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One-third of type-2 diabetic patients respond poorly to metformin. Despite extensive research, the impact of genetic and nongenetic factors on long-term outcome is unknown. In this study we combine nonlinear mixed effect modeling with computational genetic methodologies to identify predictors of long-term response. In all, 1,056 patients contributed their genetic, demographic, and long-term HbA1c data. The top nine variants (of 12,000 variants in 267 candidate genes) accounted for approximately one-third of the variability in the disease progression parameter. Average serum creatinine level, age, and weight were determinants of symptomatic response; however, explaining negligible variability. Two single nucleotide polymorphisms (SNPs) in CSMD1 gene (rs2617102, rs2954625) and one SNP in a pharmacologically relevant SLC22A2 gene (rs316009) influenced disease progression, with minor alleles leading to less and more favorable outcomes, respectively. Overall, our study highlights the influence of genetic factors on long-term HbA1c response and provides a computational model, which when validated, may be used to individualize treatment.

One-third of type 2 diabetes patients do not respond to metformin. Genetic variants in metformin transporters have been extensively studied as a likely contributor to this high failure rate. Here, we investigate, for the first time, the effect of genetic variants in transcription factors on metformin pharmacokinetics (PK) and response. Overall, 546 patients and healthy volunteers contributed their genome-wide, pharmacokinetic (235 subjects), and HbA1c data (440 patients) for this analysis. Five variants in specificity protein 1 (SP1), a transcription factor that modulates the expression of metformin transporters, were associated with changes in treatment HbA1c (P < 0.01) and metformin secretory clearance (P < 0.05). Population pharmacokinetic modeling further confirmed a 24% reduction in apparent clearance in homozygous carriers of one such variant, rs784888. Genetic variants in other transcription factors, peroxisome proliferator-activated receptor-α and hepatocyte nuclear factor 4-α, were significantly associated with HbA1c change only. Overall, our study highlights the importance of genetic variants in transcription factors as modulators of metformin PK and response.

Efforts to define the genetic architecture underlying variable statin response have met with limited success, possibly because previous studies were limited to effect based on a single dose. We leveraged electronic medical records (EMRs) to extract potency (ED50) and efficacy (Emax) of statin dose-response curves and tested them for association with 144 preselected variants. Two large biobanks were used to construct dose-response curves for 2,026 and 2,252 subjects on simvastatin and atorvastatin, respectively. Atorvastatin was more efficacious, was more potent, and demonstrated less interindividual variability than simvastatin. A pharmacodynamic variant emerging from randomized trials (PRDM16) was associated with Emax for both. For atorvastatin, Emax was 51.7 mg/dl in subjects homozygous for the minor allele vs. 75.0 mg/dl for those homozygous for the major allele. We also identified several loci associated with ED50. The extraction of rigorously defined traits from EMRs for pharmacogenetic studies represents a promising approach to further understand the genetic factors contributing to drug response.

Interindividual variation in response to metformin, first-line therapy for type 2 diabetes, is substantial. Given that transporters are determinants of metformin pharmacokinetics, we examined the effects of promoter variants in both multidrug and toxin extrusion protein 1 (MATE1) (g.-66T → C, rs2252281) and MATE2 (g.-130G → A, rs12943590) on variation in metformin disposition and response. The pharmacokinetics and glucose-lowering effects of metformin were assessed in healthy volunteers (n = 57) receiving metformin. The renal and secretory clearances of metformin were higher (22% and 26%, respectively) in carriers of variant MATE2 who were also MATE1 reference (P < 0.05). Both MATE genotypes were associated with altered post-metformin glucose tolerance, with variant carriers of MATE1 and MATE2 having an enhanced (P < 0.01) and reduced (P < 0.05) response, respectively. Consistent with these results, patients with diabetes (n = 145) carrying the MATE1 variant showed enhanced metformin response. These findings suggest that promoter variants of MATE1 and MATE2 are important determinants of metformin disposition and response in healthy volunteers and diabetic patients.

Background: Clinical trials demonstrated that women treated for breast cancer with anthracycline or trastuzumab are at increased risk for heart failure and/or cardiomyopathy (HF/CM), but the generalizability of these findings is unknown. We estimated real-world adjuvant anthracycline and trastuzumab use and their associations with incident HF/CM.Methods: We conducted a population-based, retrospective cohort study of 12,500 women diagnosed with incident, invasive breast cancer from January 1, 1999 through December 31, 2007, at eight integrated Cancer Research Network health systems. Using administrative procedure and pharmacy codes, we identified anthracycline, trastuzumab, and other chemotherapy use. We identified incident HF/CM following chemotherapy initiation and assessed risk of HF/CM with time-varying chemotherapy exposures vs no chemotherapy. Multivariable Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) with adjustment for age at diagnosis, stage, Cancer Research Network site, year of diagnosis, radiation therapy, and comorbidities.Results: Among 12 500 women (mean age = 60 years, range = 22-99 years), 29.6% received anthracycline alone, 0.9% received trastuzumab alone, 3.5% received anthracycline plus trastuzumab, 19.5% received other chemotherapy, and 46.5% received no chemotherapy. Anthracycline and trastuzumab recipients were younger, with fewer comorbidities than recipients of other chemotherapy or none. Compared with no chemotherapy, the risk of HF/CM was higher in patients treated with anthracycline alone (adjusted HR = 1.40, 95% CI = 1.11 to 1.76), although the increased risk was similar to other chemotherapy (adjusted HR = 1.49, 95% CI = 1.25 to 1.77); the risk was highly increased in patients treated with trastuzumab alone (adjusted HR = 4.12, 95% CI = 2.30 to 7.42) or anthracycline plus trastuzumab (adjusted HR = 7.19, 95% CI = 5.00 to 10.35).Conclusions: Anthracycline and trastuzumab were primarily used in younger, healthier women and associated with increased HF/CM risk compared with no chemotherapy. This population-based observational study complements findings from clinical trials on cancer treatment safety. [ABSTRACT FROM AUTHOR]

Environmental exposure to mercury can cause a number of adverse effects in humans including the disruption of endocrine function that may result in sex-specific effects. The present study was designed to characterize sex-specific effects of chronic inorganic mercury exposure on toll-like receptor (TLR) 2 and TLR4 and inflammatory signaling in the liver of prairie voles (Microtus ochrogaster). Following 10 weeks of exposure to mercury via drinking water, effects on protein expression levels of TLR2 and TLR4 and the downstream p38 mitogen-activated protein kinase (p38 MAPK) and nuclear factor-kappa (NF-κB) signaling pathways were assessed. Using immunoblot analysis, we found that mercury exposure significantly enhanced the expression of TLR4 and activated p38 MAPK and NF-κB pathways in vole livers. This is the first report indicating that TLR4 may serve as a sensor for chronic mercury exposure in the liver. Further, compared to females, mercury-treated male voles exhibited significant increases in activated p38 MAPK and a greater extent of liver damage. Together, these findings establish sex-specific liver immunomodulation and cellular signaling following chronic inorganic mercury exposure. Furthermore, this study also supports the use of voles as biomarkers of environmental mercury contamination and offers a promising in vivo tool to test various therapeutic strategies for mercury detoxification. [ABSTRACT FROM AUTHOR]

OBJECTIVES: To determine rates of potentially inappropriate medication use in elderly persons in managed care plans in the United States in 2000-2001. DESIGN: Cross-sectional study using automated medication-dispensing data. SETTING: Ten geographically distributed health maintenance organizations (HMOs). PARTICIPANTS: One hundred fifty-seven thousand five hundred seventeen members aged 65 years and older enrolled in one of the HMOs. MEASUREMENTS: Prevalence of use of 33 potentially inappropriate medications from January 1, 2000 through June 30, 2001. RESULTS: In 2000-2001, 28.8% (95% confidence interval=28.6-29.1) of elderly individuals received at least one of 33 potentially inappropriate medications. This rate ranged from 23.0% to 36.5% across the 10 HMOs. Approximately 5% of elderly patients received at least one of the 11 medications classified by an expert panel as 'always avoid,' 13% received at least one of the eight medications that would rarely be considered appropriate, and 17% received at least one of the 14 medications that have some indications but are often misused. Overall, rates of use of these medications were greater in women (32.4%) than in men (24.2%). At least 1% of elderly members received belladonna alkaloids (2.3%), dicyclomine (1.1%), or hyoscyamine (1.2%), each of which multiple expert panels have classified as always inappropriate in patients aged 65 years and older. Seven percent of elderly members received propoxyphene, an analgesic medication considered rarely appropriate in the elderly and a drug that has a long history of limited efficacy and potential for toxicity. CONCLUSION: Recent rates of potentially inappropriate medication use by elderly HMO members were at least as great as in a 1996 national sample. This study highlights the need to understand more fully the rationale behind the continued use of these medications. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To assess the possible toxicity of thimerosal-containing vaccines (TCVs) among infants. METHODS: A 2-phased retrospective cohort study was conducted using computerized health maintenance organization (HMO) databases. Phase I screened for associations between neurodevelopmental disorders and thimerosal exposure among 124 170 infants who were born during 1992 to 1999 at 2 HMOs (A and B). In phase II, the most common disorders associated with exposure in phase I were reevaluated among 16 717 children who were born during 1991 to 1997 in another HMO (C). Relative risks for neurodevelopmental disorders were calculated per increase of 12.5 micro g of estimated cumulative mercury exposure from TCVs in the first, third, and seventh months of life. RESULTS: In phase I at HMO A, cumulative exposure at 3 months resulted in a significant positive association with tics (relative risk [RR]: 1.89; 95% confidence interval [CI]: 1.05-3.38). At HMO B, increased risks of language delay were found for cumulative exposure at 3 months (RR: 1.13; 95% CI: 1.01-1.27) and 7 months (RR: 1.07; 95% CI: 1.01-1.13). In phase II at HMO C, no significant associations were found. In no analyses were significant increased risks found for autism or attention-deficit disorder. CONCLUSIONS: No consistent significant associations were found between TCVs and neurodevelopmental outcomes. Conflicting results were found at different HMOs for certain outcomes. For resolving the conflicting findings, studies with uniform neurodevelopmental assessments of children with a range of cumulative thimerosal exposures are needed. [ABSTRACT FROM AUTHOR]

BACKGROUND: Group B streptococcal disease is the leading cause of neonatal sepsis in the United States. We assessed predictors of compliance with the consensus guidelines for perinatal group B streptococcus disease prevention at two Group Health Cooperative hospitals. METHODS: A descriptive and cohort analysis was conducted of failure to comply with the screening-based approach to group B streptococcus prevention among singleton birth pregnancies in two Group Health Cooperative hospitals, September 1, 1996 to December 31, 1997. We studied determinants of failure to screen pregnant women for group B streptococcus at 35 to 37 weeks' gestation and failure to deliver intrapartum antibiotic prophylaxis to Group B streptococcus-positive women. RESULTS: Nearly 28 percent of 1969 women delivering at two Group Health Cooperative hospitals were not screened appropriately for group B streptococcus. Women who were not screened properly were more likely to be in their teens. A short length of hospital stay before delivery was the strongest predictor of the lack of administration of intrapartum antibiotic prophylaxis to infected multiparas at delivery. Group B streptococcus-positive women without pregnancy complications were less likely to receive intrapartum antibiotic prophylaxis than infected women with complications. CONCLUSIONS: The findings of this study suggest that to improve group B streptococcus disease prevention, screening efforts should focus on teenage women, and intrapartum antibiotic prophylaxis delivery efforts should be aimed at low-risk women with precipitous labor. [ABSTRACT FROM AUTHOR]

Context: Each year, approximately 5000 infants are born in the United States with moderate-to-profound, bilateral permanent hearing loss (PHL). Universal newborn hearing screening (UNHS) has been proposed as a means to speed diagnosis and treatment and thereby improve language outcomes in these children.Objectives: To identify strengths, weaknesses, and gaps in the evidence supporting UNHS and to compare the additional benefits and harms of UNHS with those of selective screening of high-risk newborns.Data Sources: We searched the MEDLINE, CINAHL, and PsychINFO databases for relevant articles published from 1994 to August 2001, using terms for hearing disorders, infants or newborns, screening, and relevant treatments. We contacted experts and reviewed reference lists to identify additional articles, including those published before 1994.Study Selection: We included controlled and observational studies of (1) the accuracy, yield, and harms of screening using otoacoustic emissions (OAEs), auditory brainstem response (ABR), or both in the general newborn population and (2) the effects of screening or early identification and treatment on language outcomes. Of an original 340 articles identified, 19 articles, including 1 controlled trial, met these inclusion criteria.Data Extraction: Data on population, test performance, outcomes, and methodological quality were extracted by 2 authors (D.C.T., H.M.) using prespecified criteria developed by the US Preventive Services Task Force. We queried authors when information needed to assess study quality was missing.Data Synthesis: Good-quality studies show that from 2041 to 2794 low-risk and 86 to 208 high-risk newborns were screened to find 1 case of moderate-to-profound PHL. The best estimate of positive predictive value was 6.7%. Six percent to 15% of infants who are missed by the screening tests are subsequently diagnosed with bilateral PHL. In a trial of UNHS vs clinical screening at age 8 months, UNHS increased the proportion of infants with moderate-to-severe hearing loss diagnosed by age 10 months (57% vs 14%) but did not reduce the rate of diagnosis after age 18 months. No good-quality controlled study has compared UNHS with selective screening of high-risk newborns. In fair- to poor-quality cohort studies, intervention before age 6 months was associated with improved language and communication skills by ages 2 to 5 years. These studies had unclear criteria for selecting subjects, and none compared an inception cohort of low-risk newborns identified by screening with those identified in usual care, making it impossible to exclude selection bias as an explanation for the results. In a mathematical model based on the literature review, we estimated that extending screening to low-risk infants would detect 1 additional case before age 10 months for every 1441 low-risk infants screened, and result in treatment before 10 months of 1 additional case for every 2401 low-risk infants screened. With UNHS, 254 newborns would be referred for audiological evaluation because of false-positive second-stage screening test results vs 48 for selective screening.Conclusions: Modern screening tests for hearing impairment can improve identification of newborns with PHL, but the efficacy of UNHS to improve long-term language outcomes remains uncertain. [ABSTRACT FROM AUTHOR]

Context: Studies have noted that health care professionals may not conform to proper immunization schedules for premature and low-birth-weight infants in the United States. Little is known about the success of current efforts to immunize these high-risk infants.Objective: To describe current immunization practices for premature and low-birth-weight infants and ascertain risk factors for poor immunization status, using large population-based data sources.Design and Setting: Cohort and case-control analyses of immunization data tracked from March 1991 through March 1997 for 3 large health maintenance organizations (HMOs) participating in the Centers for Disease Control and Prevention's Vaccine Safety Datalink project.Participants: A total of 11580 low-birth-weight and premature infants were enrolled from birth to age 2 months; 6832 of these were continuously enrolled from birth to age 24 months. At age 2 months, there were 173373 full-term, normal-birth-weight infants enrolled as controls; at age 24 months, there were 103 324.Main Outcome Measures: Age-specific immunization status by prematurity and birth weight (<1500 g, 1500-2500 g, born at <38 weeks' gestation with birth weight of >2500 g, or full-term with normal birth weight) and patient characteristics associated with up-to-date status.Results: At each age, infants weighing less than 1500 g at birth had lower up-to-date immunization levels than other infants. At age 6 months, 52% to 65% of infants weighing less than 1500 g were up-to-date at each of the 3 HMOs compared with 69% to 73% of those weighing 1500 to 2500 g, 66% to 80% of premature infants weighing more than 2500 g, and 65% to 76% of full-term, normal-birth-weight infants. By age 24 months, 78% to 86% of infants weighing less than 1500 g were up-to-date, significantly less than heavier infants, who had levels of 84% to 89%. Well-child preventive care strongly predicted immunization status, while concomitant pulmonary disease did not.Conclusions: Our data suggest that infants born prematurely are vaccinated at levels approaching that of the general population, but levels of vaccination for very low-birth-weight infants lag slightly behind. [ABSTRACT FROM AUTHOR]

There is little available information on the smoking habits of Native Americans. The authors used data from the Washington State birth certificate to determine the prevalence of smoking during pregnancy among Native American mothers in Washington State. From 1984 through 1988, 39.8 percent of all Native Americans smoked during their pregnancy. Smoking patterns during pregnancy differed markedly between Native Americans and whites according to maternal age and marital status. The smoking prevalence in Native Americans, adjusted for maternal age and marital status, was 1.3 times higher than that found in Washington State white women. This is the first analysis of statewide smoking rates during pregnancy among Native Americans. The birth certificate can serve as a readily accessible and low cost surveillance system for populations such as Native Americans, who are otherwise difficult to study. Smoking intervention programs need to be targeted at Native Americans, and how their smoking patterns differ from those of the general population needs to be recognized. [ABSTRACT FROM AUTHOR]

Context: While early discharge of newborns following routine vaginal delivery has become common practice, its safety has not been firmly established.Objective: To assess the risk for rehospitalization following newborn early discharge.Design: Population-based, case-control study.Setting: Washington State linked birth certificate and hospital discharge abstracts covering 310578 live births from 1991 through 1994.Patients: Case patients were 2029 newborns rehospitalized in the first month of life. Control subjects were 8657 randomly selected newborns not rehospitalized and frequency matched to case patients on year of birth. Cesarean deliveries, multiple births, and births at less than 36 weeks' gestation were not included.Main Outcome Measure: Stratified analyses and logistic regression were performed to assess the risk for rehospitalization within a month of birth after early discharge (<30 hours after birth) compared with later discharge (30-78 hours after birth).Results: Seventeen percent of newborns were discharged early. Newborns discharged early were more likely to be rehospitalized within 7 days (odds ratio [OR], 1.28; 95% confidence interval [CI], 1.11-1.47), 14 days (OR, 1.16; 95% CI, 1.03-1.32), and 28 days (OR, 1.12; 95% CI, 1.00-1.25) of discharge than newborns sent home later. Subgroups at increased risk for rehospitalization following early discharge included newborns born to primigravidas (OR,1.25; 95% CI, 1.07-1.45), mothers younger than 18 years (OR, 1.22; 95% CI, 0.79-1.91), and mothers with premature rupture of membranes (OR, 1.41; 95% CI, 0.85-2.36). Early discharge was also associated with an increased risk of readmission for jaundice, dehydration, and sepsis.Conclusion: Newborns discharged home early (<30 hours after birth) are at increased risk for rehospitalization during the first month of life. [ABSTRACT FROM AUTHOR]

Focuses on a study which summarizes the results of the investigation which indicates that changing to an initial doses of inactivated poliovirus vaccine was not associated with decreases in vaccination coverage levels of routinely recommended vaccinations. Information on the participants of the study; Findings of the study; How the incidence of vaccine-associated paralytic poliomyelitis was reduced.

Mitochondrial (MT) dysfunction is a hallmark of Alzheimer's Disease (AD), but the scope and severity of these specific deficits across forms of AD are not well characterized. We designed a high-throughput, longitudinal, phenotypic assay to track MT dynamics and bioenergetics in glutamatergic iPSC-derived human neurons possessing mutations in presenilin 1 (PSEN1), presenilin 2 (PSEN2) and the amyloid beta precursor protein (APP). Each gene set was comprised of iPSC-derived neurons from an AD patient as well as two to three engineered mutations with appropriate isogenic and age matched controls. These iPSC-derived neurons were imaged every other day beginning at DIV10 to assess how MT length and content change over a ten day time course using a mitochondrially targeted reporter. A second cytosolic reporter allowed for visualization of neurites. Bioenergetics assays, focusing on MT respiration and individual electron transport chain (ETC) complexes, were also surveyed over this time course. Mutations in all three genes altered MT function measured by basal, ATP-linked, and maximal oxygen consumption rate; and spare respiratory capacity, with PSEN1/PSEN2 alleles being more severe than APP mutations. Electron flow through Complexes I-IV was decreased in PSEN1/PSEN2 mutations but; in contrast, APP alleles had only modest impairments of Complexes I and II. We measured aspects of MT dynamics, including fragmentation, and neurite degeneration, both of which were dramatic in PSEN1/PSEN2 alleles, but essentially absent in APP alleles. The marked differences in MT pathology may occur from the distinct ways amyloids are processed into amyloid beta peptides (Aβ) and may correlate with the disease severity., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Individuals with sickle cell disease (SCD) face the burden of managing a life-long chronic illness, increasing vulnerability to social determinants of health (SDoH). However, how SDoH contributes to health disparities is understudied. We hypothesized that preschool children with SCD living in poor neighborhoods with higher socioeconomic distress would experience increased acute care utilization (ACU = ED visits + hospitalizations) despite disease-modifying therapy. Participants' home addresses (0-6yrs) were mapped using census tract environmental data from the US Department of Agriculture Food Access Research Atlas. In multivariable analyses controlled for sickle genotype and disease-modifying therapies (hydroxyurea and chronic transfusion), SDoH indicators - limited access to food, lack of vehicle, low income, and inadequate education, were associated with higher ACU. Living in households with children >1 mile from a supermarket was associated with more hospitalizations (OR: 1.44, 95% CI: 1.13-1.85) and ACU (OR: 1.37, 95% CI: 1.06-1.80) among children with SCD (<6 yrs). In households with at least one bachelor's degree, children with SCD experienced less ACU (OR: 0.67, 95% CI: 0.50-0.93) and hospitalizations (OR: 0.67, 95% CI: 0.49-0.92). Preschool children with SCD with limited access to food and transportation are at a higher risk of acute complications despite receiving free evidence-based therapy and social support. The family education level may have a protective effect. Although SDoH in crowded households and healthcare maintenance visits were not a focus of this study, future research should consider these factors. Understanding the SCD and SDoH association is crucial for directing resources to improve affected children's health., (Copyright © 2024 American Society of Hematology.)

Genetic sequencing technologies are evolving at a rapid pace with major implications for research and clinical practice. In this review, the authors provide an updated overview of next-generation sequencing (NGS) and emerging methodologies. NGS has tremendously improved sequencing output while being more time and cost-efficient in comparison to Sanger sequencing. The authors describe short-read sequencing approaches, such as sequencing by synthesis, ion semiconductor sequencing, and nanoball sequencing. Third-generation long-read sequencing now promises to overcome many of the limitations of short-read sequencing, such as the ability to reliably resolve repeat sequences and large genomic rearrangements. By combining complementary methods with massively parallel DNA sequencing, a greater insight into the biological context of disease mechanisms is now possible. Emerging methodologies, such as advances in nanopore technology, in situ nucleic acid sequencing, and microscopy-based sequencing, will continue the rapid evolution of this area. These new technologies hold many potential applications for hematological disorders, with the promise of precision and personalized medical care in the future., Competing Interests: None declared., (Thieme. All rights reserved.)