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Background and Objectives: Lipid metabolism in older adults is affected by various factors including biological aging, functional decline, reduced physiologic reserve, and nutrient intake. The dysregulation of lipid metabolism could adversely affect brain health. This study investigated the association between year-to-year intraindividual lipid variability and subsequent risk of cognitive decline and dementia in community-dwelling older adults., Methods: ASPirin in Reducing Events in the Elderly (ASPREE) was a randomized trial of aspirin, involving 19,114 participants aged 65 years and older from Australia and the United States who were free of dementia and major cognitive impairment. ASPREE-eXTension is the post-trial observational follow-up of participants, currently to a maximum of 11 years. This post hoc analysis included participants who had lipid levels measured at baseline and in years 1, 2, and 3. Year-to-year variability in total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c), and triglycerides over the first 3 years was quantified using variability independent of the mean. Individuals who initiated or discontinued lipid-lowering therapy during this period were excluded. Multivariable Cox proportional hazards regression was used to analyze associations with incident dementia, adjudicated by expert panels, and cognitive impairment with no dementia (CIND) confirmed by a battery of cognitive tests, occurring after year 3. A linear mixed model was used for assessing the association with changes in 4 cognitive function domains, including global, memory, processing speed, verbal fluency, and a composite score from baseline to the end of follow-up., Results: The analysis included 9,846 individuals (median [interquartile range] age: 73.9 [71.7-77.3] years, 54.9% female). 509 incident dementia and 1,760 CIND events were recorded over a median follow-up of 5.8 and 5.4 years after variability assessment. The hazard ratios (95% CI) comparing the highest and lowest quartiles of TC and LDL-c variability were 1.60 (1.23-2.08) and 1.48 (1.15-1.91) for dementia and 1.23 (1.08-1.41) and 1.27 (1.11-1.46) for CIND. Higher TC and LDL-c variability was also associated with a faster decline in global cognition, episodic memory, psychomotor speed, and the composite score (all p < 0.001). No strong evidence was found for an association of HDL-c and triglyceride variability with dementia and cognitive change., Discussion: Tracking variability of TC and LDL-c may serve as a novel biomarker of incident dementia and cognitive decline in older adults.

Objectives: To assess the clinical impact on generally healthy older Australians of changing from the 2009 CKD-EPI (CKD-EPI 2009 ) to the 2021 CKD-EPI (CKD-EPI 2021 ) equation for calculating the estimated glomerular filtration rate (eGFR)., Study Design: Secondary analysis of data from the prospective ASPirin in Reducing events in the Elderly (ASPREE) cohort study., Setting, Participants: Australians aged 70 years or older living in the community and without life-limiting medical conditions, recruited 1 March 2010 - 31 December 2014 for the ASPREE trial., Main Outcome Measures: Baseline characteristics and long term health outcomes for participants classified to different chronic kidney disease (CKD) stages by CKD-EPI 2021 and CKD-EPI 2009 , and for those classified to the same CKD stage by both equations., Results: Complete data were available for 16 244 Australian ASPREE trial participants. At baseline, their mean age was 75.3 years (standard deviation, 4.4 years), and 8938 were women (55%); the median eGFR (CKD-EPI 2009 ) was 74 mL/min/1.73 m 2 (interquartile range [IQR], 64-85 mL/min/1.73 m 2 ), the median urine albumin-to-creatinine ratio 0.8 mg/mmol (IQR, 0.5-1.4 mg/mmol). eGFR values were higher for most participants with CKD-EPI 2021 than with CKD-EPI 2009 (median difference, 3.8 mL/min/1.73 m 2 ; IQR, 3.3-4.4 mL/min/1.73 m 2 ), and 3274 participants (20%) were classified to less advanced CKD stages by CKD-EPI 2021 . The proportion of participants with eGFR values below 60 mL/min/1.73 m 2 (clinical CKD) was 17% (2770 participants) with CKD-EPI 2009 and 12% (1994 participants) with CKD-EPI 2021 . Participants were followed up at a median of 6.5 years (IQR, 5.4-7.9 years); the risks of reaching the disability-free survival composite endpoint (adjusted hazard ratio [aHR], 0.94; 95% confidence interval [CI], 0.84-1.05), all-cause mortality (aHR, 0.90; 95% CI, 0.78-1.03), major cardiac events (aHR, 0.94; 95% CI, 0.79-1.13), and hospitalisations with heart failure (aHR, 1.00; 95% CI, 0.67-1.49) were each similar for participants reclassified or not reclassified by CKD-EPI 2021 ., Conclusions: Using CKD-EPI 2021 would yield higher eGFR values than the CKD-EPI 2009 , substantially reducing the proportion of older Australian adults classified as having CKD, without any overall difference in long term health outcomes for people reclassified to less advanced CKD stages. Using the CKD-EPI 2021 could markedly reduce the number of referrals of generally healthy older adults to specialist nephrology services., (© 2024 AMPCo Pty Ltd.)

Platinum-based neoadjuvant chemotherapy prior to radical cystectomy is the preferred treatment for muscle-invasive bladder cancer despite modest survival benefit and significant associated toxicities. Here, we profile the global proteome of muscle-invasive bladder cancers pre- and post-neoadjuvant chemotherapy treatment using archival formalin-fixed paraffin-embedded tissue. We identify four pre-neoadjuvant chemotherapy proteomic clusters with distinct biology and response to therapy and integrate these with transcriptomic subtypes and immunohistochemistry. We observe proteomic plasticity post-neoadjuvant chemotherapy that is associated with increased extracellular matrix and reduced keratinisation compared to pre-neoadjuvant chemotherapy. Post-neoadjuvant chemotherapy clusters appear to be differentially enriched for druggable proteins. For example, MTOR and PARP are over-expressed at the protein level in tumours identified as neuronal-like. In addition, we determine that high intra-tumoural proteome heterogeneity in pre-neoadjuvant chemotherapy tissue is associated with worse prognosis. Our work highlights aspects of muscle-invasive bladder cancer biology associated with clinical outcomes and suggests biomarkers and therapeutic targets based on proteomic clusters., Competing Interests: Competing interests: A.C.-S. has consulted for Sustained Therapeutics. D.M.B. serves on the Scientific Advisory Board and has equity in Acrivon Therapeutics. Peter Black has consulted for AbbVie, Astellas Pharma, AstraZeneca, EMD-Serono, Ferring, Pfizer, Janssen Oncology, Bayer, Merck, Sanofi Canada, Bristol-Myers Squibb, Prokarium, Combat, Nonagen, Nanobot, NanOlogy, Photocure, Sumitomo, TerSera, Tolmar, and Verity. He shares a patent with Veracyte which played no role or is linked to the work presented here (Inventors Elai Davicioni, Hussam Al-Deen Ashab, Nicholas Erho, Peter Black; EP 3 571 322 B8 date of publication and mention of the grant patent 07.06.2023). R.S. has consulted for Janssen Oncology. He shares a patent with Veracyte which played no role or is linked to the work presented here (Inventors Elai Davicioni, Hussam Al-Deen Ashab, Nicholas Erho, Peter Black; EP 3 571 322 B8 date of publication and mention of the grant patent 07.06.2023). The rest of authors had no conflict of interest., (© 2025. The Author(s).)

Erysipelothrix rhusiopathiae is a common zoonotic pathogen that rarely causes diseases in humans. It has three main disease manifestations: a localized cutaneous, a disseminated cutaneous, and a systemic form of infection, typically characterized as bacteremia with or without endocarditis. Human infections are often associated with occupational exposure to animals, animal products, or their excreta. We present a case of a 60-year-old woman found to have E. rhusiopathiae bacteremia associated with a leg laceration sustained after she fell into a sewer drain. Germane animal exposures were not identified; thus, the source of bacterium was attributed to sewage or sewage-contaminated water. She was initially treated with intravenous penicillin with clinical improvement. However, given the patient's social factors, prolonged oral antimicrobial therapy was considered. E. rhusiopathiae is routinely susceptible to penicillin, cephalosporins, and fluoroquinolones but resistant to vancomycin. The data on alternatives to beta-lactam therapy are limited. We report a case of E. rhusiopathiae bacteremia successfully treated with oral linezolid., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Introduction: Idiopathic blepharospasm is a clinically heterogeneous form of focal dystonia, also associated with psychiatric symptoms. The identification of the most relevant sets of motor and psychiatric manifestations may help better understand the specific phenomenology of the condition and delineate blepharospasm subtypes more accurately., Methods: Patients with idiopathic blepharospasm were from the Dystonia Coalition project. Factor analysis of several motor and psychiatric scales was performed to identify the relevant determinants of blepharospasm severity. The selected items were then used in a data-driven cluster analysis to subtype blepharospasm individuals., Results: Factor analysis reduced the many variables in the motor and psychiatric scales to 13 variables distributed in four factors. When the four sets were used as clustering variables, three blepharospasm clusters were identified: cluster 1 was characterized by low levels of motor and psychiatric factors; cluster 2 showed high levels of both motor and psychiatric factors; and cluster 3 showed high levels of psychiatric factors (similar to cluster 2) but low level of motor factors (similar to that of cluster 1)., Conclusions: Factor analysis enabled the identification of key motor and psychiatric determinants of blepharospasm severity. The derived factor sets provide a streamlined tool for predicting and measuring these dimensions. This approach also facilitated more precise cluster analysis and improved recognition of clinical subtypes., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest relevant to this work., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Severe early graft dysfunction (EGD) is defined by mechanical circulatory support (MCS) <24 hours of heart transplantation (HT). We classified severe EGD based on timing of post-HT MCS: ''Immediate'' intra-operative vs ''Delayed'' post-operative MCS (after admission into intensive care unit (ICU) from operating theater). We hypothesized that (1) risk factors and clinical course differ between ''Immediate'' and ''Delayed'' MCS; and (2) diastolic perfusion pressure (DPP=diastolic blood pressure-central venous pressure) and Norepinephrine equivalents (NE=sum of vasopressor doses), as measures of vasoplegia are related to ''Delayed'' MCS., Methods: Two-center study of 216 consecutive patients who underwent HT. Recipient, donor, vasopressor doses and hemodynamic data at T0 and T6 (on admission and 6 hours after admission into ICU) were collected., Results: Of the 216 patients, 67 patients had severe EGD (''Immediate'' MCS: n = 43, ''Delayed'' MCS: n = 24). The likelihood of ''immediate'' MCS but not ''delayed'' MCS increased with increasing warm ischemic and cardiopulmonary bypass times on multinomial regression analysis with ''no MCS'' as the referent group. One-year mortality was highest in ''Immediate'' MCS vs ''no MCS'' and ''delayed'' MCS (34.9% vs 3.4% and 8% respectively, p < 0.001). Of the patients who had no immediate post-transplant MCS, DPP and NE at T6 were independently associated with subsequent ''delayed'' MCS. Sensitivity and specificity of NE≥ 0.2 mcg/kg/min for ''Delayed'' MCS were 71% and 81%. Sensitivity and specificity of DPP of ≥40 mmHg for No MCS were 83% and 74%. The discriminatory value of systemic vascular resistance for ''Delayed'' MCS was poor., Conclusion: Risk factors and 1-year survival differed significantly between ''Immediate'' and ''Delayed'' post-HT MCS. The latter is related to lower DPP and higher NE, which is consistent with vasoplegia as the dominant pathophysiology., (Copyright © 2024 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Existing research exploring predictors of success on American Board of Surgery (ABS) examinations focused on either resident or residency program characteristics, but limited studies focus on both. This study examines relationships between both resident and program characteristics and ABS qualifying (QE) and certifying examination (CE) outcomes., Study Design: Multilevel logistic regression was used to analyze the relationship between resident and program characteristics and ABS QE and CE first attempt pass and eventual certification. Resident characteristics were gender, international medical graduate (IMG) status, and previous performance, measured by the first attempt US Medical Licensing Examination (USMLE) Step 2 Clinical Knowledge and Step 3 scaled scores. Program characteristics were size, %female, %IMG, and program type. The sample included surgeons with QE and CE data from 2007 to 2019 and matched USMLE scores., Results: Controlling for other variables, previous medical performance positively related to all ABS examination outcomes. The relationships between USMLE scores and success on ABS examinations varied but were generally strong. Other resident characteristics that predicted ABS examination outcomes were gender and IMG (QE first attempt pass). The only program characteristic that significantly predicted ABS outcomes was %IMG (QE and CE first attempt pass). Despite statistical significance, gender, IMG, and %IMG translated to small differences in predicted probabilities of ABS examination success., Conclusions: This study highlights resident and program characteristics that predict success on ABS examinations. USMLE scores consistently and strongly related to ABS examination success, providing evidence that USMLE scores relate to future high-stakes consequences like board certification. After controlling for previous performance, gender, IMG, and program %IMG significantly related to ABS examination success, but effects were small., (Copyright © 2024 by the American College of Surgeons. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Objective: This systematic review and meta-analysis aimed to compare the efficacy and safety of deep brain stimulation (DBS) targeting subthalamic nucleus (STN) versus the globus pallidus internus (GPI) in the treatment of dystonia., Methods: A comprehensive search strategy was implemented up to July 2024, across five databases, identifying studies relevant to STN-DBS and GPI-DBS in dystonia. Eligibility criteria included randomized controlled trials (RCTs) and observational studies comparing the two interventions. Two independent reviewers conducted the screening and data extraction. The risk of bias was assessed using RoB-2 for RCTs and the Newcastle-Ottawa Scale for cohort studies. Statistical analysis involved meta-analysis using Review Manager, with heterogeneity assessed by I 2 and Chi-square tests. Subgroup and sensitivity analyses were performed., Results: Five studies, involving 154 patients, were included. No significant difference was found between STN-DBS and GPI-DBS in Burke-Fahn-Marsden Dystonia Rating Scale motor and disability (BFMDRS-M and BFMDRS-D) scores at 1 months, 6 and 12 months. STN-DBS showed significant improvement in mental health (SMD = 0.43, 95 % CI: [0.05, 0.8], P = 0.03). STN-DBS also showed significant improvement in Hamilton Anxiety Rating Scale (HAMA) (SMD = -2.7, 95 % CI: [-5.38, -0.02], P = 0.05). No significant difference was found in Hamilton Depression Rating Scale (HAMD) scores., Conclusions: Both STN-DBS and GPI-DBS can improve motor symptoms in dystonia, with STN-DBS potentially resulting in more superior mental health benefits. Future research should address long-term outcomes, and regional effectiveness, and include diverse populations to enhance generalizability., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Purpose: Repair of type C esophageal atresia with tracheo-esophageal fistula (EA/TEF) may be complicated by esophageal anastomotic leak. Risk factors associated with leak and the impact of leak on inpatient outcomes remains uncertain. Our objectives are to estimate the associations between clinical factors and esophageal anastomotic leak and quantify the association of leak with length of stay (LOS) in infants who underwent repair of type C EA/TEF., Methods: Using the Children's Hospitals Neonatal Database (CHND), we identified infants with type C EA/TEF from 2021 to 2023. The main outcomes were anastomotic leak and LOS. Multivariable associations between patient and clinical factors and these outcomes were quantified using logistic regression (leak) and Cox proportional hazards modelling (LOS)., Results: Among 365 infants at 36 centers, anastomotic leak occurred in 55 (15.1 %) infants, and thoracoscopic approach, lower birthweight, small for gestational age less than 10th percentile, male sex, staged repair, ventricular septal defect, and center were independently associated with leak (area under receiver operating curve = 0.853). Also, LOS was increased in infants with leak compared to those without [hazard ratio (HR): 0.655, 95 % CI = 0.431-0.996, p = 0.044], independent of birth weight, surgical approach, male sex, or VSD. The adjusted LOS demonstrated a 11-fold inter-center variation (p = 0.034)., Conclusions: Several clinical and operative factors are associated with esophageal anastomotic leak in infants after type C EA/TEF repair. Leak significantly prolongs LOS. The magnitude of inter-center variability in LOS also suggests that identifying best practices could aid in improving patient care in this patient population., Type of Study: Retrospective Comparative Study., Level of Evidence: III., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Rationale: Understanding the health risks associated with extreme weather events is needed to inform policies to protect vulnerable populations. Objectives: To estimate heat and cold wave-related mortality risks in a cohort of veteran patients with chronic obstructive pulmonary disease (COPD) and explore disparities among strata of comorbidities, tobacco exposure, and urbanicity. Methods: We designed a time-stratified case-crossover study among deceased patients with COPD between 2016 and 2021 in the Veterans Health Administration system. Distributed lag models with conditional logistic regression estimated incidence rate ratios of heat and cold wave-associated mortality risk from lag days 0 to 3 for heatwaves and lag days 0 to 7 for cold waves. Attributable risks (ARs) per 100,000 patients were also calculated. Results: Of the 377,545 deceased patients with COPD, the largest heatwave-related mortality risk was in patients with COPD and asthma (AR, 14,016; 95% confidence interval [CI], -326, 30,706) across lag days 0 to 3. The largest cold wave-related mortality burden was in patients with COPD with no other reported comorbidities (AR, 1,704; 95% CI, 759, 2,686) across lag days 0 to 7. Patients residing in urban settings had the greatest heatwave-related (AR, 1,062; 95% CI, 576, 1,559) and cold wave-related (AR, 1,261; 95% CI, 440, 2,105) mortality risk (across lag days 0 to 1 and 0 to 7, respectively). There were no differences in mortality risk by tobacco exposure. Conclusions: Our findings show that individuals with COPD are susceptible to heat and cold waves. This information can inform clinical practice and public health policy about the mortality risk vulnerable populations experience with respect to extreme weather conditions. Furthermore, our results may be used in the development and refinement of future extreme weather warning systems designed for public health purposes.

Purpose: Fear of missing neurologic disorders or visual loss from unrecognized papilledema often leads to emergency department (ED) visits for "papilledema" rule-out/workup. In 2022, our institution initiated an ED "papilledema protocol," a systematic evaluation with a median duration of 28 hours (IQR, 21-34). In 2023, we implemented a hybrid true color non-mydriatic fundus photography (NMFP) and optical coherence tomography (OCT) camera (NMFP/OCT) in our ED with the goal of facilitating ED patient evaluations. We hypothesized that the use of NMFP/OCT could avoid in-person ophthalmology consultations in the ED and accelerate the evaluation of "papilledema.", Design: Prospective quality improvement study SUBJECTS: Adult patients who had NMFP/OCT obtained in our ED from 06/9/2023 to 06/302024 for "papilledema" rule-out/workup., Methods: We collected referral questions, final diagnoses, ED length of stay and whether an in-person ophthalmology consultation was performed in addition to remote interpretation of images. We compared ED length of stay with published data prospectively collected in 2022 prior to installation of the ED NMFP/OCT., Main Outcome Measures: Median ED length of stay in hours, number of patients with papilledema ruled-out remotely RESULTS: For patients referred to the ED for "papilledema," the ED NMFP/OCT reduced the median ED length of stay to 12 hours (IQR, 7.5-26.5; 337 patients) compared to 27 hours (IQR, 19-33; 85 patients) in 2022 (P<0.001). For the 199 patients in whom papilledema was ruled-out by NMFP/OCT, the ED length of stay decreased from 24.5 hours (IQR, 10-29) in 2022 to 9 hours (IQR, 6.5-18.5) after installation of the ED NMFP/OCT (P=0.007); papilledema was ruled out remotely without in-person ophthalmology consultation in 185/199 patients (93%). For patients with previously known idiopathic intracranial hypertension, ED-stay decreased from 24 hours in 2022 (IQR, 12-28) to 10 hours after installation of the ED NMFP/OCT (IQR, 7.5-17; 50 patients, P=0.02)., Conclusion: Implementation of NMFP/OCT in our general ED reduced the ED length of stay of "papilledema" patients by 56% and consistently avoided in-person ophthalmology consultations when papilledema was ruled-out remotely on ocular imaging, reducing the burden on residents and on-call ophthalmologists. This substantiates the feasibility and potential cost-effectiveness of implementing NMFP/OCT in a general ED., (Copyright © 2025. Published by Elsevier Inc.)

Background: Reduction in cross-sectional area (CSA) of extracardiac Fontan conduits (EFC) is a known complication of the Fontan operation. Relief of obstruction is crucial for optimal Fontan physiology. The aim of this study is to describe technical aspects and outcomes of EFC stenting and short-term follow-up., Methods: A retrospective study was performed of patients who underwent stent implantation in EFCs with reduced CSA from July 2011 to February 2024. The expected conduit CSA was calculated based on the implanted EFC diameter. The minimum CSA before and after stent implantation was calculated. The minimum EFC diameter and CSA were compared pre- and post-intervention. Data are presented as median [interquartile range]., Results: Sixty-five patients with reduced EFC CSA underwent stent implantation (median age: 13.3 [12.5, 16.8] years, median weight: 49.5 [41.6, 65.4] kg). Forty-seven (72.3%) catheterizations were performed for routine surveillance. In the 63 patients with a known original EFC size, the median reduction in EFC CSA was 36.0 [29,46] %. The minimum CSA was significantly smaller than the expected CSA (157.2 [133.7, 180.1] mm 2 vs. 254.5 [254.5, 254.5] mm 2 , p < 0.0001). Including all patients the minimum EFC diameter and CSA were 12.5 [11.6, 13.4] mm and 153.8 [133.7, 179.7] mm 2 , respectively. Following stent placement EFC diameter and CSA improved to 16.8 [16.2, 17.8] mm (p < 0.0001) and 234.8 [223.4, 269.2] mm 2 (p < 0.0001), respectively. The EFC CSA was 96.8 [89.2, 108.4] % of the expected CSA based on the original EFC diameter. In 24 (36.9%) patients the EFC CSA following stent placement was greater than the expected CSA. There were nine complications in total, of which two were related to EFC stenting., Conclusions: Stent implantation can safely and effectively restore EFC CSA. In select cases, conduits can be expanded beyond the stated diameter., (© 2025 Wiley Periodicals LLC.)

Base editing shows promise for the correction of human mutations at a higher efficiency than other repair methods and is especially attractive for mutations in large genes that are not amenable to gene augmentation therapy. Here, we demonstrate a comprehensive workflow for in vitro screening of potential therapeutic base editing targets for the USH2A gene and empirically validate the efficiency of adenine and cytosine base editor/guide combinations for correcting 35 USH2A mutations. Editing efficiency and bystander edits are compared between different target templates (plasmids versus transgenes) and assays (Next generation sequencing versus Sanger), as well as comparisons between unbiased empirical results and computational predictions. Based on these observations, practical assay recommendations are discussed. Finally, a humanized knock-in mouse model was created with the best-performing target, the nonsense mutation c.11864G>A p.(Trp3955*). Split-intein AAV9 delivery of editing reagents resulted in the restoration of USH2A protein and a correction rate of 65 ± 3% at the mutant base pair and of 52 ± 3% excluding bystander amino acid changes. This efficiency is higher than that seen in a retinal gene editing program testing in a clinical trial. These results demonstrate the effectiveness of this overall strategy to identify and test base editing reagents with the potential for human therapeutic applications., (Copyright © 2025 The Author(s). Published by Elsevier Inc. All rights reserved.)

Research into novel two-dimensional (2D) materials has boomed over the past decade, with a bewildering diversity of distinct properties being discovered. In this work, layered PtSe 2 , grown by chemical vapor deposition and thermally converted to non-layered tetragonal PtSe, is experimentally and theoretically investigated. Notably, the resultant PtSe is distinctly metallic, which highlights the significance of sub-stoichiometric phases within transition metal dichalcogenide films. This shows that thermal conversion can drastically affect the atomic and electronic properties of these phases.

Despite progress in healthcare services for individuals living with sickle cell disease (SCD) in Africa, substantial gaps remain in advanced treatments for SCD. To help address this burden, Tanzania has established one of the largest single-centre SCD programmes in the world and developed an advanced therapy programme for SCD focused on patient engagement and advocacy, clinical activities involving exchange blood transfusion (ExBT) and haematopoietic stem cell transplant (HSCT), gene therapy (GT) preparedness, and enabling partnerships. This report describes the programme's genesis, structure and progress achieved. Patient engagement camps and patient-focused workshops conducted since early 2021 have involved more than 150 patients, family caregivers and healthcare providers. A patient registry was established by screening 1500 patients eligible for advanced therapies with 157 identified to benefit from advanced treatments for SCD. Out of which 22 patients received ExBT, and human leucocyte antigen typing was conducted on 127 individuals to establish a registry of family members with potential to be HSCT donors. Target product profiles were devised for minimum and optimum criteria of GT products to guide drug discovery and development efforts, and qualitative research was conducted to investigate factors anticipated to influence successful adoption of GTs for SCD in Africa. The programme's multifaceted components have been enabled by institutional networks and collaborations established at national, regional and global levels. The programme presented opportunities to deliver cost-effective advanced treatment and curative options for SCD in Tanzania and lessons learnt may be applicable to inform similar efforts in other African regions where SCD is highly endemic., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Objective: To understand parents' experiences of ethical challenges in the care of children with chronic and serious medical conditions and what resources they access for support., Study Design: We recruited English-speaking parents of children with complex and serious medical conditions via family advocacy groups to complete an electronic survey from October 2022 through February 2023. We queried respondents' experiences with specific ethical challenges in the care of their child, whether their concerns persisted, and what resources they accessed. Respondents also reported demographics, educational backgrounds, financial resources, and their child's medical needs., Results: 218 parents completed surveys. Parents reported experiencing each of the 15 presented ethical challenges with varying frequency. More than half of parents reported residual distress in 6/15 ethical challenges. Demographic variables (gender, relationship status, time since medical challenge, and ethnicity) were not associated with level of distress related to ethical challenges. When facing challenges, respondents most commonly communicated with family members, friends, doctors, and other parents of children with medical problems, accessed the internet, and relied on their instincts or prayer/meditation., Conclusions: Parents of children with medical complexity experience ethical challenges in the care of their children, although covering a broader range of experiences than typically considered by clinicians to have ethical dimensions. Many of these challenges leave residual distress. The resources that families report accessing to navigate these challenges are ones that typically do not have training, background, or specificity to medical ethics., Competing Interests: Declaration of interests ☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier Inc. All rights reserved.)

Introduction: Gallbladder specimens from cholecystectomy procedures are a common specimen evaluated by military pathologists. These are often removed for inflammatory causes. Previous studies show that the incidence of gallbladder carcinoma (GBC) is around 3%. Incidentally identified GBC is even less common at 0.36%. Incidentally found GBCs are of little clinical consequence as most are treated by cholecystectomy alone. We hypothesize that a selective approach to histologic evaluation of gallbladders could save time for pathologists to focus on more complex cancer cases and save money for the Defense Health Agency. We propose that for patients under 50 years of age with no clinical or macroscopic concern for neoplasia, histologic evaluation may be omitted with negligible risk of missing a clinically relevant diagnosis., Materials and Methods: This protocol was determined to be institutional review board exempt. All pathology reports from cholecystectomies from January 1, 1998, to August 11, 2023 were pulled. Key data from these reports were extracted. These data include age, gender, and if there was a clinical or macroscopic concern for neoplasia, macroscopic findings, and histologic findings. Additionally, the patient's active duty status was pulled from Military Health Systems Genesis and the Joint Longitudinal Viewer and included for demographic data., Results: Of 9,774 cases pulled, 2,063 of these reports underwent data extraction. In total, 63 cases were excluded, and 2,000 cases were sent to the 59th Medical Wing biostatistics department for analysis. In this dataset, there were 8 instances of malignancy, 5 of which were GBC (1 of these 5 arose from an intracholecystic papillary neoplasm), 2 of which were metastatic disease, and 1 a neuroendocrine tumor. The incidence of GBC in our dataset is 0.20%, lower than that of other studies. The sensitivity of a clinical/macroscopic concern to identify malignancy in a patient aged under 50 years is 66.67%. In the 187 cases from the active duty population, there were zero instances of dysplasia or malignancy., Conclusions: The sensitivity of a clinical/macroscopic concern for neoplasia in a patient aged under 50 years is low, identifying only 2 of 3 malignancies in our dataset. However, the case that would have been missed under our proposed guidelines was from metastatic disease of a previously known metastatic malignancy. We consider that if a selective histologic evaluation is established, a history of malignancy should be a qualifier for evaluation regardless of any other factors. A selective approach to histologic evaluation of gallbladders could save our institution $4,716 to $5,240 annually. Additional studies, incorporating prior malignancy as a qualifier, are warranted to further evaluate the potential for harm in patients aged under 50 years and a number needed to harm should be established prior to any changes in practice., (© The Association of Military Surgeons of the United States 2025. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site–for further information please contact journals.permissions@oup.com.)

Mild traumatic brain injury (mTBI) is common in adolescents. Magnetoencephalography (MEG) studies (primarily reporting on adult males) have demonstrated abnormal resting-state (RS) brain activity in mTBI. The present study sought to identify RS abnormalities in male and female adolescents with mTBI (no previous mTBI and no previous DSM-5 diagnosis) identified from an outpatient specialty care concussion program setting as a basis for evaluating potential clinical utility. Visit 1 MEG RS data were obtained from 46 adolescents with mTBI (mean age: 15.4 years, 25 females) within 4 months of a mTBI (mTBI acute to sub-acute period) as well as from 34 typically developing (TD) controls (mean age: 14.8 years; 17 females) identified from the local community. Visit 2 RS data (follow-up ∼4.3 months after Visit 1; mTBI sub-chronic period) were obtained from 36 mTBI (19 females) and 29 TD (14 females) of those participants. Source-space RS neural activity was examined from 4 to 56 Hz. Visit 1 t-tests showed that group differences were largest in the beta range (16-30 Hz; mTBI < TD), with Visit 2 whole-brain linear mixed model (LMM) analyses examining beta-band group differences as a function of Visit. A main effect of Group indicated Visit 1 and 2 beta-band group differences in midline superior frontal gyrus, right temporal pole, and right central sulcus (all mTBI < TD). The group effects were large (Cohen's d values 0.75 to 1.31). Of clinical significance in the mTBI group, a decrease in mTBI symptoms from Visit 1 to 2 was associated with an increase in beta power in 4 other brain regions. Present findings suggest that RS beta power has potential as a measure and perhaps as a mechanism of clinical recovery in adolescents with mTBI.

Purpose: To investigate the association between primary household language and vision testing among children living in the United States from 2016 to 2020., Methods: This analysis used data for children aged 3-17 years from the National Survey of Children's Health (NSCH), combining survey responses from 2016 to 2020. Primary household language and whether vision testing occurred were determined by survey responses. Complex samples logistic regression models, adjusted for insurance coverage, income (relative to the federal poverty level), race/ethnicity, educational level of household adult, and survey year, were developed to determine the likelihood of vision testing as a function of household English-language usage., Results: Among the 150,603 NSCH respondents, 9,750 (6.47%) were from non-English-speaking households. These children were less likely to undergo vision testing compared with those from English-speaking households (75.8% vs 67.6% [P < 0.001]). State requirements for vision screening among preschoolers and school-age children were associated with increased likelihood of vision testing (P < 0.05) among 3- to 5- and 12- to 17- year-olds; stratified by primary household language, this effect was greater among those from non-English-speaking households., Conclusions: In this nationally representative sample, children from non-English-speaking households were less likely than those from English-speaking ones to receive vision testing, highlighting the need to address language services, health literacy, and other potential barriers to vision services in this population., (Copyright © 2025. Published by Elsevier Inc.)

Introduction: Capnocytophaga is a genus of bacteria that are commensal to the oral microbiome of humans and some animals. Some Capnocytophaga species are found in the human oral cavity and rarely cause disease in people; the species found in animals are zoönotic and can be transmitted to people via saliva. This study describes the clinical and epidemiologic features of patients from whom Capnocytophaga spp. were isolated from blood and other clinical specimens at the California state Microbial Diseases Laboratory., Methods: Clinical information was obtained from laboratory submission forms and any accompanying medical records and/or from matching records in statewide hospital discharge and emergency department databases., Results: During the 17-year study period (2005-2021), Capnocytophaga spp. were isolated in 48 specimens from 47 patients. Capnocytophaga canimorsus, which is a zoönotic species, represented 85% of the Capnocytophaga spp. identified to the species level. The median age was 67 years (range: 30-88 years) for the 42 patients infected with a zoönotic species of Capnocytophaga and 36 years (range: 12-65 years) for the four patients infected with a non-zoönotic species. Twenty-five (60%) patients with zoönotic species infections were male, compared to two (50%) patients with non-zoönotic species infections. Capnocytophaga spp. were most frequently isolated from blood (88%), and the most common case presentation was sepsis (45%). A dog or cat bite prior to diagnosis was reported for 14% of patients infected with a zoönotic species of Capnocytophaga. Records for 45% of patients indicated at least one pre-existing health condition associated with depressed immune function., Conclusions: This study documented that Capnocytophaga spp. can cause rare, severe, invasive disease in mostly older or immunocompromised persons, often without documentation of a dog or cat bite. Providers are encouraged to consider Capnocytophaga spp. infection in immunocompromised pet owners presenting with sepsis, even in the absence of a known animal bite., (© 2025 Wiley‐VCH GmbH. Published by John Wiley & Sons Ltd.)

Background: Ultra-processed products (UPPs), high in sugar, fat and sodium, contribute to increasing burdens of obesity and non-communicable diseases in South Africa (SA). Increased consumption and acceptability of UPPs is driven, in part by aggressive marketing. Front of package labelling laws, particularly warning labels (WLs) coupled with marketing restrictions, have been recommended to improve consumer awareness of unhealthy products, incentivise reformulation and underpin other interventions. The SA government published a draft regulation to introduce WLs and restrict marketing, called R3337. This study aims to analyse on-package marketing and create a baseline to evaluate compliance with the proposed R3337., Methods: This study is an analysis of a dataset of 6768 packaged food products, collected as pictures of products in four major grocery stores in Cape Town, SA between March and July 2019. A codebook was developed based on R337. The codebook was used to identify and assess child-directed marketing (CDM) and health claims on products potentially subject to front-of-package WLs. Food packages and their nutritional information were coded and analyzed to determine whether the product would be required to carry a WL and whether the package included regulated marketing., Results: The majority (80.16%) of products analyzed would require WLs under R3337 due to high levels of sugar, sodium, or saturated fat. CDM was prevalent, with 59.26% of products displaying some form of marketing, primarily animated characters and depictions of children. Health claims were also common, with 83% occurring on WL products., Discussion: Using a WL system in SA could effectively target common forms of on-package marketing of unhealthy products, given the high prevalence of CDM and health claims on products likely to carry WLs. Such interventions may contribute to improving diets and reducing UPP consumption. Some forms of CDM are not regulated under R3337 and we recommend expanding the regulation to include these. This study provides a baseline which should be used for future research to evaluate R3337 when it is implemented., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background: Mobile devices offer an emerging opportunity for research participants to contribute person-generated health data (PGHD). There is little guidance, however, on how to best report findings from studies leveraging those data. Thus, there is a need to characterize current reporting practices so as to better understand the potential implications for producing reproducible results., Objective: The primary objective of this scoping review was to characterize publications' reporting practices for research that collects PGHD using mobile devices., Methods: We comprehensively searched PubMed and screened the results. Qualifying publications were classified according to 6 dimensions-1 covering key bibliographic details (for all articles) and 5 covering reporting criteria considered necessary for reproducible and responsible research (ie, "participant," "data," "device," "study," and "ethics," for original research). For each of the 5 reporting dimensions, we also assessed reporting completeness., Results: Out of 3602 publications screened, 100 were included in this review. We observed a rapid increase in all publications from 2016 to 2021, with the largest contribution from US authors, with 1 exception, review articles. Few original research publications used crowdsourcing platforms (7%, 3/45). Among the original research publications that reported device ownership, most (75%, 21/28) reported using participant-owned devices for data collection (ie, a Bring-Your-Own-Device [BYOD] strategy). A significant deficiency in reporting completeness was observed for the "data" and "ethics" dimensions (5 reporting factors were missing in over half of the research publications). Reporting completeness for data ownership and participants' access to data after contribution worsened over time., Conclusions: Our work depicts the reporting practices in publications about research involving PGHD from mobile devices. We found that very few papers reported crowdsourcing platforms for data collection. BYOD strategies are increasingly popular; this creates an opportunity for improved mechanisms to transfer data from device owners to researchers on crowdsourcing platforms. Given substantial reporting deficiencies, we recommend reaching a consensus on best practices for research collecting PGHD from mobile devices. Drawing from the 5 reporting dimensions in this scoping review, we share our recommendations and justifications for 9 items. These items require improved reporting to enhance data representativeness and quality and empower participants., (©Shanshan Song, Micaela Ashton, Rebecca Hahn Yoo, Zoljargal Lkhagvajav, Robert Wright, Debra J H Mathews, Casey Overby Taylor. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 20.01.2025.)

Systemic lupus erythematosus (SLE) patients are 90% women and over three times more likely to die of cardiovascular disease than women in the general population. Chest pain with no obstructive cardiac disease is associated with coronary microvascular disease (CMD), where narrowing of the small blood vessels can lead to ischemia, and frequently reported by SLE patients. Using whole blood RNA samples, we asked whether gene signatures discriminate SLE patients with coronary microvascular dysfunction (CMD) on cardiac MRI (n = 4) from those without (n = 7) and whether any signaling pathway is linked to the underlying pathobiology of SLE CMD. RNA-seq analysis revealed 143 differentially expressed (DE) genes between the SLE and healthy control (HC) groups, with virus defense and interferon (IFN) signaling being the key pathways identified as enriched in SLE as expected. We next conducted a comparative analysis of genes differentially expressed in SLE-CMD and SLE-non-CMD relative to HC samples. Our analysis highlighted differences in IFN signaling, RNA sensing and ADP-ribosylation pathways between SLE-CMD and SLE-non-CMD. This is the first study to investigate possible gene signatures associating with CMD in SLE, and our data strongly suggests that distinct molecular mechanisms underly vascular changes in CMD and non-CMD involvement in SLE., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethical approval: The experiments were approved by the institutional review board at Cedars-Sinai Medical Center, which oversees the approval of experiments, specifically in the realm of medical ethics. We confirm that all experiments were conducted in accordance with relevant guidelines and regulations, including the Principles of Human Experimentation Ethics and Good Clinical Practice., (© 2025. The Author(s).)

Competing Interests: Competing interests: None declared.

Computed tomography (CT)-derived Epicardial Adipose Tissue (EAT) is linked to cardiovascular disease outcomes. However, its role in patients undergoing Transcatheter Aortic Valve Replacement (TAVR) and the interplay with aortic stenosis (AS) cardiac damage (CD) remains unexplored. We aim to investigate the relationship between EAT characteristics, AS CD, and all-cause mortality. We retrospectively included consecutive patients who underwent CT-TAVR followed by TAVR. EAT volume and density were estimated using a deep-learning platform and CD was assessed using echocardiography. Patients were classified according to low/high EAT volume and density. All-cause mortality at 4 years was compared using Kaplan-Meier and Cox regression analyses. A total of 666 patients (median age 81 [74-86] years; 54% female) were included. After a median follow-up of 1.28 (IQR 0.53-2.57) years, 11.7% (n = 77) of patients died. The EAT volume (p = 0.017) decreased, and density increased (p < 0.001) with worsening AS CD. Patients with low EAT volume (< 49cm 3 ) and high density (≥-86 HU) had higher all-cause mortality (log-rank p = 0.02 and p = 0.01, respectively), even when adjusted for age, sex, and clinical characteristics (HR 1.71, p = 0.02 and HR 1.73, p = 0.03, respectively). When CD was added to the model, low EAT volume (HR 1.67 p = 0.03) and CD stages 3 and 4 (HR 3.14, p = 0.03) remained associated with all-cause mortality. In patients with AS undergoing TAVR, CT-derived low EAT volume, and high density were independently associated with increased 4-year mortality and worse CD stage. Only EAT volume remained associated when adjusted for CD., Competing Interests: Declarations. Ethical approval: This is an observational study. The study protocol followed the ethical guidelines of the 1975 Declaration of Helsinki as reflected in the a priori approval by the Institution’s Human Research Committee. The study was approved by our Office of Human Research Affairs at Albert Einstein College of Medicine and consent was waived due to study design. Disclosures: Annalisa Filtz, Daniel Lorenzatti, and Leandro Slipczuk are supported by institutional grants from Amgen and Philips. Damini Dey received grant support from the National Heart, Lung, and Blood Institute, software royalties from Cedars-Sinai Medical Center, and holds a patent (US8885905B2 in USA and WO patent WO2011069120A1, Method and System for Plaque Characterization). Others have nothing to declare. Competing interests: Damini Dey received grant support from the National Heart, Lung, and Blood Institute, software royalties from Cedars-Sinai Medical Center, and holds a patent (US8885905B2 in USA and WO patent WO2011069120A1, Method and System for Plaque Characterization). Others have nothing to declare., (© 2024. The Author(s).)

Introduction: Premature advanced subclinical coronary atherosclerosis among young adults is an under-recognized and unique disease phenotype that has not been well characterized., Methods: We used data from 44,047 participants with no prior CVD history (59.8% male) from the Coronary Artery Calcium (CAC) Consortium. We defined advanced disease as CAC ≥90th percentile for age, sex, and race, and compared risk factor profile of persons with advanced disease to those without CAC and those with CAC <90th percentile. Using multivariable-adjusted Cox proportional hazard and competing risks regression, we assessed the association of premature advanced disease with all-cause, cardiovascular, and CHD mortality., Results: Of 44,047 participants, 18,561 (42.2%) had CAC. Among those with CAC, 6,680 (36.0%) had CAC ≥90th percentile. Notably, 76.4% of those with CAC ≥90th percentile had multivessel CAC compared to 40.6% of those with CAC <90th percentile. After a mean follow-up of 12.5±3.6 years, the incidence per 1,000 person-years of all-cause (2.93 vs 1.85 vs 1.11), cardiovascular (1.11 vs 0.39 vs 0.21), and CHD mortality (0.65 vs 0.19 vs 0.08) was highest in the advanced disease group compared to CAC <90th percentile and the no CAC group. Persons with CAC ≥90th percentile had a higher multivariable-adjusted risk of all-cause (HR:2.17[1.83-2.57]), cardiovascular (SHR:3.89[2.78-5.44]), and CHD mortality (SHR:5.45[3.38-8.78]), compared to those without CAC. In the subgroup analysis, there was no difference in mortality between men and women with advanced CAC., Conclusions: Premature advanced atherosclerosis is a distinct clinical phenotype that strongly predicts all-cause and cause-specific mortality. Among persons with CAC at young age, those with scores ≥ 90th percentile have the highest risk of early death and should be identified in future guidelines as a focus for aggressive clinical prevention., (© The Author(s) 2025. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Objective: To assess the association between mode of delivery and 2-year motor function in children with prenatal diagnosis of myelomeningocele., Methods: A multisite retrospective cohort study of children with myelomeningocele across 14 NAFTNet (North American Fetal Therapy Network) centers born between 2007 and 2020 who had a physical examination available at 2 years of life. Exclusion criteria were in utero myelomeningocele repair, postnatal myelomeningocele diagnosis, missing data on fetal presentation at delivery, and contraindications to labor. The primary outcome was the difference between the anatomic level of the spinal lesion and functional motor level at age 2 years. A general linear model was used to determine the effect of mode of delivery on the primary outcome, and multivariable analysis was performed to control for presence of labor, gestational age at delivery, defect size and origin level, and presence of ventriculomegaly., Results: Of 566 children with myelomeningocele, 305 met inclusion criteria, with 216 (70.8%) having been delivered by cesarean and 89 (29.2%) having been delivered vaginally. Children delivered by cesarean had a mean±SE level of motor function of 0.07±0.21 segments below the anatomic level at age 2 years compared with 0.57±0.32 for children delivered vaginally (P=.19). After controlling for potential confounders, both groups improved in motor function by age 2 years compared with anatomic level. However, there was no difference in motor improvement between groups by mode of delivery (0.07 cesarean vs 0.57 vaginal delivery, adjusted difference 0.37 segments, P=.63)., Conclusion: In this multisite NAFTNet cohort, mode of delivery was not associated with lower-extremity motor function at age 2 years., Competing Interests: Financial Disclosure Jenna Miller disclosed that their institution received funding from Janssen Pharmaceuticals. She received payments from BC Platforms and UpToDate, Inc. J Newton received payment from Coplan and Crane, and Gainsburgh, Benjamin, David, Meunier, and Warshauer for providing expert opinion. The other authors did not report any potential conflicts of interest., (Copyright © 2025 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Background: Coarctation of the aorta (CoA) is a narrowing of the aorta that affects 5-8% of congenital heart defects. Treatment options include surgical repair or transcatheter management with endovascular stenting or balloon dilatation. Late complications after operative repair include systemic hypertension, aortic valve abnormalities, aortic aneurysm, and recoarctation. This study examines the association between the presence of hypertension at the diagnosis of CoA and recoarctation., Methods: This retrospective study analyzed medical records of patients at Soroka University Medical Center who underwent treatment for CoA between 1978 and 2021. The study included 128 patients diagnosed with CoA and who underwent repair; 9 were excluded, leaving 119 patients for analysis., Results: Of the 119 patients, 28 developed recoarctation within 15 years of initial repair. Patients with hypertension at initial diagnosis were more likely to develop recoarctation, adjusted to sex and ethnicity. Other patient characteristics were not significantly associated with recoarctation., Conclusions: Hypertension at the time of initial CoA diagnosis is a risk factor for the development of recoarctation within 15 years of initial repair. Close monitoring and management of blood pressure may be important for patients with CoA. Future research should investigate whether hypertension control can reduce recoarctation risk in this population., Impact: Previous studies focus on post-repair hypertension in CoA. Limited research on hypertension during CoA diagnosis. Knowledge gap on its impact on recoarctation risk. Hypertension at CoA diagnosis may predict recoarctation. Enables tailored monitoring and timely intervention., Competing Interests: Competing interests: The authors have no relevant financial or non-financial interests to disclose. Consent statement: Patient consent was not required for this study as it involved the retrospective analysis of anonymized medical records., (© 2025. The Author(s).)

Aims: Proximal coronary artery calcium (CAC) may improve prediction of major adverse cardiac events (MACE) beyond the CAC score, particularly in patients with low CAC burden. We investigated whether the proximal CAC can be detected on gated cardiac computer tomography (CT) and whether it provides prognostic significance with artificial intelligence (AI)., Methods and Results: A total of 2016 asymptomatic adults with baseline CAC CT scans from a single site were followed up for MACE for 14 years. An AI algorithm to classify CAC into proximal or not was created using expert annotations of total and proximal CAC and AI-derived cardiac structures. The algorithm was evaluated for prognostic significance on AI-derived CAC segmentation. In 303 subjects with expert annotations, the classification of proximal versus not proximal CAC reached an area under receiver operating curve of 0.93 (95% confidence interval [CI] 0.91-0.95). For prognostic evaluation, in an additional 588 subjects with mild AI-derived CAC scores, the AI proximal involvement was associated with worse MACE-free survival (P=0.008) and higher risk of MACE when adjusting for CAC score alone (hazard ratio [HR] 2.28, 95% CI 1.16-4.48, P=0.02) or CAC score and clinical risk factors (HR 2.12, 95% CI 1.03-4.36, P=0.04)., Conclusion: The AI algorithm could identify proximal CAC on CAC CT. The proximal location had modest prognostic significance in subjects with mild CAC scores. The AI identification of proximal CAC can be integrated into automatic CAC scoring and improves the risk prediction of CAC CT., (© The Author(s) 2025. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

The C3PO collaborative, with a history of successful quality improvement (QI) initiatives, leveraged registry participants to develop a multi-center QI initiative to reduce adverse events (AEs) in congenital cardiac catheterization. A 32-person, interdisciplinary working group analyzed audited data for all congenital cardiac catheterization cases from 2014-2017. The primary outcome was the occurrence of any high-severity (level 3/4/5) AE. Cases were organized from shortest to longest duration, and level 3/4/5 and 4/5 AE rates were summarized for each procedure duration decile. Observations from the root cause analysis were used to inform the creation of a key driver diagram and determine change strategies and implementation tools. To facilitate pre-procedure communication and risk assessment, an online risk calculator was developed using 2014-2019 data. Between 2014-2017, 14,717 cases were entered from 10 sites. Level 3/4/5 AEs occurred in 732 (5.0%) cases, while 4/5 AEs occurred in 224 (1.5%) cases. The key driver diagram defined three drivers: (1) Pre-Procedure Risk Assessment, (2) Possibly Preventable Events, and (3) Procedure Length Optimization. Actionable change strategies organized around five communication timepoints were developed in interdisciplinary discussions. Pre-case risk calculator outputs were available as a case summary print out and incorporated into a calendar for weekly schedule planning. Pre-intervention (2019) and preliminary intervention period data (2020-2021) are presented here. Through improved resource planning, the protocol equips catheterization teams to respond efficiently to AEs and possibly prevent escalation into dangerous events. This protocol provides reproducible interventions that can be adapted to local practice., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Phenotypic heterogeneity in genetically clonal populations facilitates cellular adaptation to adverse environmental conditions while enabling a return to the basal physiological state. It also plays a crucial role in pathogenicity and the acquisition of drug resistance in unicellular organisms and cancer cells, yet the exact contributing factors remain elusive. In this review, we outline the current state of understanding concerning the contribution of phenotypic heterogeneity to fungal pathogenesis and antifungal drug resistance., (© The Author(s) 2025. Published by Oxford University Press on behalf of FEMS.)

The framework presented in the World Bank report Open and Inclusive: Fair processes for Financing Universal Health Coverage effectively connects proposed decision-making principles with practical examples that country governments can use to pursue greater fairness. In this commentary, we consider the suggestion that international development partners might use the report's criteria to examine their own processes. We consider what the report's primary Fair Process principles - equality, impartiality and consistency - imply for development partners. Specifically, we address two questions in turn: (i) how relevant the Fair Processes report is to development assistance for health; (ii) if it is deemed relevant, what practical implications does the report have for how aid works? We address the second question by briefly applying the framework to a particular global health initiative, namely the United States President's Emergency Plan for AIDS Relief (PEPFAR). Our analysis suggests that development partners' additional sets of accountabilities, particularly linked to funding sources, may pose more fundamental challenges to impartiality than to equality and consistency in decision-making processes. A question inviting further examination, then, is how development partners can redesign their processes to optimise impartiality given institutional constraints that bind them independently of the populations they purport to serve.

Introduction: Herpes encephalitis is known to affect patients undergoing brain radiotherapy, but early diagnosis and treatment, the foremost determinants of disease outcome, remain challenging in this patient population. This can be due to attribution of symptoms to the brain tumor and radiation side effects, as well as patients' atypical clinical presentation. Here we sought to highlight pearls and pitfalls in the clinical course and diagnostic workup which may facilitate timely diagnosis and improve disease outcome., Methods: Six patients with post radiation herpes encephalitis were identified in a retrospective review of Hadassah Medical Center medical records of between 2007 and 2022. Their clinical course, brain imaging, labs and EEG findings were included in the study., Results: All six patients presented with fever and a confusional state and four had seizures. Lumbar puncture showed mild CSF pleocytosis in two of five patients, and PCR was positive for HSV1 in four out of five. MRI showed typical findings in all patients, though they were misinterpreted in two of six as disease exacerbation. EEG showed non convulsive status epilepticus in three patients. Outcome was favorable in half of patients., Discussion: In patients undergoing radiotherapy to the brain and neck, fever and confusional state accompanied by new onset seizures, seizure exacerbation, changes in seizure lateralization and status epilepticus should lead one to consider a diagnosis of herpes encephalitis. A high index of suspicion, a timely workup and empiric treatment in this patient population can alter disease outcome., (Copyright © 2025 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: mRNA-1283 is an investigational COVID-19 mRNA vaccine encoding the receptor-binding and N-terminal domains of the SARS-CoV-2 spike protein in contrast to the original mRNA-1273, which encodes the full-length spike protein., Methods: A phase 2a, dose-ranging, observer-blind, randomized study (NCT05137236) conducted in adults (≥18 years) previously vaccinated with mRNA-1273 evaluated the safety and immunogenicity of a single dose of mRNA-1283 (2.5, 5, and 10 µg) and its bivalent formulation, mRNA-1283.211 (5 and 10 µg; encoding original SARS-CoV-2 and Beta) against the comparator mRNA-1273, 50 µg (Part A). A subsequent, open-label study part (Part B) evaluated the safety and immunogenicity of a monovalent Omicron BA.1 vaccine, mRNA-1283.529 (5 and 10 µg)., Results: A total of 340 participants were randomized in Part A, and 200 participants were enrolled in Part B. All dose levels of mRNA-1283 vaccines were well tolerated and increased the neutralizing antibody (nAb) responses at Day 29 compared to baseline against SARS-CoV-2 D614G and Beta. The nAb responses elicited by mRNA-1283 were higher than those elicited by mRNA-1273. mRNA-1283.529 (Part B) increased nAb at Day 29 against Omicron BA.1. Antibody responses remained detectable for a year post-vaccination., Conclusions: mRNA-1283 was well tolerated and exhibited improved immunogenicity compared to mRNA-1273., (© The Author(s) 2025. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Purpose: The detection of circulating tumor DNA (ctDNA) after curative-intent therapy in early breast cancer (EBC) is highly prognostic of disease recurrence. Current ctDNA assays, mainly targeting single nucleotide variants (SNVs), vary in sensitivity and specificity. While increasing the number of SNVs in tumor-informed assays improves sensitivity, structural variants (SVs) may achieve similar or better sensitivity without compromising specificity. SVs occur across all cancers, linked to genomic instability and tumorigenesis, with unique tumor- and patient-specific breakpoints occurring throughout the genome. SVs in breast cancer are underexplored, and their potential for ctDNA detection and monitoring has not been fully evaluated., Experimental Design: We retrospectively analyzed a tumor-informed SV-based ctDNA assay in a cohort of EBC patients (n=100, 568 timepoints) receiving neoadjuvant systemic therapy (NAT), evaluating ctDNA dynamics and lead times to clinical recurrence in the postoperative period., Results: ctDNA was detected in 96% (91/95) of participants at baseline with a median variant allele frequency (VAF) of 0.15% (range: 0.0011-38.7%); 10% (9/91) had a VAF<0.01%. ctDNA detection at cycle 2 (C2) of NAT was associated with a higher likelihood of distant recurrence (Log-rank p=0.047) and enhanced residual cancer burden (RCB) prognostication (Log-rank p=0.041). ctDNA was detected prior to distant recurrence in all cases (100% sensitivity) with a median lead time of 417 days (range: 4-1931 days)., Conclusion: These results demonstrate the clinical validity of ultrasensitive ctDNA detection and monitoring using SVs. Prospective trials are required to evaluate ctDNA-guided treatment strategies.

Background: Diabetes mellitus is an established cardiovascular risk factor. We assessed the impact of diabetes mellitus on quantitative plaque and long-term outcomes in patients with and without diabetes mellitus in the Scottish COmputed Tomography of the HEART (SCOT-HEART) trial., Methods: Coronary artery calcium (CAC) was assessed on non-contrast computed tomography (CT). Coronary stenoses, visually assessed adverse plaque characteristics and quantitative plaque burdens (calcified, non-calcified, low attenuation and total, Autoplaque 2.5) were assessed on coronary CT angiography. Multivariable and survival analyses were performed., Results: Images of 1769 patients were assessed (56 ​% male, 58 ​± ​9 years). Diabetes mellitus was present in 196 (11 ​%) patients. Patients with diabetes mellitus had higher 10-year cardiovascular risk score (29 [interquartile range 21, 40] versus 15 [9, 21] %, p ​< ​0.001) and CAC score (71 [1, 447] versus 17 [0, 209] Agatston units, p ​< ​0.001), but were not more likely to have obstructive disease or visually assessed adverse plaque characteristics. Patients with diabetes mellitus had higher quantitatively assessed calcified, non-calcified, low attenuation and total plaque burdens. After adjustment for age and sex, diabetes mellitus was an independent predictor of calcified plaque burden (p ​= ​0.009), but not the other plaque types. During 8.7 [IQR 8, 9.6] years follow-up, diabetes mellitus was associated with an increased risk of fatal or non-fatal myocardial infarction, adjusted for age and sex (hazard ratio 1.85, 95 ​% confidence interval 1.09 to 3.17, p ​= ​0.024)., Conclusion: Diabetes mellitus was an independent predictor of quantitatively assessed plaque burden, particularly calcified plaque, and was associated with an increased risk of myocardial infarction., Competing Interests: Declaration of competing interest MCW has given talks for Canon Medical Systems and Siemens Healthineers and performed consultancy for FEOPS., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Ethnic differences in coronary atherosclerosis remain to be fully elucidated. We aimed to assess quantitative plaque characteristics from coronary CT Angiography (CCTA) in relation to ethnicity and cardiovascular risk factors in a multi-ethnic asymptomatic US population., Methods: This cross-sectional study retrospectively evaluated 388 asymptomatic patients selected from a prospective CCTA registry. A total of 194 patients from ethnic minority groups (Asian, African American, and Hispanic) were matched by age, sex, and cardiovascular risk factors to 194 White patients. Quantitative plaque volumes-including total plaque, non-calcified plaque, low-attenuation non-calcified plaque (<30 Hounsfield Units [HU]), and calcified plaque-were measured using artificial intelligence-enabled software. Pericoronary adipose tissue attenuation (PCAT) was also assessed and reported in Hounsfield Units (HU)., Results: The total study population included 388 patients (age 59.9±11.7 years, 68% male), of which 63% had coronary atherosclerosis with total plaque volumes of 149[IQR 50-438] mm 3 , driven predominantly by non-calcified plaque (122, IQR 27-369) mm 3 . Men presented higher volumes of all plaque components compared to women (P<0.05). In multivariable analysis adjusted for cardiovascular risk factors, only African American patients were associated with lower total plaque (β=-89.2, P=0.036), calcified (β=-26.1, P=0.015), and non-calcified plaque volumes (β=-62.7, P=0.022). African American patients were also associated with higher PCAT (β=5.8, P<0.001), along with family history of coronary artery disease (β=2.1, P=0.04)., Conclusions: Our study showed a uniformly high prevalence of atherosclerosis in this asymptomatic cohort, with lower plaque volumes of all sub-components in women. African American patients were associated with lower quantitative plaque volumes (total, non-calcified and calcified) but with higher PCAT compared to White patients; with no significant differences observed among other ethnic minorities., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Outside the current work, Drs Berman, Slomka, and Dey received software royalties from Cedars-Sinai Medical Center and report equity in APQ Health. Drs Slomka, Berman, and Dey hold a patent (US8885905B2 in the United States and World Intellectual Property Organization patent WO2011069120A1, “Method and System for Plaque Characterization”). The other authors declare no known competing financial interests or personal relationships that could have influenced the work reported in this paper., (© 2025 The Authors. Published by Elsevier B.V.)

The regulation of cell physiology depends largely upon interactions of functionally distinct proteins and cellular components. These interactions may be transient or long-lived, but often affect protein motion. Measurement of protein dynamics within a cellular environment, particularly while perturbing protein function with small molecules, may enable dissection of key interactions and facilitate drug discovery; however, current approaches are limited by throughput with respect to data acquisition and analysis. As a result, studies using super-resolution imaging are typically drawing conclusions from tens of cells and a few experimental conditions tested. We addressed these limitations by developing a high-throughput single-molecule tracking (htSMT) platform for pharmacologic dissection of protein dynamics in living cells at an unprecedented scale (capable of imaging >10 6 cells/day and screening >10 4 compounds). We applied htSMT to measure the cellular dynamics of fluorescently tagged estrogen receptor (ER) and screened a diverse library to identify small molecules that perturbed ER function in real time. With this one experimental modality, we determined the potency, pathway selectivity, target engagement, and mechanism of action for identified hits. Kinetic htSMT experiments were capable of distinguishing between on-target and on-pathway modulators of ER signaling. Integrated pathway analysis recapitulated the network of known ER interaction partners and suggested potentially novel, kinase-mediated regulatory mechanisms. The sensitivity of htSMT revealed a new correlation between ER dynamics and the ability of ER antagonists to suppress cancer cell growth. Therefore, measuring protein motion at scale is a powerful method to investigate dynamic interactions among proteins and may facilitate the identification and characterization of novel therapeutics., Competing Interests: DM, HL, RT, SA, LA, RB, MB, HC, XD, KF, RG, EG, AH, AH, JH, SJ, RK, AK, RK, JL, KL, BM, PM, LM, SP, AS, CS, YT, DA, HB Employee of Eikon Therapeutics Inc, (© 2023, McSwiggen et al.)

RNA interference is a natural antiviral mechanism that could be harnessed to combat SARS-CoV-2 infection by targeting and destroying the viral RNA. We identified potent lipophilic small interfering RNA (siRNA) conjugates targeting highly conserved regions of SARS-CoV-2 outside of the spike-encoding region capable of achieving ≥3-log viral reduction. Serial passaging studies demonstrated that a two-siRNA combination prevented development of resistance compared to a single siRNA approach. Viral resistance to single siRNA treatment occurred due to emergence of point mutations at critical positions required for siRNA-mediated target binding and cleavage, which led to a loss of siRNA efficacy. With a two-siRNA combination, emergence of mutations within the siRNA binding site was abolished. When delivered intranasally, two-siRNA combination protected Syrian hamsters from weight loss and lung pathology by viral infection upon prophylactic administration but not following onset of infection. Together, the data support potential utility of RNAi as a prophylactic approach with high resistance barrier to counteract SARS-CoV-2 emergent variants and complement vaccination. Most importantly, given that the siRNAs can be rapidly developed from a new pathogen sequence, this strategy has implications as a new type of preventive medicine that may protect against future coronavirus pandemics., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Importance: With the increase in trials assessing comparative effectiveness of approved products and alternative care strategies, guidance is needed to ensure ethical oversight is fit for purpose for the risks, burdens, and constraints on choice this research presents., Observations: US regulations governing human research emerged in response to horrific research abuses, reinforcing the view that research holds greater risks, uncertainties, and potential for abuse than clinical care, and thus protections and oversight are required for research, but not for care. The research oversight system established by these regulations has been effective, with most clinical research reviewed in advance for possible risk and burdens and for threats to autonomy and justice. For clinical research, however, it has become too much of a one-size-fits-all mechanism. As more comparative effectiveness and other research on widely used clinical interventions are conducted, research oversight should be fit for purpose for these kinds of trials, with the degree of oversight based on 2 morally relevant features of a trial. The first of these features is the degree to which risks and burdens increase or change when research is integrated into clinical care compared with what patient-participants would have experienced in care absent the research. The second is whether the activity restricts meaningful patient decision-making about care in morally important ways: (1) does the research restrict a choice or decision that patients ordinarily are or should be involved in and (2) does research participation remove from patients the ability to make a decision that may be meaningful to them, one based, at least in part, on their values, priorities, logistical or practical considerations, and the like? Whether clinical trials add risk or burden to what patients would otherwise have experienced, and whether studies restrict meaningful decisions patients would or should have had the opportunity to make, should help to determine whether clinical studies are designated as greater than vs minimal risk. Further, it is recommended that investigators and oversight bodies consider streamlined consent procedures for research presenting minimal additional risk or burden and that does not constrain meaningful patient decisions, rather than assuming that waiving all consent requirements is the only alternative., Conclusions and Relevance: Ethical oversight of clinical research must be fit for purpose-with greater oversight for studies with greater risks, uncertainties, and impacts on meaningful patient decisions-and more streamlined oversight for other types of research.

The current diagnosis of metabolic dysfunction-associated steatotic liver disease (MASLD) and its severe form, metabolic dysfunction-associated steatohepatitis (MASH), is suboptimal. Here, we recruited 700 individuals, including 184 from Hong Kong as a discovery cohort and 516 from San Diego, Wenzhou, and Hong Kong as three validation cohorts. A panel of 3 parameters (C-X-C motif chemokine ligand 10 [CXCL10], cytokeratin 18 fragments M30 [CK-18], and adjusted body mass index [BMI]) was formulated (termed N3-MASH), which discriminated patients with MASLD from healthy controls with an area under the receiver operating characteristic (AUROC) of 0.954. Among patients with MASLD, N3-MASH could identify patients with MASH with an AUROC of 0.823, achieving 90.0% specificity, 62.9% sensitivity, and 88.6% positive predictive value. The diagnostic performance of N3-MASH was confirmed in three validation cohorts with AUROC of 0.802, 0.805, and 0.823, respectively. Additionally, N3-MASH identifies patients with MASH improvement with an AUROC of 0.857. In summary, we developed a robust blood-based panel for the non-invasive diagnosis of MASH, which might help clinicians reduce unnecessary liver biopsies., Competing Interests: Declaration of interests R.L. serves as a consultant to Aardvark Therapeutics, Altimmune, Arrowhead Pharmaceuticals, AstraZeneca, Cascade Pharmaceuticals, Eli Lilly, Gilead, Glympse bio, Inipharma, Intercept, Inventiva, Ionis, Janssen Inc., Lipidio, Madrigal, Neurobo, Novo Nordisk, Merck, Pfizer, Sagimet, 89 bio, Takeda, Terns Pharmaceuticals, and Viking Therapeutics. In addition, his institution received research grants from Arrowhead Pharmaceuticals, Astrazeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, Galectin Therapeutics, Gilead, Intercept, Hanmi, Intercept, Inventiva, Ionis, Janssen, Madrigal Pharmaceuticals, Merck, Novo Nordisk, Pfizer, Sonic Incytes, and Terns Pharmaceuticals. He is a co-founder of LipoNexus Inc. V.W.-S.W. has served as an advisory board member or consultant for AbbVie, Boehringer Ingelheim, Echosens, Gilead Sciences, Intercept, Inventiva, Novo Nordisk, Pfizer, Sagimet Biosciences, TARGET PharmaSolutions, and Visirna and as a speaker for Abbott, AbbVie, Gilead Sciences, Novo Nordisk, and Unilab. He has received a research grant from Gilead Sciences and is a co-founder of Illuminatio Medical Technology Limited. V.W.-S.W. serves as a consultant or advisory board member for AbbVie, Boehringer Ingelheim, Echosens, Gilead Sciences, Intercept, Inventiva, Novo Nordisk, Pfizer, Sagimet Biosciences, and TARGET PharmaSolutions and as a speaker for Abbott, AbbVie, Gilead Sciences, and Novo Nordisk. He has received a grant from Gilead Sciences for fatty liver research and is a co-founder of Illuminatio Medical Technology Limited., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

DNAproDB (https://dnaprodb.usc.edu/) is a database, visualization tool, and processing pipeline for analyzing structural features of protein-DNA interactions. Here, we present a substantially updated version of the database through additional structural annotations, search, and user interface functionalities. The update expands the number of pre-analyzed protein-DNA structures, which are automatically updated weekly. The analysis pipeline identifies water-mediated hydrogen bonds that are incorporated into the visualizations of protein-DNA complexes. Tertiary structure-aware nucleotide layouts are now available. New file formats and external database annotations are supported. The website has been redesigned, and interacting with graphs and data is more intuitive. We also present a statistical analysis on the updated collection of structures revealing salient patterns in protein-DNA interactions., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Today, plastic pollution is a widespread problem in all ecosystems and has a particularly severe impact on marine ecosystems and external fertilisers such as the mussel Mytilus galloprovincialis. The present study aims to assess the toxicological reproductive health effects in this organism following exposure to two concentrations of polystyrene microplastics (PS-MPs) (0.5 and 1 μg/L), representative of conditions in the Mediterranean Sea. After exposure, the electrophoretic pattern of protamine-like (PL) proteins, the major basic protein component of Mytilus galloprovincialis sperm chromatin, was analysed. Compared to the unexposed condition, differences were observed by SDS-PAGE and an increased ability of PL to bind and protect DNA from oxidative damage was then measured, particularly for PL from mussels exposed to 1 μg/L PS-MPs. At this dose of PS-MPs, a reduced release of all PLs from the sperm nuclei was also observed, whereas the digestion by micrococcal nuclease did not show any significant differences between the exposed and the unexposed conditions. Finally, the possibility of poly(ADP)-ribosylation of the PLs was investigated. PL-II showed an increase in poly(ADP)-ribosylation after PS-MPs exposure, which may account for the difference in the ability of the PLs to bind DNA. In conclusion, while all the results might suggest a molecular mechanism of gametic plasticity occurring upon exposure of mussels to PS-MPs 1 μg/L, they also indicate that this dose of exposure could be extremely detrimental to the reproductive health of Mytilus galloprovincialis because it could prevent the release of basic nuclear proteins from the sperm DNA at fertilisation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Computed tomography coronary angiography provides a non-invasive evaluation of coronary artery disease that includes phenotyping of atherosclerotic plaques and the surrounding perivascular adipose tissue (PVAT). Image analysis techniques have been developed to quantify atherosclerotic plaque burden and morphology as well as the associated PVAT attenuation, and emerging radiomic approaches can add further contextual information. PVAT attenuation might provide a novel measure of vascular health that could be indicative of the pathogenetic processes implicated in atherosclerosis such as inflammation, fibrosis or increased vascularity. Bidirectional signalling between the coronary artery and adjacent PVAT has been hypothesized to contribute to coronary artery disease progression and provide a potential novel measure of the risk of future cardiovascular events. However, despite the development of more advanced radiomic and artificial intelligence-based algorithms, studies involving large datasets suggest that the measurement of PVAT attenuation contributes only modest additional predictive discrimination to standard cardiovascular risk scores. In this Review, we explore the pathobiology of coronary atherosclerotic plaques and PVAT, describe their phenotyping with computed tomography coronary angiography, and discuss potential future applications in clinical risk prediction and patient management., Competing Interests: Competing interests: P.J.S., D.B. and D.D. may receive royalties from Cedars-Sinai Medical Center and have equity in APQ Health. The other authors declare no competing interests., (© 2025. Springer Nature Limited.)

Objective: To develop a generalizable and accurate method for automatically analyzing wound images captured in clinical practice and extracting key wound characteristics such as surface area measurement., Methods: The authors used image processing techniques to create a robust algorithm for segmenting pressure injuries from digital images captured by nurses during clinical practice. The algorithm also measured the real-world wound surface area. They used the hue-saturation-value color space to analyze red color values and to detect and segment the wound region within the entire image. To assess the accuracy of the algorithm's wound segmentation, the authors compared the results against wound image annotations., Results: The algorithm performed impressively, achieving an intersection-over-union score of up to 0.85 and 100% intersection with the annotations. The algorithm effectively analyzed wound images obtained during clinical practice and accurately extracted the surface area of the documented pressure injuries. These results support the feasibility and applicability of this methodology., Conclusions: Accurate determination of wound size and healing supports decision-making regarding treatment and is essential to successful outcomes. This innovative approach for visual assessment of chronic wounds highlights the potential of computerized wound analysis in clinical practice. By leveraging advanced computational techniques, healthcare providers can gain valuable insights into wound progression, enabling more accurate assessments to support their decision-making., (Copyright © 2025 Wolters Kluwer Health, Inc. All rights reserved.)

Computerized chest tomography (CT)-guided screening in populations at risk for lung cancer has increased the detection of preinvasive subsolid nodules, which progress to solid invasive adenocarcinoma. Despite the clinical significance, there is a lack of effective therapies for intercepting the progression of preinvasive to invasive adenocarcinoma. To uncover determinants of early disease emergence and progression, we used integrated single-cell approaches, including scRNA-seq, multiplexed imaging mass cytometry and spatial transcriptomics, to construct the first high-resolution map of the composition, lineage/functional states, developmental trajectories and multicellular crosstalk networks from microdissected non-solid (preinvasive) and solid compartments (invasive) of individual part-solid nodules. We found that early disease initiation and subsequent progression are associated with the evolution of immune-suppressive cellular phenotypes characterized by decreased cytotoxic CD8 T and NK cells, increased T cell exhaustion and accumulation of immunosuppressive regulatory T cells (Tregs) and M2-like macrophages expressing TREM2. Within Tregs, we identified a unique population of 4-1BB+ Treg subset enriched for the IL2-STAT5 suppressive pathway with transcription profiles supporting discrete metabolic alterations. Spatial analysis showed increased density of suppressive immune cells around tumor cells, increased exhaustion phenotype of both CD4 and CD8 T cells expressing chemokine CXCL13, and spatial microcomplex of endothelial and lymphocyte interactions within tertiary lymphoid structures. The single-cell architecture identifies determinants of early disease emergence and progression, which may be developed not only as diagnostic/prognostic biomarkers but also as targets for disease interception. Additionally, our dataset constitutes a valuable resource for the preinvasive lung cancer research community., Competing Interests: Competing interests: All other authors declare no potential conflicts.

Importance: To decrease associated infectious and thrombotic morbidity, it is important to understand the indications and risks of peripherally inserted central catheters (PICCs) and other vascular access means in pregnancy., Objectives: The objectives are 3-fold: (1) discuss indications and contraindications, approach to placement, and associated complications for PICC lines, arterial catheters, centrally inserted central catheters, and peripheral intravenous catheters; (2) review available data regarding complications associated with these catheters in pregnancy; and (3) propose an evidence-based approach to clinical decision making regarding vascular access in 2 clinical scenarios among pregnant patients., Evidence Acquisition: A literature review identified relevant research, review articles, textbook chapters, databases, and societal guidelines, with a focus on obstetrical anesthesia and obstetric literature., Results: Data on vascular access complications in pregnancy are limited; therefore, rates of complications are extrapolated from studies including nonpregnant subjects. Catheter choice is dependent on resuscitation requirements, monitoring indications, parenteral therapeutic needs, need for inpatient versus outpatient care, and anticipated duration of use., Conclusions and Relevance: All pregnant patients require vascular access. A subset requires more invasive catheters for management of specific conditions such as trauma in pregnancy, postpartum hemorrhage, and puerperal sepsis. In addition, vascular access plays an important role in operative planning for patients with placenta accreta spectrum disorder and fetal disorders requiring intrauterine surgery. Gaining an understanding of the types of catheters and their associated complications will allow obstetricians, family medicine physicians, midwives, nurses, intensivists, and anesthesiologists to make informed decisions regarding catheter selection and management.