Early development and adaptive functioning in children with Bardet-Biedl syndrome.

This study had two aims. Aim one investigated achievement of 10 developmental milestones in children with Bardet-Biedl syndrome (BBS). Aim one data were derived from retrospective responses by caregivers of individuals with BBS who are enrolled in the Clinical Registry Investigating Bardet-Biedl syndrome (CRIBBS). CRIBBS is a natural history registry acquiring serial observations. Aim two investigated early adaptive skills using the Adaptive Behavior Assessment System (ABAS-II 0-5) completed by caregivers of children with BBS aged from 0 to 5. There were 652 individuals with milestone information (with some variability based on availability of information for specific milestones), and 101 individuals (including 95 among the 652) with ABAS-II information. Results revealed wide-ranging delays in adaptive skills, particularly in the domain of Self-Care. Expressive language appears to be the most frequently delayed developmental milestone. We found a difference by BBS genotype wherein individuals with BBS1 had higher adaptive/developmental scores than individuals with BBS10. Age also carried a significant association with adaptive skills diverging farther from a normative trajectory as children with BBS progress through early childhood.

Modeling longitudinal oral health status and pneumonia risk: secondary data analyses of an integrated dental-medical cohort.

BACKGROUND: Mounting evidence indicates potential associations between poor oral health status (OHS) and increased pneumonia risk. Relative pneumonia risk was assessed in the context of longitudinally documented OHS. METHODS: Electronic medical/dental patient data captured from 2007 through 2019 were retrieved from the integrated health records of Marshfield Clinic Health Systems. Participant eligibility initiated with an assessment of OHS, stratified into the best, moderate, or worst OHS groups, with the additional criterion of 'no pneumonia diagnosis in the past 90 days'. Pneumonia incidence was longitudinally monitored for up to 1 year from each qualifying dental visit. Models were assessed, with and without adjustment for prior pneumonia incidence, adjusted for smoking and subjected to confounding mitigation attributable to known pneumonia risk factors by applying propensity score analysis. Time-to-event analysis and proportional hazard modeling were applied to investigate relative pneumonia risk over time among the OHS groups. RESULTS: Modeling identified associations between any incident pneumonia subtype and 'number of missing teeth' (p < 0.001) and 'clinically assessed periodontal status' (p < 0.01), which remained significant following adjustment for prior pneumonia incidence and smoking. The hazard ratio (HR) for 'any incident pneumonia' in the best OHS group for 'number of missing teeth' was 0.65, 95% confidence interval (CI) [0.54 - 0.79] (unadjusted) and 0.744, 95% CI [0.61 - 0.91] (adjusted). The HR for 'any incident pneumonia' in the best 'clinically assessed periodontal status' group was 0.72, 95% CI [0.58 - 0.90] (unadjusted) and 0.78, 95% CI [0.62 - 0.97] (adjusted). CONCLUSION/CLINICAL RELEVANCE: Poor OHS increased pneumonia risk. Proactive attention of medical providers to patient OHS and health literacy surrounding oral-systemic disease association is vital, especially in high-risk populations.

Kidney failure in Bardet-Biedl syndrome.

The aim of this study was to explore kidney failure (KF) in Bardet-Biedl syndrome (BBS), focusing on high-risk gene variants, demographics, and morbidity. We employed the Clinical Registry Investigating BBS (CRIBBS) to identify 44 (7.2%) individuals with KF out of 607 subjects. Molecularly confirmed BBS was identified in 37 KF subjects and 364 CRIBBS registrants. KF was concomitant with recessive causal variants in 12 genes, with BBS10 the most predominant causal gene (26.6%), while disease penetrance was highest in SDCCAG8 (100%). Two truncating variants were present in 67.6% of KF cases. KF incidence was increased in genes not belonging to the BBSome or chaperonin-like genes (p < 0.001), including TTC21B, a new candidate BBS gene. Median age of KF was 12.5 years, with the vast majority of KF occurring by 30 years (86.3%). Females were disproportionately affected (77.3%). Diverse uropathies were identified, but were not more common in the KF group (p = 0.672). Kidney failure was evident in 11 of 15 (73.3%) deaths outside infancy. We conclude that KF poses a significant risk for premature morbidity in BBS. Risk factors for KF include female sex, truncating variants, and genes other than BBSome/chaperonin-like genes highlighting the value of comprehensive genetic investigation.

Hydrochlorothiazide use, sun exposure, and risk of keratinocyte cancer.

BACKGROUND: Keratinocyte cancer (KC) rates are increasing in the U.S., particularly in older age groups. Use of hydrochlorothiazide (HCTZ), due to its photosensitizing properties, and high sun exposure are two known NMSC risk factors, but their synergistic effects are undetermined. The purpose of this study was to examine the development of NMSC between adults who did and did not use HCTZ, as well as those with high and low sun exposure. METHODS: A retrospective case-control sample was assembled from adult patients in north-central Wisconsin (USA). Duration of HCTZ use and occupational sun exposure were extracted from electronic health records, along with a linked survey of lifetime sun exposure. RESULTS: There were 333 cases and 666 controls in the analytical sample. A significant main effect was observed for HCTZ duration in the full sample. Under low sun exposure, the odds of NMSC was 14% greater for each additional year of HCTZ use (aOR = 1.14 [1.11, 1.18], p < 0.001). In a sensitivity analysis of participants age 70 years and over, there was a borderline significant (p = 0.086) HCTZ use by high sun exposure interaction, suggesting modestly increased HCTZ risk in older, high sun exposure adults. CONCLUSIONS: Consistent with prior studies, longer duration of HCTZ use was a predictor of NMSC in north-central Wisconsin adults. NMSC may be accelerated in HCTZ users with outdoor lifestyles, but future studies should attempt to further disaggregate specific effects of sun exposure time, HCTZ duration, and age on NMSC development.

Injuries and illnesses to children in commercial fishing in Alaska: A brief report.

BACKGROUND: Commercial fishing is the most hazardous occupation in the United States. While the epidemiology of adult injuries and fatalities are well documented, injuries to children (<18 years old) are not described. The purpose of this report was to describe the characteristics of nonfatal injuries to children involved in commercial fishing. METHODS: Nonfatal commercial fishing injuries to children were identified in the Alaska Fishermen's Fund. The Alaska Fishermen's Fund is an emergency fund payor of last resort. Data on nonfatal injuries to victims aged 17 or younger were analyzed. Descriptive statistics were used to characterize demographics and injury characteristics. RESULTS: Forty-four nonfatal child injury claims were made between 2012 and 2016. The mean age at the time of claim was 15.6 years (SD = 1.8) and 84% were male. The most common types of injuries among children were sprains and strains and the most commonly injured body parts were upper extremities and the trunk. Most injuries occurred in salmon fisheries. CONCLUSIONS: Children are participating in commercial fishing. Based on the results of this analysis, children are also experiencing occupational injuries. The results of this analysis underscore the need for additional safety and health information, guidance for supervisors, and intervention to prevent injuries to children participating in commercial fishing.

Depression, Anxiety and Stress Among Young Farmers and Ranchers: A Pilot Study.

Agriculture has been identified as a stressful industry and there is evidence that chronic stress may contribute to the development or progression of mental health disorders, specifically anxiety and depression. Young adult farmers and ranchers may be at increased risk of mental health disorders when compared to more experienced counterparts due to additional stressors. The objectives of this study were to identify the occupational stressors of young adult farmers and ranchers in the Midwest and estimate the prevalence of anxiety and depression among this population. An online survey consisting of reliable and valid instruments was used to identify the sources of stress and prevalence of anxiety and depression among the young farming and ranching population. The survey included items related to stress, anxiety, depression, general health, and farm/personal demographics. A total of 170 young farmers and ranchers responded to the survey. The mean age of the sample was 28.9 (SD 4.4) years. Approximately 71% of respondents met the criteria for Generalized Anxiety Disorder (GAD-7 score ≥ 5) and 53% met the criteria for Major Depressive Disorder (PHQ-9 score ≥ 5). Of seven presented stress domains, personal finances and time pressures were the sources of greatest concern. Personal finances, time pressures, economic conditions, and employee relations were associated with anxiety and depression. The burden of depression and anxiety is high among young adult farmers and ranchers. Stressors commonly affiliated with farming and ranching are associated with anxiety and depression. Additional research should further explore the burden of mental health disorders among the population and examine protective factors for mental illness and opportunities for interventions.

Thromboembolic complications following a first isolated episode of superficial vein thrombosis: a cross-sectional retrospective study.

Superficial vein thrombosis (SVT) may be associated with complications such as venous thromboembolism (VTE) and recurrent SVT. The purpose of this study was to explore risk factors among patients with a first isolated episode of SVT (index SVT) involving upper and lower extremities and to estimate the prevalence of VTE complications within 1 year of index SVT. Retrospective chart review of electronic records at Marshfield Clinic in Wisconsin identified 381 subjects with a first isolated SVT diagnosis (male/female: 170/211; median age 59.4 years). Patients were stratified based on whether they did (n = 44; 11.5 %) or did not (n = 337; 88.5 %) experience VTE complications and whether they did (n = 25; 6.6 %) or did not (n = 356; 93.4 %) experience pulmonary embolism (PE) and/or deep vein thrombosis (DVT) within 1 year of index SVT. There were 49 complications among 44 patients; these included DVT (n = 18, 36.7 %), propagation of SVT (n = 18, 36.7 %), PE (n = 9, 18.4 %), new SVT at different location (n = 3, 6.1 %), and recurrent SVT (n = 1, 2.0 %). Univariate analysis of all VTE complications identified seven potential risk factors and similar analysis of PE/DVT complications identified eight potential risk factors, with six common risk factors identified in both analyses. Multivariate analysis identified indwelling venous catheter 30 days prior to SVT (p = 0.044), cancer history with treatment in the previous year (p = 0.001), and non-surgical trauma 7 days prior to SVT (p < 0.001) as independent risk factors for PE/DVT complications. Independent risk factors identified in the current study may convey greater risk for VTE complications, especially PE/DVT, following an initial isolated SVT episode.

Social environments, risk-taking and injury in farm adolescents.

BACKGROUND: Farm environments are especially hazardous for young people. While much is known about acute physical causes of traumatic farm injury, little is known about social factors that may underlie their aetiology. OBJECTIVES: In a nationally representative sample of young Canadians aged 11-15 years, we described and compared farm and non-farm adolescents in terms of the qualities of their social environments, engagement in overt multiple risk-taking as well as how such exposures relate aetiologically to their reported injury experiences. METHODS: Cross-sectional analysis of survey reports from the 2014 (Cycle 7) Canadian Health Behaviour in School-Aged Children study was conducted. Children (n=2567; 2534 weighted) who reported living or working on farms were matched within schools in a 1:1 ratio with children not living or working on farms. Scales examining quality of social environments and overt risk-taking were compared between the two groups, stratified by gender. We then related the occurrence of any serious injury to these social exposures in direct and interactive models. RESULTS: Farm and non-farm children reported social environments that were quite similar, with the exception of overt multiple risk-taking, which was demonstrably higher in farm children of both genders. Engagement in overt risk-taking, but not the other social environmental factors, was strongly and consistently associated with risks for serious injury in farm as well as non-farm children, particularly among males. CONCLUSIONS: Study findings highlight the strength of associations between overt multiple risk-taking and injury among farm children. This appears to be a normative aspect of adolescent farm culture.

Biology-Driven Gene-Gene Interaction Analysis of Age-Related Cataract in the eMERGE Network.

Bioinformatics approaches to examine gene-gene models provide a means to discover interactions between multiple genes that underlie complex disease. Extensive computational demands and adjusting for multiple testing make uncovering genetic interactions a challenge. Here, we address these issues using our knowledge-driven filtering method, Biofilter, to identify putative single nucleotide polymorphism (SNP) interaction models for cataract susceptibility, thereby reducing the number of models for analysis. Models were evaluated in 3,377 European Americans (1,185 controls, 2,192 cases) from the Marshfield Clinic, a study site of the Electronic Medical Records and Genomics (eMERGE) Network, using logistic regression. All statistically significant models from the Marshfield Clinic were then evaluated in an independent dataset of 4,311 individuals (742 controls, 3,569 cases), using independent samples from additional study sites in the eMERGE Network: Mayo Clinic, Group Health/University of Washington, Vanderbilt University Medical Center, and Geisinger Health System. Eighty-three SNP-SNP models replicated in the independent dataset at likelihood ratio test P < 0.05. Among the most significant replicating models was rs12597188 (intron of CDH1)-rs11564445 (intron of CTNNB1). These genes are known to be involved in processes that include: cell-to-cell adhesion signaling, cell-cell junction organization, and cell-cell communication. Further Biofilter analysis of all replicating models revealed a number of common functions among the genes harboring the 83 replicating SNP-SNP models, which included signal transduction and PI3K-Akt signaling pathway. These findings demonstrate the utility of Biofilter as a biology-driven method, applicable for any genome-wide association study dataset.

Reinitiating warfarin: relationships between dose and selected patient, clinical and hospital measures.

BACKGROUND: Warfarin is an oral anticoagulant used in the long-term treatment/prevention of venothromboembolic disease. Patients undergoing elective surgical and non-surgical procedures may require temporary warfarin discontinuation followed by reinitiation after their procedure. Because little information is available regarding best methods for warfarin reinitiation, we investigated current practices to inform management decisions. METHODS: Subjects were required to have a known and stable warfarin dose prior to discontinuation, which was operationalized by requiring, within 7-days prior to discontinuation, that they have at least one INR in therapeutic range (2.0-3.5), no INR(s) out of range, and no more than a 15% change in warfarin dose. Stable dose prior to discontinuation was defined as the average daily dose received in the 7 days immediately prior to discontinuation. Reinitiation dose was defined as the average daily dose received in the first 3 days after warfarin was restarted. Subjects were divided into three groups based on whether they received approximately the same, a higher, or a lower dose at reinitiation and were also grouped by calendar time into three distinct periods that reflected differing levels of availability of electronic and patient care data that may impact reinitiation dose decisions. These groupings facilitated analyses and descriptions of trends in reinitiation dosing and supported other analyses, including tests for association between dose group and selected subject demographic, clinical, medication and hospitalization measures. All study data were abstracted from Marshfield Clinic electronic patient care and administrative databases and electronic patient care databases from Ministry St. Joseph's Hospital (Marshfield, WI). RESULTS: We identified 205 subjects with warfarin temporarily discontinued between 1994 and 2012: 99 subjects in same dose group, 32 subjects in the low group, and 74 subjects in the high group. Because relatively wide differences were observed in the proportion of same dose subjects during more recent years (2007-2012) compared to earlier years (54% vs 35%), we focused our analyses on this recent period, which included 140 subjects. Review of physician notes and other documents yielded virtually no information about reasons for reinitiation dose decisions. In addition, tests for association between reinitiation dose group and subject demographic, clinical, medication and hospital measures were uniformly uninformative. CONCLUSIONS: We observed varied dosing strategies for reinitiating patients on warfarin and, in more recent years, an apparent trend toward reinitiating patients on the same dose. However we could not associate dosing strategy with specific patient demographic, clinical, medication or hospital factors. Many factors influence whether a physician reinitiates a patient at a different dose than his/her prior stable warfarin dose. However, in the absence of clinical indications for modification, we believe patients with a previously established effective dose should be reinitiated at that same dose following temporary warfarin discontinuation.

Factors that affect rate of INR decline after warfarin discontinuation.

BACKGROUND: Despite vast literature on warfarin, optimal strategies for temporarily discontinuing and restarting warfarin have not been established. To improve warfarin discontinuation processes, we investigated known medical and genetic factors that influence stable warfarin dose to determine how well they predict the time until patients become subtherapeutic after discontinuing warfarin. METHODS: This was a retrospective cohort study of patients who temporarily discontinued warfarin before an elective procedure andhad at least 2 international normalized ratio (INR) values available during the discontinuation period. Data abstracted included date of discontinuation, warfarin dose, INR values, body surface area, gender, age, indication for warfarin, current medications, eGFR, and presence of bridging therapy with heparin. DNA variants were tested in CYP2C9, VKORC1, and CYP4F2 genes. Subjects were excluded if they received vitamin K, fresh frozen plasma, or prothrombin complexes to reverse anticoagulation. Asymptotic regression models were used to approximate decline in INR during warfarin clearance. Spearman correlations and Kruskal-Wallis tests were used to characterize associations of model estimates with quantitative variables and for group comparisons, respectively. RESULTS: Other than the expected association with baseline INR, correlations of model parameter estimates with clinical variables were generally weak and not statistically significant. The strongest associations with slope were with serum creatinine and eGFR. There were no significant associations with CYP2C9, VKORC1, or CYP4F2 DNA variants, but there were few subjects combined in the nonwild groups for CYP2C9. Estimated slope showed moderate correlation with observed dose. CONCLUSION: Known clinical and genetic predictors of therapeutic dose were not found to be strongly associated with the slope of INR decline after warfarin discontinuation.

Electronic medical records and genomics (eMERGE) network exploration in cataract: several new potential susceptibility loci.

PURPOSE: Cataract is the leading cause of blindness in the world, and in the United States accounts for approximately 60% of Medicare costs related to vision. The purpose of this study was to identify genetic markers for age-related cataract through a genome-wide association study (GWAS). METHODS: In the electronic medical records and genomics (eMERGE) network, we ran an electronic phenotyping algorithm on individuals in each of five sites with electronic medical records linked to DNA biobanks. We performed a GWAS using 530,101 SNPs from the Illumina 660W-Quad in a total of 7,397 individuals (5,503 cases and 1,894 controls). We also performed an age-at-diagnosis case-only analysis. RESULTS: We identified several statistically significant associations with age-related cataract (45 SNPs) as well as age at diagnosis (44 SNPs). The 45 SNPs associated with cataract at p<1×10(-5) are in several interesting genes, including ALDOB, MAP3K1, and MEF2C. All have potential biologic relationships with cataracts. CONCLUSIONS: This is the first genome-wide association study of age-related cataract, and several regions of interest have been identified. The eMERGE network has pioneered the exploration of genomic associations in biobanks linked to electronic health records, and this study is another example of the utility of such resources. Explorations of age-related cataract including validation and replication of the association results identified herein are needed in future studies.

Relational machine learning for electronic health record-driven phenotyping.

OBJECTIVE: Electronic health records (EHR) offer medical and pharmacogenomics research unprecedented opportunities to identify and classify patients at risk. EHRs are collections of highly inter-dependent records that include biological, anatomical, physiological, and behavioral observations. They comprise a patient's clinical phenome, where each patient has thousands of date-stamped records distributed across many relational tables. Development of EHR computer-based phenotyping algorithms require time and medical insight from clinical experts, who most often can only review a small patient subset representative of the total EHR records, to identify phenotype features. In this research we evaluate whether relational machine learning (ML) using inductive logic programming (ILP) can contribute to addressing these issues as a viable approach for EHR-based phenotyping. METHODS: Two relational learning ILP approaches and three well-known WEKA (Waikato Environment for Knowledge Analysis) implementations of non-relational approaches (PART, J48, and JRIP) were used to develop models for nine phenotypes. International Classification of Diseases, Ninth Revision (ICD-9) coded EHR data were used to select training cohorts for the development of each phenotypic model. Accuracy, precision, recall, F-Measure, and Area Under the Receiver Operating Characteristic (AUROC) curve statistics were measured for each phenotypic model based on independent manually verified test cohorts. A two-sided binomial distribution test (sign test) compared the five ML approaches across phenotypes for statistical significance. RESULTS: We developed an approach to automatically label training examples using ICD-9 diagnosis codes for the ML approaches being evaluated. Nine phenotypic models for each ML approach were evaluated, resulting in better overall model performance in AUROC using ILP when compared to PART (p=0.039), J48 (p=0.003) and JRIP (p=0.003). DISCUSSION: ILP has the potential to improve phenotyping by independently delivering clinically expert interpretable rules for phenotype definitions, or intuitive phenotypes to assist experts. CONCLUSION: Relational learning using ILP offers a viable approach to EHR-driven phenotyping.

A novel method for studying the temporal relationship between type 2 diabetes mellitus and cancer using the electronic medical record.

BACKGROUND: We developed an algorithm for the identification of patients with type 2 diabetes and ascertainment of the date of diabetes onset for examination of the temporal relationship between diabetes and cancer using data in the electronic medical record (EMR). METHODS: The Marshfield Clinic EMR was searched for patients who developed type 2 diabetes between January 1, 1995 and December 31, 2009 using a combination of diagnostic codes and laboratory data. Subjects without diabetes were also identified and matched to subjects with diabetes by age, gender, smoking history, residence, and date of diabetes onset/reference date. RESULTS: The final cohort consisted of 11,236 subjects with and 54,365 subjects without diabetes. Stringent requirements for laboratory values resulted in a decrease in the number of potential subjects by nearly 70%. Mean observation time in the EMR was similar for both groups with 13-14 years before and 5-7 years after the reference date. The two cohorts were largely similar except that BMI and frequency of healthcare encounters were greater in subjects with diabetes. CONCLUSION: The cohort described here will be useful for the examination of the temporal relationship between diabetes and cancer and is unique in that it allows for determination of the date of diabetes onset with reasonable accuracy.

Asymmetry in noise-induced hearing loss: evaluation of two competing theories.

Competing theories exist about why asymmetry is observed in noise-induced hearing loss (NIHL). We evaluated these theories using a cohort of young workers studied over 16 years. The study aim was to describe and evaluate patterns of hearing loss and asymmetry by gender, agricultural exposure and gunfire exposure. This was a secondary analysis of data collected from young adults during follow-up of a randomized controlled trial. This follow-up study evaluated long-term effects of a hearing conservation intervention for rural students. The sample consisted of 392 of 690 participants from the original trial. In total, 355 young adults (aged 29-33 years) completed baseline and follow-up noise exposure surveys and clinical audiometric examinations. Data are displayed graphically as thresholds by frequency and ear and degree of asymmetry between ears (left minus right). In the primary group comparisons, low and high frequency averages and mean high frequency asymmetry were analyzed using mixed linear models. At frequencies >2000 Hz, men showed more hearing loss, with greater asymmetry and a different asymmetry pattern, than women. For men with documented hearing loss, there was a trend toward increasing asymmetry with increasing levels of hearing loss. Asymmetry at high frequencies varied substantially by level of shooting exposure. While "head shadowing" is accepted as the primary explanation for asymmetric hearing loss in the audiologic and related public health literature, our findings are more consistent with physiological differences as the primary cause of asymmetric hearing loss, with greater susceptibility to NIHL in the left ear of men.

Efficacy and safety of once-weekly subcutaneous semaglutide on weight loss in patients with overweight or obesity without diabetes mellitus-A systematic review and meta-analysis of randomized controlled trials.

Semaglutide is found to be efficient for weight loss in patients with overweight or obesity with diabetes mellitus (DM). With a wide range of adverse events reported, the efficacy and safety of once-weekly subcutaneous semaglutide in individuals without DM, with overweight or obesity, is unclear. We conducted a comprehensive meta-analysis of randomized studies on once-weekly semaglutide in this patient population. We identified nine studies with 11,641 patients in the semaglutide group and 10,479 in the placebo group. We observed that semaglutide resulted in significant benefits, including change in body weight (%): mean difference (MD) of -11.49% (p < 0.0001), change in absolute body weight: MD of -11.74 kg (p < 0.0001), and change in waist circumference: MD of -9.06 cm (p < 0.0001). Gastrointestinal side effects are predominant including nausea: odds ratio (OR) of 4.06 (p < 0.0001), vomiting: OR of 4.43 (p < 0.0001), diarrhea: OR of 2.10 (p < 0.0001), constipation: OR of 2.43 (p < 0.0001), gallbladder disorders: OR of 1.26 (p = 0.010), and cholelithiasis: OR of 2.06 (p = 0.04). Serious adverse events were not statistically significant: OR of 1.06 (p = 0.82). However, the percentage of participants discontinuing due to adverse events and gastrointestinal side effects was statistically significant: ORs of 2.22 (p < 0.0001) and 3.77 (p < 0.0001), respectively. This study shows that in patients with overweight or obesity without DM, once-weekly subcutaneous semaglutide can significantly decrease body weight without risk of serious adverse events when compared with a placebo. However, gastrointestinal side effects are predominant with semaglutide, which can result in medication discontinuation.

The Efficacy and Safety of Sacubitril/Valsartan Compared to Valsartan in Patients with Heart Failure and Mildly Reduced and Preserved Ejection Fractions: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Background: Sacubitril/valsartan improves heart failure (HF) outcomes in patients with heart failure with reduced ejection fraction (HFrEF). However, randomized controlled trials (RCTs) in patients with heart failure and mildly reduced ejection fraction (HFmrEF) and heart failure with preserved ejection fraction (HFpEF) have shown inconsistent results. We conducted this meta-analysis to comprehensively evaluate the efficacy and safety of sacubitril/valsartan compared to valsartan within this specific patient population. Methods: We searched the MEDLINE database and ClinicalTrials.gov and identified four RCTs that could be included in our analysis, with 3375 patients in the sacubitril/valsartan group and 3362 in the valsartan group. Results: Our study shows that, in patients with HFmrEF and HFpEF, sacubitril/valsartan was superior to valsartan in some of the key HF outcomes, such as the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ CSS), with a small but significant mean difference of 1.13 (95% confidence interval or CI of 0.15 to 2.11, p-value 0.024), an improvement in the New York Heart Association (NYHA) class (odds ratio or OR of 1.32, 95% CI 1.11 to 1.58, p-value 0.002), and the composite outcome of hospitalizations for HF and cardiovascular death, with a relative risk (RR) of 0.86 (95% CI 0.75 to 0.99, p-value 0.04). However, there was no additional benefit with sacubitril/valsartan compared to valsartan for the outcomes of cardiovascular death and all-cause mortality. In terms of side effects, sacubitril/valsartan was associated with a higher risk of hypotension when compared to valsartan (OR 1.67, 95% CI 1.27 to 2.19, p-value < 0.0001), but did not show an increased risk of hyperkalemia or worsening renal function. Conclusions: In individuals with HFmrEF or HFpEF, sacubitril/valsartan can result in improvements in the HF outcomes of the KCCQ CSS, the NYHA class, and the composite outcome of hospitalization for HF and cardiovascular death when compared to valsartan. While there was a higher risk of hypotension with sacubitril/valsartan compared to valsartan, there was no corresponding increase in the risk of hyperkalemia or worsening renal function.

Medically Attended Suicidality in Youth Who Live on Farms.

Suicides are increasing in U.S. youth, particularly in rural areas. The influence of farming, however, is unclear, as suicide rates are higher in individual adult farm workers, but lower in farming-reliant counties. Early recognition of suicidality (suicidal ideation, intent, or attempt) is a key element of prevention, but there are no prior studies comparing suicidality in farm vs. non-farm youth. The purpose of this study was to examine associations between farm/rural residence and suicidality. Medical records were reused from an existing cohort of child and adolescent patients under surveillance for agricultural injuries in a Wisconsin healthcare system. The sample included 2,010 youth who lived on farms and 51,900 youth who did not live on farms (57% rural). The outcome was medically attended suicidality in 2017-2022 per a composite of diagnoses for suicidal ideation, attempt, or intentional self-harm that presented to ambulatory, emergency, or inpatient care settings. Suicidality was observed in 0.8% of farm, 1.8% of non-farm rural, and 1.6% of non-farm non-rural youth. After covariate adjustment, farm youth had significantly lower odds of suicidality (adjusted odds ratio [aOR] [95% confidence interval; CI] = 0.55 [0.33, 0.91], P = .019), while non-farm rural youth had significantly greater odds of suicidality (aOR [CI] = 1.21 [1.05, 1.40], P = .007), relative to non-farm non-rural youth. Children and adolescents who live on farms are about half as likely to (medically) present for suicidality as compared to their non-farm counterparts, both rural and non-rural. Future research should identify causal suicide protection factors in farm youth.

Laboratory evaluation for vitamin B12 deficiency: the case for cascade testing.

OBJECTIVE: Potential vitamin B(12) deficiency is a common clinical diagnostic problem, and many providers have a low threshold for initiating therapy. The goal of this study was to systematically evaluate current practice patterns regarding the laboratory evaluation of suspected vitamin B(12) deficiency. METHODS: This retrospective study reviewed the electronic medical records of 192 patients initiated on intramuscular vitamin B(12) injections. RESULTS: Only 12 patients had objectively documented hematologic responses: decrease of mean corpuscular volume by ≥5 fL with stable or improved hemoglobin. Another 5 patients had equivocal hematologic responses. There was one plausible neurologic response. Thus, only 18 (9.4%) of 192 patients had data supportive of a clinical response. In these 18 patients, the baseline serum B(12) level was ≤107 pg/mL; only 3 patients also had a baseline serum methylmalonic acid level, which was ≥1.29 µmol/L in all 3 patients. CONCLUSIONS: Currently, only a small minority of patients initiated on intramuscular vitamin B(12) supplementation derive any meaningful clinical benefit. Furthermore, current testing recommendations for vitamin B(12) deficiency are usually not followed. Up-front ordering of a diagnostic testing cascade is recommended to improve compliance; an example is presented with decision points chosen to improve specificity for clinically evident vitamin B(12) deficiency without loss of sensitivity. Ultimately, a better understanding of vitamin B(12) physiology is needed to develop and evaluate laboratory tests that more accurately reflect true intracellular vitamin B(12) status.

Does CALU SNP rs1043550 contribute variability to therapeutic warfarin dosing requirements?

OBJECTIVES: Calumenin, a molecular chaperone, exerts a regulatory effect on the vitamin K-dependent γ-carboxylation redox cycle that inhibits transfer of the reduced vitamin K from VKORC1, the pharmacological target of warfarin, to the γ-carboxylase. Because of its polymorphic structure and central role in the warfarin metabolic pathway, a contributory role for calumenin to warfarin dose variability has been posited. The current study sought to validate modulation of therapeutic dosing requirements by a single nucleotide polymorphisms (SNP) occurring in the calumenin gene (CALU) reported in previous studies. The CALU SNP was further modeled to detect interaction with SNPs occurring in VKORC1, CYP2C9, and CYP4F2 genes and characterize any additional contribution to variability in therapeutic warfarin dose requirement. SETTING: The study was undertaken in an established, well-characterized cohort of subjects treated with warfarin in the Anticoagulation Clinic of Marshfield Clinic in Marshfield, Wisconsin. METHODS: Subjects (N=491) previously genotyped for SNPS known to contribute variability to therapeutic warfarin dose requirement were genotyped for CALU SNP rs1043550, using TaqMan assays. Contribution of CALU SNP rs1043550 was modeled relative to other genotypic and phenotypic characteristics including gender, diagnosis, age, body surface area, underlying indication for warfarin, comorbidities, and pharmacological exposures. Interaction between SNPs impacting on warfarin dose requirements and calumenin SNPs was also modeled. RESULTS: Small differences in warfarin dosing requirements detected among individuals encoding the mutant G allele in the calumenin SNP were not statistically or clinically significant relative to therapeutic warfarin dose requirement and did not independently contribute significantly to the warfarin dosing model. Interaction between calumenin and VKORC1 SNPs contributed only minor additional variability to that ascribed to the wild type VKORC1 genotype. CONCLUSIONS: The impact of the CALU SNP on warfarin dose variability was minor and did not contribute significantly to therapeutic warfarin dose requirement in our study cohort. While no contribution was noted for the SNP examined in the present study, further examination of interaction between genetic elements contributing major impact on therapeutic warfarin dose requirements and genes exhibiting a lesser contribution is warranted.