcomes in COVID-19 patients and could serve as a potential prognostic biomarker.

Subclinical Hypothyroidism is Not Associated with Femoral Osteoporosis in Individuals Aged 50 Years or Older.

BACKGROUND: Thyroid dysfunction and osteoporosis are conditions strongly associated with aging, and the prevalence of both conditions is expected to increase in the coming decades. Thyroid hormones regulate bone metabolism, and the role of subclinical hypothyroidism on bone mineral density (BMD) is still controversial. Hence, this study aims to assess the association of subclinical hypothyroidism with femoral osteopenia and osteoporosis in individuals aged 50 years or older. METHODOLOGY: This retrospective cohort study was carried out with 864 outpatients having at least one result for TSH levels before the first record of dual-energy X-ray absorptiometry (DXA). The primary endpoints were osteopenia (-2.5 standard deviation (SD)

The framing of time-dependent machine learning models improves risk estimation among young individuals with acute coronary syndromes.

Acute coronary syndrome (ACS) is a common cause of death in individuals older than 55 years. Although younger individuals are less frequently seen with ACS, this clinical event has increasing incidence trends, shows high recurrence rates and triggers considerable economic burden. Young individuals with ACS (yACS) are usually underrepresented and show idiosyncratic epidemiologic features compared to older subjects. These differences may justify why available risk prediction models usually penalize yACS with higher false positive rates compared to older subjects. We hypothesized that exploring temporal framing structures such as prediction time, observation windows and subgroup-specific prediction, could improve time-dependent prediction metrics. Among individuals who have experienced ACS (nglobal_cohort = 6341 and nyACS = 2242), the predictive accuracy for adverse clinical events was optimized by using specific rules for yACS and splitting short-term and long-term prediction windows, leading to the detection of 80% of events, compared to 69% by using a rule designed for the global cohort.