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Sleep-disordered breathing (SDB), with both central and obstructive sleep apneas, has been reported in association with Chiari malformation type 1 (CM1). CM1 is a congenital or acquired herniation of the cerebellar tonsils through the foramen magnum. In this case, a five-year-old girl with a history of CM1 and syringomyelia experienced worsening intracranial pressure (ICP) secondary to SDB. This case highlights the importance of early recognition of sleep related respiratory disorders in patients with Chiari malformation and its association with increased intracranial pressure., (© 2024 American Academy of Sleep Medicine.)

Objective: To evaluate the effectiveness of coordinated endoscopy with otolaryngology, pulmonology, and gastroenterology in diagnosing and managing chronic aspiration in pediatric patients., Methods: We reviewed our REDCap Pediatric Aerodigestive Database for patients with chronic aspiration who underwent coordinated endoscopy between January 2013 and July 2023. Patient demographics, comorbidities, operative findings, interventions, and outcomes were reviewed., Results: Forty-nine patients were identified with a diagnosis of aspiration. Their mean (SD) age was 28 (36) months (range 1.2-163 months) with more than half of the patients younger than 24 months. The most common findings noted on combined endoscopies were laryngeal cleft (n = 30), positive bacterial culture (n = 18), positive viral PCR (n = 17), and active reflux-induced esophagitis/gastritis (n = 9). Patients with a positive bacterial culture were associated with a history of recurrent pneumonia (p = 0.009). There were no other significant associations between endoscopy findings and patient demographics, co-morbidities, or symptoms. Twenty-five (51 %) had multiple abnormalities identified by at least 2 different specialists at the time of endoscopy and 6 patients (12 %) had abnormalities across all three specialists., Conclusion: Coordinated endoscopy should be considered in pediatric patients presenting with aspiration on MBS or non-specific symptoms suggestive for chronic aspiration for comprehensive diagnosis and management., Competing Interests: Declaration of competing interest None, (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: High quality surgical care for colorectal cancer (CRC) includes obtaining a negative surgical margin. The Michigan Surgical Quality Collaborative (MSQC) is a statewide consortium of hospitals dedicated to quality improvement; a subset of MSQC hospitals abstract quality of care measures for CRC surgery, including positive margin rate. The purpose of this study was to determine whether positive margin rates vary significantly by hospital, and whether positive margin rates should be a target for quality improvement., Methods: We performed a retrospective cohort study of patients who underwent CRC resection from 2016 to 2020. The primary outcome was the presence of a positive margin. Univariate and multivariable analyses were performed to test the association of positive margins with patient, hospital, and tumor characteristics., Results: The cohort consisted of 4211 patients from 42 hospitals (85 % colon cancer and 15 % rectal cancer). The crude positive margin rate was 6.15 % (95 % CI 4.6-7.4 %); this ranged from 0 % to 22 % at individual hospitals. In multivariable analysis, factors independently associated with positive margins included male sex, underweight BMI, metastatic cancer, rectal cancer (vs. colon), T4 T-stage, N1c/N2 N-stage, and open surgical approach. After adjusting for these factors, there remained significant variation by hospital, with 8 hospitals being statistically-significant outliers., Conclusions: Positive margins rates for CRC vary by hospital in Michigan, even after rigorous adjustment for case-mix. Furthermore, several hospitals achieved near-zero positive margin rates, suggesting opportunities for quality improvement through the identification of best practices among CRC surgery centers., Competing Interests: None., (© 2023 The Authors. Published by Elsevier Inc.)

Purpose: Patients with neurodevelopmental disorders (NDD) (i.e. autism, developmental delay, early-onset psychiatric or seizure disorders) increasingly seek evaluation of new or exacerbated symptoms concerning for autoimmune encephalitis (AE). Clinical AE evaluation can be challenging in NDD patients with symptom overlap between anti-neuronal autoimmunity and baseline atypical neurodevelopment. This study sought to explore differences in AE features by neurodevelopmental status., Methods: This retrospective chart review included 67 children with typical development (TD) or NDD evaluated for AE at the authors' institution. AE diagnosis included seronegative AE or seropositive AE with anti-NMDAR or anti-GAD antibodies. Reported AE clinical domains, symptom onset acuity, and treatment response were compared between three groups: (1) TD children with AE (TD-AE, N = 24); (2) NDD children with AE (NDD-AE, N = 21); and (3) NDD children with a non-AE diagnosis following appropriate workup (NDD-nonAE, N = 22)., Results: Children with AE had a greater number of reported clinical domains than non-AE children with NDD (p < 0.0001) regardless of baseline developmental status. There were no observed differences in reported domains between TD-AE and NDD-AE groups. Onset acuity differed across the three groups (p = 0.04). No treatment response differences were observed between groups., Conclusion: NDD children with AE had a comparable number of reported clinical domains relative to TD children and a similar treatment response. NDD patients with AE had a greater number of reported clinical domains than their NDD peers without an AE diagnosis. These findings suggest that AE is a multi-domain process in both TD and NDD children., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Individuals with hearing loss (HL) are at higher risk for hospitalizations, and may be for readmissions, compared with their hearing peers. The objective of this prospective study was to confirm retrospective studies suggesting that HL increases hospital readmissions, and, if confirmed, possible causes for it., Methods: A prospective cohort study of English-speaking patients > 55 years old admitted to general medical and surgical floors at 2 large hospital systems in southeastern Michigan over a 2-year period was conducted. All patients underwent bedside audiometric testing. HL presence and severity were categorized using World Health Organization pure tone assessment parameters. Readmission rates, Charlson comorbidity index, socio-demographic and medical variables were obtained from Epic EMR databases., Outcomes: There were 1247 hospitalized patients enrolled. Of these, 76.8% had documented HL of which 50.5% (630) was mild HL and 26.3% (328) moderate or worse HL. Patients with any HL were older and more likely to be non-Hispanic, white, male, and had less education, lower health literacy, more comorbidities, and more difficulty communicating with their doctor. Readmission rates at 30 and 90-days were similar between HL and hearing groups, after adjusting for HL severity, Charlston index, and numerous potential confounders., Conclusion: Patients with HL do not seem to have higher rates of hospital readmissions. We did find high frequency of HL in hospitalized patients along with significant communication difficulties that patients had with their clinicians. These findings have implications for measures to improve patient-physician communication, potentially improving long-term health outcomes., Competing Interests: Conflict of interest: The authors of this manuscript have no conflicts of interest, financial or otherwise., (© Copyright by the American Board of Family Medicine.)

This study was aimed to evaluate the yearly incidence of pediatric narcolepsy prior to and following the 2009 H1N1 pandemic and to evaluate seasonal patterns of narcolepsy onset and associations with H1N1 influenza infection in the United States. This was a multicenter retrospective study with prospective follow-up. Participants were recruited from members of the Pediatric Working Group of the Sleep Research Network including 22 sites across the United States. The main outcomes were monthly and yearly incident cases of childhood narcolepsy in the United States, and its relationship to historical H1N1 influenza data. A total of 950 participants were included in the analysis; 487 participants were male (51.3%). The mean age at onset of excessive daytime sleepiness (EDS) was 9.6  ±  3.9 years. Significant trend changes in pediatric narcolepsy incidence based on EDS onset (p  <  .0001) occurred over the 1998-2016 period, peaking in 2010, reflecting a 1.6-fold increase in narcolepsy incidence. In addition, there was significant seasonal variation in narcolepsy incident cases, with increased cases in spring (p  <  .05). Cross-correlation analysis demonstrated a significant correlation between monthly H1N1 infection and monthly narcolepsy incident cases (p  =  .397, p  <  .0001) with a lag time of 8 months. We conclude that there is a significant increase in pediatric narcolepsy incidence after the 2009 H1N1 pandemic in the United States. However, the magnitude of increase is lower than reported in European countries and in China. The temporal correlation between monthly H1N1 infection and monthly narcolepsy incidence, suggests that H1N1 infection may be a contributing factor to the increased pediatric narcolepsy incidence after the 2009 H1N1 pandemics., (© The Author(s) 2022. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Deaf and hard of hearing (DHH) people are an underserved population and underrepresented among healthcare professionals. A major barrier to success for DHH healthcare professionals is obtaining effective accommodations during education and employment. Our objective: describe DHH individuals' experiences with accommodations in healthcare education., Methods: We used an online survey and multipronged snowball sampling to recruit participants who identify as DHH and who had applied to a U.S. health professional school (regardless of acceptance status). One hundred forty-eight individuals representing multiple professions responded; 51 had completed their training. Over 80% had been accepted to, were currently enrolled, or had completed health professions schools or residency programs, and/or were employed. The survey included questions addressing experiences applying to health professions programs and employment; satisfaction with accommodations in school and training; having worked with a disability resource professional (DRP); and depression screening., Results: Use and type of accommodation varied widely. While in school, respondents reported spending a mean of 2.1 h weekly managing their accommodations. Only 50% were highly satisfied with the accommodations provided by their programs. Use of disability resource providers (DRPs) for accommodations was highest during school (56%) and less frequent during post-graduate training (20%) and employment (14%). Respondents who transitioned directly from school to employment (versus via additional training) were more satisfied with their accommodations during school and were more likely to find employment (p = 0.02). Seventeen respondents screened positive for risk of depression; a positive screen was statistically associated with lower school accommodation satisfaction., Conclusions: DHH people study and practice across many health professions. While respondents were mostly successful in entering health professions programs, accommodation experiences and satisfaction varied. Satisfaction with accommodations was related to successful employment and wellness. Low satisfaction was associated with higher likelihood of depression symptoms. To increase representation in the workforce, healthcare professional schools, training programs, and employers should enhance support for the learning and working climates for people with disabilities., (© 2022. The Author(s).)

Purpose: To assess the impact of the COVID-19 pandemic and associated mitigation measures on persons with sensory impairments (SI), including visual impairments (VI) and hearing impairments (HI)., Design: Cross-sectional survey., Methods: Adults with VI (best-corrected visual acuity <20/60 in the better-seeing eye), HI (International Classification of Diseases, Tenth Revision, codes), and age- and sex-matched controls (n = 375) were recruited from the University of Michigan. The 34-item Coronavirus Disability Survey was administered. Both χ 2 tests and logistic regression were used to compare survey responses between groups., Results: All groups reported high levels of disruption of daily life, with 80% reporting "a fair amount" or "a lot" of disruption (VI: 76%, HI: 83%, CT: 82%, P = .33). Participants with VI had greater difficulty with day-to-day activities and were more likely to cite the following reasons: caregiver was worried about COVID-19 (odds ratio [OR] VI  = 7.2, 95% CI = 3.5-14.4, P < .001) and decreased availability of public transportation (OR VI  = 5.0, 95% CI = 1.5-15.6, P = .006). Participants with VI, but not HI, showed a trend toward increased difficulty accessing medical care (OR VI  = 2.0, 95% CI = 0.99-4.0, P = .052) and began relying more on others for day-to-day assistance (OR VI  = 3.1, 95% CI = 1.6-5.7, P < .001). Overall, 30% reported difficulty obtaining trusted information about the pandemic. Those with VI reported more difficulty seeing or hearing trusted information (OR VI  = 6.1, 95% CI = 1.6-22.1, P = .006). Employed participants with HI were more likely to report a reduction in wages (OR HI  = 2.5, 95% CI = 1.2-5.3, P = .02)., Conclusions: Individuals with VI have experienced increased disruption and challenges in daily activities related to the pandemic. People with SI may benefit from targeted policy approaches to the current pandemic and future stressors. Minimal differences in some survey measures may be due to the large impact of the pandemic on the population as a whole. The SARS-CoV-2 (COVID-19) pandemic and public health mitigation measures have had an exceedingly large impact around the globe. As of the time of writing, more than 114 million global cases (28 million US) had been diagnosed, and there had been more than 2.5 million fatalities attributed to COVID-19 (517,000 US). 1 , 2 ., (Copyright © 2021 Elsevier Inc. All rights reserved.)

We describe the clinical features of nine unrelated individuals with rare de novo missense or in-frame deletions/duplications within the "HX motif" of exon 7 of ATN1. We previously proposed that individuals with such variants should be considered as being affected by the syndromic condition of congenital hypotonia, epilepsy, developmental delay, and digital anomalies (CHEDDA), distinct from dentatorubral-pallidoluysian atrophy (DRPLA) secondary to expansion variants in exon 5 of ATN1. We confirm that the universal phenotypic features of CHEDDA are distinctive facial features and global developmental delay. Infantile hypotonia and minor hand and feet differences are common and can present as arthrogryposis. Common comorbidities include severe feeding difficulties, often requiring gastrostomy support, as well as visual and hearing impairments. Epilepsy and congenital malformations of the brain, heart, and genitourinary systems are frequent but not universal. Our study confirms the clinical entity of CHEDDA secondary to a mutational signature restricted to exon 7 of ATN1. We propose a clinical schedule for assessment upon diagnosis, surveillance, and early intervention including the potential of neuroimaging for prognostication., (© 2021 John Wiley & Sons A/S . Published by John Wiley & Sons Ltd.)

Purpose: Hearing loss (HL) is underdiagnosed and often unaddressed. A recent study of screening for HL using an electronic prompt showed efficacy in increasing appropriate referrals for subsequent testing. We build on the results of this study using a qualitative lens to explore implementation processes through the perspectives of family medicine clinicians., Methods: We collected clinic observations and semistructured interviews of family medicine clinicians and residents who interacted with the HL prompt. All data were analyzed using thematic, framework, and mixed methods integration strategies., Results: We interviewed 27 clinicians and conducted 10 observations. Thematic analysis resulted in 6 themes: (1) the prompt was overwhelmingly viewed as easy, simple to use, accurate; (2) clinicians considered prompt as an effective way to increase awareness and conversations with patients about HL; (3) clinician and staff buy-in played a vital role in implementation; (4) clinicians prioritized prompt during annual visits; (5) medical assistant involvement in prompt workflow varied by health system, clinic, and clinician; (6) prompt resulted in more conversations about HL, but uncertain impact on patient outcomes. Themes are presented alongside constructs of normalization process theory and intervention outcomes., Conclusion: Integration of a HL screening prompt into clinical practice varied by clinician buy-in and beliefs about the impact on patient outcomes, involvement of medical assistants, and prioritization during clinical visits. Further research is needed to understand how to leverage clinician and staff buy-in and whether implementation of a new clinical prompt has sustained impact on HL screening and patient outcomes., (© 2021 Annals of Family Medicine, Inc.)

The goal of this practice resource is to provide genetic counselors and other healthcare professionals with a resource to reference when providing genetic counseling services to individuals and families undergoing evaluation for neurofibromatosis (NF) or who have received a diagnosis of NF, including NF1, NF2, and schwannomatosis. This resource represents the opinions of a multi-center working group of Certified Genetic Counselors with experience in the care of individuals with NF, providing topics to be considered for the incorporation into a clinical genetic counseling session., (© 2020 National Society of Genetic Counselors.)

We report 281 individuals carrying a pathogenic recurrent NF1 missense variant at p.Met1149, p.Arg1276, or p.Lys1423, representing three nontruncating NF1 hotspots in the University of Alabama at Birmingham (UAB) cohort, together identified in 1.8% of unrelated NF1 individuals. About 25% (95% confidence interval: 20.5-31.2%) of individuals heterozygous for a pathogenic NF1 p.Met1149, p.Arg1276, or p.Lys1423 missense variant had a Noonan-like phenotype, which is significantly more compared with the "classic" NF1-affected cohorts (all p < .0001). Furthermore, p.Arg1276 and p.Lys1423 pathogenic missense variants were associated with a high prevalence of cardiovascular abnormalities, including pulmonic stenosis (all p < .0001), while p.Arg1276 variants had a high prevalence of symptomatic spinal neurofibromas (p < .0001) compared with "classic" NF1-affected cohorts. However, p.Met1149-positive individuals had a mild phenotype, characterized mainly by pigmentary manifestations without externally visible plexiform neurofibromas, symptomatic spinal neurofibromas or symptomatic optic pathway gliomas. As up to 0.4% of unrelated individuals in the UAB cohort carries a p.Met1149 missense variant, this finding will contribute to more accurate stratification of a significant number of NF1 individuals. Although clinically relevant genotype-phenotype correlations are rare in NF1, each affecting only a small percentage of individuals, together they impact counseling and management of a significant number of the NF1 population., (© 2019 The Authors. Human Mutation Published by Wiley Periodicals, Inc.)

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a rare lethal lung developmental disease. Affected infants manifest with severe respiratory distress and refractory pulmonary hypertension and uniformly die in the first month of life. Heterozygous point mutations or copy-number variant deletions involving FOXF1 and/or its upstream lung-specific enhancer on 16q24.1 have been identified in the vast majority of ACDMPV patients. We have previously described two unrelated families with a de novo pathogenic frameshift variant c.691&#95;698del (p.Ala231Argfs*61) in the exon 1 of FOXF1. Here, we present a third unrelated ACDMPV family with the same de novo variant and propose that a direct tandem repeat of eight consecutive nucleotides GCGGCGGC within the ~4 kb CpG island in FOXF1 exon 1 is a novel mutation hotspot causative for ACDMPV., (© 2019 Wiley Periodicals, Inc.)

Study Objectives: Periodic limb movements (PLMs) have been associated with increased risk of stroke, but there is currently scarce research exploring this relationship in the setting of sickle cell disease (SCD). The aim of this study was to explore whether increased PLMs in children with SCD are associated with increased risk of cerebrovascular disease and to determine if there are any clinical or laboratory differences between children with SCD with elevated periodic limb movement index (PLMI) versus those with normal PLMI., Methods: This study is a comprehensive review of medical records of 129 children with SCD (aged ≤ 18 years) who had undergone polysomnography for evaluation of sleep-disordered breathing., Results: Elevated PLMI (PLMI > 5 events/h) was present in 42% (54/129) of children with SCD. Children with elevated PLMI were found to have higher percentage of hemoglobin S, lower total iron, higher arousal index and tendency toward elevated transcranial Doppler velocity ( P = .063, odds ratio = 3.9, 95% CI 0.93-16.22). While association between elevated PLMI and isolated cerebrovascular stenosis ( P = .050, odds ratio 5.6, 95% CI 1.0-31.10) trended toward significance, there was significantly greater proportion of children with elevated PLMI who had cerebrovascular stenosis with Moyamoya disease ( P = .046) as demonstrated by magnetic resonance imaging (MRI)., Conclusions: The prevalence of elevated PLMI in children with SCD was higher than in previously published data. Elevated PLMI was significantly associated with greater rates of cerebrovascular disease as detected by MRI., (Copyright © 2019 American Academy of Sleep Medicine. All rights reserved.)

Background: This study explores whether objective, quantitative radiomic biomarkers derived from magnetic resonance (MR), positron emission tomography (PET), and computed tomography (CT) may be useful in reliably distinguishing malignant peripheral nerve sheath tumors (MPNST) from benign plexiform neurofibromas (PN)., Methods: A registration and segmentation pipeline was established using a cohort of NF1 patients with histopathological diagnosis of PN or MPNST, and medical imaging of the PN including MR and PET-CT. The corrected MR datasets were registered to the corresponding PET-CT via landmark-based registration. PET standard-uptake value (SUV) thresholds were used to guide segmentation of volumes of interest: MPNST-associated PET-hot regions (SUV≥3.5) and PN-associated PET-elevated regions (2.0

COX20/FAM36A encodes a mitochondrial complex IV assembly factor important for COX2 activation. Only one homozygous COX20 missense mutation has been previously described in two separate consanguineous families. We report four subjects with features that include childhood hypotonia, areflexia, ataxia, dysarthria, dystonia, and sensory neuropathy. Exome sequencing in all four subjects identified the same novel COX20 variants. One variant affected the splice donor site of intron-one (c.41A>G), while the other variant (c.157+3G>C) affected the splice donor site of intron-two. cDNA and protein analysis indicated that no full-length cDNA or protein was generated. These subjects expand the phenotype associated with COX20 deficiency.

Loss of the NF1 tumor suppressor gene causes the autosomal dominant condition, neurofibromatosis type 1 (NF1). Children and adults with NF1 suffer from pathologies including benign and malignant tumors to cognitive deficits, seizures, growth abnormalities, and peripheral neuropathies. NF1 encodes neurofibromin, a Ras-GTPase activating protein, and NF1 mutations result in hyperactivated Ras signaling in patients. Existing NF1 mutant mice mimic individual aspects of NF1, but none comprehensively models the disease. We describe a potentially novel Yucatan miniswine model bearing a heterozygotic mutation in NF1 (exon 42 deletion) orthologous to a mutation found in NF1 patients. NF1+/ex42del miniswine phenocopy the wide range of manifestations seen in NF1 patients, including café au lait spots, neurofibromas, axillary freckling, and neurological defects in learning and memory. Molecular analyses verified reduced neurofibromin expression in swine NF1+/ex42del fibroblasts, as well as hyperactivation of Ras, as measured by increased expression of its downstream effectors, phosphorylated ERK1/2, SIAH, and the checkpoint regulators p53 and p21. Consistent with altered pain signaling in NF1, dysregulation of calcium and sodium channels was observed in dorsal root ganglia expressing mutant NF1. Thus, these NF1+/ex42del miniswine recapitulate the disease and provide a unique, much-needed tool to advance the study and treatment of NF1.

The usage of molecular phylogenetic approaches is critical to advance the understanding of systematics and community processes in the kingdom Fungi. Among the possible phylogenetic markers (or combinations of them), the 18S rRNA gene appears currently as the most prominent candidate due to its large availability in public databases and informative content. The purpose of this work was the creation of a reference phylogenetic framework that can serve as ready-to-use package for its application on fungal classification and community analysis. The current database contains 9329 representative 18S rRNA gene sequences covering the whole fungal kingdom, a manually curated alignment, an annotated and revised phylogenetic tree with all the sequence entries, updated information on current taxonomy, and recommendations of use. Out of 201 total fungal taxa with more than two sequences in the dataset, 179 were monophyletic. From another perspective, 66% of the entries had a tree-derived classification identical to that obtained from the NCBI taxonomy, whereas 34% differed in one or the other rank. Most of the differences were associated to missing taxonomic assignments in NCBI taxonomy, or the unexpected position of sequences that positioned out of their theoretically corresponding clades. The strong correlation observed with current fungal taxonomy evidences that 18S rRNA gene sequence-based phylogenies are adequate to reflect genealogy of Fungi at the levels of order and above, and justify their further usage and exploration., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Obstructive sleep apnea syndrome (OSAS) is associated with intermittent hypoxia and sleep loss. In children, impairments of cognitive function are important manifestations, but the underlying pathology is unknown. We hypothesized that OSAS would affect the dentate gyrus, a hippocampal subdivision essential to neurogenesis and cognition, and that this impact would further affect cognitive function in children. In children with OSAS ( n = 11) and control subjects ( n = 12; age and sex matched), we performed diffusion tensor imaging and structural MRI, polysomnography, and neuropsychological assessments. We found that OSAS was associated with decreased mean diffusivity of the left dentate gyrus ( p = 0.002; false discovery rate corrected; adjusting for sex, age, and body mass index), showing a large effect size (partial η 2 = 0.491), but not with any other structural measures across the brain. Decreased dentate gyrus mean diffusivity correlated with a higher apnea hypopnea index (Spearman's r = -0.50, p = 0.008) and a greater arousal index ( r = -0.44, p = 0.017). OSAS did not significantly affect neuropsychological measures ( p values >0.5); however, a lower verbal learning score correlated with lower dentate gyrus mean diffusivity ( r = 0.54, p = 0.004). Path analysis demonstrated that dentate gyrus mean diffusivity mediates the impact of OSAS on verbal learning capacity. Finally, the diagnostic accuracy of a regression model based on dentate gyrus mean diffusivity reached 85.8% (cross validated). This study demonstrates a likely pathway of effects of OSAS on neurocognitive function in children, as well as potential utility of the dentate gyrus mean diffusivity as an early marker of brain pathology in children with OSAS. SIGNIFICANCE STATEMENT In this study we investigate the relationships between dentate gyrus structure, hippocampus-dependent cognition, and obstructive sleep apnea syndrome (OSAS). We demonstrate lower mean diffusivity of the dentate gyrus in children with OSAS, which correlates with a lower verbal learning and memory score. This study provides new evidence of disrupted microstructure of the dentate gyrus in children with OSAS that may help explain some of the neurocognitive deficits described in these children., (Copyright © 2017 the authors 0270-6474/17/374280-09$15.00/0.)

Steroid 3-beta hydroxysteroid dehydrogenase type II (3β-HSD2) deficiency is a rare autosomal recessive form of congenital adrenal hyperplasia (CAH). We report the genetic basis of 3β-HSD2 deficiency arising from uniparental isodisomy (UPD) of chromosome 1. We describe a term undervirilized male whose newborn screen indicated borderline CAH. The patient presented on the 7 th day of life in salt-wasting adrenal crisis. Steroid hormone testing revealed a complex pattern suggestive of 3β-HSD deficiency. Chromosomal microarray and single nucleotide polymorphism analysis revealed complete UPD of chromosome 1. Sanger sequencing of HSD3B2 revealed a previously described missense mutation, c.424G>A (p.E142K) in homozygous state, thus confirming the diagnosis of 3β-HSD2 deficiency. We provide evidence of the existence of an uncommon mechanism for HSD3B2 gene-related CAH arising from UPD of chromosome 1.

Using whole-exome sequencing, we have identified in ten families 14 individuals with microcephaly, developmental delay, intellectual disability, hypotonia, spasticity, seizures, sensorineural hearing loss, cortical visual impairment, and rare autosomal-recessive predicted pathogenic variants in spermatogenesis-associated protein 5 (SPATA5). SPATA5 encodes a ubiquitously expressed member of the ATPase associated with diverse activities (AAA) protein family and is involved in mitochondrial morphogenesis during early spermatogenesis. It might also play a role in post-translational modification during cell differentiation in neuronal development. Mutations in SPATA5 might affect brain development and function, resulting in microcephaly, developmental delay, and intellectual disability., (Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Molecular diversity surveys have demonstrated that aquatic fungi are highly diverse, and that they play fundamental ecological roles in aquatic systems. Unfortunately, comparative studies of aquatic fungal communities are few and far between, due to the scarcity of adequate datasets. We combined all publicly available fungal 18S ribosomal RNA (rRNA) gene sequences with new sequence data from a marine fungi culture collection. We further enriched this dataset by adding validated contextual data. Specifically, we included data on the habitat type of the samples assigning fungal taxa to ten different habitat categories. This dataset has been created with the intention to serve as a valuable reference dataset for aquatic fungi including a phylogenetic reference tree. The combined data enabled us to infer fungal community patterns in aquatic systems. Pairwise habitat comparisons showed significant phylogenetic differences, indicating that habitat strongly affects fungal community structure. Fungal taxonomic composition differed considerably even on phylum and class level. Freshwater fungal assemblage was most different from all other habitat types and was dominated by basal fungal lineages. For most communities, phylogenetic signals indicated clustering of sequences suggesting that environmental factors were the main drivers of fungal community structure, rather than species competition. Thus, the diversification process of aquatic fungi must be highly clade specific in some cases.The combined data enabled us to infer fungal community patterns in aquatic systems. Pairwise habitat comparisons showed significant phylogenetic differences, indicating that habitat strongly affects fungal community structure. Fungal taxonomic composition differed considerably even on phylum and class level. Freshwater fungal assemblage was most different from all other habitat types and was dominated by basal fungal lineages. For most communities, phylogenetic signals indicated clustering of sequences suggesting that environmental factors were the main drivers of fungal community structure, rather than species competition. Thus, the diversification process of aquatic fungi must be highly clade specific in some cases.

Background: There is tremendous potential for genome sequencing to improve clinical diagnosis and care once it becomes routinely accessible, but this will require formalizing research methods into clinical best practices in the areas of sequence data generation, analysis, interpretation and reporting. The CLARITY Challenge was designed to spur convergence in methods for diagnosing genetic disease starting from clinical case history and genome sequencing data. DNA samples were obtained from three families with heritable genetic disorders and genomic sequence data were donated by sequencing platform vendors. The challenge was to analyze and interpret these data with the goals of identifying disease-causing variants and reporting the findings in a clinically useful format. Participating contestant groups were solicited broadly, and an independent panel of judges evaluated their performance., Results: A total of 30 international groups were engaged. The entries reveal a general convergence of practices on most elements of the analysis and interpretation process. However, even given this commonality of approach, only two groups identified the consensus candidate variants in all disease cases, demonstrating a need for consistent fine-tuning of the generally accepted methods. There was greater diversity of the final clinical report content and in the patient consenting process, demonstrating that these areas require additional exploration and standardization., Conclusions: The CLARITY Challenge provides a comprehensive assessment of current practices for using genome sequencing to diagnose and report genetic diseases. There is remarkable convergence in bioinformatic techniques, but medical interpretation and reporting are areas that require further development by many groups.

We describe a child whose original clinical and radiologic manifestations led to a diagnosis of Desbuquois dysplasia. Subsequent development of features including cervical kyphosis and cystic ears caused us to reconsider the original diagnosis. The new complement of features in this patient fell in a range between Desbuquois dysplasia and diastrophic dysplasia. Molecular testing showed that she is a compound heterozygote for mutations in the diastrophic dysplasia sulfate transporter gene (DTDST). This finding confirms that there is locus heterogeneity in apparent Desbuquois dysplasia. It also expands the phenotypic spectrum of disorders caused by mutations in DTDST., ((c) 2008 Wiley-Liss, Inc.)

Mutations in mitochondrial DNA (mtDNA) accumulate in tissues of mammalian species and have been hypothesized to contribute to aging. We show that mice expressing a proofreading-deficient version of the mitochondrial DNA polymerase g (POLG) accumulate mtDNA mutations and display features of accelerated aging. Accumulation of mtDNA mutations was not associated with increased markers of oxidative stress or a defect in cellular proliferation, but was correlated with the induction of apoptotic markers, particularly in tissues characterized by rapid cellular turnover. The levels of apoptotic markers were also found to increase during aging in normal mice. Thus, accumulation of mtDNA mutations that promote apoptosis may be a central mechanism driving mammalian aging.

Introduction of the fluoroquinolones has altered physician prescribing practices in the treatment of infectious diseases for both inpatients and outpatients. To evaluate the impact of unrestricted prescribing of these agents, the antimicrobial susceptibility of clinical isolates to ciprofloxacin and other commonly used antibiotics was prospectively studied in a 300-bed community teaching hospital. Only 0.6 percent (nine of 1,454 isolates) of fresh clinical isolates were resistant to ciprofloxacin (minimal inhibitory concentration value greater than 2 micrograms/ml) in an initial study conducted between 1984 and 1985. A similar pattern was observed in the second half of 1987 (0.5 percent, or five of 940 isolates), just prior to the release of ciprofloxacin. Throughout 1988, however, as quinolone usage rose, the incidence of ciprofloxacin resistance rose, reaching a peak of 4.0 percent in the last quarter of 1988. Of 63 ciprofloxacin-resistant isolates in 1988, 22 were Pseudomonas and 28 were staphylococci, representing resistance rates of 6.5 and 4.2 percent, respectively. Enterobacteriaceae remained exquisitely susceptible with only five of 1,720 isolates (0.3 percent) resistant to ciprofloxacin. Seventy-two percent of ciprofloxacin-resistant isolates were recovered from patients who had received a fluoroquinolone within the previous month. If these isolates are subtracted from the total number of resistant micro-organisms recovered, baseline fluoroquinolone resistance did not change significantly from 1984 to 1988. Soft-tissue infections (50 percent) represented the greatest source of ciprofloxacin-resistant organisms, including osteomyelitis, but urinary tract infections (26 percent), all associated with instrumentation, were also a significant source. Although the fluoroquinolones are extremely valuable antimicrobial agents, the emergence of drug resistance may be promoted when these drugs are used for treatment of chronic infections or when poorly drained abscesses, necrotic tissue, or indwelling foreign bodies are present.