coding variants in the gene cause a neurodevelopmental disorder with intellectual disability.

Background: High-impact pathogenic variants in more than a thousand genes are involved in Mendelian forms of neurodevelopmental disorders (NDD).

Methods: This study describes the molecular and clinical characterisation of 28 probands with NDD harbouring heterozygous coding variants, occurring de novo for all those whose transmission could have been verified (26/28).

Results: A total of 15 unique variants leading to amino acid changes or deletions were identified: 12 missense variants, two in-frame deletions of one codon, and one canonical splice variant leading to a deletion of two amino acid residues.

Reduced Necrotizing Enterocolitis after an Initiative to Promote Breastfeeding and Early Human Milk Administration.

Introduction: We sought to reduce the incidence of necrotizing enterocolitis (NEC) in premature infants (PI) by fostering the postnatal establishment of protective intestinal bacteria through early administration of human milk (HM) and probiotics.

Methods: A multidisciplinary team implemented an initiative to support breastfeeding (BF) and provide early postnatal supplemental donor human milk (DHM) and probiotics to PI. Interventions included process improvements in milk preparation, storage, and fortification.

CZ415, a Highly Selective mTOR Inhibitor Showing in Vivo Efficacy in a Collagen Induced Arthritis Model.

CZ415, a potent ATP-competitive mTOR inhibitor with unprecedented selectivity over any other kinase is described. In addition to a comprehensive characterization of its activities in vitro, in vitro ADME, and in vivo pharmacokinetic data are reported. The suitability of this inhibitor for studying in vivo mTOR biology is demonstrated in a mechanistic mouse model monitoring mTOR proximal downstream phosphorylation signaling.

KCNQ2 encephalopathy: delineation of the electroclinical phenotype and treatment response.

Neonatal-onset epilepsies are rare conditions, mostly genetically determined, that can have a benign or severe phenotype.(1,2) There is recent recognition of de novo KCNQ2 mutations in patients with severe neonatal-onset epilepsy with intractable seizures and severe psychomotor impairment, termed KCNQ2 encephalopathy.(3,4) This is a rare condition and all patients reported so far were diagnosed well after the neonatal period.

Identification of clinical isolates of α-hemolytic streptococci by 16S rRNA gene sequencing, matrix-assisted laser desorption ionization-time of flight mass spectrometry using MALDI Biotyper, and conventional phenotypic methods: a comparison.

Fifty-six α-hemolytic streptococcal isolates were identified using MALDI Biotyper MS (Bruker Daltonics), API 20 Strep (bioMérieux), and BD Phoenix (Becton, Dickinson). The gold standard for identification was 16S rRNA gene sequence analysis with 16S-23S rRNA intergenic spacer sequencing. The following percentages of isolates were correctly identified to the species level: MALDI Biotyper, 46%; BD Phoenix, 35%; and API 20 Strep, 26%.

Usability testing of a Smartphone for accessing a web-based e-diary for self-monitoring of pain and symptoms in sickle cell disease.

We examined the usability of smartphones for accessing a web-based e-Diary for self-monitoring symptoms in children and adolescents with sickle cell disease (SCD). One group of participants (n = 10; mean age, 13.1 ± 2.

Discovery of GSK1997132B a novel centrally penetrant benzimidazole PPARγ partial agonist.

The peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated nuclear receptor, thought to play a role in energy metabolism, glucose homeostasis and microglia-mediated neuroinflammation. A novel benzimidazole series of centrally penetrant PPARγ partial agonists has been identified. The optimization of PPARγ activity and in vivo pharmacokinetics leading to the identification of GSK1997132B a potent, metabolically stable and centrally penetrant PPARγ partial agonist, is described.

Making patient-centered care reliable.

Multiple reports have concluded that healthcare does not reliably meet patient needs and can even cause harm. The Institute for Healthcare Improvement (IHI) has adapted reliability principles and methods from other industries and applied them in healthcare with promising results in hospital settings. This article describes how one outpatient system successfully applied the IHI reliability methods to multiple clinical and administrative processes.

Anticoagulation in ambulatory care: an evidence-based review of the literature.

Unlabelled: PURPOSE OF THE MANUSCRIPT: Anticoagulation is warranted for the treatment of various disorders including cardiac, vascular, and postsurgical causes. Many centers have nurse case managers to coordinate care for patients on anticoagulation. This increases the demand for specific guidelines to assist nurse case managers to ensure quality of care.

Central nervous system drug disposition: the relationship between in situ brain permeability and brain free fraction.

The dispositions of 50 marketed central nervous system (CNS) drugs into the brain have been examined in terms of their rat in situ (P) and in vitro apparent membrane permeability (P(app)) alongside lipophilicity and free fraction in rat brain tissue. The inter-relationship between these parameters highlights that both permeability and brain tissue binding influence the uptake of drugs into the CNS. Hydrophilic compounds characterized by low brain tissue binding display a strong correlation (R(2) = 0.

Resource planning for patient-centered, collaborative care.

In this article, we use self-reported information from 13,271 older adults and the results from several controlled trials to construct a planned-care management strategy that cuts across diseases and conditions and also addresses health disparities attributed to low socioeconomic status. Three strata result from the interaction of patients' financial status, the presence or absence of bothersome pain and psychosocial problems, and their confidence with self-care. A majority of ambulatory patients generally fall in the first stratum.

Hydranencephaly owing to twin-twin transfusion: serial fetal ultrasonography and magnetic resonance imaging findings.

We report a newborn girl with hydranencephaly. In the setting of a monochorionic twin pregnancy, one twin's demise was detected by ultrasonography at 18 weeks of gestation, apparently the result of a twin-twin transfusion. In the surviving twin, the evolution of ventriculomegaly, first noted at 18 weeks, to hydranencephaly at 27 weeks is documented by serial sonograms.

Unilateral schizencephaly and contralateral polymicrogyria associated with umbilical cord mass.

We report a 6-month-old boy with diffuse hypertonia and developmental delay who had unilateral separated-lip schizencephaly and contralateral polymicrogyria. The contralateral polymicrogyria was associated with an incomplete clefting in that hemisphere. An umbilical cord hamartoma is presumed to have caused hypoperfusion to the early developing brain, resulting in bilateral lesions.

The identification of clinical candidate SB-480848: a potent inhibitor of lipoprotein-associated phospholipase A2.

Modification of the pyrimidone 5-substituent in clinical candidate SB-435495 has given a series of inhibitors of recombinant lipoprotein-associated phospholipase A(2) with sub-nanomolar potency. Cyclopentyl fused derivative 21, SB-480848, showed an enhanced in vitro and in vivo profile versus SB-435495 and has been selected for progression to man.

The discovery of SB-435495. A potent, orally active inhibitor of lipoprotein-associated phospholipase A(2) for evaluation in man.

The introduction of a functionalised amido substituent into a series of 1-(biphenylmethylacetamido)-pyrimidones has given a series of inhibitors of recombinant lipoprotein-associated phospholipase A(2) with sub-nanomolar potency and very encouraging developability properties. Diethylaminoethyl derivative 32, SB-435495, was selected for progression to man.

MEASURING THE HYDRAULIC DIAMETER OF A PORE OR CONDUIT.

A method for estimating the hydraulic diameter of a pore or conduit having a noncircular opening is presented with special reference to plant anatomy. An ellipse or a rectangle is inscribed within the opening, and the length of the short axis (a) is measured. The hydraulic diameter (D ) is estimated for the ellipse (D = 1.