The effects of photochemical aging and interactions with secondary organic aerosols on cellular toxicity of combustion particles.

Fine particulate matter (PM2.5) is associated with numerous adverse health effects, including pulmonary and cardiovascular diseases and premature death. Significant contributors to ambient PM2.5 include combustion particles and secondary organic aerosols (SOA). Combustion particles enter the atmosphere and undergo an aging process that changes their shape and composition, but there is limited study on the health effects of combustion particle aging and interactions with SOA. This study aimed to understand how biological responses to combustion particles would be affected by atmospheric aging and interaction with anthropogenic SOA. Fresh combustion particles underwent photochemical aging in a potential aerosol mass (PAM) oxidation flow reactor and interacted with SOA produced by the oxidation of toluene vapor in the PAM reactor. Photochemical aging and SOA interactions lead to significant changes in the PAH content and oxidative potential of the particle. Photochemical aging and SOA interactions also affected the biological responses, such as the inflammatory response and CYP1A1 induction of the particles in monoculture and coculture cells. These findings highlight the significance of photochemical aging and SOA interactions on the composition and cellular responses of combustion particles.

Burkholderia multivorans Infections Associated with Use of Ice and Water from Ice Machines for Patient Care Activities - Four Hospitals, California and Colorado, 2020-2024.

Ice machines can harbor water-related organisms, and the use of ice or tap water for clinical care activities has been associated with infections in health care settings. During 2021-2022, a total of 23 cases of infection by Burkholderia multivorans (sequence type ST659) were reported at two southern California hospitals and linked to contaminated ice and water from ice machines. In addition to these 23 cases, this report also includes 23 previously unreported cases of B. multivorans ST659 infections that occurred during 2020-2024: 13 at a northern California hospital, eight at a hospital in Colorado, and two additional cases at one of the southern California hospitals. The same brand of ice machine and brands of filters, descaling, and sanitizing products were used by all four hospitals; B. multivorans was isolated from samples collected from ice machines in two of the hospitals. Whole genome sequencing indicated that all clinical and ice machine isolates were highly genetically similar (0-14 single nucleotide variant differences across 81% of the selected reference genome). Recommendations from public health officials to halt the outbreak included avoiding ice and tap water during clinical care activities. An investigation is ongoing to determine possible sources of ice machine contamination. During outbreaks of water-related organisms in health care facilities, health care personnel should consider avoiding the use of tap water, including ice and water from ice machines, for patient care.

COVID-19-Associated Hospitalizations Among U.S. Adults Aged ≥18 Years - COVID-NET, 12 States, October 2023-April 2024.

Among adults, COVID-19 hospitalization rates increase with age. Data from the COVID-19-Associated Hospitalization Surveillance Network were analyzed to estimate population-based COVID-19-associated hospitalization rates during October 2023-April 2024 and identify demographic and clinical characteristics of adults aged ≥18 years hospitalized with COVID-19. Adults aged ≥65 years accounted for 70% of all adult COVID-19-associated hospitalizations, and their COVID-19-associated hospitalization rates were higher than those among younger adult age groups. Cumulative rates of COVID-19-associated hospitalization during October 2023-April 2024 were the lowest for all adult age groups during an October-April surveillance period since 2020-2021. However, hospitalization rates among all adults aged ≥75 years approached one COVID-19-associated hospitalization for every 100 persons. Among adults hospitalized with COVID-19, 88.1% had not received the 2023-2024 formula COVID-19 vaccine before hospitalization, 80.0% had multiple underlying medical conditions, and 16.6% were residents of long-term care facilities (LTCFs). Guidance for adults at high risk for severe COVID-19 illness, including adults aged ≥65 years and residents of LTCFs, should continue to focus on adopting measures to reduce risk for contracting COVID-19, advocating for receipt of recommended COVID-19 vaccinations, and seeking prompt outpatient antiviral treatment after receipt of a positive SARS-CoV-2 test result.

A compact stem-loop DNA aptamer targets a uracil-binding pocket in the SARS-CoV-2 nucleocapsid RNA-binding domain.

SARS-CoV-2 nucleocapsid (N) protein is a structural component of the virus with essential roles in the replication and packaging of the viral RNA genome. The N protein is also an important target of COVID-19 antigen tests and a promising vaccine candidate along with the spike protein. Here, we report a compact stem-loop DNA aptamer that binds tightly to the N-terminal RNA-binding domain of SARS-CoV-2 N protein. Crystallographic analysis shows that a hexanucleotide DNA motif (5'-TCGGAT-3') of the aptamer fits into a positively charged concave surface of N-NTD and engages essential RNA-binding residues including Tyr109, which mediates a sequence-specific interaction in a uracil-binding pocket. Avid binding of the DNA aptamer allows isolation and sensitive detection of full-length N protein from crude cell lysates, demonstrating its selectivity and utility in biochemical applications. We further designed a chemically modified DNA aptamer and used it as a probe to examine the interaction of N-NTD with various RNA motifs, which revealed a strong preference for uridine-rich sequences. Our studies provide a high-affinity chemical probe for the SARS-CoV-2 N protein RNA-binding domain, which may be useful for diagnostic applications and investigating novel antiviral agents.

Targeted Bmal1 restoration in muscle prolongs lifespan with systemic health effects in aging model.

Disruption of the circadian clock in skeletal muscle worsens local and systemic health, leading to decreased muscle strength, metabolic dysfunction, and aging-like phenotypes. Whole-body knockout mice that lack Bmal1, a key component of the molecular clock, display premature aging. Here, by using adeno-associated viruses, we rescued Bmal1 expression specifically in the skeletal muscle fibers of Bmal1-KO mice and found that this engaged the circadian clock and clock output gene expression contributing to extended lifespan. Time course phenotypic analyses found that muscle strength, mobility, and glucose tolerance were improved with no effects on muscle mass, fiber size or type. A multi-omics approach at two ages further determined that restored muscle Bmal1 improved glucose handling pathways while concomitantly reducing lipid and protein metabolic pathways. The improved glucose tolerance and metabolic flexibility resulted in the systemic reduction of inflammatory signatures across peripheral tissues including liver, lung, and white adipose fat. Together, these findings highlight the critical role of muscle Bmal1 and downstream target genes for skeletal muscle homeostasis with considerable implications for systemic health.

Removal of the Metaphyseal Screw From Tension Band Constructs After Hemiepiphysiodesis: High Rates of Physeal Tethering and Subsequent Implant Removal.

BACKGROUND: Removal of the metaphyseal screw from tension band plate constructs after correction of angular deformity in patients treated with hemiepiphysiodesis has been suggested as an alternative to removing the plate and both screws. While this has the potential benefit of easier implant removal and reinsertion in the event of rebound, there is debate in the literature regarding the benefits and risks of leaving the epiphyseal screw and plate in place. METHODS: Patients treated with hemiepiphysiodesis at the distal femur and/or proximal tibia with tension band plates and screws who underwent subsequent removal of the metaphyseal screw after correction were included. Charts and radiographs were reviewed for the need for metaphyseal screw reinsertion, subsequent removal of deep implants, and evidence of physeal tethering. Tethering was defined as progressive overcorrection in the treated bone segment after removal of the metaphyseal screw with the mechanical axis moving one full mechanical axis zone or more. Patients with tethering were compared with those without. RESULTS: A total of 215 patients with 387 limbs treated met inclusion criteria. Of those, 175 patients were treated for idiopathic genu valgum, while 40 were treated for other conditions. Fifty-nine individuals (27%) underwent replacement of the metaphyseal screw for repeat angular correction. Fifty-one percent of patients underwent secondary procedures for reasons other than metaphyseal screw reinsertion (74 symptomatic implant removal, 7 elective implant removal, 29 due to tethering). There were 44 cases of tethering in 36 patients (17%). In cases of tethering, 7 patients were treated with observation, 11 with implant removal only, 16 with hemiepiphysiodesis on the opposite side, and 2 with osteotomy. Patients with tethering were significantly younger, more likely to be male, and more likely to have had the metaphyseal screw removed more than once (P < 0.05). CONCLUSION: Removal of only the metaphyseal screw after hemiepiphysiodesis has high rates of tethering and further surgery for iatrogenic deformity correction and implant removal. This technique is not recommended. LEVEL OF EVIDENCE: Therapeutic Level III, case-control study.

Interpretation of river water quality data is strongly controlled by measurement time and frequency.

Water quality monitoring at high temporal frequency provides a detailed picture of environmental stressors and ecosystem response, which is essential to protect and restore lake and river health. An effective monitoring network requires knowledge on optimal monitoring frequency and data variability. Here, high-frequency hydrochemical datasets (dissolved oxygen, pH, electrical conductivity, turbidity, water temperature, total reactive phosphorus, total phosphorus and nitrate) from six UK catchments were analysed to 1) understand the lowest measurement frequency needed to fully capture the variation in the datasets; and 2) investigate bias caused by sampling at different times of the day. The study found that reducing the measurement frequency increasingly changed the interpretation of the data by altering the calculated median and data range. From 45 individual parameter-catchment combinations (six to eight parameters in six catchments), four-hourly data captured most of the hourly range (>90 %) for 37 combinations, whilst 41 had limited impact on the median (<0.5 % change). Twelve-hourly and daily data captured >90 % of the range with limited impact on the median in approximately half of the combinations, whereas weekly and monthly data captured this in <6 combinations. Generally, reducing sampling frequency had most impact on the median for parameters showing strong diurnal cycles, whilst parameters showing rapid responses to extreme flow conditions had most impact on the range. Diurnal cycles resulted in year-round intra-daily variation in most of the parameters, apart from nutrient concentrations, where daily variation depended on both seasonal flow patterns and anthropogenic influences. To design an optimised monitoring programme, key catchment characteristics and required data resolution for the monitoring purpose should be considered. Ideally a pilot study with high-frequency monitoring, at least four-hourly, should be used to determine the minimum frequency regime needed to capture temporal behaviours in the intended focus water quality parameters by revealing their biogeochemical response patterns.

Solvation-Enhanced Salt Bridges.

Salt bridges formed by amidines and carboxylic acids represent an important class of noncovalent interaction in biomolecular and supramolecular systems. Isothermal titration calorimetry was used to study the relationships between the strength of the interaction, the chemical structures of the components, and the nature of the solvent. The stability of the 1:1 complex formed in chloroform changed by 2 orders of magnitude depending on the basicity of the amidine and the acidity of the acid, which is consistent with proton transfer in the complex. Polar solvents reduce the stabilities of salt bridges formed with N,N'-dialkylamidines by up to 3 orders of magnitude, but this dependence on solvent polarity can be eliminated if the alkyl groups are replaced by protons in the parent amidine. The enhanced stability of the complex formed by benzamidine is due to solvation of the NH sites not directly involved in salt bridge formation, which become significantly more polar when proton transfer takes place, leading to more favorable interactions with polar solvents in the bound state. Calculation of H-bond parameters using density functional theory was used to predict solvent effects on the stabilities of salt bridges to within 1 kJ mol-1. While H-bonding interactions are strong in nonpolar solvents, and solvophobic interactions are strong in polar protic solvents, these interactions are weak in polar aprotic solvents. In contrast, amidinium-carboxylate salt bridges are stable in both polar and nonpolar aprotic solvents, which is attractive for the design of supramolecular systems that operate in different solvent environments.

Conformational Characterization of Peptides and Proteins by 193 nm Ultraviolet Photodissociation in the Collision Cell of a Trapped Ion Mobility Spectrometry-Time-of-Flight Mass Spectrometer.

Ultraviolet photodissociation (UVPD) has been shown to be a versatile ion activation strategy for the characterization of peptides and intact proteins among other classes of biological molecules. Combining the high-performance mass spectrometry (MS/MS) capabilities of UVPD with the high-resolution separation of trapped ion mobility spectrometry (TIMS) presents an opportunity for enhanced structural elucidation of biological molecules. In the present work, we integrate a 193 nm excimer laser in a TIMS-time-of-flight (TIMS-TOF) mass spectrometer for UVPD in the collision cell and use it for the analysis of several mass-mobility-selected species of ubiquitin and myoglobin. The resultant data displayed differences in fragmentation that could be correlated with changes in protein conformation. Additionally, this mobility-resolved UVPD strategy was applied to collision-induced unfolded ions of ubiquitin to follow changes in fragmentation patterns relating to the extent of protein unfolding. This platform and methodology offer new opportunities for exploring how conformational variations are manifested in the fragmentation patterns of gas-phase ions.

LSD1 and CoREST2 Potentiate STAT3 Activity to Promote Enteroendocrine Cell Differentiation in Mucinous Colorectal Cancer.

Neuroendocrine cells have been implicated in therapeutic resistance and worse overall survival in many cancer types. Mucinous colorectal cancer (mCRC) is uniquely enriched for enteroendocrine cells (EECs), the neuroendocrine cell of the normal colon epithelium, as compared to non-mCRC. Therefore, targeting EEC differentiation may have clinical value in mCRC. Here, single cell multi-omics uncovered epigenetic alterations that accompany EEC differentiation, identified STAT3 as a regulator of EEC specification, and discovered a rare cancer-specific cell type with enteric neuron-like characteristics. Furthermore, LSD1 and CoREST2 mediated STAT3 demethylation and enhanced STAT3 chromatin binding. Knockdown of CoREST2 in an orthotopic xenograft mouse model resulted in decreased primary tumor growth and lung metastases. Collectively, these results provide rationale for developing LSD1 inhibitors that target the interaction between LSD1 and STAT3 or CoREST2, which may improve clinical outcomes for patients with mCRC.

Demographics and Clinical Features Associated with Abnormal Small Bowel Motility in Systemic Sclerosis.

OBJECTIVE: The small bowel is affected in up to 50% of systemic sclerosis (SSc) patients, and some patients experience severe complications. Our aim was to use specific statistical methods to compare demographic and clinical features of SSc patients with and without abnormal small bowel to better characterize patients at risk for this complication. METHODS: SSc patients with gastrointestinal symptoms were prospectively enrolled and underwent a scintigraphy-based whole gut transit (WGT) study. A cross-sectional analysis was performed comparing clinical features between patients with and without abnormal small bowel transit by WGT. Univariate logistic regression models and multivariable models were used to examine the relationship between clinical features and abnormal small bowel transit. RESULTS: Of 130 patients enrolled in this study, 22 had abnormal small bowel transit. SSc patients with abnormal small bowel transit were more likely to be male [Odds Ratio(OR)=3.70, Confidence Interval(CI) 1.07-12.50, p= 0.038], and have more severe cardiac involvement (OR = 3.98, CI 1.10-14.38, p= 0.035), while they were less likely to have sicca symptoms (OR = 0.30, CI 0.10-0.94, p= 0.039). In multivariable analyses, sicca symptoms (OR = 0.28, CI 0.08-0.96, p= 0.043) remained negatively associated with abnormal small bowel transit. Additionally, SSc patients with abnormal small bowel transit had higher mortality than patients with normal small bowel transit [Hazard ratio(HR)=4.57, CI 1.58-13.24, p= 0.005]. CONCLUSIONS: These findings suggest that patients with abnormal small bowel transit in SSc are more likely to be male, have more severe cardiac involvement, higher mortality, and less sicca symptoms. Recognizing this patient subgroup is essential for risk stratification and optimizing clinical care.

Detection of mild sensory hearing loss using a joint reflection-distortion otoacoustic emission profile.

Measuring and analyzing both nonlinear-distortion and linear-reflection otoacoustic emissions (OAEs) combined creates what we have termed a "joint-OAE profile." Here, we test whether these two classes of emissions have different sensitivities to hearing loss and whether our joint-OAE profile can detect mild-moderate hearing loss better than conventional OAE protocols have. 2f1-f2 distortion-product OAEs and stimulus-frequency OAEs were evoked with rapidly sweeping tones in 300 normal and impaired ears. Metrics included OAE amplitude for fixed-level stimuli as well as slope and compression features derived from OAE input/output functions. Results show that mild-moderate hearing loss impacts distortion and reflection emissions differently. Clinical decision theory was applied using OAE metrics to classify all ears as either normal-hearing or hearing-impaired. Our best OAE classifiers achieved 90% or better hit rates (with false positive rates of 5%-10%) for mild hearing loss, across a nearly five-octave range. In summary, results suggest that distortion and reflection emissions have distinct sensitivities to hearing loss, which supports the use of a joint-OAE approach for diagnosis. Results also indicate that analyzing both reflection and distortion OAEs together to detect mild hearing loss produces outstanding accuracy across the frequency range, exceeding that achieved by conventional OAE protocols.

Single-cell transcriptomic atlas of enteroendocrine cells along the murine gastrointestinal tract.

BACKGROUND: Enteroendocrine cells (EECs) produce over 20 gut hormones which contribute to intestinal physiology, nutrient metabolism and the regulation of food intake. The objective of this study was to generate a comprehensive transcriptomic map of mouse EECs from the stomach to the rectum. METHODS: EECs were purified by flow-cytometry from the stomach, upper small intestine, lower small intestine, caecum and large intestine of NeuroD1-Cre mice, and analysed by single cell RNA sequencing. Regional datasets were analysed bioinformatically and combined into a large cluster map. Findings were validated by L-cell calcium imaging and measurements of CCK secretion in vitro. RESULTS: 20,006 EECs across the full gastrointestinal tract could be subdivided based on their full transcriptome into 10 major clusters, each exhibiting a different pattern of gut hormone expression. EECs from the stomach were largely distinct from those found more distally, even when expressing the same hormone. Cell clustering was also observed when performed only using genes related to GPCR cell signalling, revealing GPCRs predominating in different EEC populations. Mc4r was expressed in 55% of Cck-expressing cells in the upper small intestine, where MC4R agonism was found to stimulate CCK release in primary cultures. Many individual EECs expressed more than one hormone as well as machinery for activation by multiple nutrients, which was supported by the finding that the majority of L-cells exhibited calcium responses to multiple stimuli. CONCLUSIONS: This comprehensive transcriptomic map of mouse EECs reveals patterns of GPCR and hormone co-expression that should be helpful in predicting the effects of nutritional and pharmacological stimuli on EECs from different regions of the gut. The finding that MC4R agonism stimulates CCK secretion adds to our understanding of the melanocortin system.

Sudden cardiac death after myocardial infarction: individual participant data from pooled cohorts.

BACKGROUND AND AIMS: Risk stratification of sudden cardiac death after myocardial infarction and prevention by defibrillator rely on left ventricular ejection fraction (LVEF). Improved risk stratification across the whole LVEF range is required for decision-making on defibrillator implantation. METHODS: The analysis pooled 20 data sets with 140 204 post-myocardial infarction patients containing information on demographics, medical history, clinical characteristics, biomarkers, electrocardiography, echocardiography, and cardiac magnetic resonance imaging. Separate analyses were performed in patients (i) carrying a primary prevention cardioverter-defibrillator with LVEF ≤ 35% [implantable cardioverter-defibrillator (ICD) patients], (ii) without cardioverter-defibrillator with LVEF ≤ 35% (non-ICD patients ≤ 35%), and (iii) without cardioverter-defibrillator with LVEF > 35% (non-ICD patients >35%). Primary outcome was sudden cardiac death or, in defibrillator carriers, appropriate defibrillator therapy. Using a competing risk framework and systematic internal-external cross-validation, a model using LVEF only, a multivariable flexible parametric survival model, and a multivariable random forest survival model were developed and externally validated. Predictive performance was assessed by random effect meta-analysis. RESULTS: There were 1326 primary outcomes in 7543 ICD patients, 1193 in 25 058 non-ICD patients ≤35%, and 1567 in 107 603 non-ICD patients >35% during mean follow-up of 30.0, 46.5, and 57.6 months, respectively. In these three subgroups, LVEF poorly predicted sudden cardiac death (c-statistics between 0.50 and 0.56). Considering additional parameters did not improve calibration and discrimination, and model generalizability was poor. CONCLUSIONS: More accurate risk stratification for sudden cardiac death and identification of low-risk individuals with severely reduced LVEF or of high-risk individuals with preserved LVEF was not feasible, neither using LVEF nor using other predictors.

Anticoagulation vs Antiplatelets Across Subgroups of Embolic Stroke of Undetermined Source: A Meta-Analysis of Randomized Controlled Trials.

BACKGROUND AND OBJECTIVES: The term "embolic stroke of undetermined source" (ESUS) encompasses a substantial but heterogeneous population of patients with ischemic stroke, underscoring the importance of identifying personalized treatment strategies. In subgroups of patients randomized in ESUS trials, we evaluated the effectiveness of anticoagulation compared with antiplatelet therapy in secondary ischemic stroke prevention. METHODS: A study-level meta-analysis was conducted on randomized controlled trials of patients with ESUS, comparing anticoagulation with antiplatelet therapy. The primary efficacy outcome was recurrent ischemic stroke, and safety outcomes were major bleeding and death. Subgroups assessed were age, sex, presence of patent foramen ovale (PFO), left atrial enlargement (LAE), and atrial cardiopathy. Pooled risk ratios (RRs) were meta-analyzed. Cochrane Risk of Bias Tool 2.0 was used for risk-of-bias assessment. RESULTS: A total of 7 randomized controlled trials involving 14,804 patients were analyzed, with 7,406 patients treated with anticoagulation and 7,398 treated with antiplatelet therapy. Compared with antiplatelet therapy, anticoagulation was associated with a similar rate of recurrent ischemic stroke (RR 0.91, 95% CI 0.80-1.05; I2 = 0%). In ESUS with PFO, anticoagulation was associated with significantly lower risk of ischemic stroke (RR 0.59, 95% CI 0.35-0.98; I2 = 0%). Heterogeneity was present in those with LAE: antiplatelet therapy was superior in trials allowing cardiac monitoring after randomization (RR 6.65, 95% CI 1.26-35.08; I2 = 0%), but anticoagulation was superior in trials prohibiting cardiac monitoring after randomization (RR 0.25 95% CI 0.07-0.89). Subgroups based on age, sex, or presence of atrial cardiopathy did not benefit from anticoagulation over antiplatelet therapy. DISCUSSION: In this meta-analysis, an empiric anticoagulation approach is not beneficial for patients with ESUS. This finding highlights the importance of an individualized treatment strategy. Such a strategy should include prolonged cardiac monitoring for atrial fibrillation, particularly in patients with moderate-to-severe LAE. Anticoagulation treatment showed promise in patients with medically treated PFO. Other subgroups did not benefit from anticoagulation therapy. Large prospective studies within ESUS subgroups are needed to validate our findings.

Monitoring clonal burden as an alternative to blast count for myelodysplastic neoplasm treatment response.

Accurate assessment of therapy response in myelodysplastic neoplasm (MDS) has been challenging. Directly monitoring mutational disease burden may be useful, but is not currently included in MDS response criteria, and the correlation of mutational burden and traditional response endpoints is not completely understood. Here, we used genome-wide and targeted next-generation sequencing (NGS) to monitor clonal and subclonal molecular disease burden in 452 samples from 32 patients prospectively treated in a clinical trial. Molecular responses were compared with International Working Group (IWG) 2006-defined response assessments. We found that myeloblast percentage consistently underestimates MDS molecular disease burden and that mutational clearance patterns for marrow complete remission (mCR), which depends on myeloblast assessment, was not different than stable disease or bone marrow aplasia, underscoring a major limitation of using mCR. In contrast, achieving a complete remission (CR) was associated with the highest level of mutation clearance and lowest residual mutational burden in higher-risk MDS patients. A targeted gene panel approach was inferior to genome-wide sequencing in defining subclones and their molecular responses but may be adequate for monitoring molecular disease burden when a targeted gene is present in the founding clone. Our work supports incorporating serial NGS-based monitoring into prospective MDS clinical trials.

Novel linkage of the Society of Thoracic Surgeons database and hospital electronic health records.

BACKGROUND: Society of Thoracic Surgeons Congenital Heart Surgery Database is the largest congenital heart surgery database worldwide but does not provide information beyond primary episode of care. Linkage to hospital electronic health records would capture complications and comorbidities along with long-term outcomes for patients with CHD surgeries. The current study explores linkage success between Society of Thoracic Surgeons Congenital Heart Surgery Database and electronic health record data in North Carolina and Georgia. METHODS: The Society of Thoracic Surgeons Congenital Heart Surgery Database was linked to hospital electronic health records from four North Carolina congenital heart surgery using indirect identifiers like date of birth, sex, admission, and discharge dates, from 2008 to 2013. Indirect linkage was performed at the admissions level and compared to two other linkages using a "direct identifier," medical record number: (1) linkage between Society of Thoracic Surgeons Congenital Heart Surgery Database and electronic health records from a subset of patients from one North Carolina institution and (2) linkage between Society of Thoracic Surgeons data from two Georgia facilities and Georgia's CHD repository, which also uses direct identifiers for linkage. RESULTS: Indirect identifiers successfully linked 79% (3692/4685) of Society of Thoracic Surgeons Congenital Heart Surgery Database admissions across four North Carolina hospitals. Direct linkage techniques successfully matched Society of Thoracic Surgeons Congenital Heart Surgery Database to 90.2% of electronic health records from the North Carolina subsample. Linkage between Society of Thoracic Surgeons and Georgia's CHD repository was 99.5% (7,544/7,585). CONCLUSIONS: Linkage methodology was successfully demonstrated between surgical data and hospital-based electronic health records in North Carolina and Georgia, uniting granular procedural details with clinical, developmental, and economic data. Indirect identifiers linked most patients, consistent with similar linkages in adult populations. Future directions include applying these linkage techniques with other data sources and exploring long-term outcomes in linked populations.

Heterogeneous genetic architectures of prostate cancer susceptibility in sub-Saharan Africa.

Men of African descent have the highest prostate cancer incidence and mortality rates, yet the genetic basis of prostate cancer in African men has been understudied. We used genomic data from 3,963 cases and 3,509 controls from Ghana, Nigeria, Senegal, South Africa and Uganda to infer ancestry-specific genetic architectures and fine-map disease associations. Fifteen independent associations at 8q24.21, 6q22.1 and 11q13.3 reached genome-wide significance, including four new associations. Intriguingly, multiple lead associations are private alleles, a pattern arising from recent mutations and the out-of-Africa bottleneck. These African-specific alleles contribute to haplotypes with odds ratios above 2.4. We found that the genetic architecture of prostate cancer differs across Africa, with effect size differences contributing more to this heterogeneity than allele frequency differences. Population genetic analyses reveal that African prostate cancer associations are largely governed by neutral evolution. Collectively, our findings emphasize the utility of conducting genetic studies that use diverse populations.

Mixed-field ABO front typing as an early sign of disease recurrence in ABO-matched stem cell transplantation.

ABO group testing is critical for allogeneic stem cell transplantation because mismatches can cause both transfusion and engraftment challenges. Even with ABO-matched donor-recipient pairs, ABO group determination may provide valuable insight into allograft status. Herein, we report a case of a 76-year-old female patient with myeloid neoplasm who underwent ABO-matched stem cell transplantation and in whom mixed-field ABO antigen expression during routine follow-up testing post-transplantation was the first sign of a change in transplant graft status; the mixed-field findings pre-dated changes in formal chimerism testing. This case underscores the potential of mixed-field ABO typing as an early indicator of disease recurrence in ABO-matched stem cell transplants and suggests that, in such cases, more sensitive forms of chimerism testing and/or closer monitoring for disease recurrence, particularly in the clinical setting of myeloid neoplasms, may be warranted.

The major vault protein integrates adhesion-driven signals to regulate collagen remodeling.

DDR1 interacts with fibrillar collagen and can affect ß1 integrin-dependent signaling, but the mechanism that mediates functional interactions between these two different receptors is not defined. We searched for molecules that link DDR1 and ß1 integrin-dependent signaling in response to collagen binding. The activation of DDR1 by binding to fibrillar collagen reduced by 5-fold, ß1 integrin-dependent ERK phosphorylation that leads to MMP1 expression. In contrast, pharmacological inhibition of DDR1 or culturing cells on fibronectin restored ERK phosphorylation and MMP1 expression mediated by the ß1 integrin. A phospho-site screen indicated that collagen-induced DDR1 activation inhibited ß1 integrin-dependent ERK signaling by regulating autophosphorylation of focal adhesion kinase (FAK). Immunoprecipitation, mass spectrometry, and protein-protein interaction mapping showed that while DDR1 and FAK do not interact directly, the major vault protein (MVP) binds DDR1 and FAK depending on the substrate. MVP associated with DDR1 in cells expressing ß1 integrin that were cultured on collagen. Knockdown of MVP restored ERK activation and MMP1 expression in DDR1-expressing cells cultured on collagen. Immunostaining of invasive cancers in human colon showed colocalization of DDR1 with MVP. These data indicate that MVP interactions with DDR1 and FAK contribute to the regulation of ß1 integrin-dependent signaling pathways that drive collagen degradation.