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LBR (Lamin B Receptor) encodes a bifunctional protein important for cholesterol biosynthesis and heterochromatin organization on the inner nuclear membrane. Pathogenic variants in LBR are associated with marked phenotypic variability, ranging from the benign Pelger-Huet anomaly to lethal Greenberg Dysplasia. We performed trio exome sequencing (ES) on two patients with atypical variants of skeletal dysplasia and their unaffected parents. Patient 1 exhibited frontal bossing, mid-face hypoplasia, short stature with rhizomelic limb shortening, and relative macrocephaly at birth. Although remained short, Patient 1 later showed spontaneous improvement in her skeletal findings. Exome sequencing revealed two novel variants in LBR, c.1504C > G (p.Arg502Gly) in exon 12 and c.1748G > T (p.Arg583Leu) in exon 14, which were inherited from her unaffected father and mother, respectively. Sterol analysis revealed an increased level of cholesta‑8,14‑dien‑3β‑ol to 2.9% of total sterols, consistent with a functional deficiency of 3β‑hydroxysterol Δ14‑reductase. Patient 2 presented at birth with short stature and marked rhizomelic limb shortening but later exhibited decreasing severity of shortening of the long bones and improvement in the radiographic skeletal abnormalities although he continued to be significantly short at age 10 years. Exome sequencing revealed that Patient 2 is homozygous for a pathogenic variant c.1534C > T (p.Arg512Trp) in exon 12 of LBR, which was inherited from his unaffected consanguineous parents. This report provides further evidence for a phenotypic spectrum of LBR-associated disorders and expands the genotypic spectrum by describing 3 novel disease-causing variants that have not been previously associated with a disease. Moreover, our data on Patient 1 demonstrate that variants throughout the gene appear to influence both the sterol reductase and nuclear functions of LBR.

BACKGROUND AND OBJECTIVES: Intravenous (IV) hydration is used primarily in children with bronchiolitis at our institution. Because nasogastric (NG) hydration can provide better nutrition, the goal of our quality improvement (QI) initiative was to increase the rate of NG hydration in eligible children 1 to 23 months old with bronchiolitis by 20% over 6 months. METHODS: We used Plan-Do-Study-Act cycles to increase the use of NG hydration in eligible children. Interventions included educational and system-based changes and sharing parental feedback with providers. Chart reviews were performed to identify the rates of NG hydration, which were plotted over time in a statistical process control p chart. The balancing measure was the rate of complications in children with NG versus IV hydration. RESULTS: Two hundred and ninety-three children who were hospitalized with bronchiolitis needed supplemental hydration during the QI initiative (January 2016–April 2016). Ninety-one children were candidates for NG hydration, and 53 (58%) received NG hydration. The rates of NG hydration increased from a baseline of 0% pre-QI bronchiolitis season (January 2015–April 2015) to 58% during the initiative. There was no aspiration and no accidental placement of the NG tube into a child’s airway. Nine patients (17%) in the NG group had a progression of disease requiring nil per os status, and 6 of these were transferred to the PICU whereas none of those in the IV group were transferred to the PICU. Post-QI initiative, the majority of nurses (63%) and physicians (95%) stated that they are more likely to consider NG hydration in children with bronchiolitis. CONCLUSIONS: We successfully increased the rates of NG hydration in eligible children with bronchiolitis by using educational and system-based interventions.

Background Rare de novo mutations have been implicated as a significant cause of idiopathic intellectual disability. Large deletions encompassing 10p11.23 have been implicated in developmental delay, behavioural abnormalities and dysmorphic features, but the genotype–phenotype correlation was not delineated. Mutations in WAC have been recently reported in large screening cohorts of patients with intellectual disability or autism, but no full phenotypic characterisation was described. Methods Clinical and molecular characterisation of six patients with loss-of-function WAC mutations identified by whole exome sequencing was performed. Clinical data were obtained by retrospective chart review, parental interviews, direct patient interaction and formal neuropsychological evaluation. Results Five heterozygous de novo WAC mutations were identified in six patients. Three of the mutations were nonsense, and two were frameshift; all are predicted to cause loss of function either through nonsense-mediated mRNA decay or protein truncation. Clinical findings included developmental delay (6/6), hypotonia (6/6), behavioural problems (5/6), eye abnormalities (5/6), constipation (5/6), feeding difficulties (4/6), seizures (2/6) and sleep problems (2/6). All patients exhibited common dysmorphic features, including broad/prominent forehead, synophrys and/or bushy eyebrows, depressed nasal bridge and bulbous nasal tip. Posteriorly rotated ears, hirsutism, deep-set eyes, thin upper lip, inverted nipples, hearing loss and branchial cleft anomalies were also noted. Conclusions Our case series show that loss-of-function mutations in WAC cause a recognisable genetic syndrome characterised by a neurocognitive phenotype and facial dysmorphism. Our data highly suggest that WAC haploinsufficiency is responsible for most of the phenotypic features associated with deletions encompassing 10p11.23.

Objective: To examine long-term care facility (LTCF or nursing home) use and end-of-life care for individuals with Parkinson disease (PD). Methods: In this nationwide retrospective cohort study, we compared LTCF and hospice utilization among Medicare beneficiaries diagnosed with PD by demographic, clinical, and physician characteristics. We also examined the impact of outpatient neurologist care for institutionalized patients with PD on end-of-life care. Results: We identified 469,055 individuals with PD who received Medicare benefits in 2002. Nearly 25% (more than 100,000 in total) resided in an LTCF. Women with PD had greater odds of nursing facility residence (adjusted odds ratio [AOR] 1.34, 95% confidence interval [CI] 1.30–1.38) compared with men. Black individuals with PD were 34% more likely than white individuals to reside in an LTCF (AOR 1.34, 95% CI 1.30–1.38), contrary to the race patterns typically observed for LTCF use. Hip fracture (AOR 2.10, 95% CI 2.04–2.15) and dementia (AOR 4.06, 95% CI 4.00–4.12) were the strongest clinical predictors of LTCF placement. Only 33% (n = 38,334) of nursing home residents with PD had outpatient neurologist care. Eighty-four percent (n = 80,877) of LTCF residents with PD died by December 31, 2005. Hospice utilization varied little by race and sex. LTCF residents who had outpatient neurologist care were twice as likely to utilize hospice services before death (AOR 2.35, 95% CI 2.24–2.47). Conclusions and relevance: A large proportion of the Medicare PD population resides in an LTCF. There is substantial unmet need for palliative care in the PD population. Increased efforts to provide specialist care to dependent individuals with PD may improve end-of-life care.

This article is part of a Special Issue "Energy Balance". Natural populations display a variety of reproductive responses to environmental cues, but the underlying physiology that causes these responses is largely unknown. This study tested the hypothesis that heritable variation in reproductive traits can be described by heritable variation in concentrations of hormones critical to both energy balance and reproduction. To test this hypothesis, we used mouse lines derived from a wild population and selectively bred for response to short day photoperiod. Reproductive and metabolic traits of Peromyscus leucopus display heritable variation when held in short photoperiods typical of winter. Our two lines of mice have phenotypes spanning the full range of variation observed in nature in winter. We tested male and female mice for heritable variation in fasted serum concentrations of three hormones involved in energetic regulation: leptin, insulin-like growth factor 1 (IGF-1) and insulin, as well as the effects of exogenous leptin and a high energy diet on reproductive maturation. Exogenous leptin decreased food intake, but protected males from the reduction in testis mass caused by equivalent food restriction in pair-fed, saline-infused controls. A high energy diet resulted in calorie adjustment by the mice, and failed to alter reproductive phenotype. Concentrations of the three hormones did not differ significantly between selection lines but had correlations with measures of food intake, fertility, blood glucose, and/or body mass. There was evidence of interactions between reproductive traits and hormones related to energy balance and reproduction, but this study did not find evidence that variation in these hormones caused variation in reproductive phenotype.