Presenilin-1 mutation position influences amyloidosis, small vessel disease, and dementia with disease stage.

INTRODUCTION: Amyloidosis, including cerebral amyloid angiopathy, and markers of small vessel disease (SVD) vary across dominantly inherited Alzheimer's disease (DIAD) presenilin-1 (PSEN1) mutation carriers. We investigated how mutation position relative to codon 200 (pre-/postcodon 200) influences these pathologic features and dementia at different stages. METHODS: Individuals from families with known PSEN1 mutations (n = 393) underwent neuroimaging and clinical assessments. We cross-sectionally evaluated regional Pittsburgh compound B-positron emission tomography uptake, magnetic resonance imaging markers of SVD (diffusion tensor imaging-based white matter injury, white matter hyperintensity volumes, and microhemorrhages), and cognition. RESULTS: Postcodon 200 carriers had lower amyloid burden in all regions but worse markers of SVD and worse Clinical Dementia Rating® scores compared to precodon 200 carriers as a function of estimated years to symptom onset. Markers of SVD partially mediated the mutation position effects on clinical measures. DISCUSSION: We demonstrated the genotypic variability behind spatiotemporal amyloidosis, SVD, and clinical presentation in DIAD, which may inform patient prognosis and clinical trials. HIGHLIGHTS: Mutation position influences Aß burden, SVD, and dementia. PSEN1 pre-200 group had stronger associations between Aß burden and disease stage. PSEN1 post-200 group had stronger associations between SVD markers and disease stage. PSEN1 post-200 group had worse dementia score than pre-200 in late disease stage. Diffusion tensor imaging-based SVD markers mediated mutation position effects on dementia in the late stage.

Utilization of nonguideline concordant antibiotic treatment following acute otitis media in children in the United States.

PURPOSE: Acute otitis media (AOM) is a common indication for antibiotics in children. We sought to characterize the frequency of nonguideline concordant antibiotic therapy for AOM in the United States, by agent and duration. METHODS: Using national administrative claims data (2016-2019), we identified children aged 6 months to 17 years with an oral antibiotic dispensed within 3 days of a new diagnosis of suppurative AOM. Use of nonguideline concordant agents and durations, defined based on national treatment guidelines, were summarized by age, race, rurality, region, and insurance type. Subsequent oral antibiotic dispensing within the year after AOM diagnosis was also evaluated. We created sunburst diagrams to visualize longitudinal patterns of within-person antibiotic utilization for AOM, by agent and duration. RESULTS: We identified 789 424 eligible commercially-insured and 502 239 medicaid-insured children. Among commercially insured children, 35% received nonguideline concordant agents for AOM, including cefdinir (16%), amoxicillin-clavulanate (12%), and azithromycin (7%). Fewer children age <2 years received a nonguideline concordant initial agent (27%) compared to age ≥6 years (41%). More children age <2 years received three or more antibiotics over the following year (34% vs. 3% for children age ≥6 years). The most common treatment duration was 10 days for all ages; treatment duration for the initial antibiotic was nonguideline concordant for 95% and 89% of children age 2-5 years and ≥6 years, respectively. Patterns were similar for medicaid-insured children. CONCLUSIONS: Nonguideline concordant antibiotic use is common when treating AOM in children, including use of broad-spectrum agents and longer-than-recommended antibiotic durations.

Association of Adverse Events With Antibiotic Treatment for Urinary Tract Infection.

BACKGROUND: Little is known about the relative harms of different antibiotic regimens prescribed to treat uncomplicated urinary tract infection (UTI). We sought to compare the risk of adverse events associated with commonly used oral antibiotic regimens for the outpatient treatment of uncomplicated UTI. METHODS: Using data from the IBM® MarketScan® Commercial Database, we identified 1 169 033 otherwise healthy, nonpregnant women aged 18-44 years with uncomplicated UTI who initiated an oral antibiotic with activity against common uropathogens from 1 July 2006 to 30 September 2015. We used propensity score-weighted Kaplan-Meier methods and Cox proportional hazards regression models to estimate the association between antibiotic agent and adverse events. RESULTS: Of 2 first-line agents, trimethoprim-sulfamethoxazole (vs nitrofurantoin) was associated with higher risk of several adverse drug events including hypersensitivity reaction (hazard ratio, 2.62; 95% confidence interval, 2.30-2.98), acute renal failure (2.56; 1.55-4.25), skin rash (2.42; 2.13-2.75), urticaria (1.37; 1.19-1.57), abdominal pain (1.14; 1.09-1.19), and nausea/vomiting (1.18; 1.10-1.28), but a similar risk of potential microbiome-related adverse events. Compared with nitrofurantoin, non-first-line agents were associated with higher risk of several adverse drug events and potential microbiome-related adverse events including non-Clostridium difficile diarrhea, C. difficile infection, vaginitis/vulvovaginal candidiasis, and pneumonia. Treatment duration modified the risk of potential microbiome-related adverse events. CONCLUSIONS: The risks of adverse drug events and potential microbiome-related events differ widely by antibiotic agent and duration. These findings underscore the utility of using real-world data to fill evidentiary gaps related to antibiotic safety.

The impact of infectious diseases consultation for children with Staphylococcus aureus bacteremia.

BACKGROUND: Despite clear benefit of improved outcomes in adults, the impact of infectious diseases (ID) consultation for Staphylococcus aureus bacteremia in children remains understudied. METHODS: To assess the impact of pediatric ID consultation on management and outcomes, we conducted a cohort study of children with S. aureus bacteremia at St. Louis Children's Hospital from 2011 to 2018. We assessed adherence to six established quality-of-care indicators (QCIs). We applied propensity score methodology to examine the impact of ID consultation on risk of treatment failure, a composite of all-cause mortality or hospital readmission within 90 days. RESULTS: Of 306 patients with S. aureus bacteremia, 193 (63%) received ID consultation. ID consultation was associated with increased adherence to all QCIs, including proof-of-cure blood cultures, indicated laboratory studies, echocardiography, source control, targeted antibiotic therapy, and antibiotic duration. Obtaining proof-of-cure blood cultures and all indicated laboratory studies were associated with improved outcomes. In propensity score-weighted analyses, risk of treatment failure was similar among patients who did and did not receive ID consultation. However, the number of events was small and risk estimates were imprecise. CONCLUSIONS: For children with S. aureus bacteremia, ID consultation improved adherence to QCIs, some of which were associated with improved clinical outcomes. IMPACT: In children with Staphylococcus aureus bacteremia, consultation by an infectious diseases (ID) physician improved adherence to established quality-of-care indicators (QCIs). The current literature regarding ID consultation in pediatric S. aureus bacteremia is sparse. Three prior international studies demonstrated improved quality of care with ID consultation, though results were disparate regarding clinical outcomes. This article impacts the current literature by strengthening the evidence that ID consultation in children improves adherence to QCIs, and demonstrates that adherence to QCIs improves clinical outcomes.

Occupational characteristics associated with SARS-CoV-2 infection in the UK Biobank during August-November 2020: a cohort study.

BACKGROUND: Occupational exposures may play a key role in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection risk. We used a job-exposure matrix linked to the UK Biobank to measure occupational characteristics and estimate associations with a positive SARS-CoV-2 test. METHODS: People reporting job titles at their baseline interview in England who were < 65 years of age in 2020 were included. Healthcare workers were excluded because of differential access to testing. Jobs were linked to the US Occupational Information Network (O*NET) job exposure matrix. O*NET-based scores were examined for occupational physical proximity, exposure to diseases/infection, working outdoors exposed to weather, and working outdoors under cover (score range = 1-5). Jobs were classified as remote work using two algorithms. SARS-CoV-2 test results were evaluated between August 5th-November 10th, 2020, when the UK was released from lockdown. Cox regression was used to calculate adjusted hazard ratios (aHRs), accounting for age, sex, race, education, neighborhood deprivation, assessment center, household size, and income. RESULTS: We included 115,451 people with job titles, of whom 1746 tested positive for SARS-CoV-2. A one-point increase in physical proximity score was associated with 1.14 times higher risk of SARS-CoV-2 (95%CI = 1.05-1.24). A one-point increase in the exposure to diseases/infections score was associated with 1.09 times higher risk of SARS-CoV-2 (95%CI = 1.02-1.16). People reporting jobs that could not be done remotely had higher risk of SARS-CoV-2 regardless of the classification algorithm used (aHRs = 1.17 and 1.20). Outdoors work showed an association with SARS-CoV-2 (exposed to weather aHR = 1.06, 95%CI = 1.01-1.11; under cover aHR = 1.08, 95%CI = 1.00-1.17), but these associations were not significant after accounting for whether work could be done remotely. CONCLUSION: People in occupations that were not amenable to remote work, required closer physical proximity, and required more general exposure to diseases/infection had higher risk of a positive SARS-CoV-2 test. These findings provide additional evidence that coronavirus disease 2019 (COVID-19) is an occupational disease, even outside of the healthcare setting, and indicate that strategies for mitigating transmission in in-person work settings will remain important.

Studying the Utility of Using Genetics to Predict Smoking-Related Outcomes in a Population-Based Study and a Selected Cohort.

INTRODUCTION: The purpose of this study is to examine the predictive utility of polygenic risk scores (PRSs) for smoking behaviors. AIMS AND METHODS: Using summary statistics from the Sequencing Consortium of Alcohol and Nicotine use consortium, we generated PRSs of ever smoking, age of smoking initiation, cigarettes smoked per day, and smoking cessation for participants in the population-based Atherosclerosis Risk in Communities (ARIC) study (N = 8638), and the Collaborative Genetic Study of Nicotine Dependence (COGEND) (N = 1935). The outcomes were ever smoking, age of smoking initiation, heaviness of smoking, and smoking cessation. RESULTS: In the European ancestry cohorts, each PRS was significantly associated with the corresponding smoking behavior outcome. In the ARIC cohort, the PRS z-score for ever smoking predicted smoking (odds ratio [OR]: 1.37; 95% confidence interval [CI]: 1.31, 1.43); the PRS z-score for age of smoking initiation was associated with age of smoking initiation (OR: 0.87; 95% CI: 0.82, 0.92); the PRS z-score for cigarettes per day was associated with heavier smoking (OR: 1.17; 95% CI: 1.11, 1.25); and the PRS z-score for smoking cessation predicted successful cessation (OR: 1.24; 95% CI: 1.17, 1.32). In the African ancestry cohort, the PRSs did not predict smoking behaviors. CONCLUSIONS: Smoking-related PRSs were associated with smoking-related behaviors in European ancestry populations. This improvement in prediction is greatest in the lowest and highest genetic risk categories. The lack of prediction in African ancestry populations highlights the urgent need to increase diversity in research so that scientific advances can be applied to populations other than those of European ancestry. IMPLICATIONS: This study shows that including both genetic ancestry and PRSs in a single model increases the ability to predict smoking behaviors compared with the model including only demographic characteristics. This finding is observed for every smoking-related outcome. Even though adding genetics is more predictive, the demographics alone confer substantial and meaningful predictive power. However, with increasing work in PRSs, the predictive ability will continue to improve.

Risk of antibiotic treatment failure in premenopausal women with uncomplicated urinary tract infection.

PURPOSE: Acute uncomplicated urinary tract infections (UTIs) are among the most common indications for antibiotic prescriptions in otherwise healthy women. We compared the risk of treatment failure of antibiotic regimens for outpatient treatment of UTI in real-world practice. METHODS: We identified non-pregnant, premenopausal women diagnosed with uncomplicated, lower tract UTI and prescribed an oral antibiotic with activity against common uropathogens. We used propensity score-weighted Kaplan-Meier functions to estimate 30-day risks and risk differences (RD) for pyelonephritis and UTI-related antibiotic prescription switch. RESULTS: Of 1 140 602 patients, the distribution of index prescriptions was 44% fluoroquinolones (non-first-line), 28% trimethoprim-sulfamethoxazole (TMP/SMX) (first-line), 24% nitrofurantoin (first-line), 3% narrow-spectrum ß-lactams (non-first-line), 1% broad-spectrum ß-lactams (non-first-line), and 1% amoxicillin/ampicillin (non-recommended). Compared to the risk of pyelonephritis for nitrofurantoin (0.3%), risks were higher for TMP/SMX (RD, 0.2%; 95% CI, 0.2%-0.2%) and broad-spectrum ß-lactams (RD, 0.2%; 95% CI, 0.1%-0.4%). Compared to the risk of prescription switch for nitrofurantoin (12.7%), the risk was higher for TMP/SMX (RD 1.6%; 95% CI 1.3%-1.7%) but similar for broad-spectrum ß-lactams (RD -0.7%; 95% CI -1.4%-0.1%) and narrow-spectrum ß-lactams (RD -0.3%; 95% CI -0.8%-0.2%). Subgroup analyses suggest TMP/SMX treatment failure may be due in part to increasing uropathogen resistance over time. CONCLUSIONS: The risk of treatment failure differed by antibiotic agent, with higher risk associated with TMP/SMX versus nitrofurantoin, and lower or similar risk associated with broad- versus narrow-spectrum ß-lactams. Given serious safety warnings for fluoroquinolones, these results suggest that nitrofurantoin may be preferable as the first-line agent for outpatient treatment of uncomplicated UTI.

Variants in the CHRNA5-CHRNA3-CHRNB4 Region of Chromosome 15 Predict Gastrointestinal Adverse Events in the Transdisciplinary Tobacco Use Research Center Smoking Cessation Trial.

INTRODUCTION: Reducing adverse events from pharmacologic treatment is an important goal of precision medicine and identifying genetic predictors of adverse events is a step toward this goal. In 2012, King et al. reported associations between genetic variants and adverse events in a placebo-controlled smoking cessation trial of varenicline and bupropion. Strong associations were found between gastrointestinal adverse events and 11 variants in the CHRNA5-CHRNA3-CHRNB4 region of chromosome 15, a region repeatedly associated with smoking-related phenotypes. Our goal was to replicate, in an independent sample, the impact of variants in the CHRNA5-CHRNA3-CHRNB4 region on gastrointestinal adverse events and to extend the analyses to adherence and smoking cessation. METHODS: The University of Wisconsin Transdisciplinary Tobacco Use Research Center (TTURC) conducted a multiarmed, placebo-controlled smoking cessation trial of bupropion and nicotine replacement therapy that included 985 genotyped European-ancestry participants. We evaluated relationships between our key variables using logistic regression. RESULTS: Gastrointestinal adverse events were experienced by 31.6% TTURC participants. Each of the CHRNA5-CHRNA3-CHRNB4 associations from the King et al. study was found in TTURC, with the same direction of effect. Neither these variants nor the gastrointestinal adverse events themselves were associated with adherence to medication or successful smoking cessation. CONCLUSIONS: Variants in the CHRNA5-CHRNA3-CHRNB4 region of chromosome 15 are associated with gastrointestinal adverse events in smoking cessation. Additional independent variants in this region strengthen the association. The consistency between the results of these two independent studies supports the conclusion that these findings reflect biological response to the use of smoking cessation medication. IMPLICATIONS: The fact that our findings from the TTURC smoking cessation trial support the independent findings of King et al. suggest that associations of variants in the CHRNA5-CHRNA3-CHRNB4 region of chromosome 15 with gastrointestinal adverse events while taking medications for smoking cessation reflect biology. However, although adherence to medication was a strong predictor of successful smoking cessation in TTURC, neither adverse events nor the genetic variants associated with them predicted either adherence or successful cessation in this study. Thus, although we should strive to minimize adverse events during treatment, we should not expect that to increase successful smoking cessation substantially.

Assessing the effectiveness of the National Comprehensive Cancer Network genetic testing guidelines in identifying African American breast cancer patients with deleterious genetic mutations.

PURPOSE: Approximately, 10% of breast cancers are hereditary. Identifying women at high risk for hereditary breast and ovarian cancer allows for early detection, prevention, and individualized disease management for those diagnosed with breast cancer. There is limited data about breast cancer genetic risks among African Americans as the majority of the large studies have been conducted in European Americans. We examined the distribution of deleterious genetic mutations in African American breast cancer patients, and evaluated the effectiveness of the National Comprehensive Cancer Network (NCCN) guidelines for identifying African American women at high risk for deleterious genetic mutations. METHODS: African American participants with breast cancer underwent an interview regarding health and family history, and a 30-gene saliva test. Medical records were accessed to determine whether participants had received prior genetic testing as part of usual care, results of previous testing, and cancer characteristics. RESULTS: Two hundred and fifty participants were enrolled between February 2016 and May 2018. Twenty (8.0%) had a deleterious mutation in one of the 30 genes; BRCA2 had the highest frequency (40.0%). 187 (74.8%) met eligibility for testing based on NCCN guidelines. Only 110 (58.8%) of participants eligible for genetic testing, according to guidelines, had received prior testing as part of routine care. Using the 30-gene test, we identified deleterious mutations in 17 of 187 (9.1%) of those who met NCCN criteria for testing, and three of 63 (4.8%) of those who did not meet criteria for testing nonetheless had a deleterious mutation associated with breast cancer. CONCLUSIONS: Our results indicate that a large proportion of African American breast cancer patients who meet criteria for genetic testing do not receive it as part of routine care. Even in women who do not meet testing guidelines, nearly 5% have a known deleterious mutation associated with breast cancer.

Tobacco Use Prevalence and Smoking Cessation Pharmacotherapy Prescription Patterns Among Hospitalized Patients by Medical Specialty.

INTRODUCTION: Effective smoking cessation medications are readily available but may be underutilized in hospital settings. In our large, tertiary care hospital, we aimed to (1) characterize patient tobacco use prevalence across medical specialties, (2) determine smoking cessation pharmacotherapy prescription variation across specialties, and (3) identify opportunities for improvement in practice. METHODS: Using electronic health records at Barnes Jewish Hospital, we gathered demographic data, admitting service, admission route, length of stay, self-reported tobacco use, and smoking cessation prescriptions over a 6-year period, from 2010 to 2016. We then compared tobacco use prevalence and smoking cessation prescriptions across medical specialties using a cross-sectional, retrospective design. RESULTS: Past 12-month tobacco use was reported by patients in 27.9% of inpatient admissions; prescriptions for smoking cessation pharmacotherapy were provided during 21.5% of these hospitalizations. The proportion of patients reporting tobacco use was highest in psychiatry (55.3%) and lowest in orthopedic surgery (17.1%). Psychiatric patients who reported tobacco use were most likely to receive pharmacotherapy (71.8% of admissions), and plastic surgery patients were least likely (4.7% of admissions). Compared with Caucasian tobacco users, African American patients who used tobacco products were less likely to receive smoking cessation medications (adjusted odds ratio [aOR] = 0.65; 95% confidence interval [CI] = 0.62 to 0.68). CONCLUSIONS: Among hospitalized tobacco users, safe and cost-effective pharmacotherapies are under-prescribed. We identified substantial variation in prescribing practices across different medical specialties and demographic groups, suggesting the need for an electronic medical record protocol that facilitates consistent tobacco use cessation pharmacotherapy treatment. IMPLICATIONS: Tobacco use cessation pharmacotherapy is underutilized during hospitalization, and prescription rates vary greatly across medical specialties and patient characteristics. Hospitals may benefit from implementing policies and practices that standardize and automate the offer of smoking pharmacotherapy for all hospitalized patients who use tobacco.

E-cigarette Usage Is Associated With Increased Past-12-Month Quit Attempts and Successful Smoking Cessation in Two US Population-Based Surveys.

INTRODUCTION: We examined past-12-month quit attempts and smoking cessation from 2006 to 2016 while accounting for demographic shifts in the US population. In addition, we sought to understand whether the current use of electronic cigarettes was associated with a change in past-12-month quit attempts and successful smoking cessation at the population level. METHODS: We analyzed data from 25- to 44-year-olds from the National Health Interview Survey (NHIS) from 2006 to 2016 (N = 26,354) and the Tobacco Use Supplement to the Current Population Survey (TUS-CPS) in 2006-2007, 2010-2011, and 2014-2015 (N = 33,627). Data on e-cigarette use were available in the 2014-2016 NHIS and 2014-2015 TUS-CPS surveys. RESULTS: Past-12-month quit attempts and smoking cessation increased in recent years compared with 2006. Current e-cigarette use was associated with higher quit attempts (adjusted odds ratio [aOR] = 2.29, 95% confidence interval [CI] = 1.87 to 2.81, p < .001) and greater smoking cessation (aOR = 1.64, 95% CI = 1.21 to 2.21, p = .001) in the NHIS. Multivariable logistic regression of the TUS-CPS data showed that current e-cigarette use was similarly significantly associated with increased past-12-month quit attempts and smoking cessation. Significant interactions were found for smoking frequency (everyday and some-day smoking) and current e-cigarette use for both outcomes (p < .0001) with the strongest positive effects seen in everyday smokers. CONCLUSIONS: Compared with 2006, past-12-month quit attempts and smoking cessation increased among adults aged 25-44 in recent years. Current e-cigarette use was associated with increased past-12-month quit attempts and successful smoking cessation among established smokers. These findings are relevant to future tobacco policy decisions. IMPLICATIONS: E-cigarettes were introduced into the US market over the past decade. During this period, past-12-month quit attempts and smoking cessation have increased among US adults aged 25-44. These trends are inconsistent with the hypothesis that e-cigarette use is delaying quit attempts and leading to decreased smoking cessation. In contrast, current e-cigarette use was associated with significantly higher past-12-month quit attempts and past-12-month cessation. These findings suggest that e-cigarette use contributes to a reduction in combustible cigarette use among established smokers.

Closed-Tube PCR with Nested Serial Invasion Probe Visualization Using Gold Nanoparticles.

BACKGROUND: Detecting DNA biomarkers related to personalized medicine could improve the outcome of drug therapy. However, personalized medicine in a resource-restrained hospital is very difficult because DNA biomarker detection should be performed by well-trained staff and requires expensive laboratory facilities. METHODS: We developed a gold nanoparticle-based "Tube-Lab" to enable DNA analysis in a closed tube. Gold nanoparticle-modified probes (GNPs) were used to construct an inexpensive and simple DNA sensor for signal readout. The method consists of 3 steps (template amplification, sequence identification, and GNP-based signal readout), bridged by an invasive reaction. With temperature control at each step, the 3 reactions proceed sequentially and automatically in a closed tube without any liquid transfer. We used Tube-Lab to detect different biomarkers in blood, tissue, and plasma, including US Food and Drug Administration-approved pharmacogenomic biomarkers (single nucleotide polymorphisms, somatic mutations). RESULTS: The combination of PCR-based template replication and invader-based signal amplification allowed detection of approximately 6 copies of input DNA and the selective pick up 0.1% mutants from large amounts of background DNA. This method highly discriminated polymorphisms and somatic mutations from clinical samples and allowed a "liquid biopsy" assay with the naked eye. CONCLUSIONS: Tube-Lab provides a promising and cost-effective approach for DNA biomarker analysis, including polymorphisms and somatic mutations from blood DNA, tissue DNA, or circulating tumor DNA in plasma, which are critical for personalized medicine.

Case of idiopathic left ventricular summit premature ventricular contractions successfully treated by catheter ablation.

Key Clinical Message: CA of LVS premature beats complexes is difficult due to anatomical limitations. We report a patient with PVCs originating from the LVS region who was successfully ablated by ablation. Abstract: Catheter ablation (CA) of premature ventricular contractions (PVCs) arising from the left ventricular summit (LVS) presents technical challenges due to the regional anatomy and frequently intramural site of origin. Herein, we demonstrated a case of a successful CA, originating from the LVS region. We further discussed the detailed anatomical background and clinical feasibility of CA as an alternative ablation route for PVCs originating from the LVS.

Environmental and genetic risk factors associated with total knee arthroplasty following cruciate ligament surgery.

Aims: The purpose of this study is to determine an individual's age-specific prevalence of total knee arthroplasty (TKA) after cruciate ligament surgery, and to identify clinical and genetic risk factors associated with undergoing TKA. Methods: This study was a retrospective case-control study using the UK Biobank to identify individuals reporting a history of cruciate ligament surgery. Data from verbal history and procedural codes recorded through the NHS were used to identify instances of TKA. Patient clinical and genetic data were used to identify risk factors for progression from cruciate ligament surgery to TKA. Individuals without a history of cruciate ligament reconstruction were used for comparison. Results: A total of 2,576 individuals with a history of cruciate ligament surgery were identified, with 290 (11.25%) undergoing TKA. In patients with prior cruciate ligament surgery, prevalence of TKA was 0.75% at age 45 years, 9.10% at age 65 years, and 20.43% at age 80 years. Patients with prior cruciate ligament surgery were 4.6 times more likely to have undergone TKA by age 55 years than individuals without prior cruciate ligament surgery. In the cruciate ligament surgery cohort, BMI > 30 kg/m2 (odds ratio (OR) 4.01 (95% confidence interval (CI) 2.74 to 5.87)), a job that always involved heavy manual or physical labour (OR 2.72 (95% CI 1.57 to 4.71)), or a job that always involved walking and standing (OR 2.58 (95% CI 1.58 to 4.20)) were associated with greater TKA odds. No single-nucleotide polymorphism (SNP) was associated with risk of TKA following cruciate ligament surgery. Conclusion: Patients with a history of prior cruciate ligament surgery have substantially higher risk of TKA and undergo arthroplasty at a relatively younger age than individuals without a history of prior cruciate ligament surgery. Physically demanding work and obesity were associated with higher odds of TKA after cruciate ligament surgery, but no SNP was associated with risk of TKA.

Occupational demands associated with rotator cuff disease surgery in the UK Biobank.

OBJECTIVES: Physically-demanding occupations may increase rotator cuff disease (RCD) risk and need for surgery. We linked a job-exposure matrix (JEM) to the UK Biobank cohort study to measure physical occupational exposures and estimate associations with RCD surgery. METHODS: Jobs and UK Standard Occupational Classification (SOC) codes were recorded during the UK Biobank verbal interview. Lifetime job histories were captured through a web-based survey. UK SOC codes were linked to a JEM based on the US O*NET database. O*NET-based scores [static strength, dynamic strength, general physical activities, handling/moving objects (range=1-7), time spent using hands, whole body vibration, and cramped/awkward positions (range=1-5)] were assigned to jobs. RCD surgeries were identified through linked national hospital inpatient records. Multivariable Cox regression was used to calculate hazard ratios (HR) as estimates of associations with RCD surgery. Among those with lifetime job histories, associations were estimated for duration of time with greatest exposure (top quartile of exposure). RESULTS: Of 277 808 people reporting jobs, 1997 (0.7%) had an inpatient RCD surgery. After adjusting for age, sex, race, education, area deprivation, and body mass index, all O*NET variables considered were associated with RCD surgery (HR per point increase range=1.10-1.45, all P<0.005). A total of 100 929 people reported lifetime job histories, in which greater exposures were significantly associated with RCD surgery after >10 years of work (eg, HR for 11-20 versus 0 years with static strength score ≥4 = 2.06, 95% confidence interval 1.39-3.04). CONCLUSIONS: Workplace physical demands are an important risk factor for RCD surgery, particularly for workers with more than a decade of exposure.

Longitudinal Relationships of White Matter Hyperintensities and Alzheimer Disease Biomarkers Across the Adult Life Span.

BACKGROUND AND OBJECTIVES: White matter hyperintensities (WMH) correlate with Alzheimer disease (AD) biomarkers cross-sectionally and modulate AD pathogenesis. Longitudinal changes have been reported for AD biomarkers, including concentrations of CSF ß-amyloid (Aß) 42, Aß40, total tau and phosphorylated tau181, standardized uptake value ratio from the molecular imaging of cerebral fibrillar Aß with PET using [11C] Pittsburgh Compound-B, MRI-based hippocampal volume, and cortical thickness. Correlations between established AD biomarkers and the longitudinal change for WMH have not been fully evaluated, especially among cognitively normal individuals across the adult life span. METHODS: We jointly analyzed the longitudinal data of WMH volume and each of the established AD biomarkers and cognition from 371 cognitively normal individuals whose baseline age spanned from 19.6 to 88.20 years from 4 longitudinal studies of aging and AD. A 2-stage algorithm was applied to identify the inflection point of baseline age whereby older participants had an accelerated longitudinal change in WMH volume, in comparison with the younger participants. The longitudinal correlations between WMH volume and AD biomarkers were estimated from the bivariate linear mixed-effects models. RESULTS: A longitudinal increase in WMH volume was associated with a longitudinal increase in PET amyloid uptake and a decrease in MRI hippocampal volume, cortical thickness, and cognition. The inflection point of baseline age in WMH volume was identified at 60.46 (95% CI 56.43-64.49) years, with the annual increase for the older participants (83.12 [SE = 10.19] mm3 per year) more than 13 times faster (p < 0.0001) than that for the younger participants (6.35 [SE = 5.63] mm3 per year). Accelerated rates of change among the older participants were similarly observed in almost all the AD biomarkers. Longitudinal correlations of WMH volume with MRI, PET amyloid biomarkers, and cognition seemed to be numerically stronger for the younger participants, but not significantly different from those for the older participants. Carrying APOE ε4 alleles did not alter the longitudinal correlations between WMH and AD biomarkers. DISCUSSION: Longitudinal increases in WMH volume started to accelerate around a baseline age of 60.46 years and correlated with the longitudinal change in PET amyloid uptake, MRI structural outcomes, and cognition.

Longitudinal clinical, cognitive and biomarker profiles in dominantly inherited versus sporadic early-onset Alzheimer's disease.

Approximately 5% of Alzheimer's disease cases have an early age at onset (<65 years), with 5-10% of these cases attributed to dominantly inherited mutations and the remainder considered as sporadic. The extent to which dominantly inherited and sporadic early-onset Alzheimer's disease overlap is unknown. In this study, we explored the clinical, cognitive and biomarker profiles of early-onset Alzheimer's disease, focusing on commonalities and distinctions between dominantly inherited and sporadic cases. Our analysis included 117 participants with dominantly inherited Alzheimer's disease enrolled in the Dominantly Inherited Alzheimer Network and 118 individuals with sporadic early-onset Alzheimer's disease enrolled at the University of California San Francisco Alzheimer's Disease Research Center. Baseline differences in clinical and biomarker profiles between both groups were compared using t-tests. Differences in the rates of decline were compared using linear mixed-effects models. Individuals with dominantly inherited Alzheimer's disease exhibited an earlier age-at-symptom onset compared with the sporadic group [43.4 (SD ± 8.5) years versus 54.8 (SD ± 5.0) years, respectively, P < 0.001]. Sporadic cases showed a higher frequency of atypical clinical presentations relative to dominantly inherited (56.8% versus 8.5%, respectively) and a higher frequency of APOE-ε4 (50.0% versus 28.2%, P = 0.001). Compared with sporadic early onset, motor manifestations were higher in the dominantly inherited cohort [32.5% versus 16.9% at baseline (P = 0.006) and 46.1% versus 25.4% at last visit (P = 0.001)]. At baseline, the sporadic early-onset group performed worse on category fluency (P < 0.001), Trail Making Test Part B (P < 0.001) and digit span (P < 0.001). Longitudinally, both groups demonstrated similar rates of cognitive and functional decline in the early stages. After 10 years from symptom onset, dominantly inherited participants experienced a greater decline as measured by Clinical Dementia Rating Sum of Boxes [3.63 versus 1.82 points (P = 0.035)]. CSF amyloid beta-42 levels were comparable [244 (SD ± 39.3) pg/ml dominantly inherited versus 296 (SD ± 24.8) pg/ml sporadic early onset, P = 0.06]. CSF phosphorylated tau at threonine 181 levels were higher in the dominantly inherited Alzheimer's disease cohort (87.3 versus 59.7 pg/ml, P = 0.005), but no significant differences were found for t-tau levels (P = 0.35). In summary, sporadic and inherited Alzheimer's disease differed in baseline profiles; sporadic early onset is best distinguished from dominantly inherited by later age at onset, high frequency of atypical clinical presentations and worse executive performance at baseline. Despite these differences, shared pathways in longitudinal clinical decline and CSF biomarkers suggest potential common therapeutic targets for both populations, offering valuable insights for future research and clinical trial design.

Signal amplification by rolling circle amplification on universal flaps yielded from target-specific invasive reaction.

Detection of nucleic acids with signal amplification is preferable in clinical diagnosis. A novel approach was developed for signal amplification by coupling invasive reaction with hyperbranched rolling circle amplification (HRCA). Invasive reaction, which does not rely on specific recognition sequences in a target but a specific structure formed by the specific binding of an upstream probe and a downstream probe to a target DNA, can generate thousands of flaps from one target DNA; then the flaps are ligated with padlock probes to form circles, which are the templates of HRCA. As HRCA amplicon sequence is free of target DNA sequence, signal amplification is achieved. Because flap sequence is the same to any target of interest, HRCA is universal; the detection cost is hence greatly reduced. The sensitivity of the proposed method is less than 1 fM artificial DNA targets; and the specificity of the method is high enough to discriminate one base difference in the target sequence. The feasibility was verified by detecting real biological samples from HBV carriers, indicating that the method is highly sensitive, cost-effective, and has a low risk of cross-contamination from amplicons. These properties should give great potential in clinical diagnosis.

Explaining the Varying Patterns of COVID-19 Deaths Across the United States: 2-Stage Time Series Clustering Framework.

BACKGROUND: Socially vulnerable communities are at increased risk for adverse health outcomes during a pandemic. Although this association has been established for H1N1, Middle East respiratory syndrome (MERS), and COVID-19 outbreaks, understanding the factors influencing the outbreak pattern for different communities remains limited. OBJECTIVE: Our 3 objectives are to determine how many distinct clusters of time series there are for COVID-19 deaths in 3108 contiguous counties in the United States, how the clusters are geographically distributed, and what factors influence the probability of cluster membership. METHODS: We proposed a 2-stage data analytic framework that can account for different levels of temporal aggregation for the pandemic outcomes and community-level predictors. Specifically, we used time-series clustering to identify clusters with similar outcome patterns for the 3108 contiguous US counties. Multinomial logistic regression was used to explain the relationship between community-level predictors and cluster assignment. We analyzed county-level confirmed COVID-19 deaths from Sunday, March 1, 2020, to Saturday, February 27, 2021. RESULTS: Four distinct patterns of deaths were observed across the contiguous US counties. The multinomial regression model correctly classified 1904 (61.25%) of the counties' outbreak patterns/clusters. CONCLUSIONS: Our results provide evidence that county-level patterns of COVID-19 deaths are different and can be explained in part by social and political predictors.

Digital analysis of the expression levels of multiple colorectal cancer-related genes by multiplexed digital-PCR coupled with hydrogel bead-array.

To digitally analyze expression levels of multiple genes in one reaction, we proposed a method termed as 'MDHB' (Multiplexed Digital-PCR coupled with Hydrogel Bead-array). The template for bead-based emulsion PCR (emPCR) was prepared by reverse transcription using sequence-tagged primers. The beads recovered from emPCR were immobilized with hydrogel to form a single-bead layer on a chip, and then decoded by gene-specific probe hybridization and Cy3-dUTP based primer extension reaction. The specificity of probe hybridization was improved by using electrophoresis to remove mismatched probes on the bead's surface. The number of positive beads reflects the abundance of expressed genes; the expression levels of target genes were normalized to a housekeeping gene and expressed as the number ratio of green beads to red beads. The discrimination limit of MDHB is 0.1% (i.e., one target molecule from 1000 background molecules), and the sensitivity of the method is below 100 cells when using the ß-actin gene as the detection target. We have successfully employed MDHB to detect the relative expression levels of four colorectal cancer (CRC)-related genes (c-myc, COX-2, MMP7, and DPEP1) in 8 tissue samples and 9 stool samples from CRC patients, giving the detection rates of 100% and 77%, respectively. The results suggest that MDHB could be a potential tool for early non-invasive diagnosis of CRC.