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The purpose of this study was to assess clinical practice patterns with regard to diagnosis and management of testicular regression syndrome (TRS), a condition in 46,XY males with male phenotypic genitalia and bilateral absence of testes. A retrospective review was conducted at two large pediatric academic centers to examine diagnostic and management approaches for TRS. Records of 57 patients were reviewed. Diagnostic methods varied widely between patients and included hormonal testing, karyotype, imaging, and surgical exploration, with multiple diagnostic methods frequently used in each patient. Of the 30 subjects that had reached adolescence at the time of the study, 17 (57%) had gaps in care of more than 5 years during childhood. Thirty subjects had received testosterone replacement therapy at a mean age of 12.1 ± 1.0 years. Forty-seven percent had a documented discussion of infertility. Eighty-two percent discussed prosthesis placement, with 35% having prostheses placed. Twenty-three percent were seen by a psychosocial provider. The between-site differences were age at fertility discussion, age at and number of prostheses placed, and type/age of testosterone initiation. Our findings highlight the wide variation in diagnostic approaches, follow-up frequency, testosterone initiation, fertility counseling, and psychosocial support for patients with TRS. Developing evidence-based guidelines for the evaluation and management of TRS would help reduce inconsistencies in care and unnecessary testing. Ongoing follow-up and coordination of care, even during the years when no hormonal treatment is being administered, could lead to opportunities for psychosocial support and improved interdisciplinary approach to care. = antimüllerian hormone; = congenital adrenal hyperplasia; = differences/disorders of sex development; = human chorionic gonadotropin; = testicular regression syndrome.

Abstract Children with hepatoblastoma have an increased incidence of fractures, but data are limited. Previous reports document an average of 4 fractures per child with hepatoblastoma. We present a severe case of a premature 4-month-old with multiple fractures in the setting of Beckwith-Wiedemann syndrome and hepatoblastoma. Although prematurity is a known risk for metabolic bone disease, it did not entirely explain the severity. Our patient underwent chemotherapy and surgical resection of his hepatoblastoma. Once deemed stable, he received a dose of zoledronic acid (ZA). One month post treatment with ZA, a skeletal survey revealed healing of the rib and femoral fractures and no new fractures. Five months post ZA, the skeletal survey revealed no new fractures and motor development was appropriate. An extensive search revealed scant literature on the rate or cause of pathologic fractures in patients with newly diagnosed hepatoblastoma. A better understanding of fracture risk in this population may guide prevention strategies, screening, and treatment. In our case, prematurity and substantial chronic illness may have compounded the known fracture risk associated with hepatoblastoma and may provide insight into the pathophysiology and prevention of fractures in this setting.

Background: Cockayne syndrome is an autosomal recessive, heterogeneous syndrome with classical features, including short stature, microcephaly, developmental delay, neuropathy, and photosensitivity. New genomic approaches offer improved molecular diagnostic potential. Methods: Whole-exome sequencing was employed to study a consanguineous extended family with severe short stature and variable presentations of peripheral neuropathy, lipoatrophy, photosensitivity, webbed neck, and hirsutism. Results: We identified a novel homozygous ERCC6 variant at the donor splice site of intron 9 (c.1992 + 3A>G), which was predicted to only slightly perturb splicing efficiencies. Assessment of primary fibroblast-derived mRNAs, however, revealed a dominant splicing species that utilized an unsuspected putative donor splice site within exon 9, resulting in predicted early protein termination (p.Arg637Serfs*34). Conclusions: We describe a new splicing ERCC6 defect causal of Cockayne syndrome. The application of exome sequence analysis was integral to diagnosis, given the complexity of phenotypic presentation in the affected family members. The novel splicing defect, furthermore, illustrates how a seemingly minor change in the relative strength of a splice site can have significant biological consequences.

Abstract Congenital hyperinsulinism is the most common cause of persistent hypoglycemia in early infancy. Mutations in the gene for heterozygous hepatocyte nuclear transcription factor 4-alpha (HNF4A) account for approximately 5% of cases and are inherited in an autosomal dominant fashion or arise as de novo mutations. This case describes a unique presentation of parental gonadal, or germline, mosaicism as the suspected inheritance pattern for siblings with congenital hyperinsulinism caused by HNF4A mutations. Two siblings presented with hypoglycemia in the first hours of life and were subsequently confirmed to have hyperinsulinism. In each patient, glycemic control was achieved at relatively low doses of diazoxide. Both siblings tested positive for the same HNF4A mutation, whereas the parents tested negative for HNF4A mutations. Gonadal, or germline, mosaicism became the presumed leading diagnosis, given 2 unaffected parents with 2 children with congenital hyperinsulinism. The older sibling demonstrated additional clinical features of liver disease and renal Fanconi syndrome, both of which are associated with HNF4A mutations. Genetic testing plays an important role in the diagnosis and management of congenital hyperinsulinism. HNF4A mutations may arise by a range of mechanisms, including gonadal, or germline, mosaicism. HNF4A mutations have phenotypic variance that may affect multiple organ systems at any age.

Context:Heterozygous mutations in the aggrecan gene (ACAN) cause autosomal dominant short stature with accelerated skeletal maturation.Objective:We sought to characterize the phenotypic spectrum and response to growth-promoting therapies.Patients and Methods:One hundred three individuals (57 females, 46 males) from 20 families with autosomal dominant short stature and heterozygous ACAN mutations were identified and confirmed using whole-exome sequencing, targeted next-generation sequencing, and/or Sanger sequencing. Clinical information was collected from the medical records.Results:Identified ACAN variants showed perfect cosegregation with phenotype. Adult individuals had mildly disproportionate short stature [median height, −2.8 standard deviation score (SDS); range, −5.9 to −0.9] and a history of early growth cessation. The condition was frequently associated with early-onset osteoarthritis (12 families) and intervertebral disc disease (9 families). No apparent genotype–phenotype correlation was found between the type of ACAN mutation and the presence of joint complaints. Childhood height was less affected (median height, −2.0 SDS; range, −4.2 to −0.6). Most children with ACAN mutations had advanced bone age (bone age − chronologic age; median, +1.3 years; range, +0.0 to +3.7 years). Nineteen individuals had received growth hormone therapy with some evidence of increased growth velocity.Conclusions:Heterozygous ACAN mutations result in a phenotypic spectrum ranging from mild and proportionate short stature to a mild skeletal dysplasia with disproportionate short stature and brachydactyly. Many affected individuals developed early-onset osteoarthritis and degenerative disc disease, suggesting dysfunction of the articular cartilage and intervertebral disc cartilage. Additional studies are needed to determine the optimal treatment strategy for these patients.Heterozygous ACAN mutations cause short stature with bone age acceleration and premature growth cessation and are frequently associated with early-onset osteoarthritis and degenerative disc disease.

Objective. In response to the current CDC recommendations for routine HIV testing in clinical settings, the Adolescent AIDS Program at Montefiore Medical Center in the Bronx, New York, developed the Advise, Consent, Test, Support routine HIV testing model (ACTS) in 2003. ACTS was piloted in 10 community health centers operated by Montefiore because they serve populations most at risk for HIV/AIDS. Methods. ACTS streamlined and codified the counseling and testing process, provided a routine HIV testing practice change plan, and provided training and communication materials that promoted routine HIV testing. To determine program success, we measured the number of patients seen at the clinics, the number of HIV test-eligible patients (those aged 13-64 years and not pregnant), the number and percent of patients receiving HIV testing, HIV test results, and the number of patients linked to care. Results. HIV testing in the 10 sites increased nearly threefold during the pilot period (2003-2007), from 3,944 of 49,125 eligible patients (8%) tested in 2003 to 11,212 of 55,629 eligible patients (20%) tested in 2007. With little ongoing support, the sites continued or maintained improvements: 13,226 of 56,686 eligible patients (23%) were tested in 2008, 15,965 of 57,025 eligible patients (28%) were tested in 2011, 17,483 of 60,514 eligible patients (29%) were tested in 2012, and 17,971 of 63,172 eligible patients (28%) were tested in 2013. Sites identified 433 HIV-positive patients from 2006 to 2013 (0.2%-0.6% annual seropositivity), and 96% of them were linked to care within 90 days of HIV diagnoses (range: 92% to 98% annually). Conclusion. ACTS demonstrated that substantial and sustained increases in routine HIV testing can be achieved in health-care settings, not by adding personnel or financial resources, but by using the model's practice change plan and streamlined HIV testing approach.

On July 31, 2001, the U.S. House of Representatives passed The Human Cloning Prohibition Act of 2001. The legislation proposes a complete ban on somatic cell nuclear transfer to create cloned human embryos; it threatens transgressors with criminal punishment and civil fines. House Bill 2505 is the first human cloning prohibition to pass either chamber of Congress. This note argues that the bill is unconstitutionally vague and inconsistent with the Supreme Court's recent Commerce Clause jurisprudence.

Bifid scrotum and hypospadias suggest undervirilization, yet boys presenting with these findings often do not receive a genetic diagnosis. Some of these individuals fall on the spectrum toward genital ambiguity, which often has an identifiable genetic etiology. In some cases, identifying an underlying genetic diagnosis can help optimize clinical care. The objectives of this work include characterizing current practice for genetic evaluation for patients with bifid scrotum, identifying approaches with a good diagnostic yield, as well as using whole-exome sequencing to study ten undervirilized 46,XY subjects with bifid scrotum. These studies demonstrate that the majority of individuals with bifid scrotum do not receive a genetic diagnosis on clinical workup. Over a third of subjects did not have any genetic testing, even though karyotype analysis and androgen receptor sequencing were both relatively high yield for identifying a genetic etiology. Increased utilization of traditional genetic approaches could significantly improve the ability to find a genetic diagnosis. Furthermore, using whole-exome sequencing on ten 46,XY boys with bifid scrotum identified two novel NR5A1 variants, both impacting exon 7. One of these variants demonstrated significant genotype-phenotype variability in the setting of a rare instance of paternal inheritance from an unaffected father.

We present fVDB, a novel GPU-optimized framework for deep learning on large-scale 3D data. fVDB provides a complete set of differentiable primitives to build deep learning architectures for common tasks in 3D learning such as convolution, pooling, attention, ray-tracing, meshing, etc. fVDB simultaneously provides a much larger feature set (primitives and operators) than established frameworks with no loss in efficiency: our operators match or exceed the performance of other frameworks with narrower scope. Furthermore, fVDB can process datasets with much larger footprint and spatial resolution than prior works, while providing a competitive memory footprint on small inputs. To achieve this combination of versatility and performance, fVDB relies on a single novel VDB index grid acceleration structure paired with several key innovations including GPU accelerated sparse grid construction, convolution using tensorcores, fast ray tracing kernels using a Hierarchical Digital Differential Analyzer algorithm (HDDA), and jagged tensors. Our framework is fully integrated with PyTorch enabling interoperability with existing pipelines, and we demonstrate its effectiveness on a number of representative tasks such as large-scale point-cloud segmentation, high resolution 3D generative modeling, unbounded scale Neural Radiance Fields, and large-scale point cloud reconstruction.

In late November, Judge Stuart Bernstein of the U.S. Bankruptcy Court in New York said he would , concluding a nearly year-long effort to reorganize its finances. Avaya, which spun off from Lucent Technologies in 2000, filed for bankruptcy protection in January amid a shift in its industry from hardware to software services.