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Objective To compare the gut microbiome composition and serum metabolome profile among individuals with spinal cord injury (SCI) and normal glucose tolerance (NGT) or prediabetes/type 2 diabetes (preDM/T2D). Design Cross-sectional design. Setting Research university. Participants A total of 25 adults (N=25) with SCI were included in the analysis and categorized as NGT (n=16) or preDM/T2D (n=9) based on their glucose concentration at minute 120 during a 75-g oral glucose tolerance test. The American Diabetes Association diagnosis guideline was used for grouping participants. Interventions Not applicable. Main Outcome Measures A stool sample was collected and used to assess the gut microbiome composition (alpha and beta diversity, microbial abundance) via the 16s ribosomal RNA sequencing technique. A fasting serum sample was used for liquid chromatography–mass spectrometry–based untargeted metabolomics analysis, the results from which reflect the relative quantity of metabolites detected and identified. Gut microbiome and metabolomics data were analyzed by the Quantitative Insights into Microbial Ecology 2 and Metaboanalyst platforms, respectively. Results Gut microbiome alpha diversity (Pielou's evenness index, Shannon's index) and beta diversity (weighted UniFrac distances) differed between groups. Compared with participants with NGT, participants with preDM/T2D had less evenness in microbial communities. In particular, those with preDM/T2D had a lower abundance of the Clostridiales order and higher abundance of the Akkermansia genus, as well as higher serum levels of gut-derived metabolites, including indoxyl sulfate and phenylacetylglutamine (P Conclusions Our results provide evidence for altered gut microbiome composition and dysregulation of gut-derived metabolites in participants with SCI and preDM/T2D. Both indoxyl sulfate and phenylacetylglutamine have been implicated in the development of cardiovascular diseases in the able-bodied population. These findings may inform future investigations in the field of SCI and cardiometabolic health.

Background: Circulating high-sensitivity cardiac troponin T (hsTnT) predominantly reflects myocardial injury, and higher levels are associated with a higher risk of worsening heart failure and death in patients with heart failure with reduced ejection fraction. Less is known about the prognostic significance of changes in hsTnT over time, the effects of dapagliflozin on clinical outcomes in relation to baseline hsTnT levels, and the effect of dapagliflozin on hsTnT levels. Methods: DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) was a randomized, double-blind, placebo-controlled trial of dapagliflozin (10 mg daily) in patients with New York Heart Association class II to IV symptoms and left ventricular ejection fraction ≤40% (median follow-up, 18.2 months). hsTnT (Roche Diagnostics) was measured at baseline in 3112 patients and at 1 year in 2506 patients. The primary end point was adjudicated worsening heart failure or cardiovascular death. Clinical end points were analyzed according to baseline hsTnT and change in hsTnT from baseline to 1 year. Comparative treatment effects on clinical end points with dapagliflozin versus placebo were assessed by baseline hsTnT. The effect of dapagliflozin on hsTnT was explored. Results: Median baseline hsTnT concentration was 20.0 (25th–75th percentile, 13.7–30.2) ng/L. Over 1 year, 67.9% of patients had a ≥10% relative increase or decrease in hsTnT concentrations, and 43.5% had a ≥20% relative change. A stepwise gradient of higher risk for the primary end point was observed across increasing quartiles of baseline hsTnT concentration (adjusted hazard ratio Q4 versus Q1, 3.44 [95% CI, 2.46–4.82]). Relative and absolute increases in hsTnT over 1 year were associated with higher subsequent risk of the primary end point. The relative reduction in the primary end point with dapagliflozin was consistent across quartiles of baseline hsTnT ( P -interaction=0.55), but patients in the top quartile tended to have the greatest absolute risk reduction (absolute risk difference, 7.5% [95% CI, 1.0%–14.0%]). Dapagliflozin tended to attenuate the increase in hsTnT over time compared with placebo (relative least squares mean reduction, –3% [–6% to 0%]; P =0.076). Conclusions: Higher baseline hsTnT and greater increase in hsTnT over 1 year are associated with worse clinical outcomes. Dapagliflozin consistently reduced the risk of the primary end point, irrespective of baseline hsTnT levels. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03036124.

Background: Semaphorins and plexins are ligands and cell surface receptors that regulate multiple neurodevelopmental processes such as axonal growth and guidance. PLXNA3 is a plexin gene located on the X chromosome that encodes the most widely expressed plexin receptor in fetal brain, plexin-A3. Plexin-A3 knockout mice demonstrate its role in semaphorin signaling in vivo. The clinical manifestations of semaphorin/plexin neurodevelopmental disorders have been less widely explored. This study describes the neurological and neurodevelopmental phenotypes of boys with maternally inherited hemizygous PLXNA3 variants. Methods: Data-sharing through GeneDx and GeneMatcher allowed identification of individuals with autism or intellectual disabilities (autism/ID) and hemizygous PLXNA3 variants in collaboration with their physicians and genetic counselors, who completed questionnaires about their patients. In silico analyses predicted pathogenicity for each PLXNA3 variant. Results: We assessed 14 boys (mean age, 10.7 [range 2 to 25] years) with maternally inherited hemizygous PLXNA3 variants and autism/ID ranging from mild to severe. Other findings included fine motor dyspraxia (92%), attention-deficit/hyperactivity traits, and aggressive behaviors (63%). Six patients (43%) had seizures. Thirteen boys (93%) with PLXNA3 variants showed novel or very low allele frequencies and probable damaging/disease-causing pathogenicity in one or more predictors. We found a genotype-phenotype correlation between PLXNA3 cytoplasmic domain variants (exons 22 to 32) and more severe neurodevelopmental disorder phenotypes (P < 0.05). Conclusions: We report 14 boys with maternally inherited, hemizygous PLXNA3 variants and a range of neurodevelopmental disorders suggesting a novel X-linked intellectual disability syndrome. Greater understanding of PLXNA3 variant pathogenicity in humans will require additional clinical, computational, and experimental validation.

Central giant cell granuloma (CGCG) is a rare tumour. The aetiology remains controversial with immunohistological features suggestive of inflammatory, vascular and proliferative markers. It is most often diagnosed in children and young adults under the age of 30 years with a predilection for the mandible. We herein present a case in a paediatric age group of a maxillary lesion of CGCG with a novel genetic translocation. A combination of surgical intervention including enucleation and embolization produced a good result. The importance of long term follow up for facial growth and recurrence is terribly important for the child.

Background Although multiple risk factors for development of pneumonia in patients with trauma sustained in a motor vehicle accident have been studied, the effect of prehospital time on pneumonia incidence post-trauma is unknown. Research Question Is prolonged prehospital time an independent risk factor for pneumonia? Study Design and Methods We retrospectively analyzed prospectively collected clinical data from 806,012 motor vehicle accident trauma incidents from the roughly 750 trauma hospitals contributing data to the National Trauma Data Bank between 2010 and 2016. Results Prehospital time was independently associated with development of pneumonia post-motor vehicle trauma (P Interpretation Increased prehospital time is an independent risk factor for development of pneumonia and increased mortality in patients with trauma caused by a motor vehicle accident. Although prehospital time is often not modifiable, its recognition as a pneumonia risk factor is important, because prolonged prehospital time may need to be considered in subsequent decision-making.

Questions: What airway clearance techniques and exercise regimens are used by adults with cystic fibrosis (CF) in Australia when well or unwell? What proportion of these adults believe that exercise can be used as a substitute for traditional airway clearance techniques, and how have they come to this belief? What type of exercise is used as a substitute for traditional airway clearance techniques? Design: Cross-sectional survey at 13 CF centres in Australia, using a purpose-designed questionnaire. Participants: Six hundred and ninety-two adults with CF completed the questionnaire. Outcome measures: The questionnaire included questions about: the participants' current use of traditional airway clearance techniques and exercise, when well and unwell; and beliefs regarding the use of exercise as a substitute for traditional airway clearance techniques. Results: Coughing, huffing and positive expiratory pressure were the most commonly used airway clearance techniques. Walking, jogging and lifting weights were the most commonly used forms of exercise. Overall, 43% of participants believed that exercise could be used as a substitute for traditional airway clearance techniques, with 44% having substituted exercise for traditional airway clearance techniques in the previous 3 months. Personal experience was the most commonly reported factor influencing participants' beliefs about the use of exercise as a substitute for traditional airway clearance techniques. Conclusion: Exercise is commonly used as a substitute for traditional airway clearance techniques. Physiotherapists should advise patients that whilst there is some research suggesting a possible mechanism for exercise as a form of airway clearance, there are currently no medium-term to long-term data supporting exercise as a stand-alone form of airway clearance. These results suggest that future research to investigate the clinical effectiveness of exercise as a substitute for traditional airway clearance techniques should be a priority. Registration: ACTRN12616000994482. Key words: Cystic fibrosis, Exercise, Physical therapy modalities, Respiratory therapy

BACKGROUND Opioid misuse during pregnancy has been associated with adverse infant outcomes including preterm birth, stillbirth, and neonatal opioid withdrawal syndrome. The Pregnancy Risk Assessment Monitoring System (PRAMS) is an on-going state-based surveillance system of maternal behaviors, attitudes, and experiences prior to, during, and after pregnancy. Methods: We analyzed qualitative comments related to opioid use during pregnancy collected in 2016 from an open-ended prompt at the end of the PRAMS survey in 35 states (N = 40,408). Key word searches were conducted on the open-ended responses (n = 9,549) to identify opioid-related content with an automated function using Microsoft Excel. All responses from the initial screening (n = 1,035) were manually reviewed, and 69 responses were confirmed to relate to the respondent's personal experience with opioid use during pregnancy. Content analysis was conducted by 3 independent coders; key themes were compiled, discussed, and finalized by the coding team. Results: Five key themes related to opioid use during pregnancy were identified: (1) gratitude for treatment, recovery, and healthy infants; (2) pregnancy as motivation to seek treatment; (3) difficulty finding prenatal care providers with training in substance use disorders; (4) concern about the effects of treatment on the infant; and (5) experiences of discrimination and stigma in the hospital around the time of delivery. Conclusions: Women may be aware of the potential impact of opioid use during pregnancy on the health of their infants and motivated to seek treatment. Findings may help inform new and ongoing initiatives designed to improve care and reduce stigma for women needing or seeking treatment.

PURPOSE. Routine use of the Oncotype DX Recurrence Score (RS) in patients with early-stage, estrogen receptor-positive, HER2-negative (ER+/HER2−) breast cancer is limited internationally by cost and availability. We created a supervised machine learning model using clinicopathologic variables to predict RS risk category in patients aged over 50 years. METHODS. From January 2012–December 2018, we identified patients aged over 50 years with T1-2, ER+/HER2−, node-negative tumors. Clinicopathologic data and RS results were randomly split into training and validation cohorts. A random forest model with 500 trees was developed on the training cohort, using age, pathologic tumor size, histology, progesterone receptor (PR) expression, lymphovascular invasion (LVI), and grade as predictors. We predicted risk category (low: RS ≤25, high: RS >25) using the validation cohort. RESULTS. Of the 3880 tumors identified, 1293 tumors comprised the validation cohort in patients of median (IQR) age 62 years (56–68) with median (IQR) tumor size 1.2 cm (0.8–1.7). Most tumors were invasive ductal (80.3%) of low-intermediate grade (80.5%) without LVI (80.9%). PR expression was ≤20% in 27.3% of tumors. Specificity for identifying RS ≤25 was 96.3% (95% CI 95.0–97.4), and the negative predictive value was 92.9% (95% CI 91.2–94.4). Sensitivity and positive predictive value for predicting RS >25 was lower (48.3% and 65.1%, respectively). CONCLUSION. Our model was highly specific for identifying eligible patients aged over 50 years for whom chemotherapy can be omitted. Following external validation, it may be used to triage patients for RS testing, if predicted to be high risk, in resource-limited settings.

The 17th St Gallen International Breast Cancer Consensus Conference in 2021 was held virtually, owing to the global COVID-19 pandemic. More than 3300 participants took part in this important bi-annual critical review of the 'state of the art' in the multidisciplinary care of early-stage breast cancer. Seventy-four expert panelists (see Appendix 1) from all continents discussed and commented on the previously elaborated consensus questions, as well as many key questions on early breast cancer diagnosis and treatment asked by the audience. The theme of this year's conference was 'Customizing local and systemic therapies.' A well-organized program of pre-recorded symposia, live panel discussions and real-time panel voting results drew a worldwide audience of thousands, reflecting the farreaching impact of breast cancer on every continent. The interactive technology platform allowed, for the first time, audience members to ask direct questions to panelists, and to weigh in with their own vote on several key panel questions. A hallmark of this meeting was to focus on customized recommendations for treatment of early-stage breast cancer. There is increasing recognition that the care of a breast cancer patient depends on highly individualized clinical features, including the stage at presentation, the biological subset of breast cancer, the genetic factors that may underlie breast cancer risk, the genomic signatures that inform treatment recommendations, the extent of response before surgery in patients who receive neoadjuvant therapy, and patient preferences. This customized approach to treatment requires integration of clinical care between patients and radiology, pathology, genetics, and surgical, medical and radiation oncology providers. It also requires a dynamic response from clinicians as they encounter accumulating clinical information at the time of diagnosis and then serially with each step in the treatment plan and follow-up, reflecting patient experiences and treatment response.

The human microbiome has a role in the development of multiple diseases. Individual microbiome profiles are highly personalized, though many species are shared. Understanding the relationship between the human microbiome and disease may inform future individualized treatments. We hypothesize the blood microbiome signature may be a surrogate for some lung microbial characteristics. We sought associations between the blood microbiome signature and lung-relevant host factors. Based on reads not mapped to the human genome, we detected microbial nucleic acids through secondary use of peripheral blood RNA-sequencing from 2,590 current and former smokers with and without chronic obstructive pulmonary disease (COPD) from the COPDGene study. We used the Genome Analysis Toolkit (GATK) microbial pipeline PathSeq to infer microbial profiles. We tested associations between the inferred profiles and lung disease relevant phenotypes and examined links to host gene expression pathways. We replicated our analyses using a second independent set of blood RNA-seq data from 1,065 COPDGene study subjects and performed a meta-analysis across the two studies. The four phyla with highest abundance across all subjects were Proteobacteria, Actinobacteria, Firmicutes and Bacteroidetes. In our meta-analysis, we observed associations (q-value Acinetobacter, Serratia, Streptococcus and Bacillus inferred abundances and Modified Medical Research Council (mMRC) dyspnea score. Current smoking status was associated (q Acinetobacter, Serratia and Cutibacterium abundance. All 12 taxa investigated were associated with at least one white blood cell distribution variable. Abundance for nine of the 12 taxa was associated with sex, and seven of the 12 taxa were associated with race. Host-microbiome interaction analysis revealed clustering of genera associated with mMRC dyspnea score and smoking status, through shared links to several host pathways. This study is the first to identify a bacterial microbiome signature in the peripheral blood of current and former smokers. Understanding the relationships between systemic microbial signatures and lung-related phenotypes may inform novel interventions and aid understanding of the systemic effects of smoking.

School-aged children with type 1 diabetes (T1D) and their parents are at risk for sleep disturbances, yet few studies have used objective measures to assess sleep characteristics in young children with T1D.Forty children (ages 5-9) with T1D and their parents wore actigraph watches and completed sleep diaries for 7 nights. Parents also completed questionnaires about demographic information, diabetes distress, fear of hypoglycemia, and family routines. Children's clinical data (HbA1c and blood glucose data) were extracted from the medical record.Most of the children and their parents obtained insufficient sleep. Based on actigraphy data, children slept an average of 7.9 hours/night and parents slept 6.7 hours/night, below the recommendations of 9-11 and 7-9 hours of sleep, respectively. Shorter child sleep latency was significantly associated with better glycemic levels, and parents' sleep duration and efficiency were related to child's glycemic levels. Parental fear of hypoglycemia and lack of family routines were associated with poorer sleep quality in parents and children, and with parental diabetes distress.Sleep duration and quality is a modifiable target for potentially improving glycemic levels and parental distress in early school-aged children with T1D.

AIM To explore the lived experiences of pain in children and young people with cerebral palsy (CP). METHOD Participants were recruited from the Sydney Children's Hospitals Network and the New South Wales/Australian Capital Territory CP Registers. Inclusion criteria were as follows: CP; aged 9 to 17 years; current/past experience of pain; fluent in English; no greater than mild intellectual disability. Purposive sampling ensured representation across age, motor subtypes, and Gross Motor Function Classification System (GMFCS) levels. Semi-structured face-to-face interviews were conducted. Data were analysed following an interpretative phenomenological approach. RESULTS Ten participants (three male) were included (mean age 14y 5mo, SD 2y), GMFCS levels I (n=4), II (n=3), III (n=2), and IV (n=1). Analysis led to three superordinate themes: (1) Everybody's experience of pain is different; (2) When the pain is winning; (3) 'I know how to deal with it'. Pain contributors and locations varied between children. Pain intruded on school, physical activity, and psychosocial functioning. Children described personalized strategies used to deal with pain. INTERPRETATION In this study, children self-reported highly individualized pain experiences which interfered with their daily life and psychosocial well-being. There is a need for improvement in pain assessment and a personalized approach to pain management.

Loss-of-function mutations in endosomal Na+/H+exchanger 6 (NHE6) cause the X-linked neurologic disorder Christianson syndrome. Patients exhibit symptoms associated with both neurodevelopmental and neurodegenerative abnormalities. While loss of NHE6 has been shown to overacidify the endosome lumen, and is associated with endolysosome neuropathology, NHE6-mediated mechanisms in endosome trafficking and lysosome function have been understudied. Here, we show that NHE6-null mouse neurons demonstrate worsening lysosome function with time in culture, likely as a result of defective endosome trafficking. NHE6-null neurons exhibit overall reduced lysosomal proteolysis despite overacidification of the endosome and lysosome lumen. Akin to Nhx1 mutants inSaccharomyces cerevisiae, we observe decreased endosome-lysosome fusion in NHE6-null neurons. Also, we find premature activation of pH-dependent cathepsin D (CatD) in endosomes. While active CatD is increased in endosomes, CatD activation and CatD protein levels are reduced in the lysosome. Protein levels of another mannose 6-phosphate receptor (M6PR)-dependent enzyme, β-N-acetylglucosaminidase, were also decreased in lysosomes of NHE6-null neurons. M6PRs accumulate in late endosomes, suggesting defective M6PR recycling and retromer function in NHE6-null neurons. Finally, coincident with decreased endosome-lysosome fusion, using total internal reflection fluorescence, we also find a prominent increase in fusion between endosomal multivesicular bodies and the plasma membrane, indicating enhanced exosome secretion from NHE6-null neurons. In summary, in addition to overacidification of endosomes and lysosomes, loss of NHE6 leads to defects in endosome maturation and trafficking, including enhanced exosome release, contributing to lysosome deficiency and potentially leading to neurodegenerative disease.SIGNIFICANCE STATEMENTLoss-of-function mutations in the endosomal Na+/H+exchanger 6 (NHE6) cause Christianson syndrome, an X-linked neurologic disorder. Loss of NHE6 has been shown to overacidify endosomes; however, endosome trafficking mechanisms have been understudied, and the mechanisms leading to neurodegeneration are largely unknown. In NHE6-null mouse neuronsin vitro, we find worsening lysosome function with days in culture. Notably, pH-dependent lysosome enzymes, such as cathepsin D, have reduced activity in lysosomes yet increased, precocious activity in endosomes in NHE6-null neurons. Further, endosomes show reduced fusion to lysosomes, and increased fusion to the plasma membrane with increased exosome release. This study identifies new mechanisms involving defective endosome maturation and trafficking that impair lysosome function in Christianson syndrome, likely contributing to neurodegeneration.

Introduction Although prolonged respiratory symptoms following severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection have been described in adults, data are emerging that children also experience long‐term sequelae of coronavirus disease 2019 (COVID‐19). The respiratory sequelae of COVID‐19 in children remain poorly characterized. In this study we describe health data and respiratory findings in pediatric patients presenting with persistent respiratory symptoms following COVID‐19. Methods This study included patients referred to Pulmonary Clinic at the Children's Hospital of Philadelphia between December 2020 and April 2021 (n = 29). Inclusion criteria included a history of SARS‐CoV‐2 RNA positivity or confirmed close household contact and suggestive symptoms. A retrospective chart review was performed and demographic, clinical, imaging, and functional test data were collected. Results The mean age at presentation to clinic was 13.1 years (range: 4–19 years). Patients had persistent respiratory symptoms ranging from 1.3 to 6.7 months postacute infection. Persistent dyspnea and/or exertional dyspnea were present in nearly all (96.6%) patients at the time of clinic presentation. Other reported chronic symptoms included cough (51.7%) and exercise intolerance (48.3%). Fatigue was reported in 13.8% of subjects. Many subjects were overweight or obese (62.1%) and 11 subjects (37.9%) had a prior history of asthma. Spirometry and plethysmography were normal in most patients. The six‐minute walk test (6MWT) revealed exercise intolerance and significant tachycardia in two‐thirds of the nine children tested. Conclusion Exertional dyspnea, cough and exercise intolerance were the most common respiratory symptoms in children with postacute COVID‐19 respiratory symptoms seen in an outpatient pulmonary clinic. Spirometry (and plethysmography when available), however, was mostly normal, and exertional intolerance was frequently demonstrated using the 6MWT.

Racial health disparities persist among black and white women for colorectal cancer. Understanding racial differences in the gut microbiota and related covariates (e.g., stress) may yield new insight into unexplained colorectal cancer disparities.Healthy non-Hispanic black or white women (age ≥19 years) provided survey data, anthropometrics, and stool samples. Fecal DNA was collected and isolated from a wipe. Polymerase chain reaction was used to amplify the V4 region of the 16SrRNA gene and 250 bases were sequenced using the MiSeq platform. Microbiome data were analyzed using QIIME. Operational taxonomic unit data were log transformed and normalized. Analyses were conducted using linear models in R Package "limma."Fecal samples were analyzed for 80 women (M (SD) age = 39.9 (14.0) years, 47 black, 33 white). Blacks had greater average body mass index (33.3 versus 27.5 kg/m, p.01) and waist circumference (98.3 versus 86.6 cm, p = .003) than whites. Whites reported more stressful life events (p = .026) and greater distress (p = .052) than blacks. Final models accounted for these differences. There were no significant differences in dietary variables. Unadjusted comparisons revealed no racial differences in alpha diversity. Racial differences were observed in beta diversity and abundance of top 10 operational taxonomic units. Blacks had higher abundances than whites of Faecalibacterium (p = .034) and Bacteroides (p = .038). Stress was associated with abundances of Bifidobacterium. The association between race and Bacteroides (logFC = 1.72, 0 = 0.020) persisted in fully adjusted models.Racial differences in the gut microbiota were observed including higher Bacteroides among blacks. Efforts to cultivate an "ideal" gut microbiota may help reduce colorectal cancer risk.

BACKGROUND: Among patients with stable coronary disease and moderate or severe ischemia, whether clinical outcomes are better in those who receive an invasive intervention plus medical therapy than in those who receive medical therapy alone is uncertain. METHODS: We randomly assigned 5179 patients with moderate or severe ischemia to an initial invasive strategy (angiography and revascularization when feasible) and medical therapy or to an initial conservative strategy of medical therapy alone and angiography if medical therapy failed. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. A key secondary outcome was death from cardiovascular causes or myocardial infarction. RESULTS: Over a median of 3.2 years, 318 primary outcome events occurred in the invasive-strategy group and 352 occurred in the conservative-strategy group. At 6 months, the cumulative event rate was 5.3% in the invasive-strategy group and 3.4% in the conservative-strategy group (difference, 1.9 percentage points; 95% confidence interval [CI], 0.8 to 3.0); at 5 years, the cumulative event rate was 16.4% and 18.2%, respectively (difference, -1.8 percentage points; 95% CI, -4.7 to 1.0). Results were similar with respect to the key secondary outcome. The incidence of the primary outcome was sensitive to the definition of myocardial infarction; a secondary analysis yielded more procedural myocardial infarctions of uncertain clinical importance. There were 145 deaths in the invasive-strategy group and 144 deaths in the conservative-strategy group (hazard ratio, 1.05; 95% CI, 0.83 to 1.32). CONCLUSIONS: Among patients with stable coronary disease and moderate or severe ischemia, we did not find evidence that an initial invasive strategy, as compared with an initial conservative strategy, reduced the risk of ischemic cardiovascular events or death from any cause over a median of 3.2 years. The trial findings were sensitive to the definition of myocardial infarction that was used. (Funded by the National Heart, Lung, and Blood Institute and others; ISCHEMIA ClinicalTrials.gov number, NCT01471522.).

Blood and blood clots should be removed from the heart chambers before being weighed. The actual method in removing blood and blood clots may vary and can include manual removal with subsequent rinsing the heart in water. It is unclear whether drying the rinsed heart affects the heart weight. The objective of this article was to investigate the effects drying the rinsed dissected heart (residual rinsing water) on postmortem heart weight. The prospective study compared 44 dissected heart weights after being rinsed and after being pat dried. An average 18-20 g of residual rinsing water (4% of heart weight) was present in the dissected heart. The amount of residual rinsing water correlates positively with heart weight. The effects of drying the rinsed dissected heart were considered clinically insignificant. Although being clinically insignificant, this study highlights the lack of standardized approach in weighing the heart and the potential implications in interpreting heart weights.

Background Breast cancer and ovarian cancer patients increasingly undergo germline genetic testing. However, little is known about cancer-specific mortality among carriers of a pathogenic variant (PV) in BRCA1/2 or other genes in a population-based setting. Methods Georgia and California Surveillance Epidemiology and End Results (SEER) registry records were linked to clinical genetic testing results. Women were included who had stages I-IV breast cancer or ovarian cancer diagnosed in 2013-2017, received chemotherapy, and were linked to genetic testing results. Multivariable Cox proportional hazard models were used to examine the association of genetic results with cancer-specific mortality. Results 22 495 breast cancer and 4320 ovarian cancer patients were analyzed, with a median follow-up of 41 months. PVs were present in 12.7% of breast cancer patients with estrogen and/or progesterone receptor-positive, HER2-negative cancer, 9.8% with HER2-positive cancer, 16.8% with triple-negative breast cancer, and 17.2% with ovarian cancer. Among triple-negative breast cancer patients, cancer-specific mortality was lower with BRCA1 (hazard ratio [HR] = 0.49, 95% confidence interval [CI] = 0.35 to 0.69) and BRCA2 PVs (HR = 0.60, 95% CI = 0.41 to 0.89), and equivalent with PVs in other genes (HR = 0.65, 95% CI = 0.37 to 1.13), vs noncarriers. Among ovarian cancer patients, cancer-specific mortality was lower with PVs in BRCA2 (HR = 0.35, 95% CI = 0.25 to 0.49) and genes other than BRCA1/2 (HR = 0.47, 95% CI = 0.32 to 0.69). No PV was associated with higher cancer-specific mortality. Conclusions Among breast cancer and ovarian cancer patients treated with chemotherapy in the community, BRCA1/2 and other gene PV carriers had equivalent or lower short-term cancer-specific mortality than noncarriers. These results may reassure newly diagnosed patients, and longer follow-up is ongoing.

Obesity is a risk factor for the development of post-menopausal breast cancer. Breast white adipose tissue (WAT) inflammation, which is commonly found in women with excess body fat, is also associated with increased breast cancer risk. Both local and systemic effects are probably important for explaining the link between excess body fat, adipose inflammation and breast cancer. The first goal of this cross-sectional study of 196 women was to carry out transcriptome profiling to define the molecular changes that occur in the breast related to excess body fat and WAT inflammation. A second objective was to determine if commonly measured blood biomarkers of risk and prognosis reflect molecular changes in the breast. Breast WAT inflammation was assessed by immunohistochemistry. Bulk RNA-sequencing was carried out to assess gene expression in non-tumorous breast. Obesity and WAT inflammation were associated with a large number of differentially expressed genes and changes in multiple pathways linked to the development and progression of breast cancer. Altered pathways included inflammatory response, complement, KRAS signaling, tumor necrosis factor α signaling via NFkB, interleukin (IL)6-JAK-STAT3 signaling, epithelial mesenchymal transition, angiogenesis, interferon γ response and transforming growth factor (TGF)-β signaling. Increased expression of several drug targets such as aromatase, TGF-β1, IDO-1 and PD-1 were observed. Levels of various blood biomarkers including high sensitivity C-reactive protein, IL6, leptin, adiponectin, triglycerides, high-density lipoprotein cholesterol and insulin were altered and correlated with molecular changes in the breast. Collectively, this study helps to explain both the link between obesity and breast cancer and the utility of blood biomarkers for determining risk and prognosis.

Background Selective dorsal rhizotomy (SDR) is a neurosurgical intervention to reduce spasticity in children with cerebral palsy. Parents researching SDR for their child may be influenced by framing of SDR in news media articles they read. This study examined framing of SDR in English-language news media. Methods Content analysis of English-language news media articles including the search term 'rhizotomy' in the Factiva database published July 2015 to July 2018 in online or print form in Canada, New Zealand, Australia, United States of America and the United Kingdom. Results One hundred and eighty-six articles were identified describing 91 different children (45 male), almost all with cerebral palsy, median age 4 years old. One hundred and twenty-six articles were written prior to surgery; in many articles, SDR surgery involved travel overseas and/or fundraising. SDR was described universally in positive terms with little discussion of risks. Content of articles variably included the specialized nature of SDR, parental frustration with their local health system and their hope for positive outcomes. There was geographical variation in both numbers of articles and content. Conclusions SDR is a common focus in cerebral palsy news media articles in some countries. Framing in these articles supports SDR as a beneficial and specialized procedure and may lead families to believe they need to work outside their local health systems. As news media are likely an important influence on families' attitudes to SDR, clinicians should be aware of this influence.

HER2 +- amplified breast cancer patients derive benefit from treatment with anti-HER2-targeted therapy. Though adjuvant treatment is based on final pathology, decisions regarding neoadjuvant chemotherapy are made in the preoperative setting with imaging playing a key role in staging. We examined the accuracy of pre-operative imaging in determining pathological tumor size (pT) in patients undergoing upfront surgery. Early (cT1–T2N0) HER2 + breast cancer patients who underwent upfront surgery between 2015 and 2016 were identified from a prospective institutional database. We compared data for both clinical and final pathologic stage. Only those who underwent magnetic resonance imaging (MRI), mammography, and ultrasound in the preoperative setting were included in the analysis. Adjuvant treatment regimens were reviewed. We identified 87 cT1–2N0 patients with invasive HER2 + breast cancer who underwent upfront surgery. Median age was 52 years (IQR 43, 58) and median tumor size was 1.1 cm (IQR 0.5, 1.6). Fifteen patients (17%) were upstaged to stage II/III based on final pathology. Thirty-seven patients were T1cN0 on final pathology; 8 were cT1a–bN0 preop and 12 had pT overestimated by MRI by an average of 1.5 cm (> 0.5–1.5 cm). Compared to both mammography and MRI, the imaging modality most predictive of pT was ultrasound (p = 0.000072 ultrasound vs mammography and 0.000042 ultrasound vs MRI). For small HER2 + cN0 tumors undergoing upfront surgery, ultrasound was the imaging modality most predictive of pT. MRI overestimated tumor size in approximately 40% of patients. MRI may not accurately discriminate low-volume tumor burden in the breast and carries the potential of overtreatment in the upfront setting.

Introduction In this single-centre retrospective observational study, the 8-week safety and the efficiency of a single dose of BNT162b2 vaccine was studied in 83 HD patients. Methods All clinically stable adult ESRD patients on chronic HD for at least 4 weeks were screened for participation in the study. Exclusion criteria for enrollment in the study included a medical history of COVID-19 infection within the last 12 weeks or delivery of both vaccine doses less than 8 weeks apart from each other. The same patients during the 8-week period that preceded the vaccination served as controls of themselves. The vaccine was administered intramuscularly in the deltoid muscle, on a dialysis day, at least 30 min either pre- or post-dialysis. The primary end-point of the study was severe COVID-19 infection, and/or death due to COVID-19 pneumonitis. Furthermore, all vaccinated patients were scrutinized for any local or systemic reactions within the first 7 days post-vaccination. Results Amongst 113 adult HD patients in our Unit, in total 83 patients had the first 30 μg dose of the BNT162b2 vaccine and were considered eligible to be included in the study. The 8-week survival rate was 91% for the controls and 100% for the vaccine group. No life-threatening allergic reaction or other side-effect was observed post-vaccination. Conclusion The BNT162b2 vaccine can be safely used in HD patients and seems to offer significant protection against the infection even after the first vaccine dose.

Overall cancer death rates have fallen since a peak in 1991 due to declining death rates for lung, colorectal, breast, and prostate cancers. A "cancer survivor" is defined as anyone with a cancer diagnosis. Their numbers are increasing for several reasons including better screening, earlier detection, and improved treatments. The American Cancer Society's projections for colorectal cancer in 2020 are 147,950 new cases and 53,200 deaths. By 2024, there will be an estimated 1.71 million colorectal cancer survivors (17% of all cancer survivors) and many will experience long-term consequences. These problems may be the result of one or more treatment options: surgical resection, systemic chemotherapy, and radiation therapy. Problems include issues with bowel, ostomy, bladder, sexual health, peripheral neuropathy, and mental health. Colorectal cancer survivors are especially receptive to making lifestyle changes to improve their long-term health. Gastroenterology nurses can utilize evidence-based recommendations for weight management, diet, physical activity, and lifestyle with the goal of preventing recurrence and a second primary cancer and promoting overall long-term health.

INTRODUCTION: Environmental factors play a critical role in the progression or resolution of chronic respiratory diseases. However, studies are limited on the impact of environmental risk factors on individuals born prematurely with lung disease after they leave the neonatal intensive care unit and are discharged into the home environment. AREAS COVERED: In this review, we cover current knowledge of environmental exposures that impact outcomes of preterm respiratory disease, including air pollution, infections, and disparities. The limited data do suggest that certain exposures should be avoided and there are potential preventative strategies for other exposures. There is a need for additional research outside the neonatal intensive care unit that focuses on individual and community-level factors that affect long-term outcomes. EXPERT OPINION: Preterm respiratory disease can impose a significant burden on infants, children, and young adults born prematurely, but may improve for many individuals over time. In this review, we outline the exposures that may potentially hasten, delay, or prevent resolution of lung injury in preterm children.

Background: The coronavirus disease 2019 (COVID-19) pandemic has exposed longstanding racial and ethnic inequities in health risks and outcomes in the United States. We aimed to identify racial and ethnic differences in presentation and outcomes for patients hospitalized with COVID-19. Methods: The American Heart Association COVID-19 Cardiovascular Disease Registry is a retrospective observational registry capturing consecutive patients hospitalized with COVID-19. We present data on the first 7868 patients by race/ethnicity treated at 88 hospitals across the United States between January 17, 2020, and July 22, 2020. The primary outcome was in-hospital mortality. Secondary outcomes included major adverse cardiovascular events (death, myocardial infarction, stroke, heart failure) and COVID-19 cardiorespiratory ordinal severity score (worst to best: death, cardiac arrest, mechanical ventilation with mechanical circulatory support, mechanical ventilation with vasopressors/inotrope support, mechanical ventilation without hemodynamic support, and hospitalization alone. Multivariable logistic regression analyses were performed to assess the relationship between race/ethnicity and each outcome adjusting for differences in sociodemographic, clinical, and presentation features, and accounting for clustering by hospital. Results: Among 7868 patients hospitalized with COVID-19, 33.0% were Hispanic, 25.5% were non-Hispanic Black, 6.3% were Asian, and 35.2% were non-Hispanic White. Hispanic and Black patients were younger than non-Hispanic White and Asian patients and were more likely to be uninsured. Black patients had the highest prevalence of obesity, hypertension, and diabetes. Black patients also had the highest rates of mechanical ventilation (23.2%) and renal replacement therapy (6.6%) but the lowest rates of remdesivir use (6.1%). Overall mortality was 18.4% with 53% of all deaths occurring in Black and Hispanic patients. The adjusted odds ratios for mortality were 0.93 (95% CI, 0.76–1.14) for Black patients, 0.90 (95% CI, 0.73–1.11) for Hispanic patients, and 1.31 (95% CI, 0.96–1.80) for Asian patients compared with non-Hispanic White patients. The median odds ratio across hospitals was 1.99 (95% CI, 1.74–2.48). Results were similar for major adverse cardiovascular events. Asian patients had the highest COVID-19 cardiorespiratory severity at presentation (adjusted odds ratio, 1.48 [95% CI, 1.16–1.90]). Conclusions: Although in-hospital mortality and major adverse cardiovascular events did not differ by race/ethnicity after adjustment, Black and Hispanic patients bore a greater burden of mortality and morbidity because of their disproportionate representation among COVID-19 hospitalizations.

The use of stereotactic body radiation therapy (SBRT) to treat many canine tumors is rapidly expanding. However, published studies are lacking regarding use of SBRT for management of canine anal sac adenocarcinoma (ASAC), primarily due to concerns regarding intolerable late effects. The objective of this retrospective, pilot study was to describe the efficacy and safety profile of coarse fractions administered with an SBRT regime to manage a group of dogs with ASAC. A total of 12 dogs with ASAC that received SBRT as a component of their treatment were sampled. Three patients had macroscopic primary tumors irradiated, while nine patients received SBRT following incomplete surgical resection. Seven patients also received metastatic regional lymph node irradiation. Primary tumor and nodal irradiation sites received three fractions totaling 22-24 Gy and 22.5-24 Gy, respectively, over three consecutive days. All patients developed acute effects including mild colitis, alopecia, and erythema. Late effects included alopecia, variable dermal pigmentation and leuko- or melanotrichia within radiation fields, and rectal stricture in one patient. A median progression free survival time of 549 days and median survival time of 991 days were achieved in this study. These results should be considered preliminary data suggesting that coarse fractionation administered with an SBRT technique is a safe and effective treatment regime for the management of canine ASAC, with the aim to conduct prospective studies in the future.

Purpose To expand the recent description of a new neurodevelopmental syndrome related to alterations in CDK19. Methods Individuals were identified through international collaboration. Functional studies included autophosphorylation assays for CDK19 Gly28Arg and Tyr32His variants and in vivo zebrafish assays of the CDK19(G28R) and CDK19(Y32H). Results We describe 11 unrelated individuals (age range: 9 months to 14 years) with de novo missense variants mapped to the kinase domain of CDK19, including two recurrent changes at residues Tyr32 and Gly28. In vitro autophosphorylation and substrate phosphorylation assays revealed that kinase activity of protein was lower for p.Gly28Arg and higher for p.Tyr32His substitutions compared with that of the wild-type protein. Injection of CDK19 messenger RNA (mRNA) with either the Tyr32His or the Gly28Arg variants using in vivo zebrafish model significantly increased fraction of embryos with morphological abnormalities. Overall, the phenotype of the now 14 individuals with CDK19-related disorder includes universal developmental delay and facial dysmorphism, hypotonia (79%), seizures (64%), ophthalmologic anomalies (64%), and autism/autistic traits (56%). Conclusion CDK19 de novo missense variants are responsible for a novel neurodevelopmental disorder. Both kinase assay and zebrafish experiments showed that the pathogenetic mechanism may be more diverse than previously thought.

Ataxia telangiectasia (A-T) is a rare autosomal recessive disease caused by mutations in the ataxia telangiectasia mutated (ATM) gene. In the absence of a family history, the diagnosis of A-T is usually not made until the child is older and symptomatic. Classic A-T is characterized by a constellation of clinical symptoms including progressive ataxia, oculocutaneous telangiectasias and sinopulmonary disease and is usually associated with absence of ATM protein. Other laboratory features associated with A-T include elevated serum levels of alpha-fetoprotein (AFP) and increased chromosomal breakage with in vitro exposure to ionizing radiation. Sinopulmonary symptoms can occur to varying degrees across the lifespan. Some children will also have hypogammaglobulinemia and impaired antibody responses requiring supplemental gamma globulin. People with hypomorphic ATM mutations are often considered to have mild A-T with onset of ataxia and neurological progression occurring later in life with less impairment of the immune system. The risk of malignancy, however, is significantly increased in people with either classic or mild A-T. While hematological malignancies are most common in the first two decades of life, solid organ malignancies become increasingly common during young adulthood. Deterioration of neurologic function with age is associated with dysphagia with aspiration, growth faltering, loss of ambulation and decline in pulmonary function, morbidities that contribute to shortened life expectancy and decreased quality of life. Premature death is often due to malignancies or chronic respiratory insufficiency. A-T is currently managed with supportive care and symptomatic treatment. Current clinical trials, however, represent progress and hope towards disease-modifying therapies for A-T.

Purpose of review Cardiogenic shock is a complex clinical syndrome of end-organ hypoperfusion due to impaired cardiac performance. Although cardiogenic shock has traditionally been viewed as a monolithic disorder predominantly caused by severe left ventricular dysfunction complicating acute myocardial infarction (AMI), there is increasing recognition of the diverse causes of cardiogenic shock and wide spectrum of clinical severity. The purpose of this review is to describe the contemporary epidemiology of cardiogenic shock, including trends in clinical outcomes and recent efforts to refine risk assessment. Recent findings The incidence of cardiogenic shock among patients with AMI has remained remarkably stable at 3-10%; however, the proportion of cardiogenic shock cases related to AMI has decreased over time to ∼30%, while the proportion of cardiogenic shock cases due to acute decompensated heart failure has steadily increased. Estimated in-hospital mortality from cardiogenic shock in contemporary registries is approximately 30-40%, suggesting modest improvement in cardiogenic shock outcomes over the last decade. There is a wide spectrum of clinical severity among patients presenting with cardiogenic shock, which is described by the Society for Cardiovascular Angiography and Interventions clinical staging criteria. Summary Improved clinical characterization and risk assessment of patients with cardiogenic shock may facilitate more effective clinical investigations of this morbid clinical syndrome.

Purpose While there is literature that examines factors associated with low participation in cancer screening among Canadian ethnic groups, there is limited understanding of black visible minorities, particularly Somalis. Thus, the purpose of this study is to synthesize knowledge pertaining to the perceptions, beliefs and barriers of Somali women and men toward screening for breast, cervical and colorectal cancers in countries such as Canada. Design/methodology/approach The scoping review methodology was used to search for peer-reviewed articles that explicitly examined perceptions, beliefs and barriers among Somalis toward screening for breast, cervical and colorectal cancers in developed countries. The following electronic databases were searched without time frame restrictions, namely, OVID Medline, Embase, CINHAL, PubMed, Scopes and ProQuest. A total of 402 peer-reviewed articles were identified and screened. Three articles were identified through reference list screening (one eligible) and consultation with experts in the networks (two eligible). In total, 12 studies met the inclusion criteria for synthesis. Thematic analysis was used to analyze the selected articles for key themes and the synthesis was informed by the socio-ecological model. Findings The majority of studies originated from the USA and focused primarily on Somali women and cervical cancer screening. Themes that emerged from the literature include individual-level negative experiences and socio-cultural perceptions/beliefs; community-level barriers in cancer screening; and systemic challenges in navigating the health-care system. Many of the studies focused on individual and community-level determinants of cancer screening, with little attention to systemic level determinants. Other gaps identified include factors influencing Somali men’s low participation in cancer screening; limited studies on colorectal cancer and Somali women; and specific cancer-screening barriers faced by Somalis within the Canadian context. Originality/value The findings of the review reveal multiple cancer screening challenges for Somali communities and the gained insights should inform both health and social care practitioners and policymakers.

The objective of this study was to determine the clinical features that moderate a later age at ASD diagnosis in females in a large sample of females with ASD. Within two large and independent ASD datasets (> 20,000 females), females were first diagnosed with ASD 14-months later relative to males. This later age at diagnosis was moderated by a mild or atypical presentation, wherein repetitive behaviors were limited, IQ and language were broadly intact, and recognized symptoms emerged later in development. Females are at risk for a later age at ASD diagnosis and treatment implementation, and modification of early childhood ASD screening methods for females may be warranted.

Background Published data suggest worse outcomes in acute coronary syndrome (ACS) patients and concurrent coronavirus disease 2019 (COVID-19) infection. Mechanisms remain unclear. Objectives The purpose of this study was to report the demographics, angiographic findings, and in-hospital outcomes of COVID-19 ACS patients and compare these with pre–COVID-19 cohorts. Methods From March 1, 2020 to July 31, 2020, data from 55 international centers were entered into a prospective, COVID-ACS Registry. Patients were COVID-19 positive (or had a high index of clinical suspicion) and underwent invasive coronary angiography for suspected ACS. Outcomes were in-hospital major cardiovascular events (all-cause mortality, re–myocardial infarction, heart failure, stroke, unplanned revascularization, or stent thrombosis). Results were compared with national pre–COVID-19 databases (MINAP [Myocardial Ischaemia National Audit Project] 2019 and BCIS [British Cardiovascular Intervention Society] 2018 to 2019). Results In 144 ST-segment elevation myocardial infarction (STEMI) and 121 non–ST-segment elevation acute coronary syndrome (NSTE-ACS) patients, symptom-to-admission times were significantly prolonged (COVID-STEMI vs. BCIS: median 339.0 min vs. 173.0 min; p, Central Illustration

As neoadjuvant chemotherapy (NAC) for breast cancer has become more widely used, so has nipple-sparing mastectomy. A common criterion for eligibility is a 1 cm tumor-to-nipple distance (TND), but its suitability after NAC is unclear. In this study, we examined factors predictive of negative nipple pathologic status (NS−) in women undergoing total mastectomy after NAC. Women with invasive breast cancer treated with NAC and total mastectomy from August 2014 to April 2018 at our institution were retrospectively identified. Following review of pre- and post-NAC magnetic resonance imaging (MRI) and mammograms, the association of clinicopathologic and imaging variables with NS− was examined and the accuracy of 1 cm TND on imaging for predicting NS− was determined. Among 175 women undergoing 179 mastectomies, 74% of tumors were cT1-T2 and 67% were cN+ on pre-NAC staging; 10% (18/179) had invasive or in situ carcinoma in the nipple on final pathology. On multivariable analysis, after adjusting for age, grade, and tumor stage, three factors, namely number of positive nodes, pre-NAC nipple-areolar complex retraction, and decreasing TND, were significant predictors of nipple involvement (p

Background Although resuscitation with IV fluids is the cornerstone of sepsis management, consensus regarding their association with improvement in clinical outcomes is lacking. Research Question Is there a difference in the incidence of respiratory failure in patients with sepsis who received guideline-recommended initial IV fluid bolus of 30 mL/kg or more conservative resuscitation of less than 30 mL/kg? Study Design and Methods This was a retrospective analysis of prospectively collected clinical data conducted at an academic medical center in Omaha, Nebraska. We abstracted data from 214 patients with sepsis admitted to a single academic medical center between June 2017 and June 2018. Patients were stratified by receipt of guideline-recommended fluid bolus. The primary outcome was respiratory failure defined as an increase in oxygen flow rate or more intense oxygenation and ventilation support; oxygen requirement and volume were measured at admission, 6 h, 12 h, 24 h, and at discharge. Subgroup analyses were conducted in high-risk patients with congestive heart failure (CHF) as well as those with chronic kidney disease (CKD). Results A total of 62 patients (29.0%) received appropriate bolus treatment. The overall rate of respiratory failure was not statistically different between patients who received appropriate bolus or did not (40.3% vs 36.8%; P = .634). Likewise, no differences were observed in time to respiratory failure (P = .645) or risk of respiratory failure (adjusted hazard ratio, 1.1 [95% CI, 0.7-1.7]; P = .774). Results were similar within the high-risk CHF and CKD subgroups. Interpretation In this single-center retrospective study, we found that by broadly defining respiratory failure as an increase in oxygen requirements, a conservative initial IV fluid resuscitation strategy did not correlate with decreased rates of hypoxemic respiratory failure.

Radiotherapy (RT) after breast-conserving surgery (BCS) halves the risk of local recurrence, and it is considered the standard of care for the vast majority of patients with early invasive breast cancer. However, the majority of patients treated with BCS will not recur locally, even in the absence of RT. Over the past several decades, the improved and widespread use of systemic therapy has significantly decreased the rate of local recurrence. This has stimulated interest in identifying favorable patient subsets not requiring RT. Randomized controlled trials have shown in women aged ≥ 70 years with stage I estrogen receptor-positive (ER+) tumors, RT can be safely omitted. To better identify patients with favorable prognosis, ongoing trials have incorporated biological markers and genomic assays. Despite great research efforts to de-escalate locoregional treatment, real-world data indicate that omission of RT in low-risk patients is inconsistent. Better decision-making is warranted to reduce overtreatment and financial toxicity.

A hallmark of subclinical atherosclerosis is the accumulation of vascular smooth muscle cell (SMC)-like cells leading to intimal thickening and lesion formation. While medial SMCs contribute to vascular lesions, the involvement of resident vascular stem cells (vSCs) remains unclear. We evaluated single cell photonics as a discriminator of cell phenotype in vitro before the presence of vSC within vascular lesions was assessed ex vivo using supervised machine learning and further validated using lineage tracing analysis. Using a novel lab-on-a-Disk(Load) platform, label-free single cell photonic emissions from normal and injured vessels ex vivo were interrogated and compared to freshly isolated aortic SMCs, cultured Movas SMCs, macrophages, B-cells, S100β+ mVSc, bone marrow derived mesenchymal stem cells (MSC) and their respective myogenic progeny across five broadband light wavelengths (λ465 - λ670 ± 20 nm). We found that profiles were of sufficient coverage, specificity, and quality to clearly distinguish medial SMCs from different vascular beds (carotid vs aorta), discriminate normal carotid medial SMCs from lesional SMC-like cells ex vivo following flow restriction, and identify SMC differentiation of a series of multipotent stem cells following treatment with transforming growth factor beta 1 (TGF- β1), the Notch ligand Jagged1, and Sonic Hedgehog using multivariate analysis, in part, due to photonic emissions from enhanced collagen III and elastin expression. Supervised machine learning supported genetic lineage tracing analysis of S100β+ vSCs and identified the presence of S100β+vSC-derived myogenic progeny within vascular lesions. We conclude disease-relevant photonic signatures may have predictive value for vascular disease. Graphical abstract

INTRODUCTION Bronchopulmonary dysplasia (BPD) is a common respiratory sequelae of preterm birth, for which longitudinal outpatient data are limited. Our objective was to describe a geographically diverse outpatient cohort of former preterm infants followed in BPD-disease specific clinics. METHODS Seven BPD specialty clinics contributed data using standardized instruments to this retrospective cohort study. Inclusion criteria included preterm birth (

Haemolysis is reported to be an artefact that may alter post-mortem tryptase levels. However, previous studies did not sample peripheral blood using newly standardised methods. Recent studies have shown that some previously recognised peri- and post-mortem confounders can be muted by careful sample collection with first clamping and then sampling the femoral vein. This prospective study investigated the relationship between the degree of haemolysis of the blood samples and femoral vein post-mortem tryptase levels when sampled using this recommended method. Seventy consecutive post-mortem tryptase levels in non-anaphylactic deaths were compared to the degree of haemolysis of these samples, and results showed no significant correlation between them. The mean post-mortem tryptase level was 9.5 μg/L. This study demonstrated that the effects of haemolysis on femoral vein post-mortem tryptase was negligible when the blood was sampled using the recommended sampling method. Future studies on post-mortem tryptase as well as other typically used blood markers in forensics are recommended to adopt this method of blood sampling in routine practice.

Prostate cancer is a leading cause of morbidity and mortality for adult males in the US. The diagnosis of prostate carcinoma is usually made on prostate core needle biopsies obtained through a transrectal approach. These biopsies may account for a significant portion of the pathologists' workload, yet variability in the experience and expertise, as well as fatigue of the pathologist may adversely affect the reliability of cancer detection. Machine-learning algorithms are increasingly being developed as tools to aid and improve diagnostic accuracy in anatomic pathology. The Paige Prostate AI-based digital diagnostic is one such tool trained on the digital slide archive of New York's Memorial Sloan Kettering Cancer Center (MSKCC) that categorizes a prostate biopsy whole-slide image as either "Suspicious" or "Not Suspicious" for prostatic adenocarcinoma. To evaluate the performance of this program on prostate biopsies secured, processed, and independently diagnosed at an unrelated institution, we used Paige Prostate to review 1876 prostate core biopsy whole-slide images (WSIs) from our practice at Yale Medicine. Paige Prostate categorizations were compared to the pathology diagnosis originally rendered on the glass slides for each core biopsy. Discrepancies between the rendered diagnosis and categorization by Paige Prostate were each manually reviewed by pathologists with specialized genitourinary pathology expertise. Paige Prostate showed a sensitivity of 97.7% and positive predictive value of 97.9%, and a specificity of 99.3% and negative predictive value of 99.2% in identifying core biopsies with cancer in a data set derived from an independent institution. Areas for improvement were identified in Paige Prostate's handling of poor quality scans. Overall, these results demonstrate the feasibility of porting a machine-learning algorithm to an institution remote from its training set, and highlight the potential of such algorithms as a powerful workflow tool for the evaluation of prostate core biopsies in surgical pathology practices.

Obesity is associated with an increased risk of breast cancer in post-menopausal women and decreased risk in pre-menopausal women. Conversely, in BRCA1/2 mutation carriers, pre-menopausal obesity is associated with early-onset breast cancer. Here we show that obese, pre-menopausal BRCA1/2 mutation carriers have increased levels of aromatase and inflammation in the breast, as occurs in post-menopausal women. In a prospective cohort study of 141 women with germline BRCA1 (n = 74) or BRCA2 (n = 67) mutations, leptin, and aromatase expression were higher in the breast tissue of obese versus lean individuals (P P P BRCA1/2 mutation carriers.

The neuronal membrane-associated periodic spectrin skeleton (MPS) contributes to neuronal development, remodeling, and organization. Post-translational modifications impinge on spectrin, the major component of the MPS, but their role remains poorly understood. One modification targeting spectrin is cleavage by calpains, a family of calcium-activated proteases. Spectrin cleavage is regulated by activated calpain, but also by the calcium-dependent binding of calmodulin (CaM) to spectrin. The physiologic significance of this balance between calpain activation and substrate-level regulation of spectrin cleavage is unknown. We report a strain of C57BL/6J mice harboring a single αII spectrin point mutation (Sptan1 c.3293G > A:p.R1098Q) with reduced CaM affinity and intrinsically enhanced sensitivity to calpain proteolysis. Homozygotes are embryonic lethal. Newborn heterozygotes of either gender appear normal, but soon develop a progressive ataxia characterized biochemically by accelerated calpain-mediated spectrin cleavage and morphologically by disruption of axonal and dendritic integrity and global neurodegeneration. Molecular modeling predicts unconstrained exposure of the mutant spectrin’s calpain-cleavage site. These results reveal the critical importance of substrate-level regulation of spectrin cleavage for the maintenance of neuronal integrity. Given that excessive activation of calpain proteases is a common feature of neurodegenerative disease and traumatic encephalopathy, we propose that damage to the spectrin MPS may contribute to the neuropathology of many disorders.

Background Ataxia telangiectasia (A-T) is a DNA repair disorder that affects multiple body systems. Neurological problems and immunodeficiency are two important features of this disease. At this time, two main severity groups are defined in A-T: classic (the more severe form) and mild. Poor growth is a common problem in classic A-T. An objective of this study was to develop growth references for classic A-T. Another objective was to compare growth patterns in classic A-T and mild A-T with each other and with the general population, using the CDC growth references. A final objective was to examine the effects of chronic infection on height. Results We found that classic A-T patients were smaller overall, and suffered from height and weight faltering that continued throughout childhood and adolescence. When compared to the CDC growth references, the median heights and weights for both male and female patients eventually fell to or below the 3rd centile on the CDC charts. Height faltering was more pronounced in females. Birthweight was lower in the classic A-T group compared to mild A-T and the general population, whereas birth length was not. Finally, we investigated height and BMI faltering in relation to number of infections and found no association. Conclusions Classic A-T appears to affect growth in utero. Although children appear to grow well in very early life, faltering begins early, and is unrelenting.

Background Non-vitamin K antagonist oral anticoagulants (NOACs) are the preferred class of medications for prevention of stroke and systemic embolism in patients with atrial fibrillation unless contraindications exist. Five large, international, randomized, controlled trials of NOACs versus either warfarin or aspirin have been completed to date. Design COMBINE AF incorporates de-identified individual patient data from 77,282 patients with atrial fibrillation at risk for stroke randomized to NOAC, warfarin, or aspirin from 5 pivotal randomized controlled trials. All patients randomized in the constituent trials are included. Variables common to ≥3 of the constituent trials are included in the master database. Individual trial data sets from the 4 coordinating centers were combined at the Duke Clinical Research Institute. The final database will be securely shared with the 4 academic coordinating centers. The combined master database will be used to perform statistical analyses aimed at better understanding underlying risk factors and outcomes in patients with atrial fibrillation treated with oral anticoagulants, with a special focus on patient subgroups and uncommon outcomes. The initial analysis from COMBINE AF will be a network meta-analysis investigating the relative efficacy and safety of pooled higher-dose NOACs versus pooled lower-dose NOACs versus warfarin with respect to multiple time-to-event efficacy and safety outcomes. COMBINE AF is registered with PROSPERO (CRD42020178771). Conclusion In conclusion, COMBINE AF provides a rich and robust database consisting of individual patient data and will offer opportunities to investigate oral anticoagulants across many patient subgroups. Data sharing and collaboration across academic institutions and investigators will serve as overarching themes.

The characterization of cancer genomes has provided insight into somatically altered genes across tumors, transformed our understanding of cancer biology, and enabled tailoring of therapeutic strategies. However, the function of most cancer alleles remains mysterious, and many cancer features transcend their genomes. Consequently, tumor genomic characterization does not influence therapy for most patients. Approaches to understand the function and circuitry of cancer genes provide complementary approaches to elucidate both oncogene and non-oncogene dependencies. Emerging work indicates that the diversity of therapeutic targets engendered by non-oncogene dependencies is much larger than the list of recurrently mutated genes. Here we describe a framework for this expanded list of cancer targets, providing novel opportunities for clinical translation.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

High rates of attrition to post-bariatric surgical care continue to be common, despite recommendations for lifelong follow-up. There is little available work focusing on the etiology of attrition to post-bariatric surgical follow-up. Patient-reported outcomes (PROs) are metrics of patients’ perceptions of their own health and have been used for their predictive value in other specialties. The relationships between PROs and loss to follow-up have not been explored. PRO data from patients who met the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program (MBSAQIP) definition of loss to follow-up at 1-year postoperatively were reviewed and compared to patients who were compliant with 1-year follow-up. Patient-reported outcomes measurement information system (PROMIS) measures are routinely collected pre- and postoperatively at our institution using a series of validated computer-adaptive tests that assess depression, satisfaction with social roles, pain interference, and physical function. A series of univariate logistic regressions tested whether baseline PROs or change in PROs from baseline to 6-month postoperatively predicted loss to follow-up at 1 year. Neither baseline PROs nor change in depression, satisfaction with social roles, pain interference, or physical function were significant predictors of loss to follow-up. Similarly, patient state of residence, Charlson Comorbidity Index, BMI, and percent excess weight loss were not significant predictors of follow-up attrition. The PROs in this study were not significant predictors of loss to follow-up at 1-year postoperatively. The rate of bariatric procedures continues to increase nationally, so does the potential for late post-surgical complications. Given the potential impact of loss to follow-up on adverse late post-surgical outcomes, there is a need to facilitate long-term post-surgical follow-up and more investigation is needed to identify and intervene on underlying causes of bariatric patient follow-up attrition.

Individualized dosing is an established approach in intravenous immunoglobulin (IVIg) treatment for inflammatory neuropathies. There is less experience in effective dosing strategies for subcutaneous (SC) immunoglobulin. We conducted a retrospective cohort study of patients with inflammatory neuropathies transferring from IVIg to SCIg in two UK peripheral nerve services. I-RODS and grip strength were used to measure outcome. Dose and clinical progress were documented at 1 year and at last review. 44/56 patients remained on maintenance SCIg beyond 1 year (mean 3.3 years, range 1–9 years) with stable clinical outcomes. Clinical deteriorations were corrected by small increases in SCIg dose in 20 patients at 1 year, a further 9 requiring subsequent further up-titrations. Sixteen tolerated dose reduction. Mean dose change was + 2.4% from baseline. Two patients required IVIg bolus rescue (2 g/kg). Three patients successfully discontinued Ig therapy. Nine patients returned to IVIg due to clinical relapse or patient preference. Overall tolerance was good. Dose titration to clinical response is an effective approach in SCIg maintenance therapy.

Background: AZD9833 is an oral selective estrogen receptor (ER) antagonist and degrader (SERD) in Phase 2 clinical development for the treatment of ER+ HER2− breast cancer. Here we report data from Parts C and D of the ongoing Phase 1 study (SERENA-1) examining AZD9833 in combination with palbociclib, together with updated data from Parts A and B examining AZD9833 monotherapy. Methods: SERENA-1 (NCT03616587) is an ongoing open-label Phase 1 study of AZD9833 in pre- and post-menopausal women with ER+, HER2− advanced breast cancer who have previously received ≥1 endocrine therapy and ≤2 prior chemotherapies. Prior treatment with fulvestrant and/or CDK4/6 inhibitors was permitted. The primary objective is to determine the safety and tolerability of once daily (QD) AZD9833, with dose-limiting toxicities (DLTs) in the first 28 days defining the maximum tolerated dose. Secondary objectives include anti-tumor response (including circulating tumor [ct] DNA response) and pharmacokinetics. Parts A (escalation) and B (expansion) assess AZD9833 as a monotherapy, and Parts C (escalation) and D (expansion) assess AZD9833 in combination with palbociclib. Results: At a data cut-off of March 24 2020, 17 patients had received either 150 mg or 300 mg AZD9833 in combination with palbociclib, given according to its product labeling. Eighty patients had received AZD9833 monotherapy at doses of 25, 75, 150, 300, and 450 mg QD. In patients treated with AZD9833 and palbociclib, treatment-related adverse events (AEs; experienced by ≥10% of patients) included visual disturbances*, bradycardia*, asthenia, anemia, QTcF prolongation, nausea, neutropenia, decreased white blood cell count, and vomiting (*combined terms). All instances of AZD9833-related bradycardia were Grade 1. One DLT was observed in the 150 mg cohort: CTCAE Grade 2 visual disturbances, which began on Cycle 1 Day 8 and resolved by Cycle 1 Day 9 following dose interruption. The patient restarted treatment on Cycle 1 Day 15 at 75 mg and continued this dose until data cut-off. No causally related AEs led to discontinuation of AZD9833. The tolerability of AZD9833 with palbociclib was consistent with the observed tolerability profile of AZD9833 monotherapy, and the known tolerability profile of palbociclib. Pharmacokinetic analysis showed similar AZD9833 exposure for monotherapy and palbociclib combination therapy. Similarly, palbociclib exposure was comparable with simulations using a published population pharmacokinetic model. In Part A, ESR1 hotspot mutations were detected in ctDNA at baseline in 26/56 (46%) patients; 13/26 (50%) of these patients achieved a partial response or stable disease at 24 weeks, including 5/10 (50%) with a Y537S ESR1 mutation. Further, in patients with ESR1 mutations and samples available for longitudinal ctDNA analysis, 17/20 (85%) exhibited a reduction or loss of mutant ESR1 on treatment with AZD9833. Efficacy data to be presented include objective response rate and clinical benefit rate at 24 weeks. Of note, unconfirmed partial responses have been observed in Part C after the data cut-off for this abstract. Conclusions: AZD9833 continues to show an encouraging efficacy and dose-dependent safety profile as a monotherapy or in combination with palbociclib. A Phase 2 study comparing the efficacy and safety of three doses of AZD9833 versus fulvestrant (NCT04214288), and a Phase 2 pre-surgical ‘window of opportunity’ study (EUDRA-CT; 2019-003706-2) are ongoing. Citation Format: Richard Baird, Mafalda Oliveira, Eva Maria Ciruelos Gil, Manish R Patel, Begoña Bermejo de las Heras, Manuel Ruiz-Borrego, Javier García-Corbacho, Anne Armstrong, Udai Banerji, Chris Twelves, Valentina Boni, Jason Incorvati, Peter Kabos, Adam L Cohen, Bruno de Paula, Marta Capelán Rodríguez, Judy S Wang, Christina Hernando, Alejandro Falcón Gonzalez, Ivan Victoria Ruiz, Julia Lai-Kwon, Anosheh Afghani, Christos Vaklavas, Tim Brier, Steven Fox, Bistra Kirova, Teresa Klinowska, Chris Leach, Justin PO Lindemann, Richard Mather, Rhiannon Maudsley, Christopher J Morrow, Nitharsan Sathiyayogan, Andy Sykes, Li Zhang, Erika Hamilton. Updated data from SERENA-1: A Phase 1 dose escalation and expansion study of the next generation oral SERD AZD9833 as a monotherapy and in combination with palbociclib, in women with ER-positive, HER2-negative advanced breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS11-05.

Rationale Bronchopulmonary dysplasia (BPD) is a major complication of premature birth and the most common cause of chronic lung disease in infancy. Previous studies have shown that children with a history of BPD have impaired lung function in childhood compared to their term counterparts. However, little is known about potential modifiable factors that alter lung function trajectories and subsequent respiratory morbidity in this population. Objectives To identify potential modifiable risk factors for the development of impaired lung function in patients with a history of prematurity and bronchopulmonary dysplasia. Methods Growth parameters (birth, 2 years old, 6 years old) and pulmonary function testing (6 years old) were retrospectively reviewed for subjects (n = 598) recruited from an outpatient BPD clinic who were born ≤36 weeks gestation and were ≥5 years of age. Results Of the 598 recruited subjects, 88 (14.7%) performed adequate pulmonary function testing at approximately 6 years of age. The mean forced expiratory volume in 1 s global lung initiative (GLI) Z-score was -1.31 with lower values associated with Nissen fundoplication. The mean forced vital capacity GLI Z-score was -0.72 with lower values associated with higher amounts of oxygen required at time of initial hospital discharge and Nissen fundoplication. Conclusion Our study found that children with BPD have lower predicted lung function values. Although growth parameters at age 2 and 6 years did not correlate with lung function values at 6 years of age; use and greater requirement for supplemental oxygen and the presence of a Nissen fundoplication at discharge were associated with lower lung function. Prospective studies should focus on identifying modifiable risk factors that could minimize the impact of BPD on later lung function.