Predictors and patterns of weight gain during treatment for tuberculosis in the United States of America

SummaryObjectivesPatients with tuberculosis (TB) often present with weight loss. Lack of weight gain with TB treatment has been associated with treatment failure. The purpose of this study was to examine patterns of weight gain in patients with TB and determine the disease characteristics that predict weight gain.MethodsThis was a retrospective cohort study of adults with TB treated in a county health system in the USA. Demographic, clinical, radiographic, and microbiological data were recorded in addition to monthly weights during treatment.ResultsOverall, patients had a significant change in weight over the course of treatment (p<0.0001). After 2 months of treatment, 31.9% of patients had gained at least 5% body weight; by the end of treatment, 62.4% of patients had gained at least 5% weight. Patients who gained weight did so in a linear fashion throughout treatment. Cavitary and extensive disease, a positive smear, and a positive culture were predictors of weight gain (p<0.05). No patients had relapses during the time period of the study.ConclusionsOnly a subset of patients treated for TB gain significant weight. A greater burden of disease was predictive of weight gain

Tooth Whitening Effects on Bracket Bond Strength In Vivo

Objective: To test the hypothesis that there is no difference between the bracket survival rate of brackets bonded to bleached and unbleached teeth. Materials and Methods: Thirty-eight patients who required comprehensive orthodontic treatment were included in the study. A split mouth technique was used with one arch exposed to in-office whitening gel containing 38% hydrogen peroxide for 30 minutes, while the unbleached arch served as the control. Patients were divided into two groups: Brackets bonded within 24 hours after bleaching and brackets bonded 2–3 weeks after bleaching. The bracket survival rate was computed using the log-rank test (Kaplan-Meier Analysis). Results: A significantly higher rate of bracket failure was found with bleached teeth (16.6%) compared with unbleached teeth (1.8%) after 180 days. Brackets bonded within 24 hours of bleaching resulted in significantly higher clinical failure (14.5%) compared with those bonded after 3 weeks (2.1%). Adhesive Remnant Index scores of failed brackets revealed that the majority of failure in bleached teeth occurred in the enamel/resin interface. Conclusions: The hypothesis was rejected. Brackets bonded within 24 hours after bleaching have a significantly higher risk for bond failure. Orthodontic bonding should be delayed for 2–3 weeks if patients have a history of in-office bleaching with 38% hydrogen peroxide

Association of Intracranial Hypertension With Calvarial and Skull Base Thinning

Objective: Determine if patients with increased opening pressure (OP) on lumbar puncture (LP) have thinner calvaria and skull bases. Study Design: Retrospective cohort study. Setting: Tertiary referral center. Patients: Patients (≥18 yr of age) who had a recorded OP on LP and high-resolution computed tomography imaging of the head. Patient age, sex, body mass index were calculated. Intracranial hypertension (IH) was defined with an OP≥25 cm-H2O and low intracranial pressure with an OP<15 cm-H2O. Intervention: Measurement of calvarial, zygoma, and skull base thickness when blinded to OP with three-dimensional slicer and radiologic calipers. Main Outcome Measures: Association of calvarial, skull base, and zygoma thickness with OP and age. Results: Fifty-eight patients were included with a mean (SD) age of 53.1 (16.2) years and average (SD) body mass index of 30.1 (9.1) kg/m2. Patients with IH had thinner mean (SD) calvaria (3.01 [0.81] versus 2.70 [0.58] mm; p = 0.036) and skull bases (5.17 [1.22] versus 4.60 [1.42] mm; p = 0.043) when compared with patients without IH. The mean (SD) extracranial zygoma thickness was similar between the two groups (5.09 [0.76] versus 5.00 [0.73] mm; p = 0.56). General linear model regression demonstrated advancing age was associated with increasing calvarial thickness in patients without IH and calvarial thinning in patients with IH (p = 0.038). Conclusion: IH is independently associated with intracranial bone (calvaria and skull base) thinning and not extracranial (zygoma) thinning. Skull thinning occurs with IH and advancing age. These findings support a possible role of increased ICP in the pathophysiologic development of spontaneous cerebrospinal fluid leaks

Using multiple measures for quantitative trait association analyses: application to estimated glomerular filtration rate

Studies of multiple measures of a quantitative trait can have greater precision and thus statistical power compared to single measure studies, but this has rarely been studied in the relation to quantitative trait measurement error models in genetic association studies. Using estimated glomerular filtration rate (eGFR), a quantitative measure of kidney function, as an example we constructed measurement error models of a quantitative trait with systematic and random error components. We then examined the effects on precision of the parameter estimate between genetic loci and eGFR resulting from varying the correlation and contribution of the error components. We also compared the empirical results from 3 genome-wide association studies (GWAS) of kidney function in 9049 European Americans: a single measure, a 3-measure model of the same biomarker of kidney function, and a 6-measure model of different biomarkers of kidney function. Simulations showed that given the same amount of overall errors, inclusion of measures with less correlated systematic errors led to greater gain in precision. The empirical GWAS results confirmed that both the 3- and 6-measure models detected more eGFR-associated genomic loci with stronger statistical association than the single-measure model despite some heterogeneity among the measures. Multiple measures of a quantitative trait can increase the statistical power of a study without additional participant recruitment. However, careful attention must be paid to the correlation of systematic errors and inconsistent associations when different biomarkers or methods are used to measure the quantitative trait

Results from the Atherosclerosis Risk in Communities study suggest that low serum magnesium is associated with incident kidney disease

Low serum magnesium has been associated with kidney function decline in persons with diabetes as well as cardiovascular disease in the general population. Since the association of serum magnesium with incident kidney disease in the general population is unknown, we assessed this in 13,226 participants (aged 45 to 65) in the Atherosclerosis Risk in Communities study with baseline estimated glomerular filtration rate of at least 60 ml/min/1.73m2 in years 1987–89 and followed through 2010. The risks for incident chronic kidney disease (CKD) and end-stage renal disease (ESRD) associated with baseline total serum magnesium levels were evaluated using Cox regression. There were 1,965 CKD and 208 ESRD events during a median follow-up of 21 years. In adjusted analysis, low serum magnesium levels (0.7mmol/L or less) had significant associations with incident CKD and ESRD compared with the highest quartile with adjusted hazard ratio of 1.58 (95% CI: 1.35–1.87) for CKD and 2.39 (95% CI: 1.61–3.56) for ESRD. These associations remained significant after excluding users of diuretics and across subgroups stratified by hypertension, diabetes, and self-reported race. Thus, in a large sample of middle-aged adults, low total serum magnesium was independently associated with incident CKD and ESRD. Further studies are needed to determine whether modification of serum magnesium levels might alter subsequent incident kidney disease rates

Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD

Genetic Association for Renal Traits among Participants of African Ancestry Reveals New Loci for Renal Function

Chronic kidney disease (CKD) is an increasing global public health concern, particularly among populations of African ancestry. We performed an interrogation of known renal loci, genome-wide association (GWA), and IBC candidate-gene SNP association analyses in African Americans from the CARe Renal Consortium. In up to 8,110 participants, we performed meta-analyses of GWA and IBC array data for estimated glomerular filtration rate (eGFR), CKD (eGFR <60 mL/min/1.73 m2), urinary albumin-to-creatinine ratio (UACR), and microalbuminuria (UACR >30 mg/g) and interrogated the 250 kb flanking region around 24 SNPs previously identified in European Ancestry renal GWAS analyses. Findings were replicated in up to 4,358 African Americans. To assess function, individually identified genes were knocked down in zebrafish embryos by morpholino antisense oligonucleotides. Expression of kidney-specific genes was assessed by in situ hybridization, and glomerular filtration was evaluated by dextran clearance. Overall, 23 of 24 previously identified SNPs had direction-consistent associations with eGFR in African Americans, 2 of which achieved nominal significance (UMOD, PIP5K1B). Interrogation of the flanking regions uncovered 24 new index SNPs in African Americans, 12 of which were replicated (UMOD, ANXA9, GCKR, TFDP2, DAB2, VEGFA, ATXN2, GATM, SLC22A2, TMEM60, SLC6A13, and BCAS3). In addition, we identified 3 suggestive loci at DOK6 (p-value = 5.3×10−7) and FNDC1 (p-value = 3.0×10−7) for UACR, and KCNQ1 with eGFR (p = 3.6×10−6). Morpholino knockdown of kcnq1 in the zebrafish resulted in abnormal kidney development and filtration capacity. We identified several SNPs in association with eGFR in African Ancestry individuals, as well as 3 suggestive loci for UACR and eGFR. Functional genetic studies support a role for kcnq1 in glomerular development in zebrafish

Dengue: a continuing global threat.

Dengue fever and dengue haemorrhagic fever are important arthropod-borne viral diseases. Each year, there are ∼50 million dengue infections and ∼500,000 individuals are hospitalized with dengue haemorrhagic fever, mainly in Southeast Asia, the Pacific and the Americas. Illness is produced by any of the four dengue virus serotypes. A global strategy aimed at increasing the capacity for surveillance and outbreak response, changing behaviours and reducing the disease burden using integrated vector management in conjunction with early and accurate diagnosis has been advocated. Antiviral drugs and vaccines that are currently under development could also make an important contribution to dengue control in the future

Trans-ethnic Meta-analysis and Functional Annotation Illuminates the Genetic Architecture of Fasting Glucose and Insulin

Knowledge of the genetic basis of the type 2 diabetes (T2D)-related quantitative traits fasting glucose (FG) and insulin (FI) in African ancestry (AA) individuals has been limited. In non-diabetic subjects of AA (n = 20,209) and European ancestry (EA; n = 57,292), we performed trans-ethnic (AA+EA) fine-mapping of 54 established EA FG or FI loci with detailed functional annotation, assessed their relevance in AA individuals, and sought previously undescribed loci through trans-ethnic (AA+EA) meta-analysis. We narrowed credible sets of variants driving association signals for 22/54 EA-associated loci; 18/22 credible sets overlapped with active islet-specific enhancers or transcription factor (TF) binding sites, and 21/22 contained at least one TF motif. Of the 54 EA-associated loci, 23 were shared between EA and AA. Replication with an additional 10,096 AA individuals identified two previously undescribed FI loci, chrX FAM133A (rs213676) and chr5 PELO (rs6450057). Trans-ethnic analyses with regulatory annotation illuminate the genetic architecture of glycemic traits and suggest gene regulation as a target to advance precision medicine for T2D. Our approach to utilize state-of-the-art functional annotation and implement trans-ethnic association analysis for discovery and fine-mapping offers a framework for further follow-up and characterization of GWAS signals of complex trait loc

Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function

In conducting genome-wide association studies (GWAS), analytical approaches leveraging biological information may further understanding of the pathophysiology of clinical traits. To discover novel associations with estimated glomerular filtration rate (eGFR), a measure of kidney function, we developed a strategy for integrating prior biological knowledge into the existing GWAS data for eGFR from the CKDGen Consortium. Our strategy focuses on single nucleotide polymorphism (SNPs) in genes that are connected by functional evidence, determined by literature mining and gene ontology (GO) hierarchies, to genes near previously validated eGFR associations. It then requires association thresholds consistent with multiple testing, and finally evaluates novel candidates by independent replication. Among the samples of European ancestry, we identified a genome-wide significant SNP in FBXL20 (P = 5.6 × 10−9) in meta-analysis of all available data, and additional SNPs at the INHBC, LRP2, PLEKHA1, SLC3A2 and SLC7A6 genes meeting multiple-testing corrected significance for replication and overall P-values of 4.5 × 10−4-2.2 × 10−7. Neither the novel PLEKHA1 nor FBXL20 associations, both further supported by association with eGFR among African Americans and with transcript abundance, would have been implicated by eGFR candidate gene approaches. LRP2, encoding the megalin receptor, was identified through connection with the previously known eGFR gene DAB2 and extends understanding of the megalin system in kidney function. These findings highlight integration of existing genome-wide association data with independent biological knowledge to uncover novel candidate eGFR associations, including candidates lacking known connections to kidney-specific pathways. The strategy may also be applicable to other clinical phenotypes, although more testing will be needed to assess its potential for discovery in genera