Mazhar Ali

Colorectal carcinoma (CRC) remains a major cause of cancer mortality in the United States (U.S.); however, contemporary long-term projections by demographic and geographic strata are limited. This study examined national colorectal cancer mortality trends from 1999 to 2025 and projected age-adjusted mortality rates (AAMRs) through 2050. We conducted an ecological time-series analysis of U.S. adults aged ≥ 25 years using Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research Multiple Cause of Death data. CRC-related deaths were identified by any mention of International Classification of Diseases, Tenth Revision codes C18–C20 on the death certificate. AAMRs per 100,000 population were calculated overall and stratified by sex, age group, race and ethnicity, urbanization, census region, state, and place of death. Joinpoint regression was used to estimate the annual percent change and average annual percent change. A demographically optimized ensemble forecasting model was used to project AAMRs from 2026 to 2050. From 1999 to 2025, 1,674,393 CRC-related deaths were recorded. Overall, the AAMR declined from 38.11 in 1999 to 23.14 in 2025 (average annual percent change, −1.99%; 95% confidence interval, −2.13 to −1.85; P < .001), but recent rates have stabilized. The mean AAMR was higher among men than women (34.13 vs 23.43) and higher in nonmetropolitan than metropolitan areas (32.43 vs 28.49). Non-Hispanic Black adults had the highest racial and ethnic burdens (37.45). Adults aged 25 to 44 years showed a significant increase in mortality (annual percent change, 1.13%; 95% confidence interval, 0.93 to 1.33; P < .001). Most deaths occurred at home (41.15% of deaths). The overall AAMR was projected to continue declining slowly, from 23.02 in 2026 to 21.56 in 2050, at a slower pace than the 1999 to 2016 decline. U.S. CRC mortality has declined substantially and is projected to continue declining slowly through 2050, rather than resume its earlier faster decline, with persistent sex, racial, rural, age, and geographic disparities. Targeted strategies are needed to improve screening completion, diagnostic follow-up, rural access, equity, and early-onset colorectal cancer detection.

Background: The efficacy of tenecteplase for acute ischemic stroke (AIS) beyond 4.5 h remains uncertain, particularly across care pathways with and without endovascular thrombectomy (EVT). We performed an updated systematic review and meta-analysis using an EVT-stratified framework. Methods: PubMed, Embase, Scopus, and the Cochrane Library were searched through February 2026 for randomized controlled trials comparing tenecteplase with control in imaging-selected patients with AIS presenting 4.5–24 h from last known well. The primary outcome was excellent functional outcome (mRS 0–1) at 90 days. Secondary outcomes were good functional outcome (mRS 0–2), recanalization, early neurological improvement, symptomatic intracranial hemorrhage, and 90-day mortality. Random-effects models with Hartung–Knapp adjustment were used. Subgroup analyses by EVT availability were interpreted as exploratory because of the limited number of trials. Results: Five trials including 1844 patients were analyzed. Tenecteplase improved excellent functional outcome (RR 1.25, 95% CI 1.10–1.42; p = 0.0005) with no heterogeneity (I² = 0%) and no interaction by EVT status (p-interaction = 0.961). Good functional outcome was not significantly different overall (RR 1.10, 95% CI 0.97–1.24; p = 0.135). Significant subgroup interactions were observed for recanalization (p-interaction = 0.004) and early neurological improvement (p-interaction = 0.002), with benefits concentrated in non-EVT settings. However, the larger effect on recanalization did not translate proportionally into functional recovery, supporting separation of vessel-opening outcomes from patient-centered outcomes. Symptomatic intracranial hemorrhage showed a nonsignificant increase in four estimable studies (RR 1.88, 95% CI 0.94–3.78; p = 0.074), whereas 90-day mortality did not differ significantly (RR 1.11, 95% CI 0.85–1.43; p = 0.43). Conclusions: In imaging-selected AIS presenting 4.5–24 h after onset, tenecteplase improved excellent functional outcome irrespective of EVT availability, while benefits for recanalization and early neurological improvement were largely confined to non-EVT settings. Because recanalization is an intermediate endpoint, these findings should not be interpreted as proof of a proportional clinical benefit. Future extended-window trials should specify EVT status.

Background/Objectives: Drowning is a leading preventable cause of unintentional injury death, yet U.S. prevention efforts have largely focused on children. Despite international declines in pediatric drowning mortality, adult trends remain poorly characterized. We examined long-term trends and disparities in unintentional drowning mortality among U.S. adults aged ≥25 years from 1999 to 2024. Methods: Using CDC WONDER Multiple Cause of Death data, drowning deaths were identified using ICD-10 codes W65–W74, V90, and V92. Age-adjusted mortality rates (AAMRs) per 100,000 were computed by direct standardization to the 2000 U.S. standard population. Joinpoint regression estimated the annual percent change (APC) and average annual percent change (AAPC). Three sensitivity analyses assessed transport-related code exclusion, pandemic-era restriction, and multiple cause-of-death coding. Results: During 1999–2024, 101,743 unintentional drowning deaths occurred among U.S. adults aged ≥25 years (76,554 males; 25,201 females), with 58.09% in natural water or outdoor settings. The overall AAMR showed a non-significant increase (AAPC: 0.55%, p = 0.054); however, joinpoint analysis identified stable rates through 2013 followed by a significant sustained increase (APC: 1.32%, 95% CI: 0.32–2.32, p = 0.012). The male-to-female rate ratio narrowed significantly from 4.00 (1999) to 3.32 (2024) (ratio of rate ratios: 0.83, p = 0.0006), driven by a sustained female increase (AAPC: 1.27%, p < 0.001). Adults aged 65–85+ showed the steepest rise (AAPC: 1.15%, p < 0.001). Non-Hispanic AI/AN adults had the highest rates (3.47–5.44 per 100,000), and non-metropolitan areas consistently exceeded metropolitan rates. Conclusions: A significant upward trajectory has persisted since 2013, with marked disparities by age, sex, race/ethnicity, and geography. Adult-focused, equity-driven prevention strategies aligned with USNWSAP implementation are needed to address this underrecognized burden.

Background: Tirzepatide, a dual GIP/GLP-1 receptor agonist, demonstrates substantial glycemic and weight benefits versus GLP-1 receptor agonists in indirect comparisons, but direct comparative safety evidence versus dulaglutide remains limited. We evaluated comparative safety (primary outcome: overall adverse events) and efficacy. Methods: Following PRISMA 2020 (prospectively registered: PROSPERO CRD420251276594), we searched MEDLINE, Embase, Scopus, and CENTRAL (inception–31 December 2025) for randomized controlled trials (≥26 weeks) comparing once-weekly tirzepatide with dulaglutide in adults with type 2 diabetes. Three trials (N = 13,590 participants) were included. Dichotomous outcomes were pooled using random-effects models (risk ratios [RRs], 95% confidence intervals [CIs]). GRADE assessed certainty of evidence. Results: Overall adverse event incidence did not differ significantly (RR 1.04 [0.98–1.10]; I² = 36%; moderate-certainty evidence). Discontinuation due to adverse events was consistently higher with tirzepatide (RR 1.32 [1.20–1.45]; I² = 0%; high-certainty evidence), representing a 32% increased risk across all populations. Categorical HbA1c target achievement was analyzed in two trials; the third trial reported HbA1c as a continuous outcome only. At the primary threshold (HbA1c < 7.0%), tirzepatide was consistently superior with no heterogeneity (RR 1.48 [1.33–1.64]; I² = 0%; p < 0.00001). Across all thresholds combined, heterogeneity was extreme (I² = 92%), limiting confidence in any pooled summary estimate; the greatest instability occurred at the strictest threshold (HbA1c < 5.7%; I² = 98%; p = 0.40). Tirzepatide showed greater HbA1c target attainment in treatment-naive patients receiving dulaglutide 0.75 mg, whereas the glycemic advantage was smaller in patients with established cardiovascular disease receiving dulaglutide 1.5 mg. Categorical weight-loss outcomes were analyzed in two trials; tirzepatide was associated with greater weight-loss threshold achievement (RR 8.80 [4.04–19.17]; very low-certainty evidence), although interpretation is limited by substantial heterogeneity and restricted generalizability. Serious adverse events were not significantly different (RR 0.82 [0.47–1.43]; I² = 42%). Conclusions: Overall adverse events were similar between treatments, but tirzepatide consistently increased discontinuation risk, indicating a clinically important tolerability-persistence trade-off. Glycemic efficacy was highly population-dependent: benefits were consistent at the primary HbA1c target (2 = 0%) in early-stage disease, whereas the advantage was smaller in long-standing disease with established cardiovascular disease. Tirzepatide may be favored when glycemic or weight efficacy is prioritized in earlier-stage disease, provided tolerability is proactively managed. Dulaglutide remains appropriate when persistence is threatened by tolerability concerns or cardiovascular risk reduction is the primary goal.