Maternal obesity, gestational weight gain, and offspring asthma and atopy.

BACKGROUND: Maternal obesity may affect offspring asthma and atopic disease risk by altering fetal immune system development. However, few studies evaluate gestational weight gain (GWG). OBJECTIVE: To evaluate relationships between maternal body mass index (BMI), GWG, and persistent wheeze, eczema, allergy, and asthma risk in offspring through middle childhood. METHODS: A total of 5939 children from Upstate KIDS, a population-based longitudinal cohort of children born in upstate New York (2008-2019) were included in the analysis. Persistent wheeze or asthma, eczema, and allergy were maternally reported at multiple study time points throughout early and middle childhood. Poisson regression models with robust SEs were used to estimate adjusted risk ratios (aRRs) and 95% confidence intervals (CIs) for offspring atopic outcomes by maternal prepregnancy BMI and GWG. RESULTS: Prepregnancy BMI was associated with increased risk of persistent wheeze by 3 years of age even after adjustments for maternal atopy (class I obesity: aRR, 1.58; 95% CI, 1.13-2.20; class II or III obesity: aRR, 1.69; 95% CI, 1.22-2.35). Associations with reported asthma in middle childhood did not reach statistical significance. Furthermore, no associations were found between prepregnancy BMI and atopic outcomes in either early or middle childhood. GWG was not associated with higher risk of early childhood persistent wheeze or middle childhood asthma. CONCLUSION: Maternal prepregnancy BMI was associated with increased risk of offspring wheeze, whereas excessive GWG was generally not associated with childhood asthma or atopy.

Health facility management and primary health care performance in Uganda.

BACKGROUND: Primary health care is a critical foundation of high-quality health systems. Health facility management has been studied in high-income countries, but there are significant measurement gaps about facility management and primary health care performance in low and middle-income countries. A primary health care facility management evaluation tool (PRIME-Tool) was initially piloted in Ghana where better facility management was associated with higher performance on select primary health care outcomes such as essential drug availability, trust in providers, ease of following a provider's advice, and overall patient-reported quality rating. In this study, we sought to understand health facility management within Uganda's decentralized primary health care system. METHODS: We administered and analyzed a cross-sectional household and health facility survey conducted in Uganda in 2019, assessing facility management using the PRIME-Tool. RESULTS: Better facility management was associated with better essential drug availability but not better performance on measures of stocking equipment. Facilities with better PRIME-Tool management scores trended towards better performance on a number of experiential quality measures. We found significant disparities in the management performance of primary health care facilities. In particular, patients with greater wealth and education and those living in urban areas sought care at facilities that performed better on management. Private facilities and hospitals performed better on the management index than public facilities and health centers and clinics. CONCLUSIONS: These results suggest that investments in stronger facility management in Uganda may strengthen key aspects of facility readiness such as essential drug availability and potentially could affect experiential quality of care. Nevertheless, the stark disparities demonstrate that Uganda policymakers need to target investments strategically in order to improve primary health care equitably across socioeconomic status and geography. Moreover, other low and middle-income countries may benefit from the use of the PRIME-Tool to rapidly assess facility management with the goal of understanding and improving primary health care performance.

Predictors of patient-reported quality of care in low- and middle-income countries: a four-country survey of person-centered care.

BACKGROUND: Person-centeredness is a foundation of high-quality health systems but is poorly measured in low- and middle-income countries (LMICs). We piloted an online survey of four LMICs to identify the prevalence and correlates of excellent patient-reported quality of care (QOC). OBJECTIVE: The aims of this study were to investigate the examine people's overall ratings of care quality in relation to their experiences seeking care in their respective health systems as well as individual-, provider- and facility-level predictors. METHODS: We administered a cross-sectional online survey using Random Domain Intercept Technology to collect a sample of random internet users across India, Kenya, Mexico and Nigeria in November 2016. The primary outcome was patient-reported QOC. Covariates included age, gender, level of education, urban/rural residence, person for whom care was sought, type of provider seen, public or private sector status of the health facility and type of facility. The exposure was an index of health system responsiveness based on a framework from the World Health Organization. We used descriptive statistics to determine the prevalence of excellent patient-reported QOC and multivariable Poisson regression to calculate adjusted prevalence ratios (aPRs) for predictors of excellent patient-reported quality. RESULTS: Fourteen thousand and eight people completed the survey (22.6% completion rate). Survey respondents tended to be young, male, well-educated and urban-dwelling, reflective of the demographic of the internet-using population. Four thousand one and ninety-one (29.9%) respondents sought care in the prior 6 months. Of those, 21.8% rated their QOC as excellent. The highest proportion of respondents gave the top rating for wait time (44.6%), while the lowest proportion gave the top rating for facility cleanliness (21.7%). In an adjusted analysis, people who experienced the highest level of health system responsiveness were significantly more likely to report excellent QOC compared to those who did not (aPR 8.61, 95% confidence interval [95% CI]: 7.50, 9.89). In the adjusted model, urban-dwelling individuals were less likely to report excellent quality compared to rural-dwelling individuals (aPR 0.88, 95% CI: 0.78, 0.99). People who saw community health workers (aPR 1.37, 95% CI: 1.12, 1.67) and specialists (aPR 1.30, 95% CI: 1.12, 1.50) were more likely to report excellent quality than those who saw primary care providers. High perceived respect from the provider or staff was most highly associated with excellent ratings of quality, while ratings of wait time corresponded the least. CONCLUSION: Patient-reported QOC is low in four LMICs, even among a well-educated, young population of internet users. Better health system responsiveness may be associated with better ratings of care quality. Improving person-centered care will be an important component of building high-quality health systems in these LMICs.

A multi-terawatt two-color beam for high-power field-controlled nonlinear optics.

Two-color laser beams are instrumental in light-field control and enhancement of high-order harmonic, spectral supercontinuum, and terahertz radiation generated in gases, plasmas, and solids. We demonstrate a multi-terawatt two-color beam produced using a relativistic plasma mirror, with 110 mJ at 800 nm and 30 mJ at 400 nm. Both color components have high spatial quality and can be simultaneously focused, provided that the plasma mirror lies within a Rayleigh range of the driving fundamental beam. Favorable scaling of second-harmonic generation by plasma mirrors at relativistic intensities suggests them as an excellent tool for multi-color waveform synthesis beyond the petawatt level.

Exposure to Persistent Organic Pollutants and Birth Characteristics: The Upstate KIDS Study.

BACKGROUND: Prenatal exposure to persistent organic pollutants (POPs) may be associated with obesogenic effects in offspring. Our study is the first to investigate associations between concentrations of POPs from newborn dried blood spots (DBS) and birth characteristics. METHODS: Concentrations of 10 polychlorinated biphenyl congeners (PCBs), polybrominated diphenyl ether-47 (PBDE-47), and p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE) were measured from DBSs collected at birth from 2,065 singleton infants. DBS samples were pooled in groups of five and assayed together to reach limits of detection. Differences in risk of large for gestational age (LGA, defined as >90th percentile of birth weight for sex and gestational age), small for gestational age (SGA, <10th), and preterm birth (gestational age <37 weeks) were estimated using logistic regression per unit (ng/ml) increase in concentration of each chemical, adjusting for individual-level covariates, including maternal age, race/ethnicity, prepregnancy BMI, education, parity, smoking, and infant sex while assuming a gamma distribution and using multiple imputation to account for pools. RESULTS: There were 215 (11.3%) singletons born LGA, 158 (7.5%) born SGA, and 157 (7.6%) born preterm. Higher concentrations of POPs were positively associated with slightly higher risk of LGA and higher birth weight. CONCLUSIONS: Relationships between POPs measured in newborn DBS and birth size were mixed. Pooled analysis methods using DBS could address challenges in limits of detection and costs for population-based research.

The joint role of thyroid function and iodine concentration on gestational diabetes risk in a population-based study.

INTRODUCTION: Iodine is essential for thyroid function, and iodine deficiency during pregnancy is common in Europe and the USA. However, no published studies have examined the role of iodine deficiency in the relation between thyroid function and gestational diabetes mellitus (GDM). MATERIAL AND METHODS: We conducted a population-based, nested case-control study within the Finnish Maternity Cohort using pregnancy and perinatal outcome data from the Finnish Maternal Birth Register. We randomly selected 224 GDM cases with singleton pregnancies and 224 controls without GDM from all singleton births occurring in Finland during 2012-2013. Blood was drawn at 10-14 weeks' gestation and analyzed for serum iodide, thyroglobulin, and thyroid-stimulating hormone (TSH) concentrations. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CI) of GDM. RESULTS: Very high thyroglobulin concentration (>95% percentile; >83 µg/L) was not associated with significantly altered odds of GDM compared to those with normal levels (OR 0.41; 95% CI: 0.12, 1.38). High concentrations of TSH were also not associated with increased odds of GDM compared to normal levels of TSH (OR 0.45; 95% CI: 0.06, 3.18). Women in the lowest 5th percentile (<1.58 ng/mL) of iodine did not have increased odds of GDM compared to those with iodide in the highest quartile (OR 0.39; 95% CI: 0.11, 1.35). CONCLUSIONS: Low levels of iodide and thyroid function in early pregnancy are not associated with increased risk of GDM in this mildly iodine-deficient population.

Maternal polycystic ovarian syndrome and early offspring development.

STUDY QUESTION: Is maternal polycystic ovarian syndrome (PCOS) associated with developmental delays in offspring? SUMMARY ANSWER: Offspring of mothers with PCOS were at higher risk of failure on the Ages and Stages Questionnaire (ASQ). WHAT IS KNOWN ALREADY: There is growing evidence that offspring of mothers with PCOS may be at higher risk for developmental disorders due to potential exposure to hyperandrogenism and insulin resistance. Few studies exist regarding maternal PCOS and early childhood development in the USA. STUDY DESIGN, SIZE, DURATION: The Upstate KIDS Study is a population-based prospective cohort study of infants born between 2008 and 2010 in New York State (excluding New York City), originally designed to study-and finding no impact of-infertility treatment exposure on child development. Children were followed up to 36 months of age. In all, 4453 mothers completed one or more developmental screening instruments for 5388 children (35.5% twins) up to 36 months of age. PARTICIPANTS/MATERIALS, SETTING, METHODS: In our study, 458 mothers (10.3%) reported a healthcare provider's diagnosis of PCOS, as well as the related treatment received, on the baseline study questionnaire. Parents completed the ASQ on their child's development at 4, 8, 12, 18, 24, 30 and 36 months of age to assess fine motor, gross motor, communication, personal-social functioning and problem-solving cognitive domains. We used generalized linear mixed models to estimate odds ratios (OR) between PCOS diagnosis and failures in the ASQ adjusted for maternal age, race, BMI, education, marital status, smoking, alcohol consumption, diabetes, insurance and plurality. MAIN RESULTS AND THE ROLE OF CHANCE: Diagnosis of PCOS was associated with increased risk of the offspring failing the fine motor domain (adjusted odds ratio (aOR) = 1.77; 95% CI: 1.09, 2.89), largely driven by higher risk in female singletons (aOR = 2.23; 1.16, 4.29). Twins of mothers with PCOS had higher risk of failing the communication (aOR = 1.94; 1.19, 3.18) and personal-social functioning (aOR = 1.76; 1.12, 2.77) domains compared to twins born to mothers without PCOS. Compared to offspring of women without PCOS, offspring of women who reported receiving no treatment for their PCOS had a stronger association with failing the ASQ (aOR = 1.68; 0.95, 2.75) than the association among offspring of women who reported PCOS treatment (aOR = 1.16; 0.79, 1.73). LIMITATIONS, REASONS FOR CAUTION: Further study is needed to confirm the role of maternal PCOS in early offspring development with provider-validated diagnosis of PCOS. WIDER IMPLICATIONS OF THE FINDINGS: If confirmed, these findings suggest that offspring of women with PCOS may be at increased risk for developmental delay. STUDY FUNDING/COMPETING INTEREST(S): Supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD; contracts HHSN275201200005C, #HHSN267200700019C). Authors have no competing interests to declare. TRIAL REGISTRATION NUMBER: Not applicable.

Unresolved questions regarding human hereditary deafness.

Human hearing loss is a common neurosensory disorder about which many basic research and clinically relevant questions are unresolved. This review on hereditary deafness focuses on three examples considered at first glance to be uncomplicated, however, upon inspection, are enigmatic and ripe for future research efforts. The three examples of clinical and genetic complexities are drawn from studies of (i) Pendred syndrome/DFNB4 (PDS, OMIM 274600), (ii) Perrault syndrome (deafness and infertility) due to mutations of CLPP (PRTLS3, OMIM 614129), and (iii) the unexplained extensive clinical variability associated with TBC1D24 mutations. At present, it is unknown how different mutations of TBC1D24 cause non-syndromic deafness (DFNB86, OMIM 614617), epilepsy (OMIM 605021), epilepsy with deafness, or DOORS syndrome (OMIM 220500) that is characterized by deafness, onychodystrophy (alteration of toenail or fingernail morphology), osteodystrophy (defective development of bone), mental retardation, and seizures. A comprehensive understanding of the multifaceted roles of each gene associated with human deafness is expected to provide future opportunities for restoration as well as preservation of normal hearing.

The cost of feeding bred dairy heifers on native warm-season grasses and harvested feedstuffs.

Heifer rearing is one of the largest production expenses for dairy cattle operations, which is one reason milking operations outsource heifer rearing to custom developers. The cost of harvested feedstuffs is a major expense in heifer rearing. A possible way to lower feed costs is to graze dairy heifers, but little research exists on this topic in the mid-south United States. The objectives of this research were to determine the cost of feeding bred dairy heifers grazing native warm-season grasses (NWSG), with and without legumes, and compare the cost of grazing with the cost of rearing heifers using 3 traditional rations. The 3 rations were corn silage with soybean meal, corn silage with dry distillers grain, and a wet distillers grain-based ration. Bred Holstein heifers between 15- and 20-mo-old continuously grazed switchgrass (SG), SG with red clover (SG+RC), a big bluestem and Indiangrass mixture (BBIG), and BBIG with red clover (BBIG+RC) in Tennessee during the summer months. Total grazing days were calculated for each NWSG to determine the average cost/animal per grazing day. The average daily gain (ADG) was calculated for each NWSG to develop 3 harvested feed rations that would result in the same ADG over the same number of grazing day as each NWSG treatment. The average cost/animal per grazing day was lowest for SG ($0.48/animal/grazing d) and highest for BBIG+RC ($1.10/animal/grazing d). For both BBIG and SG, legumes increased the average cost/animal per grazing day because grazing days did not increase enough to account for the additional cost of the legumes. No difference was observed in ADG for heifers grazing BBIG (0.85 kg/d) and BBIG+RC (0.94 kg/d), and no difference was observed in ADG for heifers grazing SG (0.71 kg/d) and SG+RC (0.70 kg/d). However, the ADG for heifers grazing SG and SG+RC was lower than the ADG for heifers grazing either BBIG or BBIG+RC. The average cost/animal per grazing day was lower for all NWSG treatments than the average cost/animal per day for all comparable feed rations at a low, average, and high yardage fee. Results of this study suggest that SG was the most cost-effective NWSG alternative to harvested feeds for bred dairy heifer rearing.

Intake of long-chain ω-3 fatty acids from diet and supplements in relation to mortality.

Evidence from experimental studies suggests that the long-chain ω-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid have beneficial effects that may lead to reduced mortality from chronic diseases, but epidemiologic evidence is mixed. Our objective was to evaluate whether intake of long-chain ω-3 fatty acids from diet and supplements is associated with cause-specific and total mortality. Study participants (n = 70,495) were members of a cohort study (the Vitamins and Lifestyle Study) who were residents of Washington State aged 50-76 years at the start of the study (2000-2002). Participants were followed for mortality through 2006 (n = 3,051 deaths). Higher combined intake of eicosapentaenoic acid and docosahexaenoic acid from diet and supplements was associated with a decreased risk of total mortality (hazard ratio (HR) = 0.82, 95% confidence interval (CI): 0.73, 0.93) and mortality from cancer (HR = 0.77, 95% CI: 0.64, 0.92) but only a small reduction in risk of death from cardiovascular disease (HR = 0.87, 95% CI: 0.68, 1.10). These results suggest that intake of long-chain ω-3 fatty acids may reduce risk of total and cancer-specific mortality.

Dominant modifier DFNM1 suppresses recessive deafness DFNB26.

More than 50% of severe childhood deafness is genetically determined, approximately 70% of which occurs without other abnormalities and is thus termed nonsyndromic. So far, 30 nonsyndromic recessive deafness loci have been mapped and the defective genes at 6 loci, DFNB1, DFNB2, DFNB3, DFNB4, DFNB9 and DNFB21, have been identified, encoding connexin-26 (ref. 3), myosin VIIA (ref. 4), myosin XV (ref. 5), pendrin, otoferlin and alpha-tectorin, respectively. Here we map a new recessive nonsyndromic deafness locus, DFNB26, to a 1.5-cM interval of chromosome 4q31 in a consanguineous Pakistani family. A maximum lod score of 8.10 at theta=0 was obtained with D4S1610 when only the 8 affected individuals in this family were included in the calculation. There are seven unaffected family members who are also homozygous for the DFNB26-linked haplotype and thus are non-penetrant. A dominant modifier, DFNM1, that suppresses deafness in the 7 nonpenetrant individuals was mapped to a 5.6-cM region on chromosome 1q24 with a lod score of 4.31 at theta=0 for D1S2815.

Mutations in COL11A2 cause non-syndromic hearing loss (DFNA13).

We report that mutation of COL11A2 causes deafness previously mapped to the DFNA13 locus on chromosome 6p. We found two families (one American and one Dutch) with autosomal dominant, non-syndromic hearing loss to have mutations in COL11A2 that are predicted to affect the triple-helix domain of the collagen protein. In both families, deafness is non-progressive and predominantly affects middle frequencies. Mice with a targeted disruption of Col11a2 also were shown to have hearing loss. Electron microscopy of the tectorial membrane of these mice revealed loss of organization of the collagen fibrils. Our findings revealed a unique ultrastructural malformation of inner-ear architecture associated with non-syndromic hearing loss, and suggest that tectorial membrane abnormalities may be one aetiology of sensorineural hearing loss primarily affecting the mid-frequencies.

Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease.

BACKGROUND: Recent studies indicate an increased frequency of mutations in the gene encoding glucocerebrosidase (GBA), a deficiency of which causes Gaucher's disease, among patients with Parkinson's disease. We aimed to ascertain the frequency of GBA mutations in an ethnically diverse group of patients with Parkinson's disease. METHODS: Sixteen centers participated in our international, collaborative study: five from the Americas, six from Europe, two from Israel, and three from Asia. Each center genotyped a standard DNA panel to permit comparison of the genotyping results across centers. Genotypes and phenotypic data from a total of 5691 patients with Parkinson's disease (780 Ashkenazi Jews) and 4898 controls (387 Ashkenazi Jews) were analyzed, with multivariate logistic-regression models and the Mantel-Haenszel procedure used to estimate odds ratios across centers. RESULTS: All 16 centers could detect two GBA mutations, L444P and N370S. Among Ashkenazi Jewish subjects, either mutation was found in 15% of patients and 3% of controls, and among non-Ashkenazi Jewish subjects, either mutation was found in 3% of patients and less than 1% of controls. GBA was fully sequenced for 1883 non-Ashkenazi Jewish patients, and mutations were identified in 7%, showing that limited mutation screening can miss half the mutant alleles. The odds ratio for any GBA mutation in patients versus controls was 5.43 across centers. As compared with patients who did not carry a GBA mutation, those with a GBA mutation presented earlier with the disease, were more likely to have affected relatives, and were more likely to have atypical clinical manifestations. CONCLUSIONS: Data collected from 16 centers demonstrate that there is a strong association between GBA mutations and Parkinson's disease.

Use of glucosamine and chondroitin in relation to mortality.

Glucosamine and chondroitin are products commonly used by older adults in the US and Europe. There is limited evidence that they have anti-inflammatory properties, which could provide risk reduction of several diseases. However, data on their long-term health effects is lacking. To evaluate whether use of glucosamine and chondroitin are associated with cause-specific and total mortality. Participants (n = 77,510) were members of a cohort study of Washington State (US) residents aged 50-76 years who entered the cohort in 2000-2002 by completing a baseline questionnaire that included questions on glucosamine and chondroitin use. Participants were followed for mortality through 2008 (n = 5,362 deaths). Hazard ratios (HR) for death adjusted for multiple covariates were estimated using Cox models. Current (baseline) glucosamine and chondroitin use were associated with a decreased risk of total mortality compared to never use. The adjusted HR associated with current use of glucosamine (with or without chondroitin) was 0.82 (95 % CI 0.75-0.90) and 0.86 (95 % CI 0.78-0.96) for chondroitin (included in two-thirds of glucosamine supplements). Current use of glucosamine was associated with a significant decreased risk of death from cancer (HR 0.87 95 % CI 0.76-0.98) and with a large risk reduction for death from respiratory diseases (HR 0.59 95 % CI 0.41-0.83). Use of glucosamine with or without chondroitin was associated with reduced total mortality and with reductions of several broad causes of death. Although bias cannot be ruled out, these results suggest that glucosamine may provide some mortality benefit.

Costs of Horn Fly (Diptera: Muscidae) Control for Cow-calf Producers in Tennessee and Texas, 2016.

Tennessee and Texas cow-calf producers were surveyed to assess their 2016 expenses for horn fly control methods. Cattle producers who were members of the Texas and Southwestern Cattle Raisers Association and Tennessee cattle producers who have participated in the Tennessee Agricultural Enhancement Program participated in the survey. Average horn fly management costs in Tennessee and Texas were $9.50/head and $12.40/head, respectively. An ordinary least squares regression and quantile regression were estimated to examine how horn fly costs are influenced by producer and farm demographics, seasonality of horn flies, producer horn fly perceptions, and management practices. When controlling for these variables, Tennessee and Texas cattle producers did not spend significantly different amounts on horn fly control methods. Horn fly costs were associated with producer and farm demographics, producer perceptions of horn flies, and management practices. For example, results indicate that horn fly management costs vary depending on a producer's level of education and income. Having Angus cattle and larger herd sizes were associated with lower costs per head spent on horn fly management. Producers who did not consider horn flies to be a problem until greater quantities of flies were present on the animal spent 15% less per head on managing horn flies. In terms of horn fly control methods, feedthrough insecticides increased horn fly costs the most, followed by using ear tags. This is the first known research to estimate horn fly management costs among cattle producers.

Utility of FDG PET/CT in assessing bowel inflammation.

PURPOSE: To develop a methodology for the quantification of gastrointestinal (GI) inflammation as indicated by 2-deoxy-2-(18F)fluoro-D-glucose (FDG) uptake on positron-emissions tomography/computed tomography (PET/CT) imaging. This is intended to investigate the feasibility of using standard uptake value (SUV) levels to assess levels of GI inflammation in humans. METHODS: 131 participants were injected with a weight-controlled dose of FDG 180 minutes prior to PET/CT scanning. Operator-guided software was used to segment the GI tract and perform (SUV) calculations. Regions of interest (ROIs) were created using CT images and stacked to create three dimensional volumes of interest (VOIs). These VOIs defined 6 sections of the GI tract: esophagus, stomach, descending colon, ascending and transverse colon, bowel below the ilium and small bowel above the ilium. RESULTS: This study found a significant correlation between age and average FDG uptake (avg-SUV) of the GI tract (P=.0003) with the esophagus showing the highest significance. Correlations were found between avg-SUV of the sigmoid segment and the group average (P<.0001), and between the descending colon VOI and the group (P<.0001). Intra-operator reproducibility over 3 trials showed a coefficient of variation (CV) of .63%. Inter-operator CV over 5 randomly selected patients was 5.6% over the entire GI tract. CONCLUSION: This study shows that FDG-PET/CT imaging is a promising technique for quantifying bowel inflammation, despite the fact that age related inflammation may not be of clinical utility. The fact that we were able to detect these subtle changes indicates this as an avenue for potential future investigation.

Do mutations of the Pendred syndrome gene, SLC26A4, confer resistance to asthma and hypertension?

BACKGROUND AND AIMS: Mutations of SLC26A4 cause Pendred syndrome, an autosomal recessive disorder comprising goitre and deafness with enlarged vestibular aqueducts (EVA). Recent studies in mouse models implicate Slc26a4 in the pathogenesis of asthma and hypertension. We hypothesise that asthma and hypertension are less prevalent among humans with SLC26A4 mutations. METHODS: We reviewed medical histories and SLC26A4 genotypes for 80 individuals with EVA and 130 of their unaffected family members enrolled in a study of EVA. We used Fisher's exact test to compare the prevalence of asthma and hypertension among groups of subjects with zero, one, or two mutant alleles of SLC26A4. RESULTS: Although none of the 21 subjects with two mutant alleles of SLC26A4 had asthma or hypertension, there were no statistically significant differences in the prevalence of asthma or hypertension among subjects with zero, one, or two mutant alleles. CONCLUSION: There might be a protective effect of SLC26A4 mutations for asthma and hypertension but our study is statistically underpowered to detect this effect. Study sizes of at least 1125 and 504 individuals will be needed for 80% power to detect an effect at alpha = 0.05 for asthma and hypertension, respectively. Our hypothesis merits a larger study since it has implications for potential strategies to treat hearing loss by manipulating SLC26A4 expression or function.

Segregation of enlarged vestibular aqueducts in families with non-diagnostic SLC26A4 genotypes.

BACKGROUND: Hearing loss with enlarged vestibular aqueduct (EVA) can be inherited as an autosomal recessive trait caused by bi-allelic mutations of SLC26A4. However, many EVA patients have non-diagnostic SLC26A4 genotypes with only one or no detectable mutant alleles. METHODS AND RESULTS: In this study, the authors were unable to detect occult SLC26A4 mutations in EVA patients with non-diagnostic genotypes by custom comparative genomic hybridisation (CGH) microarray analysis or by sequence analysis of conserved non-coding regions. The authors sought to compare the segregation of EVA among 71 families with two (M2), one (M1) or no (M0) detectable mutant alleles of SLC26A4. The segregation ratios of EVA in the M1 and M2 groups were similar, but the segregation ratio for M1 was significantly higher than in the M0 group. Haplotype analyses of SLC26A4-linked STR markers in M0 and M1 families revealed discordant segregation of EVA with these markers in eight of 24 M0 families. CONCLUSION: The results support the hypothesis of a second, undetected SLC26A4 mutation that accounts for EVA in the M1 patients, in contrast to non-genetic factors, complex inheritance, or aetiologic heterogeneity in the M0 group of patients. These results will be helpful for counselling EVA families with non-diagnostic SLC26A4 genotypes.

Identities and frequencies of mutations of the otoferlin gene (OTOF) causing DFNB9 deafness in Pakistan.

Mutations in OTOF, encoding otoferlin, cause non-syndromic recessive hearing loss. The goal of our study was to define the identities and frequencies of OTOF mutations in a model population. We screened a cohort of 557 large consanguineous Pakistani families segregating recessive, severe-to-profound, prelingual-onset deafness for linkage to DFNB9. There were 13 families segregating deafness consistent with linkage to markers for DFNB9. We analyzed the genomic nucleotide sequence of OTOF and detected probable pathogenic sequence variants among all 13 families. These include the previously reported nonsense mutation p.R708X and 10 novel variants: 3 nonsense mutations (p.R425X, p.W536X, and p.Y1603X), 1 frameshift (c.1103_1104delinsC), 1 single amino acid deletion (p.E766del) and 5 missense substitutions of conserved residues (p.L573R, p.A1090E, p.E1733K, p.R1856Q and p.R1939W). OTOF mutations thus account for deafness in 13 (2.3%) of 557 Pakistani families. This overall prevalence is similar, but the mutation spectrum is different from those for Western populations. In addition, we demonstrate the existence of an alternative splice isoform of OTOF expressed in the human cochlea. This isoform must be required for human hearing because it encodes a unique alternative C-terminus affected by some DFNB9 mutations.