Citations

Abstract The purpose of this study was to assess the long-term clinical and radiographic outcomes after distal ulna resection (Darrach procedure) in young adults. A retrospective chart review identified all adult patients who underwent Darrach resection at 40 years of age or younger and had a minimum of 5-year follow-up. Twenty-one patients (24 wrists) were available for final follow-up. Fifteen patients (16 wrists) returned for in-person evaluation, and seven patients (eight wrists) completed questionnaires by phone. Mean PRWE and QuickDASH scores were 32 and 34, respectively. The median visual analog scale at rest was 0 and 1 with activity. In 88% of cases, patients reported they would have the same surgery again. Of those who were employed preoperatively, 81% (13/16) returned to work, with all but one patient returning to their preoperative job. Radioulnar convergence occurred in all patients, but only three (23%) were symptomatic. The Darrach procedure may be a viable surgical option for DRUJ pathology in younger adults when other options are unavailable. Therapeutic IV.

Abstract Background Noninvasive prenatal screening for common autosomal trisomies, sex chromosome aneuploidies and microdeletions vary by methodology and laboratory practice. The fetal portion of all cell-free DNA in the maternal circulation defines the fetal fraction (FF). The minimum specimen FF levels for reporting results vary between laboratories as well as the screening target (e.g., common trisomies vs select microdeletions). This variability can lead to confusion for both healthcare providers and patients. Methods Participants in the College of American Pathologists Non-Invasive Prenatal Testing 2021-B Exercise provided FF estimates for 3 manufactured samples. Responses to supplemental questions were also collected and analyzed. Results Overall, 72 of 77 participants responded. FF was measured by 66 participants using sequence counts (40), single nucleotide polymorphisms (15), fragment length (24), and Y chromosome sequences (24). Nearly half (48%) used multiple methods. For common trisomies, minimum FFs were none or <1% (n = 7), 1.0% to 3.9% (n = 35), 4.0% to 6.9% (n = 23), and ≥7.0% (n = 1); 4 participants did not measure FF. Challenge-specific FFs were variable with CVs of 13%, 15%, and 36%; the latter rate appears due to that sample’s fetal karyotype of 47,XYY. Comparing adjusted FF results for the 3 samples shows that 85% of participant results were within 20% of the consensus. Conclusions Using multiple methods to estimate FF was common, and cutoff levels for sample suitability varied widely. Within-laboratory FFs were less variable than between laboratories. Current FF estimates from clinical laboratories are not standardized and should be considered laboratory-specific.

Background: Young women with breast cancer (YWBC) typically undergo intensive treatment that negatively impacts their quality of life (QoL). However, limited information is available on how their QoL changes, as most research has focused on older patients. Objectives: To assess changes in QoL among YWBC, identify the most affected QoL domains, and identify the factors associated with these changes. Design: Joven & Fuerte is a multicenter cohort of women aged ⩽40 in Mexico with newly diagnosed BC from 2014 to 2020. Methods: Participants completed the European Organization for Research and Treatment of Cancer Breast Cancer module QLQ-BR23 questionnaire at five different time points from enrollment until year 5 postdiagnosis. Clinical and treatment data were also collected. Group-based multivariate trajectory modeling was used to analyze longitudinal changes across QoL domains and classify patients into appropriate groups. Logistic models were then employed to identify associations between variables and group classification. Results: A total of 477 women (median age: 36 years; interquartile range 32–38) were included. Most had public health insurance (87%) and were diagnosed with stage II (49%) or III (39%) BC. Two trajectory groups, namely, “good” and “poor,” were identified based on QLQ-BR23 scores. Most patients ( n = 294, 62%) were in the poor group. In the good group, sexual enjoyment scores remained stable from baseline to year 5 (51.4), whereas those in the poor group decreased (51.0–37.3). Distress related to hair loss over time declined, with scores decreasing from 36.3 to 27.0 in the good trajectory group and from 43.4 to 31.2 in the poor trajectory group. For future perspective, the good group improved from 56.4 to 79.0, while the poor group increased from 39.3 to 57.2. Patients with human epidermal growth factor receptor 2-positive BC (adjusted odds ratio (aOR) = 0.57, 95% confidence interval (CI) 0.35–0.94, p = 0.028) and those with public health insurance (aOR = 0.41, 95% CI 0.16–0.90, p = 0.035) were less likely to belong to the poor trajectory group. Conclusion: A high proportion of YWBC experience a poor QoL trajectory over time, particularly in areas related to sexual health, future perspective, and hair loss.

Abstract RATIONALE: The alveolar epithelium is primarily comprised of two cell types – the flat alveolar type I (AT1) cell responsible for gas exchange, and the cuboidal AT2 cell responsible for surfactant secretion, alveolar defense and acts as facultative stem cells in injury repair. Both cell types emerge from a population of bipotent distal progenitors (DPs). While the FGF signaling involved in directing AT2 fate has been identified, the mechanism by which AT2 differentiation is precisely timed is not well understood. In embryonic stem cells, it has been demonstrated that differentiation is regulated by a biophysical parameter, cell membrane tension (CMT), that acts upstream of FGF signaling by suppressing receptor endocytosis. Given this, we sought to investigate whether and how CMT plays a role in timing the alveolar epithelial differentiation, particularly focusing on how CMT might regulate FGF signaling. METHODS: DPs were isolated from E15.5 mice and plated on top of or embedded in Matrigel. DPs were treated with small molecules, to rise CMT (CHIR22901 and Methyl Beta cyclodextrin; MBCD), inhibiting either endocytosis (Dynasore) or pathways downstream of FGF signaling (FR180204, Akt VIII, KRpep-2d, NSC 74859). CMT is measured both with optical trap technology and FlipTR dye, which uses fluorescence lifetime imaging microscopy. Tissues and cells were immunostained and imaged using markers for AT1 and AT2 cells, Fgfr2, and the endocytosis marker EEA1. The transgenic mice for this project are in a C57B6 strain background and include a pan-lung epithelial Cre (TgNkx2.1-Cre) bred to Cre-dependent ERK reporter (Rosa26SAE). RESULTS: We found that CMT reduces immediately prior to alveolar differentiation, and that increasing CMT with CHIR and MBCD blocks differentiation of DPs in culture. As CMT reduces, we observe an increase in endocytosis and internalization of Fgfr2 in both cultured cells and in vivo at E17.5. Further, scRNAseq analysis showed an upregulation of ERK target genes and we have validated higher ERK activity in nAT2s in the reporter line. Further, we validated that CMT regulates FGF signaling, as decrease in CMT results in more Fgfr2 endocytosis that likely activates ERK and Akt signaling. Our small molecule inhibition data suggests that ERK and Akt signaling are required for AT2 fate selection and we propose that they are the downstream targets of FGF signaling that are activated following lowered CMT and increased Fgfr2 endocytosis. Our findings are of fundamental importance for understanding how cell mechanics regulates biochemical signaling and fate selection during lung development.

Abstract RATIONALE: Susceptibility to severe COVID-19 and long COVID may be influenced by pre-existing lung structure. ECG-gated, non-contrast cardiac CT scans, originally acquired for assessing coronary artery calcium, are available in multiple longitudinal cohort studies and have been previously validated against lung CT scans for densitometry; however, protocol variation across cohorts may hinder direct comparison. To address this, we developed a quality control (QC) rubric to grade cardiac CT scans for standardized quantitative lung measures across cohorts. METHODS: C4R assessed SARS-CoV-2 infection and outcomes in 14 NHLBI cohorts, of which 10 (six community-based and four longitudinal case-control studies) included CT scans (12,459 participants with lung and 13,752 with cardiac CTs). Logic rules were applied to categorize scans (Table): Grade “A-B” scans had 2-3.5mm slice thickness, at least 20 axial slices, no lung cropping in axial view and lung and airway volumes greater than the cohort-specific 1st percentile. “C-D” scans had one lung obscured by cropping around the heart, so quantitative measures were restricted to the lung in complete view. “F-H” scans were deemed unusable, suffering from low slice count (<20), severe image cropping, low lung or airway volumes (< 1st%ile). Visual inspection was performed on a sample from each category to ensure accuracy. Percent of lung voxels in low attenuation areas < -950 HU (LAA950), high attenuation areas (-600 to -250 HU, HAA) and 15th percentile HU value (perc15) were measured. Within-participant variability was quantified using the intraclass correlation coefficient (ICC). RESULTS: We performed QC on cardiac CT scans from an initial sample of 6,275 participants from three C4R cohorts (ARIC, CARDIA, MASALA), imaged with GE or Siemens scanners. Of these, 5,125 (81.7%) were graded “A-B”, 496 (7.9%) were “C-D” and 654 (10.4%) were “F-H”. The percentage of “F-H” scans varied widely across cohorts [<1% to 26%] due to image cropping. Among the 5,621 cardiac CT scans graded A-D, the mean±SD for LAA950, HAA and perc15 respectively were 1.1±2.1%, 7.2±4.7% and -887±33 HU. Repeated imaging was available for 107 participants (time interval 5.1±0.7y). For paired scans in grades A-B (n=101/107), the within-participant correlation for LAA950, HAA and perc15 were 0.91, 0.38 and 0.74 respectively. CONCLUSION: Initial application of QC to cardiac CT scans identified scans with high reproducibility, with the aim to provide valid quantitative lung metrics on over 20,000 highly characterized participants in C4R.

Abstract Rationale: SARS-CoV-2 infection may be associated with new or worsening respiratory symptoms that, if persistent, may contribute to “Long COVID.” Research is needed on the prevalence and risk determinants of Long COVID and related respiratory symptoms in adults with and without pre-existing obstructive lung disease or smoking history. Methods: C4R is a prospective, observational study that collected information on SARS-CoV-2 infection using standardized methods across 14 NIH-funded cohorts. The third wave of C4R questionnaires, administered June 2023 to January 2025, assessed self-reported Long COVID via the question, “Do you think that you are experiencing, or have ever experienced, what has been called “long COVID,” or symptoms related to COVID at least a month after your infection?” Questionnaires also assessed the presence (vs absence) of 22 symptoms that have been linked to Long COVID, including cough, shortness of breath, and post-exertional malaise. Pre-pandemic obstructive lung disease (COPD or asthma) and smoking status (ever/never) were harmonized from self-reported data collected at the most recent pre-pandemic cohort exam. Poisson regression was used to assess prevalence ratios (PRs) adjusting for age, sex, BMI, education, and pre-pandemic hypertension, diabetes, cardiovascular disease, and depressive symptoms. PRs for respiratory symptoms were tested according to self-reported Long COVID and history of non-hospitalized or hospitalized infection; effect modification by pre-pandemic lung disease and smoking was assessed by multiplicative interaction terms and in fully stratified models. Results: Among 23,434 questionnaire respondents, 1,484 (6.3%) self-reported Long COVID, including 246/1,262 (19.5%) with pre-pandemic lung disease and 664/4,018 (16.5%) with smoking history. The adjusted PR for Long COVID was 1.17 (95%CI:0.99-1.39;P=0.06) comparing participants with/without lung disease and 1.17 (95%CI:1.04-1.32;P=0.01) comparing participants with/without smoking history. Respiratory symptoms were more prevalent in those with self-reported Long COVID, as well as in those with a history of hospitalized or non-hospitalized infection (Table). Associations were generally stronger in participants without pre-pandemic lung disease (p-interaction<0.05 for all comparisons). Respiratory symptoms were also more prevalent with a history of repeated, and pre-Omicron infections, and were less prevalent among participants vaccinated prior to their first infection; findings were similar even after excluding participants with self-reported Long COVID. Conclusions: Long COVID is common, particularly in adults with pre-existing COPD or asthma or smoking history. Long COVID and history of SARS-CoV-2 infection, including non-hospitalized infections, was associated with greater respiratory symptom burden. Whether SARS-CoV-2 infection or Long COVID are associated with development or progression of obstructive lung diseases warrants future studies.

Abstract Rationale: Current guidelines recommend a short course of antibiotic therapy for ventilator-associated pneumonia (VAP) caused by non-fermenting gram-negative bacilli (NF-GNB). However, this approach has been associated with an increased risk of pneumonia recurrence. This meta-analysis aims to address inconsistencies in the literature and evaluate the efficacy of short-course versus long-course antibiotic therapy for VAP, particularly in cases due to NF- GNB. Methods: We systematically searched PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov for randomized controlled trials (RCTs) comparing short versus long courses of antibiotic therapy in patients with VAP. The primary outcomes were the risk of all-cause mortality and pneumonia recurrence. Data were analyzed using RevMan 5.4, with risk ratio (RR) and mean difference (MD) as effect measures. Results: Our pooled analysis included seven RCTs. There was no significant difference in all- cause mortality between short- and long-course antibiotic regimens (RR 1.02; 95% CI: 0.88-1.18; Figure 1). However, a short course of antibiotics increased the incidence ofpneumonia recurrence, particularly in patients with VAP due to NF-GNB (RR 1.64; 95% CI: 1.18-2.29; Figure 1). There were no significant differences between the two regimens regarding the duration of mechanical ventilation (MD 0.01 days; 95% CI: -0.51 to 0.53 days), ICU (MD 0.10 days; 95% CI: -1.00 to 1.20 days) and hospital stay (MD -0.63 days; 95% CI: -3.18 to 1.91 days), or subsequent infection with or acquisition of resistant organisms (RR 0.89; 95% CI: 0.63-1.24). Conclusions: Our meta-analysis suggests that while a short course of antibiotics increases the risk of pneumonia recurrence in NF-GNB VAP, it does not impact mortality compared to a longer course. The clinical significance of the increased recurrence of pneumonia remains uncertain, as it did not result in worse clinical outcomes. A practical approach incorporating validated clinical criteria and biomarker thresholds to guide the duration of antibiotic therapy may be more effective for patients with NF-GNB VAP. Larger RCTs are needed to drawdefinitive conclusions in this population.

Abstract RATIONALE: Long-term survival after lung transplantation is challenging, with limited research on risk and protective factors. Clinical factors such as younger age, female sex, fewer acute rejection hospitalizations, and double lung transplants are associated with better outcomes. However, the role of psychosocial health and socioeconomic status (SES) remains underexplored. This study aimed to assess the influence of pre-transplant psychosocial health and SES on long-term survival in adult lung transplant recipients. METHODS: We conducted a single-center, retrospective case-control study using the Mayo Clinic Rochester lung transplant registry. Cases (survivors ≥ 6 years) and controls (survivors <6 years) were matched by transplant date (+/- 5 years) and indication for transplant, resulting in 190 subjects (63 cases, 127 controls). We assessed the impact of pre-transplant psychosocial health and SES on long-term survival using initial PACT scores (<2), the HOUSES index, and the national/state area deprivation index (ADI). Additional factors included proximity to the transplant center, insurance type, marital status, primary caregiver status, and employment status. Statistical analyses used the paired Wilcoxon rank-sum test for continuous variables and McNemar's test for categorical variables, with results reported as median (IQR) or percentages. RESULTS: Donor characteristics (age, sex, smoking history, risk criteria, cause of death) and recipient characteristics (age at transplant, sex, BMI, medical condition, functional status, type of transplant) were similar between cases and controls, with no statistically significant differences (all p>0.05). CMV mismatch, waitlist time, and transplant hospital length of stay were also comparable (all p>0.05). Psychosocial health indicators, including proximity to the transplant center, pre-transplant initial PACT score, insurance type, marital status, primary caregiver, and employment status, did not differ significantly between groups (all p>0.05). The HOUSES index was similar between cases and controls (p=0.179). However, long-term survivors had significantly higher national and state ADI scores than controls (national ADI: p=0.029; state ADI: p=0.019). CONCLUSIONS: Pre-transplant psychosocial health indicators, including proximity to the transplant center, initial PACT score, and caregiver support, did not differ significantly between long-term lung transplant survivors and those with shorter survival. Although SES measured by the HOUSES index was not associated with long-term survival, higher national and state ADI scores were linked to increased long-term survival, suggesting unique protective factors for patients from socioeconomically deprived areas. These findings highlight the complex role of socioeconomic factors in lung transplant outcomes and underscore the need for further research into how specific socioeconomic and environmental factors influence long-term survival.

Despite advances in cardiovascular care and improved outcomes, fragmented healthcare systems, nonequitable access to health care, and nonuniform and unbiased collection and access to healthcare data have exacerbated disparities in healthcare provision and further delayed the technological-enabled implementation of precision medicine. Precision medicine relies on a foundation of accurate and valid omics and phenomics that can be harnessed at scale from electronic health records. Big data approaches in noncardiovascular healthcare domains have helped improve efficiency and expedite the development of novel therapeutics; therefore, applying such an approach to cardiovascular precision medicine is an opportunity to further advance the field. Several endeavors, including the American Heart Association Precision Medicine platform and public-private partnerships (such as BigData@Heart in Europe), as well as cloud-based platforms, such as Terra used for the National Institutes of Health All of Us, are attempting to temporally and ontologically harmonize data. This state-of-the-art review summarizes best practices used in cardiovascular genomic and precision medicine and provides recommendations for systems’ requirements that could enhance and accelerate the integration of these platforms.