Citations

Abstract Alzheimer’s disease (AD) is characterized by diminished capacity to mount adaptive cellular stress responses required to maintain energy homeostasis and proteostasis. An emerging therapeutic strategy is to restore adaptive stress responses by inducing mild energetic stress through inhibition of mitochondrial complex I (mtCI). However, pharmacological inhibition of the respiratory chain has remained challenging, as it can induce bioenergetic failure rather than beneficial signaling. Here, we describe C273, a brain-penetrant small molecule that delivers controlled, weak attenuation of mtCI activity to therapeutically restore endogenous adaptive stress pathways. This work establishes a first-in-class mechanism in which calibrated activation of multifaceted adaptive mechanisms enhances cellular resilience, rather than impairing mitochondrial function. Structure-activity relationship optimization yielded a compound with high potency against Aβ-induced cellular toxicity, strong selectivity for mtCI, and favorable drug-like properties. C273 demonstrated excellent oral bioavailability, metabolic stability in mouse, rat, and human microsomes, minimal CYP liabilities, and a clean ancillary pharmacology profile in the Eurofins CEREP44 panel. In vivo , C273 readily crosses the blood-brain barrier and activates AMP-activated protein kinase (AMPK), initiating a coordinated hormetic response characterized by enhanced antioxidant defenses, suppression of inflammatory signaling, induction of autophagy, and increased mitochondrial biogenesis and turnover. Genetic deletion of AMPKα1/α2 abolished these responses, establishing AMPK as a critical mediator of C273 activity. Pharmacological competition experiments further confirmed the target, as pretreatment with non-toxic concentrations of rotenone blocked C273 interaction with the quinone-binding site of mtCI and eliminated its neuroprotective effects. Repeated oral administration of C273 (20-80 mg/kg/day) to wild-type mice for one month produced no detectable cardiac or hepatic toxicity, indicating a favorable in vivo safety margin. Importantly, C273 activated these mechanisms and reduced Aβ and p-Tau levels in induced pluripotent stem cell-derived cerebral organoids from patients with sporadic AD. Collectively, these results establish controlled mtCI modulation as a therapeutic strategy and position C273 as a promising disease-modifying candidate for AD.

BACKGROUND: Blood pressure management following successful reperfusion with endovascular thrombectomy for acute ischemic stroke due to large vessel occlusion remains debated. This meta-analysis aimed to determine whether intensive systolic blood pressure (SBP) management improves clinical outcomes compared with a standard approach after endovascular thrombectomy. METHODS: We systematically searched PubMed, Scopus, Embase, and Web of Science through October 2025 for relevant randomized controlled trials comparing intensive (SBP target <140 mm Hg) versus standard (SBP target <180 mm Hg) management. The primary efficacy and safety outcomes were functional independence (modified Rankin Scale score, 0–2) and any intracranial hemorrhage, respectively. We performed frequentist and Bayesian random-effects meta-analyses, supplemented by trial sequential analysis. RESULTS: Six randomized controlled trials comprising 1972 patients were included. In frequentist analysis, intensive SBP management was associated with a significantly reduced likelihood of achieving functional independence (risk ratio, 0.83 [95% CI, 0.73–0.93]). Bayesian analysis confirmed this harmful effect (posterior median risk ratio, 0.83 [95% credible interval, 0.7–1.02]), with a posterior probability of benefit of only 3.2%. Furthermore, ordinal shift analysis indicated that intensive SBP management was associated with a significant shift toward worse functional outcomes across the full modified Rankin Scale score distribution (common odds ratio, 1.26 [95% CI, 1.10–1.44]), a finding supported by a low posterior probability of benefit of 2.1%. No significant differences were observed in the risk of any intracranial hemorrhage (risk ratio, 1.05 [95% CI, 0.96–1.16]). The corresponding Bayesian analysis yielded a posterior risk ratio estimate of 1.05 (95% credible interval, 0.90–1.21) for any intracranial hemorrhage, with a posterior probability of benefit of 23%. Trial sequential analysis indicated that the cumulative evidence reached the boundary for harm and futility for the primary efficacy and safety outcomes, respectively. CONCLUSIONS: In patients with acute ischemic stroke following successful endovascular thrombectomy, intensive SBP management was associated with worse functional outcomes and provided no clear safety benefit. These findings support a standard, guideline-based SBP management strategy over an intensive approach.

Abstract Purpose The purpose of this systematic review was to compare the inter‐ and intra‐observer reliability of Kellgren–Lawrence (KL) grading versus minimum joint space width (mJSW) measurement on knee radiographs, and to examine the influence of rater type, radiographic view and atlas‐based training. Methods A systematic search of PubMed/MEDLINE, Embase, Scopus and Web of Science was conducted through July 2025 following Preferred Reporting Items for Systematic reviews and Meta‐Analyses (PRISMA) guidelines. Studies reporting inter‐ and/or intra‐observer reliability for KL or mJSW on standard knee radiographs were included. Extracted data included kappa ( κ ) and intraclass correlation coefficient (ICC) values, rater expertise, radiographic view and atlas usage. Raters were categorized as expert, trainee/non‐expert or artificial intelligence (AI)‐assisted/automated. Results Twenty‐four studies (10,394 radiographs) met the inclusion criteria. Inter‐observer reliability was generally higher for mJSW (mean ICC = 0.82 ± 0.17) compared with KL (mean k = 0.72 ± 0.17), with similar trends observed for intra‐observer reliability. Experts and AI‐assisted systems outperformed trainees/non‐experts for both metrics. Reliability improved with semiflexed posteroanterior/Rosenberg views and atlas‐guided training. Conclusion This systematic review demonstrates that mJSW measurement generally shows higher reproducibility than KL grading. Reliability improved with expertise, standardized imaging and structured training, and AI‐assisted approaches performed comparably to expert raters. Quantitative mJSW should complement KL grading, particularly when combined with alignment measures, to enhance consistency and clinical relevance of radiographic assessment. Level of Evidence Level III.

Abstract In this systematic review, we aimed to assess the sensitivity of serum immunofixation (SIFE), urine immunofixation (UIFE), and serum free light chain (sFLC) in detecting plasma cell dyscrasia associated with light chain (AL) amyloidosis. We searched the literature using PubMed, Embase, and CENTRAL databases since inception through March 2024. We included studies reporting the diagnostic accuracy of immunofixation and/or sFLC in patients with AL amyloidosis. We used the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach to assess the certainty of the evidence and QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies-2) to assess the risk of bias. After deduplication, 29 237 records were screened, and 44 studies (n = 18 071) were included. For the meta-analysis, 28 studies reported sensitivity for SIFE (n = 3390), 24 studies for UIFE (n = 2830), 19 studies for SIFE and UIFE (n = 2819), 21 studies for sFLC ratio (n = 3678), 6 studies for SIFE and sFLC ratio (n = 372), 3 studies for UIFE and sFLC ratio (n = 242), and 10 studies for all 3 tests (n = 1430). Pooled sensitivities were as follows: SIFE, 0.68 (95% confidence interval [CI], 0.62-0.73); UIFE, 0.77 (95% CI, 0.72-0.81); SIFE and UIFE, 0.89 (95% CI, 0.84-0.93); and sFLC ratio, 0.82 (95% CI, 0.78-0.86). When SIFE, UIFE, and sFLC ratio were combined, the sensitivity reached 0.99 (95% CI, 0.96-1.00). The high sensitivity of combining SIFE, UIFE, and sFLC ratio supports their use as a reliable initial testing strategy to raise suspicion for AL amyloidosis and guide decisions regarding future diagnostic modalities.

Abstract We evaluated outcomes by management type for patients with stage IA nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) in the Global NLPHL One Working Group retrospective database of 2243 patients with stages I to IV disease diagnosed from 1992 to 2021 at 38 international institutions. A total of 779 patients had stage IA disease with median age of 35 years (range, 3-89) and median follow-up of 6.1 years. The 6-year progression-free survival (PFS) and overall survival were 86.3% and 97.7%, respectively. Outcomes were analyzed for the 2 groups: complete resection and unresected disease. Patients with a complete resection and observation alone (n = 99) had a 6-year PFS of 65.5% vs 90.5% for those who received radiotherapy (RT) (n = 53). Patients with unresected disease (n = 627; 80.5%) had a 6-year PFS of 62.0% for rituximab alone (n = 31), 89.6% for RT alone (n = 325), 76.8% for ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) alone (n = 40), and 94.3% for ABVD plus RT (n = 130). A total of 127 patients relapsed (16.3%), of which 25 (19.7%) had transformation. Our analysis suggests the following: (1) RT improves the PFS in patients with completely resected disease; (2) rituximab or ABVD alone does not appear to achieve a durable response; and (3) chemotherapy was not observed to add additional PFS benefit when used in combination with RT. Thus, for stage IA NLPHL, RT alone is likely sufficient for definitive treatment.

Abstract Background Central precocious puberty (CPP), which is traditionally defined as the development of secondary sexual characteristics before age 8 years in girls and age 9 years in boys, results from the premature activation of the hypothalamic–pituitary–gonadal (HPG) axis. CPP can be associated with short adult stature, adverse psychosocial outcomes, and increased cardiometabolic and cancer risks in adulthood. Gonadotropin-releasing hormone (GnRH) agonists can effectively suppress premature activation of the HPG axis and have the potential to increase adult height as well as improve psychosocial and long-term health outcomes among patients with CPP. However, as secular trends have continued to shift toward earlier age of pubertal onset, some subpopulations of children with CPP, as it is currently defined, may not require the same extent of diagnostic evaluation and treatment. Objective Develop evidence-based recommendations related to the diagnosis and treatment of CPP. Methods A multidisciplinary panel of clinical experts, along with experts in guideline methodology and systematic literature review, used the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach to address 10 clinical questions related to the diagnosis and treatment of CPP. Systematic reviews of health-related benefits and harms were conducted for each clinical question. The guideline development panel (GDP) also used the GRADE evidence-to-decision (EtD) framework to address stakeholder values and preferences, costs and required resources, cost-effectiveness, acceptability, feasibility, and potential impacts on health equity. Results In girls with thelarche (Tanner stage B2) between ages 7.0 and 8.0 years, the GDP suggests watchful waiting via periodic physical examinations (every 4-6 months) rather than immediately performing evaluation with laboratory testing or radiologic imaging. In addition, the GDP suggests that all girls with breast development (ie, Tanner stage B2) before age 7 years should first be observed for 4 to 6 months to differentiate unsustained or slowly progressive puberty vs rapidly progressive puberty. These recommendations are largely based on evidence that girls with slowly progressive puberty attain a normal adult height without treatment. When hormonal evaluation is performed to confirm central (GnRH-dependent) activation as the cause of precocious puberty, the GDP suggests starting the evaluation with ultrasensitive basal luteinizing hormone (LH) concentration rather than routine GnRH/GnRH agonist (GnRHa) stimulation testing for all patients. While brain magnetic resonance imaging has been a traditional part of CPP evaluation, the GDP suggests that it should not be routinely performed in girls ages 6.0 to 8.0 years and boys ages 8.0 to 9.0 years without central nervous system (eg, neuro-ophthalmologic) symptoms, largely based on a low prevalence of pathologic intracranial findings in these age groups. The GDP suggests against routine genetic testing for patients with CPP, although they judged that genetic testing (eg, MKRN3 sequencing) should be considered for patients with familial CPP through a shared decision-making process. The GDP suggests GnRHa treatment for many children with CPP, although available evidence suggests that some patient subgroups (eg, older girls with slowly progressive CPP) may be less likely to receive a net benefit with this treatment. Rather than always starting GnRHa treatment with a monthly injectable formulation, the GDP suggests that treatment should be initiated with the formulation (such as a longer-acting formulation) that is anticipated to be used long-term. The GDP suggests against routine addition of growth hormone therapy to increase adult height. They also suggest against the routine biochemical testing (eg, LH, sex steroids) to monitor pubertal suppression while receiving GnRHa, instead reserving biochemical testing to confirm clinically suspected treatment failure. Finally, the GDP suggests against routinely continuing GnRHa treatment beyond chronologic age 10.0 to 11.0 years (girls) or 11.0 to 12.0 years (boys) and/or bone age 11.0 to 12.0 years (girls) or 12.0 to 13.0 years (boys). Conclusion These clinical recommendations were developed to address important uncertainties in the diagnosis and treatment of children with CPP. They are based on the best available scientific evidence regarding clinical outcomes judged to be most important to patients and families. The GDP's overarching goal was to suggest diagnostic and therapeutic strategies that will most likely provide net clinical benefits while simultaneously considering important contextual factors such as cost and feasibility. The guideline-development process highlighted important knowledge gaps and the substantial need for additional research.

Abstract Background Repotrectinib, a next-generation ROS1/TRK tyrosine kinase inhibitor, is approved for ROS1 fusion-positive non-small cell lung cancer and NTRK fusion-positive solid tumors. Its side effects and safety management strategies require further characterization. Patients and Methods The safety profile of repotrectinib (treatment-emergent/related adverse events [TEAEs/TRAEs]) was established in patients who initiated treatment at the recommended dose (160 mg daily [QD] for 14 days, then 160 mg twice daily [BID]) across all cohorts of the global, multicenter phase 1/2 TRIDENT-1 study. AE management strategies were outlined. Results In 472 patients, the most common TRAEs (dizziness [58%] and dysgeusia [50%]) were likely TRK inhibition-related. Median relative dose intensity was 90%; 14% (n = 66/472) of patients did not increase their initial QD dose to BID (mostly due to CNS AEs). Rates of dizziness (median onset, 7 days) were similar in patients with/without baseline brain metastases. Dose modifications downgraded severity or resolved dizziness in 78% of patients; 58% of patients had pharmacologic intervention without dose modification. Dizziness was downgraded/resolved in 62% (n = 120/195) of patients who did not receive dose modification or pharmacologic intervention. Treatment-related cognitive impairment and weight gain occurred in 19% and 12% of patients, respectively. Treatment-emergent withdrawal pain occurred in 14% of patients (median resolution time, 2.1 weeks). Dose interruption and reduction from TRAEs occurred in 39% and 38% of patients, respectively; 10% reported later re-escalation back to 160 mg BID. Conclusion Many repotrectinib AEs, including neurological AEs secondary to TRK inhibition, were mitigated with appropriate management, including dose modification and/or pharmacologic intervention.

Abstract Photon-counting detector CT (PCD-CT) directly detects individual photons and measures their energies, enabling the acquisition of multi-energy data from a single x-ray source with higher spatial resolution, thereby allowing visualization of smaller arteries and veins and other important imaging features not seen at conventional CT. It also substantially reduces calcium and stent blooming artifacts. Appropriate patient selection and task-based optimization of acquisition, reconstruction, and interpretation are critical to realize these benefits. Vascular imaging examinations for which early evidence shows that PCD-CT demonstrates higher diagnostic performance compared to conventional CT include coronary CT angiography (CTA) for evaluation of partially calcified plaques or stents, peripheral runoff CTA, detection of cerebrospinal fluid-venous fistulas, and head CTA for evaluation of small intracranial vessels and aneurysms. Current limitations include excessive image noise with the sharpest reconstruction kernels and challenges when adapting conventional CT protocols (eg, requiring sharper kernels, thinner slices, higher matrices, tailored scan modes) to achieve time-efficient image reconstruction and hanging protocols. New solutions and directions will include deep-learning-based image noise reduction, improved spectral separation, strategic triage of specific patient populations to PCD-CT systems, and subspecialty clinical practice recommendations for this new technology.

The focus of this review is the clinical and pathologic presentations of hereditary cancer syndromes with cutaneous manifestations, with the goal of providing a reference for the multidisciplinary care teams involved in the diagnosis and management of these conditions. Advancements in genomics have led to newly recognized syndromes and a deeper understanding of established syndromes. We focus on those with the most relevant cutaneous manifestations. Clinical and histopathologic images provide visual context for these findings, many of which are rare. We summarize the established literature and incorporate new research and noteworthy case reports.

Background: Surgical trauma disrupts hormone networks, but the duration required for these systems to recover remains unclear. We hypothesize that significant perioperative stress would trigger protracted abnormalities of the thyroid axis extending past 28 days. Methods: This retrospective exploratory study analyzed opportunistically obtained thyroid-related laboratory values (free T3 [FT3], free T4 [FT4], and thyroid-stimulating hormone [TSH]) and serum albumin from electronic medical records of patients undergoing CABG, AVR, or PCI between 2017 and 2022. Preprocedural baseline values were compared with post-procedural serum levels measured during the acute peri-procedural period (0–30 days), early recovery (31–90 days), intermediate recovery (91–180 days), late recovery (181–365 days), medium-term follow-up (1–2 years), and long-term follow-up (>2 years). Results: Free T3 demonstrated early suppression across all procedures, most pronounced in CABG during the acute peri-procedural period, with partial recovery at later timepoints. AVR showed moderate suppression at early and long-term follow-up, while PCI demonstrated minimal and inconsistent changes. Free T4 remained relatively stable across procedures, with limited significant post hoc differences after adjustment. TSH showed significant temporal variability in CABG and AVR but not in PCI. Serum albumin demonstrated marked early decline, most pronounced in CABG, with partial recovery over time, whereas AVR showed delayed long-term suppression. Data availability declined substantially at later timepoints across all biomarkers. Conclusions: In this retrospective exploratory analysis, CABG was associated with the most pronounced early perturbations in thyroid and albumin trajectories, while PCI and AVR demonstrated more heterogeneous temporal patterns. These findings are hypothesis-generating and should be interpreted cautiously given non-protocolized laboratory follow-up, substantial missingness, and potential selection bias.