Cell-of-Origin Patterns Dominate the Molecular Classification of 10,000 Tumors from 33 Types of Cancer.

We conducted comprehensive integrative molecular analyses of the complete set of tumors in The Cancer Genome Atlas (TCGA), consisting of approximately 10,000 specimens and representing 33 types of cancer. We performed molecular clustering using data on chromosome-arm-level aneuploidy, DNA hypermethylation, mRNA, and miRNA expression levels and reverse-phase protein arrays, of which all, except for aneuploidy, revealed clustering primarily organized by histology, tissue type, or anatomic origin. The influence of cell type was evident in DNA-methylation-based clustering, even after excluding sites with known preexisting tissue-type-specific methylation. Integrative clustering further emphasized the dominant role of cell-of-origin patterns. Molecular similarities among histologically or anatomically related cancer types provide a basis for focused pan-cancer analyses, such as pan-gastrointestinal, pan-gynecological, pan-kidney, and pan-squamous cancers, and those related by stemness features, which in turn may inform strategies for future therapeutic development.

Phosphoproteome Integration Reveals Patient-Specific Networks in Prostate Cancer.

We used clinical tissue from lethal metastatic castration-resistant prostate cancer (CRPC) patients obtained at rapid autopsy to evaluate diverse genomic, transcriptomic, and phosphoproteomic datasets for pathway analysis. Using Tied Diffusion through Interacting Events (TieDIE), we integrated differentially expressed master transcriptional regulators, functionally mutated genes, and differentially activated kinases in CRPC tissues to synthesize a robust signaling network consisting of druggable kinase pathways. Using MSigDB hallmark gene sets, six major signaling pathways with phosphorylation of several key residues were significantly enriched in CRPC tumors after incorporation of phosphoproteomic data. Individual autopsy profiles developed using these hallmarks revealed clinically relevant pathway information potentially suitable for patient stratification and targeted therapies in late stage prostate cancer. Here, we describe phosphorylation-based cancer hallmarks using integrated personalized signatures (pCHIPS) that shed light on the diversity of activated signaling pathways in metastatic CRPC while providing an integrative, pathway-based reference for drug prioritization in individual patients.

Germline stem cell integrity and quiescence are controlled by an AMPK-dependent neuronal trafficking pathway.

During periods of energetic stress, Caenorhabditis elegans can execute a developmentally quiescent stage called "dauer", during which all germline stem cells undergo a G2 cell cycle arrest. In animals that lack AMP-activated protein kinase (AMPK) signalling, the germ cells fail to arrest, undergo uncontrolled proliferation, and lose their reproductive capacity upon recovery from this quiescent stage. These germline defects are accompanied by, and likely result from, an altered chromatin landscape and gene expression program. Through genetic analysis we identified an allele of tbc-7, a predicted RabGAP protein that functions in the neurons, which when compromised, suppresses the germline hyperplasia in the dauer larvae, as well as the post-dauer sterility and somatic defects characteristic of AMPK mutants. This mutation also corrects the abundance and aberrant distribution of transcriptionally activating and repressive chromatin marks in animals that otherwise lack all AMPK signalling. We identified RAB-7 as one of the potential RAB proteins that is modulated by tbc-7 and show that the activity of RAB-7 is critical for the maintenance of germ cell integrity during the dauer stage. We reveal that TBC-7 is regulated by AMPK through two mechanisms when the animals enter the dauer stage. Acutely, the AMPK-mediated phosphorylation of TBC-7 reduces its activity, potentially by autoinhibition, thereby preventing the inactivation of RAB-7. In the more long term, AMPK regulates the miRNAs mir-1 and mir-44 to attenuate tbc-7 expression. Consistent with this, animals lacking mir-1 and mir-44 are post-dauer sterile, phenocopying the germline defects of AMPK mutants. Altogether, we have uncovered an AMPK-dependent and microRNA-regulated cellular trafficking pathway that is initiated in the neurons, and is critical to control germline gene expression cell non-autonomously in response to adverse environmental conditions.

Sex and ethnic disparities in hepatitis B evaluation and treatment across the world.

BACKGROUND & AIMS: Oral antiviral therapy with nucleos(t)ide analogues (NAs) for chronic hepatitis B (CHB) is well-tolerated and lifesaving, but real-world data on utilization are limited. We examined rates of evaluation and treatment in patients from the REAL-B consortium. METHODS: This was a cross-sectional study nested within our retrospective multinational clinical consortium (2000-2021). We determined the proportions of patients receiving adequate evaluation, meeting AASLD treatment criteria, and initiating treatment at any time during the study period. We also identified factors associated with receiving adequate evaluation and treatment using multivariable logistic regression analyses. RESULTS: We analyzed 12,566 adult treatment-naïve patients with CHB from 25 centers in 9 countries (mean age 47.1 years, 41.7% female, 96.1% Asian, 49.6% Western region, 8.7% cirrhosis). Overall, 73.3% (9,206 patients) received adequate evaluation. Among the adequately evaluated, 32.6% (3,001 patients) were treatment eligible by AASLD criteria, 83.3% (2,500 patients) of whom were initiated on NAs, with consistent findings in analyses using EASL criteria. On multivariable logistic regression adjusting for age, sex, cirrhosis, and ethnicity plus region, female sex was associated with adequate evaluation (adjusted odds ratio [aOR] 1.13, p = 0.004), but female treatment-eligible patients were about 50% less likely to initiate NAs (aOR 0.54, p <0.001). Additionally, the lowest evaluation and treatment rates were among Asian patients from the West, but no difference was observed between non-Asian patients and Asian patients from the East. Asian patients from the West (vs. East) were about 40-50% less likely to undergo adequate evaluation (aOR 0.60) and initiate NAs (aOR 0.54) (both p <0.001). CONCLUSIONS: Evaluation and treatment rates were suboptimal for patients with CHB in both the East and West, with significant sex and ethnic disparities. Improved linkage to care with linguistically competent and culturally sensitive approaches is needed. IMPACT AND IMPLICATIONS: Significant sex and ethnic disparities exist in hepatitis B evaluation and treatment, with female treatment-eligible patients about 50% less likely to receive antiviral treatment and Asian patients from Western regions also about 50% less likely to receive adequate evaluation or treatment compared to Asians from the East (there was no significant difference between Asian patients from the East and non-Asian patients). Improved linkage to care with linguistically competent and culturally sensitive approaches is needed.

Cash critical care time prices vary substantially by region and hospital ownership: A cross-sectional study.

OBJECTIVES: Emergency department (ED) patients may be billed for critical care time (current procedural terminology codes 99291 and 99292) if they receive at least 30 min of critical care services. We sought to determine the median cash (self-pay) prices for critical care time performed in the ED in the United States and assess for associations between hospital characteristics and prices. METHODS: We performed a cross-sectional analysis of hospital cash prices for critical care time performed in the ED using the first 25 alphabetical states. For each hospital, we recorded hospital characteristics including state, control (nonprofit, governmental, or for-profit), size, teaching status, and system. We then searched for each hospital's cash prices for 99291 and 99292 using Turquoise and hospital websites. We determined the median price for 99291 nationally, regionally, and for large hospital systems. We performed multivariable quantile regression to assess for associations between hospital characteristics and prices for 99291. RESULTS: Of the 2629 eligible hospitals, 2245 (85.4%) and 1893 (72.0%) reported cash prices for 99291 and 99292, respectively. For 99291, the cash price ranged from $45 to $84,775 with a median of $1816 (IQR: $1039-3237). For 99292, the median price was $567 (IQR: $298-1008). On multivariable analysis, hospitals had higher cash prices for 99291 if they were located in the West, for-profit, or part of a large system. In particular, hospitals owned by Tenet Healthcare charged the most for 99291 (median $28,244). CONCLUSION: The cash prices for critical care time vary substantially based on hospital characteristics. In particular, for-profit hospitals and those in the West tend to charge the most. Given that patients who require critical care are unlikely to be able to choose the hospital to which they present, standardization of critical care time fees should be considered.

Prevalence of Coronary Vasomotor Disorders in Patients With Angina and Nonobstructive Coronary Arteries: A Sydney Experience.

BACKGROUND: Patients with angina and non-obstructive coronary arteries (ANOCA) frequently have coronary vasomotor disorders (CVaD), characterised by transient pathological vasoconstriction and/or impaired microvascular vasodilatation. Functional coronary angiography is the gold standard for diagnosing CVaD. Despite recommendations, testing is only available at a limited number of Australian and New Zealand centres. This study aimed to determine the prevalence of CVaDs in an Australian ANOCA population and identify predictive factors associated with specific endotypes. METHOD: Functional coronary angiography was performed in patients with suspected ANOCA. Vasoreactivity testing was performed using intracoronary acetylcholine provocation. A pressure-temperature sensor guidewire was used for coronary physiology assessment. Comprehensive clinical data on patient characteristics, cardiac risk factors, and symptom profiles was collected before testing. RESULTS: This prospective observational study at Royal Prince Alfred and Concord Repatriation General Hospital included 110 patients (58±13 years with 63.6% women), with 81.8% (90/110) having a CVaD. Regarding specific ANOCA endotypes, microvascular angina (MVA) occurred in 31.8% (35/110) of cases, vasospastic angina (VSA) in 25.5% (28/110) and a mixed presentation of MVA and VSA in 24.5% (27/110) of patients. Patients with CVaD were found to be older (59±11 vs 51±15, p=0.024), overweight (61.1% vs 15.0%, p<0.001) and had a worse quality of life (EuroQol 5 Dimensions-5 Levels; 0.61 vs 0.67, p=0.043). MVA was associated with being overweight (odds ratio [OR] 4.2 [95% confidence interval [CI] 1.9-9.3]; p=0.015) and ischaemia on stress testing (OR 2.4 [95% CI 1.1-4.3]; p=0.028), while VSA was associated with smoking (OR 9.1 [95% CI 2.21-39.3]; p=0.007). CONCLUSIONS: Coronary vasomotor disorders are highly prevalent among ANOCA patients. This study highlights the importance of increasing national awareness and the use of functional coronary angiography to evaluate and manage this unique cohort.

Adolescent pregnancy is associated with child undernutrition: Systematic review and meta-analysis.

Adolescent pregnancy is associated with poor fetal growth and development which, in turn, increases the risk of childhood wasting and underweight. However, evidence on how young maternal age affects childhood anthropometry beyond the neonatal period is limited. This systematic review and meta-analysis examined associations between adolescent pregnancy and child wasting and underweight and explored potential underlying social and biological factors. Peer-reviewed literature published in English since 1990 was systematically searched. Eligible studies presented data on wasting and/or underweight in children (≤59 months) born to adolescent mothers (10-19, or ≤24 years where applicable) from low- and middle-income countries. Data extraction used a predefined extraction sheet. Both meta-analysis and qualitative synthesis were performed. Of 92 identified studies, 57 were included in the meta-analysis. The meta-analysis showed that children born to adolescent versus adult mothers were at a higher risk of moderate (odds ratio [OR]: 1.12, 95% confidence interval [CI]: 1.00-1.26 p = 0.04) and severe underweight (OR: 1.21, 95% CI: 1.08-1.35 p < 0.01). Associated risk of wasting was not statistically significant: (OR: 1.05, 95% CI: 0.98-1.12 p = 0.17); severe wasting (OR: 1.16, 95% CI: 0.68-1.96 p = 0.59). These findings were supported by the qualitative synthesis. Evidence on the potential role of biological/social factors was limited, but suggested an intermediary role of maternal nutritional status which warrants further exploration. Particularly in contexts where adolescent pregnancy remains common, interventions to both delay adolescent pregnancy and improve adolescent nutritional status could help reduce the risk of undernutrition in children and contribute to breaking the intergenerational cycle of malnutrition.

Liver Complications in Untreated Treatment-Ineligible versus Treated Treatment-Eligible Patients with Hepatitis B.

BACKGROUND: A substantial number of patients who do not meet treatment criteria for chronic hepatitis B (CHB) later develop adverse outcomes such as cirrhosis and hepatocellular carcinoma (HCC). Our aim was to determine whether current practice guidelines adequately identify CHB patients who will benefit from antiviral therapy. METHODS: We performed a retrospective cohort study comparing the incidence of adverse liver outcomes (cirrhosis and/or HCC) in untreated treatment-ineligible (at baseline and throughout follow-up) versus treated treatment-eligible patients according to standard American Association for the Study of Liver Diseases (AASLD) 2018 guidance (alanine aminotransferase [ALT] >70/50 U/L for men/women plus hepatitis B virus [HBV] DNA >20,000/2,000 IU/mL for HBeAg+/-) and with a sensitivity analyses using a lower threshold (ALT >40 U/L and HBV DNA >2,000 IU/mL). RESULTS: We reviewed records of 5,840 patients from 5 clinics in California and identified 2,987 treatment-naive non-HCC CHB patients. Of those, 271 patients remained untreated treatment-ineligible, 514 patients were treatment-eligible and initiated treatment, with 5-year cumulative adverse liver incidences of 12.5% versus 7.2%, p = 0.074. On multivariable analysis adjusting for age, sex, diabetes, albumin, platelet count, and HBV DNA, compared to treated treatment-eligible patients, untreated treatment-ineligible patients had a significantly higher risk of adverse liver outcomes (adjusted hazard ratio: 2.38, 95% confidence interval 1.03-5.48, p = 0.04) in main analysis by AASLD 2018 criteria but not in sensitivity analysis using the lower treatment threshold (p = 0.09). CONCLUSION: Patients never meeting standard AASLD 2018 criteria for antiviral therapy and never treated had twice the risk of developing cirrhosis and/or HCC when compared to eligible and treated patients.

Heart failure among Indigenous and non-Indigenous Australians in remote Central Australia.

BACKGROUND: There is a paucity of data on the burden of heart failure (HF) in Central Australia, the most populous Indigenous region in the country. AIMS: To characterize Indigenous and non-Indigenous Australians with HF in Central Australia. METHODS: Consecutive patients with HF and reduced ejection fraction <50% were included for the period 2019 to 2021. Clinical, echocardiographic and major adverse cardiovascular events (MACE) data were collected. RESULTS: Four hundred twenty-four patients with HF were included (70% Indigenous, 59% male; follow-up 2.2 ± 0.5 years). Indigenous Australians were younger (53 ± 15 vs 68 ± 13 years, P < 0.001) with higher rates of rheumatic heart disease (18% vs 1%, P < 0.001), diabetes (63% vs 33%, P < 0.001) and severe chronic kidney disease (CKD; 32% vs 7%, P < 0.001). HF was more prevalent among Indigenous (138 [95% confidence interval (CI), 123-155] per 10 000) compared with non-Indigenous Australians (53 [95% CI, 44-63] per 10 000), particularly among younger individuals and females. There were similar HF aetiologies between groups. Guideline-directed medical therapy (GDMT) was suboptimal and similar between the groups: angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (64% vs 67%, P = 0.47) and ß-blockers (68% vs 71%, P = 0.47). Indigenous Australians had a significantly higher rate of MACE (54% vs 28%, P < 0.001) and death from any cause (24% vs 13%, P = 0.013). CONCLUSIONS: HF is more than two times as prevalent among Indigenous Central Australians, particularly among younger individuals and females. Despite similar HF aetiologies and GDMT, MACE and mortality outcomes are higher in Indigenous individuals with HF. These data have implications for efforts to close the Indigenous gap in morbidity and mortality.

The Burden of Cardiac Implantable Electronic Device Checks in the Peri-MRI Setting: The CHECK-MRI Study.

BACKGROUND: Most modern cardiac implantable electronic device (CIED) systems are now compatible with magnetic resonance imaging (MRI) scans. The requirement for both pre- and post-MRI CIED checks imposes significant workload to the cardiac electrophysiology service. Here, we sought to determine the burden of CIED checks associated with MRI scans. METHODS: We identified all CIED checks performed peri-MRI scans at our institution over a 3-year period between 1 July 2017 to 30 June 2020, comprising three separate financial years (FY). Device check reports, MRI scan reports and clinical summaries were collated. The workload burden was determined by assessing the occasions and duration of service. Analysis was performed to determine cost burden/projections for this service and identify factors contributing to the workload. RESULTS: A total of 739 CIED checks were performed in the peri-MRI scan setting (370 pre- and 369 post-MRI scan), including 5% (n=39) that were performed outside of routine hours (weekday <8 am or >5 pm, and weekends). MRIs were performed for 295 patients (75±13 years old, 64% male) with a CIED (88% permanent pacemaker, and 12% high voltage device), including 49 who had more than one MRI scan. The proportion of total MRI scans for patients with a CIED in-situ increased each FY (from 0.5% of all MRIs in FY1, to 0.9% in FY2, to 1.0% in FY3). The weekly workload increased (R2=0.2, p<0.001), but with week-to-week variability due to ad hoc scheduling (209 days with only one MRI vs 78 days with ≥2 MRIs for CIED patients). The projected annual cost of this service will increase to AUD$161,695 in 10 years for an estimated annual 546 MRI scans for CIED patients. CONCLUSIONS: There is an increasing workload burden and expense associated with CIED checks in the peri-MRI setting. Appropriate budgeting, staff allocation and standardisation of automated CIED pre-programming features among manufacturers are urgently needed.

Developmental plasticity and the response to nutrient stress in Caenorhabditis elegans.

Developmental plasticity refers the ability of an organism to adapt to various environmental stressors, one of which is nutritional stress. Caenorhabditis elegans require various nutrients to successfully progress through all the larval stages to become a reproductive adult. If nutritional criteria are not satisfied, development can slow or completely arrest. In poor growth conditions, the animal can enter various diapause stages, depending on its developmental progress. In C. elegans, there are three well-characterized diapauses: the L1 arrest, the dauer diapause, and adult reproductive diapause, each associated with drastic changes in metabolism and germline development. At the centre of these changes is AMP-activated protein kinase (AMPK). AMPK is a metabolic regulator that maintains energy homeostasis, particularly during times of nutrient stress. Without AMPK, metabolism is disrupted during dauer, leading to the rapid consumption of lipid stores as well as misregulation of metabolic enzymes, leading to reduced survival. During the L1 arrest and dauer diapause, AMPK is responsible for ensuring germline quiescence by modifying the germline chromatin landscape to maintain germ cell integrity until conditions improve. Similar to classic hormonal signalling, small RNAs also play a critical role in regulating development and behaviour in a cell non-autonomous fashion. Thus, during the challenges associated with developmental plasticity, AMPK summons an army of signalling pathways to work collectively to preserve reproductive fitness during these periods of unprecedented uncertainty.

First Identified Case of Fatal Fulminant Necrotizing Eosinophilic Myocarditis Following the Initial Dose of the Pfizer-BioNTech mRNA COVID-19 Vaccine (BNT162b2, Comirnaty): an Extremely Rare Idiosyncratic Hypersensitivity Reaction.

RATIONALE: Transient myopericarditis has been recognised as an uncommon and usually mild adverse event predominantly linked to mRNA-based COVID-19 vaccines. These have mostly occurred in young males after the second dose of mRNA COVID-19 vaccines. OBJECTIVES: Fulminant necrotising eosinophilic myocarditis triggered by a variety of drugs or vaccines is an extremely rare hypersensitivity reaction carrying a substantial mortality risk. Early recognition of this medical emergency may facilitate urgent hospital admission for investigation and treatment. Timely intervention can lead to complete cardiac recovery, but the non-specific clinical features and rarity make early diagnosis challenging. FINDINGS: The clinical and pathological observations from a case of fatal fulminant necrotising myocarditis in a 57-year-old woman, following the first dose of the Pfizer-BioNTech vaccine, are described. Other causes have been discounted with reasonable certainty. CONCLUSION: These extremely rare vaccine-related adverse events are much less common than the risk of myocarditis and other lethal complications from COVID-19 infection. The benefits of vaccination far exceed the risks of COVID-19 infection.

Natural History and Hepatocellular Carcinoma Risk in Untreated Chronic Hepatitis B Patients With Indeterminate Phase.

BACKGROUND & AIMS: Many patients with chronic hepatitis B (CHB) may not conform to any of the defined phases and hence are classified as indeterminate. We aimed to characterize the baseline prevalence of indeterminate patients and their natural history, phase transition, and hepatocellular carcinoma (HCC) risk. METHODS: This was a retrospective cohort study of 3366 adult untreated noncirrhotic CHB patients seen at 5 US clinics and 7 Taiwanese townships who had at least 1 year of serial laboratory data before enrollment with a mean follow-up period of 12.5 years. Patients' clinical phases were determined at baseline and through serial data during follow-up evaluation, based on the American Association for the Study of Liver Diseases 2018 guidance. RESULTS: At baseline, 1303 (38.7%) patients were in the indeterminate phase. By up to year 10 of follow-up evaluation, 686 patients (52.7%) remained indeterminate, while 283 patients (21.7%) became immune active. Compared with patients who remained inactive, patients who remained indeterminate had a higher 10-year cumulative HCC incidence (4.6% vs 0.5%; P < .0001) and adjusted hazard ratio for HCC of 14.1 (P = .03). Among patients who remained indeterminate, age 45 years and older (adjusted hazard ratio, 18.4; P = .005) was associated independently with HCC development. CONCLUSIONS: Nearly 40% of patients had indeterminate CHB phase. Of these, half remained indeterminate and one-fifth transitioned to the immune active phase. HCC risk in persistently indeterminate CHB was 14 times higher than inactive CHB. Among persistently indeterminate CHB patients, age 45 years and older was associated with an 18 times higher risk for HCC development. Further studies are needed to evaluate the potential benefit of antiviral therapy for indeterminate patients, especially in the older subgroup.

Progression Rates by Age, Sex, Treatment, and Disease Activity by AASLD and EASL Criteria: Data for Precision Medicine.

BACKGROUND & AIMS: Antiviral treatment criteria are based on disease progression risk, and hepatocellular carcinoma (HCC) surveillance recommendations for patients with chronic hepatitis B (CHB) without cirrhosis is based on an annual incidence threshold of 0.2%. However, accurate and precise disease progression estimate data are limited. Thus, we aimed to determine rates of cirrhosis and HCC development stratified by age, sex, treatment status, and disease activity based on the 2018 American Association for the Study of Liver Diseases and 2017 European Association for the Study of the Liver guidelines. METHODS: We analyzed 18,338 patients (8914 treated, 9424 untreated) from 6 centers from the United States and 27 centers from Asia-Pacific countries. The Kaplan-Meier method was used to estimate annual progression rates to cirrhosis or HCC in person-years. RESULTS: The cohort was 63% male, with a mean age of 46.19 years, with baseline cirrhosis of 14.3% and median follow up of 9.60 years. By American Association for the Study of Liver Diseases criteria, depending on age, sex, and disease activity, annual incidence rates ranged from 0.07% to 3.94% for cirrhosis, from 0.04% to 2.19% for HCC in patients without cirrhosis, and from 0.40% to 8.83% for HCC in patients with cirrhosis. Several subgroups of patients without cirrhosis including males younger than 40 years of age and females younger than 50 years of age had annual HCC risk near or exceeding 0.2%. Similar results were found using European Association for the Study of the Liver criteria. CONCLUSION: There is great variability in CHB disease progression rates even among "lower-risk" populations. Future CHB modeling studies, public health planning, and HCC surveillance recommendation should be based on more precise disease progression rates based on sex, age, and disease activity, plus treatment status.

Accurate cancer phenotype prediction with AKLIMATE, a stacked kernel learner integrating multimodal genomic data and pathway knowledge.

Advancements in sequencing have led to the proliferation of multi-omic profiles of human cells under different conditions and perturbations. In addition, many databases have amassed information about pathways and gene "signatures"-patterns of gene expression associated with specific cellular and phenotypic contexts. An important current challenge in systems biology is to leverage such knowledge about gene coordination to maximize the predictive power and generalization of models applied to high-throughput datasets. However, few such integrative approaches exist that also provide interpretable results quantifying the importance of individual genes and pathways to model accuracy. We introduce AKLIMATE, a first kernel-based stacked learner that seamlessly incorporates multi-omics feature data with prior information in the form of pathways for either regression or classification tasks. AKLIMATE uses a novel multiple-kernel learning framework where individual kernels capture the prediction propensities recorded in random forests, each built from a specific pathway gene set that integrates all omics data for its member genes. AKLIMATE has comparable or improved performance relative to state-of-the-art methods on diverse phenotype learning tasks, including predicting microsatellite instability in endometrial and colorectal cancer, survival in breast cancer, and cell line response to gene knockdowns. We show how AKLIMATE is able to connect feature data across data platforms through their common pathways to identify examples of several known and novel contributors of cancer and synthetic lethality.

Detecting accelerometer non-wear periods using change in acceleration combined with rate-of-change in temperature.

BACKGROUND: Accelerometery is commonly used to estimate physical activity, sleep, and sedentary behavior. In free-living conditions, periods of device removal (non-wear) can lead to misclassification of behavior with consequences for research outcomes and clinical decision making. Common methods for non-wear detection are limited by data transformations (e.g., activity counts) or algorithm parameters such as minimum durations or absolute temperature thresholds that risk over- or under-estimating non-wear time. This study aimed to advance non-wear detection methods by integrating a 'rate-of-change' criterion for temperature into a combined temperature-acceleration algorithm. METHODS: Data were from 39 participants with neurodegenerative disease (36% female; age: 45-83 years) who wore a tri-axial accelerometer (GENEActiv) on their wrist 24-h per day for 7-days as part of a multi-sensor protocol. The reference dataset was derived from visual inspection conducted by two expert analysts. Linear regression was used to establish temperature rate-of-change as a criterion for non-wear detection. A classification and regression tree (CART) decision tree classifier determined optimal parameters separately for non-wear start and end detection. Classifiers were trained using data from 15 participants (38.5%). Outputs from the CART analysis were supplemented based on edge cases and published parameters. RESULTS: The dataset included 186 non-wear periods (85.5% < 60 min). Temperature rate-of-change over the first five minutes of non-wear was - 0.40 ± 0.17 °C/minute and 0.36 ± 0.21 °C/minute for the first five minutes following device donning. Performance of the DETACH (DEvice Temperature and Accelerometer CHange) algorithm was improved compared to existing algorithms with recall of 0.942 (95% CI 0.883 to 1.0), precision of 0.942 (95% CI 0.844 to 1.0), F1-Score of 0.942 (95% CI 0.880 to 1.0) and accuracy of 0.996 (0.994-1.000). CONCLUSION: The DETACH algorithm accurately detected non-wear intervals as short as five minutes; improving non-wear classification relative to current interval-based methods. Using temperature rate-of-change combined with acceleration results in a robust algorithm appropriate for use across different temperature ranges and settings. The ability to detect short non-wear periods is particularly relevant to free-living scenarios where brief but frequent removals occur, and for clinical application where misclassification of behavior may have important implications for healthcare decision-making.

Alcohol intake and bradyarrhythmia risk: a cohort study of 407 948 individuals.

AIMS: There is a paucity of epidemiological evidence on alcohol and the risk of bradyarrhythmias. We thus characterized associations of total and beverage-specific alcohol consumption with incident bradyarrhythmias using data from the UK Biobank. METHODS AND RESULTS: Alcohol consumption reported at baseline was calculated as UK standard drinks (8 g alcohol)/week. Bradyarrhythmia events were defined as sinus node dysfunction (SND), high-level atrioventricular block (AVB), and permanent pacemaker implantations. Outcomes were assessed through hospitalization and death records, and dose-response associations were characterized using Cox regression models with correction for regression dilution bias. We studied 407 948 middle-aged individuals (52.4% female). Over a median follow-up time of 11.5 years, a total of 8 344 incident bradyarrhythmia events occurred. Increasing total alcohol consumption was not associated with an increased risk of bradyarrhythmias. Beer and cider intake were associated with increased bradyarrhythmia risk up to 12 drinks/week; however, no significant associations were observed with red wine, white wine, or spirit intake. When bradyarrhythmia outcomes were analysed separately, a negative curvilinear was observed for total alcohol consumption and risk of SND, but no clear association with AVB was observed. CONCLUSION: In this predominantly White British cohort, increasing total alcohol consumption was not associated with an increased risk of bradyarrhythmias. Associations appeared to vary according to the type of alcoholic beverage and between different types of bradyarrhythmias. Further epidemiological and experimental studies are required to clarify these findings.

Anemia and iron deficiency in patients with atrial fibrillation.

Atrial fibrillation (AF) is the most common cardiac tachyarrhythmia and has a rising global prevalence. Given the increasing burden of AF-related symptoms and complications, new approaches to management are required. Anemia and iron deficiency are common conditions in patients with AF. Furthermore, emerging evidence suggests that the presence of anemia may be associated with worse outcome in these patients. The role of anemia and iron deficiency has been extensively explored in other cardiovascular states, such as heart failure and ischemic heart disease. In particular, the role of iron repletion amongst patients with heart failure is now an established treatment modality. However, despite the strong bidirectional inter-relationship between AF and heart failure, the implications of anemia and iron-deficiency in AF have been scarcely studied. This area is of mechanistic and clinical relevance given the potential that treatment of these conditions may improve symptoms and prognosis in the increasing number of individuals with AF. In this review, we summarise the current published literature on anemia and iron deficiency in patients with AF. We discuss AF complications such as stroke, bleeding, and heart failure, in addition to AF-related symptoms such as exercise intolerance, and the potential impact of anemia and iron deficiency on these. Finally, we summarize current research gaps on anemia, iron deficiency, and AF, and underscore potential research directions.

Impact of device length on electrogram sensing in miniaturized insertable cardiac monitors.

BACKGROUND: Little data exists on electrogram sensing in current generation of miniaturized insertable cardiac monitors (ICMs). OBJECTIVE: To compare the sensing capability of ICM with different vector length: Medtronic Reveal LINQ (~40 mm) vs. Biotronik Biomonitor III (BM-III, ~70 mm). METHODS: De-identified remote monitoring transmissions from n = 40 patients with BM-III were compared with n = 80 gender and body mass index (BMI)-matched patients with Reveal LINQ. Digital measurement of P- and R-wave amplitude from calibrated ICM electrograms was undertaken by 3 investigators independently. Further, we evaluated the impact of BMI and gender on P-wave visibility. RESULTS: Patients in both groups were well matched for gender and BMI (53% male, mean BMI 26.7 kg/m2, both p = NS). Median P- and R-wave amplitude were 97% & 56% larger in the BM-III vs. LINQ [0.065 (IQR 0.039-0.10) vs. 0.033 (IQR 0.022-0.050) mV, p < .0001; & 0.78 (IQR 0.52-1.10) vs. 0.50 (IQR 0.41-0.89) mV, p = .012 respectively). The P/R-wave ratio was 36% greater with the BM-III (p < .001). The 25th percentile of P-wave amplitude for all 120 patients was .026 mV. Logistic regression analysis showed BM-III was more likely than LINQ to have P-wave amplitude ≥.026 mV (OR 7.47, 95%CI 1.965-29.42, p = .003), and increasing BMI was negatively associated with P-wave amplitude ≥.026 mV (OR 0.84, 95%CI 0.75-0.95, p = .004). However, gender was not significantly associated with P-wave amplitude ≥.026 mV (p = .37). CONCLUSION: The longer ICM sensing vector of BM-III yielded larger overall P- and R- wave amplitude than LINQ. Both longer sensing vector and lower BMI were independently associated with greater P-wave visibility.

From education to action: Development and evaluation of a student-directed service learning program.

PURPOSE: Service learning consists of service activities that respond to community-identified concerns, active learning about the population being served, and self-reflecting on the experience. The Service Learning Program (SLP) is a novel, student-led, longitudinal volunteering experience designed to address social determinants of health (SDOH) education in the undergraduate medical school curriculum. In this program, medical students complete requirements in three domains of service, education, and self-reflection over the span of one academic year. METHODS AND MATERIALS: Participating students are sent surveys prior to and after a year of participation in SLP, which are aimed to measure changes in their perceived knowledge, attitudes, and skills in multiple domains related to service learning and social determinants of health. RESULTS: Over the course of the 2019-2020 year, 110 students who participated in SLP responded to both pre- and post-surveys. These students reported significant improvements in their confidence in various knowledge and skills related to SDOH, such as identifying vulnerable populations and assessing community needs. They also were more likely to report that learning about social determinants of health was 'very important' after participating the program. CONCLUSIONS: Medical students participating in a longitudinal service learning program focused on SDOH can acquire knowledge and skills that will empower them to understand, advocate, and care for underserved populations as future physicians. This program provides a model for integrating service learning into undergraduate medical education.