Inner Ear Breaches from Vestibular Schwannoma Surgery: Revisiting the Incidence of Otologic Injury from Retrosigmoid and Middle Cranial Fossa Approaches.

OBJECTIVE: To assess the rate of iatrogenic injury to the inner ear in vestibular schwannoma resections. STUDY DESIGN: Retrospective case review. SETTING: Multiple academic tertiary care hospitals. PATIENTS: Patients who underwent retrosigmoid or middle cranial fossa approaches for vestibular schwannoma resection between 1993 and 2015. INTERVENTION: Diagnostic with therapeutic implications. MAIN OUTCOME MEASURE: Drilling breach of the inner ear as confirmed by operative note or postoperative computed tomography (CT). RESULTS: 21.5% of patients undergoing either retrosigmoid or middle fossa approaches to the internal auditory canal were identified with a breach of the vestibulocochlear system. Because of the lack of postoperative CT imaging in this cohort, this is likely an underestimation of the true incidence of inner ear breaches. Of all postoperative CT scans reviewed, 51.8% had an inner ear breach. As there may be bias in patients undergoing postoperative CT, a middle figure based on sensitivity analyses estimates the incidence of inner ear breaches from lateral skull base surgery to be 34.7%. CONCLUSIONS: A high percentage of vestibular schwannoma surgeries via retrosigmoid and middle cranial fossa approaches result in drilling breaches of the inner ear. This study reinforces the value of preoperative image analysis for determining risk of inner ear breaches during vestibular schwannoma surgery and the importance of acquiring CT studies postoperatively to evaluate the integrity of the inner ear.

An AAV capsid increases transduction of striatum and a ChAT promoter allows selective cholinergic neuron transduction.

Adeno-associated virus (AAV) vectors are currently the most efficient option for intracranial gene therapies to treat neurodegenerative disease. Increased efficacy and safety will depend upon robust and specific expression of therapeutic genes into target cell-types within the human brain. In this study, we set out with two objectives: (1) to identify capsids with broader transduction of the striatum upon intracranial injection in mice and (2) to test a truncated human choline acetyltransferase (ChAT) promoter that would allow efficient and selective transduction of cholinergic neurons. We compared AAV9 and an engineered capsid, AAV-S, to mediate widespread reporter gene expression throughout the striatum. We observed that AAV-S transduced a significantly greater area of the injected hemisphere primarily in the rostral direction compared with AAV9 (CAG promoter). We tested AAV9 vectors packaging a reporter gene expression cassette driven by either the ChAT or CAG promoter. Specificity of transgene expression of ChAT neurons over other cells was 7-fold higher, and efficiency was 3-fold higher for the ChAT promoter compared with the CAG promoter. The AAV-ChAT transgene expression cassette should be a useful tool for the study of cholinergic neurons in mice, and the broader transduction area of AAV-S warrants further evaluation of this capsid.

Tebentafusp-tebn: A Novel Bispecific T-Cell Engager for Metastatic Uveal Melanoma.

Uveal melanoma is the most common intraocular cancer in adults. Metastatic uveal melanoma has a poor prognosis. Tebentafusp-tebn is the first drug in the new immune mobilizing monoclonal T-cell receptors against cancer (ImmTAC) class of T cell-directed therapy. Tebentafusp-tebn has been shown in a randomized phase III clinical trial to lead to improved overall survival and progression-free survival when compared with single-agent pembrolizumab, ipilimumab, or dacarbazine in previously untreated human leukocyte antigen (HLA)-A*02:01-positive metastatic uveal melanoma patients. Tebentafusp-tebn is now approved by the US Food and Drug Administration in HLA-A*02:01-positive uveal melanoma patients as first-line therapy in the metastatic setting.

Dental services use before and after inpatient admission among privately insured adults in the United States.

BACKGROUND: Oral health has been connected to worse outcomes among hospitalized patients, but access to oral health care services in the hospital setting is limited. It is unknown how a hospital admission affects subsequent dental services use. METHODS: The authors conducted a retrospective analysis of insurance claims data from a national private insurer. Patients were included if they were admitted to the hospital and had visited a dentist at least once in the year before or after admission. Total number of dental visits, as well as Code on Dental Procedures and Nomenclature codes associated with these visits in the year before and after a hospital stay, patient demographic characteristics, hospital admission diagnosis, and length of stay were recorded. Differences in dental services use before and after the hospital stay were calculated. RESULTS: In total, 107,116 patients met inclusion criteria. There were fewer dental visits after admission (mean [standard deviation {SD}] 1.6 [1.7] than before admission (mean [SD] 1.9 [1.8]; P < .0001). Fewer procedures were recorded in the year after discharge (mean [SD] 7.0 [11.4] total Code on Dental Procedures and Nomenclature codes versus 8.5 [12.5] in the year before admission; P < .0001). The number of diagnostic and restorative services delivered was higher after admission, and the number of periodontic, endodontic, oral surgery, and prosthodontic services decreased (overall Pearson χ2, P < .0001). CONCLUSIONS: Patients are less likely to visit a dentist after a hospital stay, although impact on oral health is unknown. PRACTICAL IMPLICATIONS: Hospitalization may contribute to already existing oral health disparities. Hospital teams and dentists should work together to enhance access to oral health care after hospital admission.

Unjamming and collective migration in MCF10A breast cancer cell lines.

Each cell comprising an intact, healthy, confluent epithelial layer ordinarily remains sedentary, firmly adherent to and caged by its neighbors, and thus defines an elemental constituent of a solid-like cellular collective [1,2]. After malignant transformation, however, the cellular collective can become fluid-like and migratory, as evidenced by collective motions that arise in characteristic swirls, strands, ducts, sheets, or clusters [3,4]. To transition from a solid-like to a fluid-like phase and thereafter to migrate collectively, it has been recently argued that cells comprising the disordered but confluent epithelial collective can undergo changes of cell shape so as to overcome geometric constraints attributable to the newly discovered phenomenon of cell jamming and the associated unjamming transition (UJT) [1,2,5-9]. Relevance of the jamming concept to carcinoma cells lines of graded degrees of invasive potential has never been investigated, however. Using classical in vitro cultures of six breast cancer model systems, here we investigate structural and dynamical signatures of cell jamming, and the relationship between them [1,2,10,11]. In order of roughly increasing invasive potential as previously reported, model systems examined included MCF10A, MCF10A.Vector; MCF10A.14-3-3ζ; MCF10.ErbB2, MCF10AT; and MCF10CA1a [12-15]. Migratory speed depended on the particular cell line. Unsurprisingly, for example, the MCF10CA1a cell line exhibited much faster migratory speed relative to the others. But unexpectedly, across different cell lines higher speeds were associated with enhanced size of cooperative cell packs in a manner reminiscent of a peloton [9]. Nevertheless, within each of the cell lines evaluated, cell shape and shape variability from cell-to-cell conformed with predicted structural signatures of cell layer unjamming [1]. Moreover, both structure and migratory dynamics were compatible with previous theoretical descriptions of the cell jamming mechanism [2,10,11,16,17]. As such, these findings demonstrate the richness of the cell jamming mechanism, which is now seen to apply across these cancer cell lines but remains poorly understood.

Surgical Approach and Periprocedural Outcomes by Race and Ethnicity of Children Undergoing Craniosynostosis Surgery.

BACKGROUND: Surgical repair for craniosynostosis varies depending on the infant's age, location of suture fusion, and approach (e.g., open versus endoscopic). Existing data suggest possible racial and ethnic disparities in timely access to surgical care for craniosynostosis that may, in turn, be associated with surgical approach and perioperative outcomes. This study examined racial and ethnic variation in craniosynostosis operations by surgical approach and perioperative outcomes. METHODS: Data were collected by the 2013 to 2015 Pediatric National Surgical Quality Improvement Program. Patients aged younger than 24 months with diagnoses and procedure codes consistent with surgery for craniosynostosis were identified. Periprocedural characteristics and surgical approach (open, endoscopic/minimally invasive, or both) were examined descriptively, overall, and separately by race and ethnicity. RESULTS: The authors identified 1982 admissions. Mean age at surgery was 7.8 ± 4.7 months. Ninety-one percent of procedures were classified as open operations, 5.8 percent were endoscopic, and 3.4 percent were both open and endoscopic. Relative to white/non-Hispanic patients, Hispanic and nonwhite patients underwent surgery at older ages, experienced longer operative and anesthesia times, and were hospitalized longer. Hispanic patients had the highest rates of open operations. CONCLUSIONS: These data suggest that Hispanic and nonwhite patients tend to undergo craniosynostosis repair at older ages and to have lengthier operations than white/non-Hispanic patients. Although we were unable to examine the root cause(s) of these differences, delayed diagnosis is one factor that might result in surgery at an older age and more complex operations requiring open surgery. Prospective studies examining racial/ethnic disparities are needed to inform a comparison of outcomes associated with surgical approach.

Geometric constraints during epithelial jamming.

As an injury heals, an embryo develops, or a carcinoma spreads, epithelial cells systematically change their shape. In each of these processes cell shape is studied extensively whereas variability of shape from cell-to-cell is regarded most often as biological noise. But where do cell shape and its variability come from? Here we report that cell shape and shape variability are mutually constrained through a relationship that is purely geometrical. That relationship is shown to govern processes as diverse as maturation of the pseudostratified bronchial epithelial layer cultured from non-asthmatic or asthmatic donors, and formation of the ventral furrow in the Drosophila embryo. Across these and other epithelial systems, shape variability collapses to a family of distributions that is common to all. That distribution, in turn, is accounted for by a mechanistic theory of cell-cell interaction showing that cell shape becomes progressively less elongated and less variable as the layer becomes progressively more jammed. These findings suggest a connection between jamming and geometry that spans living organisms and inert jammed systems, and thus transcends system details. Although molecular events are needed for any complete theory of cell shape and cell packing, observations point to the hypothesis that jamming behavior at larger scales of organization sets overriding geometrical constraints.

Variants in BAK1, SPRY4, and GAB2 are associated with pediatric germ cell tumors: A report from the children's oncology group.

Germ cell tumors (GCT) are a rare form of childhood cancer that originate from the primordial germ cell. Recent genome-wide association studies (GWAS) have identified susceptibility alleles for adult testicular GCT (TGCT). We test whether these SNPs are associated with GCT in pediatric and adolescent populations. This case-parent triad study includes individuals with GCT diagnosed between ages 0 and 19. We evaluated 26 SNPs from GWAS of adult TGCT and estimated main effects for pediatric GCT within complete trios (N = 366) using the transmission disequilibrium test. We used Estimation of Maternal, Imprinting and interaction effects using Multinomial modelling to evaluate maternal effects in non-Hispanic white trios and dyads (N = 244). We accounted for multiple comparisons using a Bonferroni correction. A variant in SPRY4 (rs4624820) was associated with reduced risk of GCT (OR [95% CI]: 0.70 [0.57, 0.86]). A variant in BAK1 (rs210138) was positively associated with GCT (OR [95% CI]: 1.70 [1.32, 2.18]), with a strong estimated effect for testis tumors (OR [95% CI]: 3.31 [1.89, 5.79]). Finally, a SNP in GAB2 (rs948662) was associated with increased risk for GCT (OR [95% CI]: 1.56 [1.20, 2.03]). Nominal associations (P < 0.05) were noted for eight additional loci. A maternal effect was observed for KITLG SNP rs4474514 (OR [95% CI]: 1.66 [1.21, 2.28]) and a paternal parent-of-origin effect was observed for rs7221274 (P = 0.00007), near TEX14, RAD51C, and PPM1E. We observed associations between SNPs in SPRY4, BAK1, and GAB2 and GCTs. This analysis suggests there may be common genetic risk factors for GCT in all age groups.

Cystic Fibrosis is Associated with Adverse Neonatal Outcomes in Washington State, 1996-2013.

OBJECTIVE: To determine whether cystic fibrosis (CF) is associated with adverse neonatal outcomes in a recent birth cohort in the US. STUDY DESIGN: A retrospective matched cohort study of infants born in Washington State from 1996 to 2013 was identified through birth certificate data and linked to statewide hospital discharge data. Infants with CF were identified by hospitalization (through age 5 years) in which a CF-specific International Classification of Diseases, Ninth Revision code was recorded. "Unexposed" infants lacked CF-related International Classification of Diseases, Ninth Revision codes and were randomly selected among births, frequency-matched to "exposed" infants on birth year. Associations of CF with adverse neonatal outcomes (low birth weight [LBW], small for gestational age [SGA], preterm birth, and infant mortality) were estimated through Poisson regression. We performed extreme value imputation to address possible ascertainment bias. RESULTS: We identified 170 infants with CF and 3400 unexposed infants. CF was associated with increased relative risk (95% CI) of 3.5 (2.5-4.9), 1.6 (1.1-2.4), 3.0 (2.2-4.0), and 6.8 (1.7-26.5) for LBW, SGA, preterm birth, and infant death, respectively. The estimated relative risks were similar among infants born from 2006 to 2013, except SGA was no longer associated with CF diagnosis. Results were robust to extreme value imputation and exclusion of infants with meconium ileus. CONCLUSIONS: Observed associations of CF with LBW, preterm birth, and infant death are unlikely to be due to ascertainment bias. Further work is needed to determine how to prevent these adverse neonatal outcomes.

Consumption of alcoholic beverages in adolescence and adulthood and risk of testicular germ cell tumor.

The etiology of testicular germ cell tumor (TGCT) remains obscure and accumulating evidence suggests that postnatal environmental or lifestyle factors may play a role. To investigate whether consumption of alcoholic beverages during adolescence or adulthood is associated with TGCT risk, we analyzed data from a USA population-based case-control study of 540 18-44 year-old TGCT cases and 1,280 age-matched controls. Participants were queried separately about consumption of beer, wine and liquor during grades 7-8, grades 9-12 and the 5 years before reference date (date of diagnosis for cases and corresponding date for controls). We used logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) for the association of TGCT risk with alcoholic beverage consumption during the different periods, both total and by specific beverage types and separately for seminomas and nonseminomas. Compared with nondrinkers in the 5 years before reference date, the OR (95% CI) for 1-6, 7-13 and ≥14 drinks per week were 1.20 (0.85, 1.69), 1.23 (0.81, 1.85) and 1.56 (1.03, 2.37), respectively (p-trend = 0.04). The corresponding results for alcohol consumption in grades 9-12 were 1.39 (1.06, 1.82), 1.07 (0.72, 1.60), 1.53 (1.01, 2.31) (p-trend = 0.05). Alcohol consumption in grades 7-8 was uncommon and no statistically significant associations with TGCT were observed. Associations with alcohol consumption in the 5 years before reference date appeared stronger for nonseminomas than for seminomas, but the differences were not statistically significant (p≥0.10). Associations were similar across different alcoholic beverage types. Consumption of alcoholic beverages may be associated with an increased TGCT risk.

Associations Between Sex Hormone Levels and Periodontitis in Men: Results From NHANES III.

BACKGROUND: Sex hormones are linked to inflammation and bone turnover. The goal of this study is to explore the association between sex hormone levels and periodontitis in men using data from the third National Health and Nutrition Examination Survey (NHANES III). METHODS: Data from 755 men (aged ≥ 30 years), including serum levels of testosterone, estradiol, sex hormone binding globulin, and androstenediol glucuronide, were analyzed. Calculated bioavailable testosterone (CBT) and estradiol-to-testosterone ratio were calculated. Periodontitis was defined using the latest classification of extent and severity of periodontitis for NHANES data (≥ 2 interproximal sites with ≥ 3 mm attachment loss, ≥ 2 interproximal sites with probing depth [PD] ≥ 4 mm not on the same tooth, or one site with PD ≥ 5 mm). Sex hormones were evaluated as categorized and continuous variables. Correlations between the presence and severity of periodontitis and levels of sex hormones were determined and expressed as odds ratios (ORs). RESULTS: When adjusted for confounding factors, high total testosterone (TT) and CBT levels correlated with both the prevalence (OR [95% confidence interval (CI)], 2.1 [1 to 4.5] and 3.9 [1 to 14.8], respectively) and severity (OR [95% CI], 2.1 [1 to 4.3] and 3.4 [1.2 to 9.8]) of periodontitis. When continuous variables were used, the ORs (95% CIs) for presence and severity of periodontitis were 1.4 (0.6 to 3.3) and 1.5 (0.6 to 3.6) for TT and 1.3 (0.9 to 1.9) and 1.3 (0.9 to 1.8) for CBT, respectively. CONCLUSIONS: These findings are consistent with the existence of an association of periodontitis with sex hormone levels, especially testosterone, in men.

Intellectual and academic functioning of school-age children with single-suture craniosynostosis.

OBJECTIVE: We compared the developmental status of school-age children with single-suture craniosynostosis (case group) and unaffected children (control group). Within the case group we compared the performance of children distinguished by location of suture fusion (sagittal, metopic, unicoronal, lambdoid). METHODS: We administered standardized tests of intelligence, reading, spelling, and math to 182 case participants and 183 control participants. This sample represented 70% of those tested during infancy before case participants had corrective surgery. RESULTS: After adjustment for demographics, case participants' average scores were lower than those of control participants on all measures. The largest observed differences were in Full-Scale IQ and math computation, where case participants' adjusted mean scores were 2.5 to 4 points lower than those of control participants (Ps ranged from .002 to .09). Adjusted mean case-control differences on other measures of achievement were modest, although case deficits became more pronounced after adjustment for participation in developmental interventions. Among case participants, 58% had no discernible learning problem (score <25th percentile on a standardized achievement test). Children with metopic, unicoronal, and lambdoid synostosis tended to score lower on most measures than did children with sagittal fusions (Ps ranged from <.001 to .82). CONCLUSIONS: The developmental delays observed among infants with single-suture craniosynostosis are partially evident at school age, as manifested by lower average scores than those of control participants on measures of IQ and math. However, case participants' average scores were only slightly lower than those of control participants on reading and spelling measures, and the frequency of specific learning problems was comparable. Among case participants, those with unicoronal and lambdoid fusions appear to be the most neurodevelopmentally vulnerable.

Predicting developmental delay in a longitudinal cohort of preschool children with single-suture craniosynostosis: is neurobehavioral assessment important?

AIM: The aim of this study was to determine whether neurobehavioral assessment before and after cranial vault surgery can improve prediction of developmental delay in children with single-suture craniosynostosis (SSC), after accounting for 'baseline' demographic and clinical variables (SSC diagnosis and surgery age). METHOD: Children with SSC were referred by the treating surgeon or pediatrician before surgery. Neurobehavioral assessments were performed at ages of approximately 6, 18, and 36 months. Iterative models were developed to predict delay, as determined by one or more tests of cognitive, motor, and language skills at 36 months. We selected from groups of variables entered in order of timing (before or after corrective surgery), and source of information (parent questionnaire or psychometric testing). RESULTS: Good predictive accuracy as determined by area under the receiver operating characteristic curve (AUC), was obtained with the baseline model (AUC=0.66), which incorporated age at surgery, sex, and socio-economic status. However, predictive accuracy was improved by including pre- and post-surgery neurobehavioral assessments. Models incorporating post-surgery neurobehavioral testing (AUC=0.79), pre-surgery testing (AUC=0.74), or both pre- and post-surgery testing (AUC=0.79) performed similarly. However, the specifity of all models was considered to be moderate (≤0.62). INTERPRETATION: Prediction of delay was enhanced by assessment of neurobehavioral status. Findings provide tentative support for guidelines of care that call for routine testing of children with SSC.

Leukocyte telomere length and age at menopause.

BACKGROUND: Telomere length is a marker of cellular aging that varies with the individual, is inherited, and is highly correlated across somatic cell types within persons. Interindividual variability of telomere length may partly explain differences in reproductive aging rates. We examined whether leukocyte telomere length was associated with menopausal age. METHODS: We evaluated the relationship between leukocyte telomere length and age at natural menopause in 486 white women ≥65 years of age. We fit linear regression models adjusted for age, income, education, body mass index, physical activity, smoking, and alcohol intake. We repeated the analysis in women with surgical menopause. We also performed sensitivity analyses excluding women (1) with unilateral oophorectomy, (2) who were nulliparous, or (3) reporting menopausal age <40 years, among other exclusions. RESULTS: For every 1-kb increase in leukocyte telomere length, average age at natural menopause increased by 10.2 months (95% confidence interval = 1.3 to 19.0). There was no association among 179 women reporting surgical menopause. In all but one sensitivity analysis, the association between leukocyte telomere length and age at menopause became stronger. However, when excluding women with menopausal age <40 years, the association decreased to 7.5 months (-0.4 to 15.5). CONCLUSIONS: Women with the longest leukocyte telomere length underwent menopause 3 years later than those with the shortest leukocyte telomere length. If an artifact, an association would likely also have been observed in women with surgical menopause. If these results are replicated, leukocyte telomere length may prove to be a useful predictor of age at menopause.

Duration of exposure to cranial vault surgery: associations with neurodevelopment among children with single-suture craniosynostosis.

OBJECTIVE: To evaluate associations between neurodevelopment and exposure to surgery and anesthetic agents in children with single-suture craniosynostosis (SSC). BACKGROUND: Young children with SSC have unexplained neurodevelopmental delays. The possible contributions of factors related to cranial vault surgery - including anesthesia - have not been previously examined. METHODS/MATERIALS: Two anesthesiologists reviewed the surgical records of 89 infants (70 had complete data). Primary exposures were duration of surgery and anesthesia and total duration of inhaled anesthesia (at age 6 months on average). Outcomes were the cognitive and motor scores from the Bayley Scales of Infant Development-II and language scores from the Preschool Language Scale, 3rd edition, given at age 36 months. Linear regression using robust standard error estimates was performed, adjusting for age at surgery and suture site. RESULTS: Anesthesia duration ranged from 155 to 547 min. For every 30-min increase in anesthesia duration, the estimated average decrease in developmental test scores ranged from 1.1 to 2.9 (P ranged from <0.001 to 0.30). Similar, but weaker findings were observed with surgery duration and total duration of inhaled anesthesia. Inverse relations between exposure amounts and neurodevelopment were stronger in children with nonsagittal synostosis. CONCLUSIONS: Average neurodevelopmental scores were lower among children experiencing longer surgeries and higher exposures to inhaled anesthesia. These associations may be due to anesthesia exposure, nonspecific effects of surgery, or unmeasured variables that correlate with surgery duration. Further study of potential causal mechanisms is warranted.

Multicenter study of neurodevelopment in 3-year-old children with and without single-suture craniosynostosis.

OBJECTIVE: To evaluate the hypothesis that 3-year-old children with single-suture craniosynostosis would receive lower neurodevelopmental scores than a comparable group of children born with patent sutures. DESIGN: Longitudinal comparison study. SETTING: Five tertiary care craniofacial centers. PARTICIPANTS: Patients with craniosynostosis (cases) and a comparison group of children without craniosynostosis(controls). Patients diagnosed with single-suture craniosynostosis from 2002 to 2006 were eligible as cases.Controls were frequency-matched to cases on age, sex, race, socioeconomic status, and study site. MAIN EXPOSURE: Craniosynostosis. MAIN OUTCOME MEASURES: We administered the Bayley Scales of Infant Development, Second Edition, mental and motor development indices and the Preschool Language Scales, Third Edition, receptive and expressive communication scales. Children were evaluated at baseline (before surgery in cases and at a similar age in controls)and at 18 and 36 months of age. We compared the groups' performances at 36 months by fitting adjusted linear and logistic regression models. We also estimated adjusted associations between age at surgery and neurodevelopmental scores. RESULTS: Adjusted mean case deficits ranged from 3 to 6 points (P≤ .008 for all comparisons). Compared with controls, the odds of cases being delayed ranged from 1.5 to 2.0, depending on the neurodevelopmental scale (P values ranged from .03 to .09). Cases' ages at craniosynostosis repair were not strongly related to neurodevelopmental performance. CONCLUSIONS: In this large, carefully controlled, multicenter study, we observed consistently lower mean neurodevelopmental scores in children with single-suture craniosynostosis compared with controls. These results provide further support for neurodevelopmental screening in young children with single-suture craniosynostosis.

A second independent locus within DMRT1 is associated with testicular germ cell tumor susceptibility.

Susceptibility to testicular germ cell tumors (TGCT) has a significant heritable component, and genome-wide association studies (GWASs) have identified association with variants in several genes, including KITLG, SPRY4, BAK1, TERT, DMRT1 and ATF7IP. In our GWAS, we genotyped 349 TGCT cases and 919 controls and replicated top hits in an independent set of 439 cases and 960 controls in an attempt to find novel TGCT susceptibility loci. We identified a second marker (rs7040024) in the doublesex and mab-3-related transcription factor 1 (DMRT1) gene that is independent of the previously described risk allele (rs755383) at this locus. In combined analysis that mutually conditions on both DMRT1 single nucleotide polymorphism markers, TGCT cases had elevated odds of carriage of the rs7040024 major A allele [per-allele odds ratio (OR) = 1.48, 95% confidence interval (CI) 1.23, 1.78; P = 2.52 × 10(-5)] compared with controls, while the association with rs755383 persisted (per allele OR = 1.26, 95% CI 1.08, 1.47, P = 0.0036). In similar analyses, the association of rs7040024 among men with seminomatous tumors did not differ from that among men with non-seminomatous tumors. In combination with KITLG, the strongest TGCT susceptibility locus found to date, men with TGCT had greatly elevated odds (OR = 14.1, 95% CI 5.12, 38.6; P = 2.98 × 10(-7)) of being double homozygotes for the risk (major) alleles at DMRT (rs7040024) and KITLG (rs4474514) when compared with men without TGCT. Our findings continue to corroborate that genes influencing male germ cell development and differentiation have emerged as the major players in inherited TGCT susceptibility.

No association between maternal pre-pregnancy obesity and risk of hypospadias or cryptorchidism in male newborns.

BACKGROUND: Hypospadias and cryptorchidism, two relatively common male genital anomalies, may be caused by altered maternal hormone levels, blood glucose levels, or nutritional deficiencies. Maternal obesity, which increases risk of diabetes and could influence hormone levels, may, therefore, be associated with risk of hypospadias and cryptorchidism. The purpose of this study was to assess the association between pre-pregnancy maternal obesity and hypospadias and cryptorchidism. METHODS: We conducted a case-control study of hypospadias and cryptorchidism in male singleton newborns using Washington State birth records from 1992 to 2008 linked to birth-hospitalization discharge records. Maternal pre-pregnancy body mass index (BMI) was calculated from pre-pregnancy weight and height. Adjusted odds ratios (aORs) and 95% confidence intervals (95% CIs) for hypospadias or cryptorchidism were estimated by fitting multivariable logistic regression models adjusted for year of birth, and maternal age, education, parity, race, and cigarette smoking during pregnancy. RESULTS: The complete-case analysis included 2219 hypospadias cases, 2563 cryptorchidism cases, and 32,734 controls. Maternal obesity (BMI ≥30 kg/m(2) ) was not associated with risk of hypospadias or cryptorchidism in male offspring: hypospadias (aOR, 1.07; 95% CI, 0.95-1.21); cryptorchidism (aOR, 0.99; 95% CI, 0.89-1.11), and no trend in risk with increasing maternal BMI was found. There was little indication of risk associated with BMI among any subgroup of mothers examined, including women with pre-existing diabetes or hypertension, women who developed preeclampsia, non-Hispanic white women, first-time mothers, or mothers aged ≥30 years. CONCLUSIONS: The results of this study do not support the hypothesis that pre-pregnancy maternal obesity is a cause of hypospadias or cryptorchidism in male infants.

Mothers' and fathers' reports of stress in families of infants with and without single-suture craniosynostosis.

OBJECTIVE: To compare relative levels of stress reported by mothers and fathers in families containing infants with and without single-suture craniosynostosis. DESIGN: Case-control study. PARTICIPANTS: Mothers and fathers of 246 infants with recently diagnosed single-suture craniosynostosis and 253 frequency-matched control infants completed the Parenting Stress Index just prior to their infant's cranioplastic surgery. Family demographic information and mothers' ratings of the severity of their child's single-suture craniosynostosis were obtained. RESULTS: Average Parent Domain scores for parents of infants with single-suture craniosynostosis differed little from those reported by parents of control infants; however, Child Domain scores among parents of infants with single-suture craniosynostosis were higher on some subscales, primarily related to unexpected infant health and appearance issues. In both groups, fathers reported higher Child Domain stress than mothers, and mothers reported higher Parent Domain stress than fathers. Case mothers reported greater stress if they perceived their child's condition as more noticeable to others. CONCLUSIONS: Prior to cases' cranioplastic surgery, parents of children with and without single-suture craniosynostosis reported similar levels of stress in relation to their parenting roles and the behavioral characteristics of their infants. Visibility of condition should be considered a risk for increased stress for mothers of infants with single-suture craniosynostosis. Stress differences between mothers and fathers were far more discernible than those associated with the presence or absence of single-suture craniosynostosis.