De novo coding variants in the AGO1 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 AGO1 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. Recurrently identified variants were present in several unrelated individuals: p.(Phe180del), p.(Leu190Pro), p.(Leu190Arg), p.(Gly199Ser), p.(Val254Ile) and p.(Glu376del). AGO1 encodes the Argonaute 1 protein, which functions in gene-silencing pathways mediated by small non-coding RNAs. Three-dimensional protein structure predictions suggest that these variants might alter the flexibility of the AGO1 linker domains, which likely would impair its function in mRNA processing. Affected individuals present with intellectual disability of varying severity, as well as speech and motor delay, autistic behaviour and additional behavioural manifestations. CONCLUSION: Our study establishes that de novo coding variants in AGO1 are involved in a novel monogenic form of NDD, highly similar to the recently reported AGO2-related NDD.

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%.

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.

A Survey of Community Dermatologists Reveals the Unnecessary Impact of Trial-and-Error Behavior on the Psoriasis Biologic Treatment Paradigm.

INTRODUCTION: In the USA, psoriasis affects approximately 3% of the population and costs more than $110 billion annually. The development of targeted biologics has revolutionized psoriasis management, but at an increasing cost. According to Joint AAD/NPF guidelines, an important need exists to identify biomarkers that can predict the appropriate biologic agent for patients. METHODS: A survey of community dermatologists was developed to address (1) significant factors influencing biologic therapy utilization in psoriasis; (2) the clinical utility of a test stratifying biologic response. RESULTS: Respondents confirmed that trial and error leads to frequent biologic switching. The survey indicated that 82% of dermatologists switch 10-30% of their patients in the first year and 98% switch intra-class for at least 50% of non-responding patients. The trial and error is due, in part, to formularies influencing the physician 77% of the time, with only 14% reporting that their first choice and the formulary alignment is greater than 75%. Compounding trial and error, 93% of the physicians report that they wait at least 12 weeks before determining non-response, in alignment with AAD/NPF guidelines. The lack of precision medicine and this trial-and-error approach result in unnecessary wasted spending and suboptimal patient outcomes. After being given an overview of Mind.Px, a dermal biomarker patch used to predict therapeutic response to a biologic class, survey participants expressed that: 93% would utilize Mind.Px results to determine first-line therapy even if this differed from initial clinical choice 100% would utilize Mind.Px if part of the prior authorization process 98% say Mind.Px would improve patient outcomes 81% reported Mind.Px would help with prior authorization process CONCLUSIONS: Surveyed dermatologists believe a test that predicts psoriasis treatment response to a class of biologic drugs would lessen trial and error, provide a tool for physicians to make more informed decisions about drug selection, improve patient outcomes, and significantly reduce wasted spending.

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. How the application may differ in outpatient environments is also discussed. In particular, the patient role is much more central, and a strong collaborative engagement with the patient is likely necessary to achieve high reliability. Applying reliability principles to patient-centered processes is a critical and undeveloped area.

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. PI admitted to our NICU between 2006 and 2015 were monitored for feeding of HM, DHM, and preterm formula (PF), frequency of early feedings, and incidence of NEC. RESULTS: Retrospective review of 2557 cases revealed post-initiative increases in the percentage of PI receiving HM (91.5% to 96.1%), HM within 48 hours of birth (75% to 90.6%), and DHM (17.7% to 71.9%). The percentage of infants receiving feedings on day one increased from 23.9% to 44.6% while the percentage receiving PF within the first 72 hours declined (31.2% to 10.3%). The NEC rate declined from 4.1% to 0.4%. Reduction in NEC occurred despite a simultaneous increase in perinatal antibiotic exposure and the universal but late administration of bovine HM fortifier. The improvement associated with the decrease in NEC included initiation of probiotic administration, a reduction in PF feeding, and improvements in milk preparation, storage, and fortification processes. CONCLUSIONS: Early exclusive feedings of HM and avoidance of PF together with probiotics and milkhygiene may decrease NEC in PI. Neither brief perinatal antibiotic exposure nor late introduction of bovine fortifiers appears detrimental in this context.

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. More resources are required in the 2 remaining strata to attain patient-centered, collaborative care. Because the planned-care management strategy is behaviorally sophisticated, it is likely to be more efficient and effective than strategies based on concepts of disease management that focus on either a single disease or groupings of patients who are "high utilizers" of healthcare. We conclude that modern technologies and related approaches make resource planning for patient-centered, collaborative care feasible and desirable.

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. Furthermore, the compound reported here is the first ATP-competitive mTOR inhibitor described to show efficacy in a semitherapeutic collagen induced arthritis (CIA) mouse model.

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 (Dh ) is estimated for the ellipse (Dh = 1.4a) or rectangle (Dh = 2a). Use of these equations often gives a more accurate estimate of the hydraulic diameter of a pore or conduit than does averaging the lengths of the short and long axes (Dh = [a + b]/2, b is the long axis) or assuming that the opening is circular (Dh = a). A table of the error in each method is included, and the errors inherent in the use of Dh are discussed. Because fewer measurements are required, estimation based on the measurement of one axis is much faster than calculation using both the short and long axes. The equations and table should permit anatomists and physiologists to rapidly determine the best method for estimating the hydraulic diameter of a pore or conduit, and to more accurately and quickly estimate the hydraulic diameters of large numbers of openings. However, because of potential pitfalls in applying theoretical fluid dynamics equations to real-world functional anatomy, botanists must ensure that their applications of hydraulic diameter are appropriate in each case.

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.

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. These findings were confirmed with fetal and postnatal magnetic resonance imaging.

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.(3,4) We report on 3 new cases of KCNQ2 encephalopathy diagnosed in the neonatal period and studied with continuous video-EEG recording. We describe a distinct electroclinical phenotype and report on efficacy of antiepileptic drug (AED) therapies.

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. This review will address guidelines for nurse case managers and providers regarding initiating anticoagulation treatment and monitoring prothrombin time and international normalized ratio. Information will also be provided regarding when the nurse case manager should notify the providers to establish target international normalized ratio. This review will also provide educational tools to serve as standards for patient teaching, including drug and food interactions. PRIMARY PRACTICE SETTING(S): This article applies to adult ambulatory practice that includes primary care, cardiology, and vascular and surgical settings. IMPLICATIONS FOR CASE MANAGEMENT PRACTICE: The complexity of managing anticoagulation in ambulatory practice warrants case management. The nurse case manager will establish a rapport with patients to improve compliance, providing patient education about diet, dosages, and drug interactions to reduce medication errors and bleeding complications. This review on anticoagulation management will assist nurse case managers and providers to provide better 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) = 0.82) between P and P(app), whereas the uptake of more lipophilic compounds seems to be influenced by both P(app) and brain free fraction. A nonlinear relationship is observed between logP(oct) and P over the 6 orders of magnitude range in lipophilicity studied. These findings corroborate recent reports in the literature that brain penetration is a function of both rate and extent of drug uptake into the CNS.