Citations

Krabbe disease (KD) is a rare, inherited leukodystrophy associated with early mortality. Infantile Krabbe disease (IKD) was added to the Recommended Uniform Screening Panel (RUSP) in July 2024. Since then, U.S. states have continued to evaluate implementing KD newborn screening (NBS), and RUSP inclusion has hastened adoption efforts. This study aimed to characterize NBS program responses to this recommendation and identify factors influencing adoption and implementation. A mixed-methods approach was used, including a case review of Wisconsin’s process to add conditions to its NBS panel and a cross-sectional survey of U.S. NBS programs. Responses were obtained from 50 of 51 NBS programs. Twenty-two programs actively screen for KD, with ten additional programs in the implementation process. Screening approaches varied, particularly in psychosine (PSY) cutoff thresholds and testing algorithms. Programs reported a range of adoption pathways, including legislative mandates, advisory committee review, and state-specific nomination processes. Key factors impacting KD NBS adoption included uncertainty regarding treatment safety, efficacy, and availability, ethical considerations related to identifying later-onset disease, and logistical challenges such as laboratory readiness and clinical follow-up resources. This study provides a contemporary overview of national implementation of KD NBS and offers practical insights for programs considering adoption.

Objective Hospitalization, particularly for surgery, represents a period of heightened stress. We evaluated how frailty attenuates the association of rheumatoid arthritis (RA) with negative health outcomes after elective noncardiac surgery. Methods We conducted a cross‐sectional study using the National Inpatient Sample (2018 to 2020), including adults (aged ≥18 years) with elective hospitalizations with noncardiac surgery. Frailty was measured using the Hospital Frailty Risk Score (HFRS). Surgeries were categorized by risk level. Outcomes included discharge health resources need (DHRN), composite adverse clinical events (CACE), and death. Results Among 8,800,359 hospitalizations (2.14% among patients with RA), 73.36% underwent intermediate‐risk surgery and 62.25% had HFRS above 0. DHRN occurred in 28.9%, CACE occurred in 0.93%, and all‐cause mortality occurred in 0.17%. A 10‐point increase in HFRS was associated with a 3.8‐fold increased DHRN, 8.5‐fold increased CACE, and 22.8‐fold increased mortality. RA was not independently associated with CACE (adjusted odds ratio [aOR] 0.91; 95% confidence interval [CI] 0.82–1.01; P = 0.08) or death (aOR 0.90; 95% CI 0.71–1.15; P = 0.41) but was significantly associated with DHRN (aOR 1.28, 95% CI 1.25–1.31; P < 0.001) after adjusting for confounders and frailty. In sensitivity analysis, RA had 10% higher relative odds of DHRN following orthopedic (aOR 1.10; 95% CI 1.07–1.13; P < 0.001) but not nonorthopedic intermediate‐risk surgery (aOR 1.10; 95% CI 0.98–1.23; P = 0.11). Conclusion RA was associated with higher odds of DHRN after orthopedic intermediate‐risk surgery but not CACE or inpatient mortality. Moreover, HFRS was associated with DHRN, CACE, and death. These findings underscore the need for disease‐specific clinical considerations and highlight the potential utility of HFRS in discharge planning.

ABSTRACT Commercial antimicrobial susceptibility testing (AST) systems for gram-negative bacteria provide operational advantages over reference broth microdilution (BMD) testing, but the results produced by commercial AST systems might not be as accurate as the reference method. Assessing and comparing the performance of AST systems can be informative for clinical microbiology practice. In total, 280 clinical isolates and 100 isolates from the U.S. Centers for Disease Control and Prevention Antimicrobial Resistance Isolate Bank, including Enterobacterales and Pseudomonas aeruginosa, were intended to be tested using disk diffusion (DD) and automated commercial AST systems, such as Selux AST System (Selux Diagnostics), MicroScan (Beckman Coulter), Phoenix (Becton, Dickinson and Company), and Vitek 2 (bioMérieux). These results were compared to BMD as the reference standard. In total, 372 isolates were assessed. For Enterobacterales, the greatest frequency of very major errors was identified with cefepime by Vitek 2 (29.0%) and ertapenem by DD (9.1%); essential agreement less than 90% was identified with the following combinations: aztreonam by MicroScan (86.4%), aztreonam by Vitek 2 (88.9%), cefepime by Selux (86.3%), cefepime by Vitek 2 (76.8%), ceftazidime by Vitek 2 (89.9%), and levofloxacin by MicroScan (83.4%). For P. aeruginosa , essential agreement less than 90% was identified with the following combinations: gentamicin by Selux (87.2%), tobramycin by Selux (86.6%), and ciprofloxacin by Phoenix (88.4%). Overall, antimicrobials that had low demonstrable bias across all automated commercial AST systems included ampicillin, amoxicillin-clavulanate, ceftazidime-avibactam, ertapenem, and trimethoprim-sulfamethoxazole. Comparing commercial testing systems head-to-head against a reference standard provides insight into the strengths and weaknesses of the performance of these test systems, and these insights can subsequently inform local decisions regarding further investigations and potential operational mitigation strategies. IMPORTANCE This study assessed and compared the performance of multiple commercial antimicrobial susceptibility testing (AST) systems and disk diffusion methods. The accuracy of determining minimum inhibitory concentrations or zone diameters of antimicrobials and the associated interpretive categories were studied for 372 isolates of Enterobacterales and Pseudomonas aeruginosa . Performance of the evaluated systems revealed that multiple antimicrobial-organism combinations were below the standards typically required by regulatory agencies and clinical laboratories. These deficiencies varied across the commercial platforms and disk diffusion methods, highlighting the importance of benchmarking studies that compare the performance using identical isolates. These identified performance weaknesses may warrant further study and/or the implementation of mitigation strategies in clinical laboratory operations to prevent the reporting of errant results.

Breast cancer incidence rises with age and peaks across the menopausal transition, yet why some postmenopausal lobules persist, and why that persistence predicts cancer risk, remains unresolved. Incomplete age-related lobular involution is one of the strongest tissue-level predictors of subsequent breast cancer, but it is still commonly viewed as passive failure of hormonally driven regression. This Review proposes a different framework: persistent lobules are maintained by an active reserve niche that outlasts its reproductive function. By integrating breast epidemiology, mammary stromal biology, cellular senescence, immune surveillance, and comparative reserve systems in skeletal muscle, hematopoiesis, and postmenopausal endometrium, we argue that menopause is a biological control point at which tissue fate diverges. Efficient clearance of senescent cells permits lobular regression to complete, whereas impaired immune surveillance may allow inflammatory paracrine signaling, macrophage reprogramming, and immune evasion to create a self-sustaining senescent-immune niche lock. This framework explains why persistent lobules are biologically active, shifts attention from epithelial quantity to microenvironmental state, and identifies the perimenopausal window as a promising interval for biomarker-guided risk stratification and prevention.

Breast cancer incidence rises with age and peaks across the menopausal transition, yet why some postmenopausal lobules persist, and why that persistence predicts cancer risk, remains unresolved. Incomplete age-related lobular involution is one of the strongest tissue-level predictors of subsequent breast cancer, but it is still commonly viewed as passive failure of hormonally driven regression. This Review proposes a different framework: persistent lobules are maintained by an active reserve niche that outlasts its reproductive function. By integrating breast epidemiology, mammary stromal biology, cellular senescence, immune surveillance, and comparative reserve systems in skeletal muscle, hematopoiesis, and postmenopausal endometrium, we argue that menopause is a biological control point at which tissue fate diverges. Efficient clearance of senescent cells permits lobular regression to complete, whereas impaired immune surveillance may allow inflammatory paracrine signaling, macrophage reprogramming, and immune evasion to create a self-sustaining senescent-immune niche lock. This framework explains why persistent lobules are biologically active, shifts attention from epithelial quantity to microenvironmental state, and identifies the perimenopausal window as a promising interval for biomarker-guided risk stratification and prevention.

Polycythemia vera is characterized by erythrocytosis and increased risk of thrombosis. Sapablursen is an antisense oligonucleotide that suppresses transmembrane serine protease 6 (TMPRSS6), increases hepcidin production, and reduces iron availability for erythropoiesis. IMPRSSION; an ongoing phase 2a, randomized, open-label study includes patients meeting 2016 WHO criteria for polycythemia vera, requiring ≥3 phlebotomies within 6 months of screening and ≥1 phlebotomy within the last 12 weeks. Cohort A (120 or 80 mg) and Cohort B (40 mg) received sapablursen subcutaneously once every 4 weeks (Q4W). The primary efficacy endpoint was the reduction in phlebotomy frequency from baseline to weeks 17-37 in patients who received ≥1 dose. Forty-nine patients received ≥1 sapablursen dose (median age 61 years; 82% male). The baseline mean±SD weekly phlebotomy rate was 0.15±0.07 in Cohort A; 0.17±0.07 in Cohort B and was reduced by -0.10 (95%CI, -0.13, -0.07; n=32;p&lt;0.0001) in Cohort A; -0.10 (95%CI, -0.14, -0.06; n=17;p=0.0001) in Cohort B. Sapablursen reduced the median (IQR) number of phlebotomies from 5.0 (3.0-6.0,Cohort A; 3.5-6.5,Cohort B) at baseline (26-weeks) to 0 (0-1.0) in the efficacy evaluation window (20-weeks) in Cohort A and 1.5 (0-2.5) in Cohort B. Most adverse events were mild or moderate; anemia and fatigue were most common. The mean change in MPN-SAF-TSS at week 37 was -6.21 points (95%CI: -10.56, -1.85, p=0.0052) in Cohort A; -2.71 points in Cohort B (95% CI: -8.33, 2.91, p=0.34). Sapablursen reduced phlebotomy need, improved symptoms, and was safe and well-tolerated in patients with polycythemia vera. (Funded by Ionis Pharmaceuticals; ClinicalTrials.gov: NCT05143957)

Left atrial (LA) myopathy plays a critical role in the pathophysiology of heart failure with preserved ejection fraction (HFpEF). This study aimed to evaluate LA function in a murine model of hypertension-induced HFpEF, with and without obesity, by analyzing left ventricular (LV) pressure signals to quantify the contribution of LA systole to total LV volume. HFpEF was induced in C57BL/6J mice using the SAUNA model, which involves uninephrectomy, chronic aldosterone infusion, and high-salt drinking water for four weeks. To model obesity-associated HFpEF, a high-fat diet (HFD) was added to the SAUNA protocol. Invasive hemodynamic measurements were obtained, and a novel method was developed to assess atrial systole using the second-order derivative of the LV pressure signal during diastolic filling. SAUNA HFpEF mice exhibited preserved LVEF, moderate hypertension, pulmonary congestion, and diastolic dysfunction as evidenced by a prolonged time constant of relaxation (Tau). In sham control mice, atrial systole accounted for 23.0 ± 2.4% of LV volume, whereas this contribution was significantly reduced to 13.9 ± 2.3% in SAUNA HFpEF mice ( P &lt; 0.01). In obese sham controls, atrial systole contributed 53.1 ± 2.2%, which was markedly decreased to 36.8 ± 3.6% in obese-SAUNA HFpEF mice ( P &lt; 0.003). This novel method enables precise quantification of LA systolic contribution to LV filling in mice and highlights the pathophysiological effects of hypertension and obesity on LA function in HFpEF.

The NCCN Guidelines for Survivorship offer guidance for health care providers who care for survivors of adult-onset cancer. These guidelines include screening, evaluation, and treatment recommendations for common physical and psychosocial problems resulting from cancer and its treatment and provide a framework for care coordination. They also present guidance for helping cancer survivors to enhance their wellness and maintain a healthy lifestyle. This article summarizes the panel’s current recommendations and recent updates regarding anxiety, depression, distress, and trauma in cancer survivors.

Importance Elevated low-density lipoprotein cholesterol (LDL-C) is a modifiable risk factor for cardiovascular disease, the leading cause of premature death worldwide. Assessing the LDL-C–related burden is critical for guiding prevention and treatment strategies. Objectives To estimate the global, regional, and national burden of ischemic heart disease and ischemic stroke attributable to elevated LDL-C (relative to 35-54 mg/dL) from 1990 to 2023 and to quantify the contributions of population growth, aging, risk-deleted burden, and exposure changes to burden trends. Design, Setting, and Population This comparative risk assessment, part of the Global Burden of Disease Study 2023, estimated population-level LDL-C exposure and associated health loss in 204 countries and territories. Mean LDL-C levels were estimated using spatiotemporal gaussian process regression based on 806 studies across 161 countries. Relative risks were derived from meta-analyses of 38 randomized clinical trials. Population-attributable fractions for deaths and disability-adjusted life-years (DALYs) were estimated by age and sex for adults aged 25 years or older from 1990 to 2023, with 95% uncertainty intervals. Exposure Population-level LDL-C concentrations. Main Outcomes and Measures Population-attributable fractions, counts, and rates (all ages and age standardized per 100 000) of LDL-C–attributable deaths and DALYs from ischemic heart disease and ischemic stroke, with uncertainty intervals. Results In 2023, elevated LDL-C accounted for 3.6 million deaths (95% uncertainty interval, 2.2-5.4 million; 6.0% of global mortality) and 90.7 million DALYs (95% uncertainty interval, 58.9-123.3 million; 3.2% of DALYs). Although global all-ages rates remained stable, age-standardized death and DALY rates decreased by 45.6% and 39.5%, respectively, since 1990. In 2023, age-standardized LDL-C–attributable DALY rates were highest in Eastern Europe and lowest in high-income Asia-Pacific. One-third of the global LDL-C burden occurred in India and China. Population growth and aging drove the increasing burden, with notable regional disparities in LDL-C exposure and risk-deleted DALY rates shifting toward middle-sociodemographic settings. Conclusions and Relevance Despite declining age-standardized rates, the absolute LDL-C burden has increased since 1990 due to demographic changes and has shifted toward middle-sociodemographic countries. Measurement and surveillance gaps persist. Strengthened prevention, diagnosis, and treatment access strategies are essential to mitigate the health burden of LDL-C.