INTRODUCTION:Patients with a CTA spot sign could benefit more from interventions to limit ICH expansion. We evaluated whether its presence modifies the association between systolic blood pressure (SBP) reduction and ICH outcomes. PATIENTS AND METHODS:A prospective study of patients with ICH < 6 hours and SBP ≥ 150 mmHg at 2 Comprehensive Stroke Centers in Barcelona over 4.5 years. Patients underwent multiphase CTA (arterial, peak venous and late venous phases) and received treatment targeting SBP ≤ 140 mmHg ≤ 60 minutes. We assessed independent associations and interaction of achieving SBP target ≤ 60 minutes and spot sign status (arterial, or secondarily any phase) with hematoma expansion (>6 mL or > 33%) at 24 hours (primary outcome) and 90-day mRS. RESULTS:Among 207 patients (mean age 71 ± 13.2 years, 134 [64.7%] male), 67 (32.4%) presented an arterial spot sign and 122 (58.9%) achieved SBP target ≤ 60 minutes. Target rates were similar with and without arterial spot sign (38 [56.7%] vs 84 [60.0%], P = .653). Hematoma expansion occurred in 46/177 (26.0%), and median 90-day mRS was 4 (2-5). Arterial spot sign and SBP target ≤ 60 minutes were independently associated with hematoma expansion (adjusted odds ratio [aOR] 4.07; 95% CI, 1.74-9.89 and aOR 0.27; 95% CI, 0.11-0.64) and 90-day mRS (aOR 2.23; 95% CI, 1.23-4.07 and aOR 0.43; 95% CI, 0.24-0.76), with no interaction between them (P = .575 and P = .187, respectively). Similar results were observed considering spot sign in any multiphase CTA phase. CONCLUSION:The association between rapidly achieving SBP reduction and ICH outcomes appears neither dependent on nor modified by spot sign status.
Several cancer potency estimates have been proposed by regulatory agencies to characterize the dose response of cobalt and/or cobalt compounds. The objective of this research is to investigate whether these proposed cancer potency estimates for certain cobalt substances align with the available epidemiology literature. After review of the epidemiological literature, we identified a study appropriate for our analysis. We established whether our identified study was adequately powered to detect an elevated lung cancer risk. The power analysis assumed a Poisson distribution and used a one-sided significance level of 0.05. Lung tumors in animals served as the basis for cancer potency estimates for several regulatory bodies. The study population from our identified study was used to calculate predicted excess lung cancer deaths using potency values reported by four regulatory organizations, which were then compared to observed lung cancer deaths. Monte Carlo methods were used to estimate sample size and cobalt exposure distribution of the highest exposure group. We determined that the our identified study has ≥ 98% statistical power to detect a 1.5-fold or greater increase in lung cancer due to cobalt exposure in all but the lowest exposure group and all four exposure groups had 100% statistical power to detect a 2.0-fold or greater increase in lung cancer due to cobalt exposure. Cobalt exposure at the estimated median of the highest exposure group resulted in hypothetical standardized mortality ratios (SMR) estimated from the regulatory potency values ranging from 3.54 to 8.61 compared to an observed SMR of 1.15 (95% CI: 0.92-1.43) in our identified study. On the basis of this analysis, the cancer potency estimates proposed by the included regulatory organizations are likely overestimations of excess lifetime human cancer risk after cobalt inhalation exposure.
Summary Background: Genetic risk scores (GRS) for type 1 diabetes (T1D) have been developed primarily in European populations, limiting their generalisability across ancestries. Indians differ from Europeans in clinical characteristics of T1D and overall genetic architecture, yet systematic evaluation of T1D GRS performance in multi-regional Indian cohorts is lacking. Methods: The study included 597 T1D patients and 3347 non-diabetic controls from different regions in India. Genotyping, imputation, quality control analysis, and construction of the 67-SNPs T1D GRS were performed using standardised pipelines. Discriminative performance was assessed using Receiver Operative Curve-Area under Curve (ROC-AUC) analysis, and optimal thresholds were derived using Youden's index. HLA-DQ diplotype frequencies were compared, and association analysis was conducted using multivariable logistic regression. Findings: T1D GRS showed consistent discriminative performance across Indian cohorts [ROC-AUC=0.84 (range=0.78-0.87)], supporting its comprehensive use for T1D classification in India. Notably, its performance was lower in islet cell autoantibody (IA) negative compared with IA positive T1D patients (ROC-AUC, 0.75 vs 0.85) and in adult-onset than in childhood-onset patients (0.74 vs 0.84). We observed a lower frequency of protective HLA-DQ diplotypes and a strong association of HLA-DQ81 containing diplotypes in childhood-onset T1D. Application of an India-specific T1D GRS score improved the sensitivity than the European cut-off. Interpretation: T1D GRS is a valuable unified diagnostic tool in Indians, but its performance varies by islet cell autoantibody status and age at onset, likely reflecting population-specific HLA architecture. European-derived T1D GRS thresholds under-classify the genetic risk, highlighting the importance of ancestry-aware optimisation in Indians. Funding: CDRC grant CDRC202111026 and CSIR Intramural Grant P50. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The study was funded by Chellaram Diabetes and Research Centre (CDRC), Pune, India (CDRC grant CDRC202111026) and the Council of Scientific and Industrial Research (CSIR), Ministry of Science and Technology, Government of India, New Delhi, India (CSIR Intramural Grant P50). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The collection of clinical data and use of bio-banked samples for the biochemical, immunological, and genetic measurements was sanctioned by the Ethics committee of the respective collaborating institutes. CSIR-CCMB (IEC-92/2022), TDRC (IHEC-TDRC-HYD/1/2022), CDI (CDI/BR/2024/058), JSS (JSSMC/IEC/19052022/01NCT/2022-23), OSM (IEC-BHR/OMC/M.NO(07)/P-89). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Requests to data access should be submitted to the corresponding author Dr. Giriraj R. Chandak (chandakgrc.ccmb{at}csir.res.in).
When matrix effects are present in alloys, the content of the metal ingredients is no longer reliable to predict the metal ion release and hence toxicity. Thus, the metals’ industry proposed an alternative concept for self-classification based on the comparison of the metal releases between alloys and their ingredients; this approach better reflects the toxicity of the alloys when matrix effects are present. Samples of alloy and ingredients (reference) often differ in particle size. This study assessed the impact of particle sizes on cobalt (Co) and nickel (Ni) releases from different particle size fractions of an alloy powder, following a bioelution gastric fluid protocol. Results were considered together with those from reference pure Co and Ni powders. Co-release per gram of alloy increased (3- to 4-fold) when median particle diameter decreased (17-fold). For Ni, the releases were much lower, but the relative increases with decreasing particle diameter were greater (38-fold). Results from the < 100 µm fraction were lower than those for the fraction matching the particle size of the reference samples (by 2.1-fold for Co and 7.6-fold for Ni) but were higher (by 1.2-fold for Co and 2.0-fold for Ni) than those from the sample on the market. For all fractions, an alloy matrix effect lowering metal releases was evident. Based on the above results, we made particle size recommendations when testing alloy powders in a surrogate gastric fluid protocol relevant to the oral route of exposure. Our work provides guidance for testing alloy powders to generate data relevant to hazard self-classification.
