New insights into pemphigoid diseases

Abstract

Pemphigus and pemphigoid diseases are organ-specific autoimmune blistering diseases (AIBD), characterized and caused by autoantibodies to structural components of the skin (1). The autoantigens targeted in pemphigus are desmoglein 1 and 3, two proteins of the desmosomal structure, while the autoantigens in pemphigoid diseases (PD) are components of the basal membrane. For example, bullous pemphigoid (BP), the most frequent PD is characterized by autoantibodies against type XVII collagen (COL17, BP180) and BP230, and epidermolysis bullosa acquisita (EBA) is caused by autoantibodies against type VII collagen (COL7).

This article is protected by copyright. All rights reserved.

http://ift.tt/2iBUEv3

Temple syndrome as a differential diagnosis to Prader–Willi syndrome: Identifying three new patients

The two imprinting syndromes Temple syndrome (TS14) and Prader–Willi syndrome (PWS) share many features in infancy and childhood. TS14 is an important, yet often neglected, differential diagnosis to PWS. We wanted to assess the frequency of TS14 among patients tested for PWS. In all samples submitted to our lab for genetic PWS testing during 2014 and 2015, we consecutively conducted additional analyses for TS14. A total of 143 samples were included. The most frequent indications for testing were developmental delay, overweight, and hypotonia. For TS14 testing, we performed a methylation-sensitive MLPA-kit detecting deletions and methylation aberrations in chromosomal region 14q32. TS14 was confirmed in 3 out of 143 patients (2.1%). In comparison, PWS was also confirmed in three patients. Brief clinical descriptions of the TS14 patients are presented. Temple syndrome is presumably underdiagnosed, and should be considered when testing children for PWS.

http://ift.tt/2iDh2nZ

Mosaic uniparental disomy results in GM1 gangliosidosis with normal enzyme assay

Inherited metabolic disorders are traditionally diagnosed using broad and expensive panels of screening tests, often including invasive skin and muscle biopsy. Proponents of next-generation genetic sequencing have argued that replacing these screening panels with whole exome sequencing (WES) would save money. Here, we present a complex patient in whom WES allowed diagnosis of GM1 gangliosidosis, caused by homozygous GLB1 mutations, resulting in β-galactosidase deficiency. A 10-year-old girl had progressive neurologic deterioration, macular cherry-red spot, and cornea verticillata. She had marked clinical improvement with initiation of the ketogenic diet. Comparative genomic hybridization microarray showed mosaic chromosome 3 paternal uniparental disomy (UPD). GM1 gangliosidosis was suspected, however β-galactosidase assay was normal. Trio WES identified a paternally-inherited pathogenic splice-site GLB1 mutation (c.75+2dupT). The girl had GM1 gangliosidosis; however, enzymatic testing in blood was normal, presumably compensated for by non-UPD cells. Severe neurologic dysfunction occurred due to disruptive effects of UPD brain cells.

http://ift.tt/2AYiF64

Whole exome sequencing reveals a mutation in ARMC9 as a cause of mental retardation, ptosis, and polydactyly

Intellectual disability (ID) refers to deficits in mental abilities, social behavior, and motor skills to perform activities of daily living as compared to peers. Numerous genetic and environmental factors may be responsible for ID. We report on elucidation of molecular basis for syndromic ID associated with ptosis, polydactyly, and MRI features suggestive of Joubert syndrome using homozygosity mapping followed by exome sequencing. The analysis revealed a novel synonymous variation p.T293T (c.879G>A) which leads to a splicing defect in ARMC9 gene. The variant is present in conserved region of ARM domain of ARMC9 protein, which is predicted to form a platform for protein interaction. This domain is likely to be altered in patient due to splicing defect caused by this synonymous variation. Our report of variant in ARMC9 Leading to Joubert syndrome phenotype (JS30), elucidates the genetic heterogeneity of Joubert syndrome, and expands the gene list for ciliopathies.

http://ift.tt/2iDazJI

Kaufman oculocerebrofacial syndrome: Novel UBE3B mutations and clinical features in four unrelated patients

The "blepharophimosis-mental retardation" syndromes (BMRS) consist of a group of clinically and genetically heterogeneous congenital malformation syndromes, where short palpebral fissures and intellectual disability associate with a distinct set of other morphological features. Kaufman oculocerebrofacial syndrome represents a rare and recently reevaluated entity within the BMR syndromes and is caused by biallelic mutations of UBE3B. Affected individuals typically show microcephaly, impaired somatic growth, gastrointestinal and genitourinary problems, ectodermal anomalies and a characteristic face with short, upslanted palpebral fissures, depressed nasal bridge. and anteverted nares. Here we present four patients with five novel UBE3B mutations and propose the inclusion of clinical features to the characteristics of Kaufman oculocerebrofacial syndrome, including prominence of the cheeks and limb anomalies.

http://ift.tt/2AYiCqU

MED13L loss-of-function variants in two patients with syndromic Pierre Robin sequence

We report two unrelated patients with Pierre Robin sequence (PRS) and a strikingly similar combination of associated features. Whole exome sequencing was performed for both patients. No single gene containing likely pathogenic point mutations in both patients could be identified, but the finding of an essential splice site mutation in mediator complex subunit 13 like (MED13L) in one patient prompted the investigation of copy number variants in MED13L in the other, leading to the identification of an intragenic deletion. Disruption of MED13L, encoding a component of the Mediator complex, is increasingly recognized as the cause of an intellectual disability syndrome with associated facial dysmorphism. Our findings suggest that MED13L–related disorders are a possible differential diagnosis for syndromic PRS.

http://ift.tt/2iBdxyh

FGFR1 disruption identified by whole genome sequencing in a male with a complex chromosomal rearrangement and hypogonadotropic hypogonadism

http://ift.tt/2AYiyHG

Discordant fetal phenotype of hypophosphatasia in two siblings

Hypophosphatasia (HPP) is an autosomal recessive metabolic disorder with impaired bone mineralization due to mutations in the ALPL gene. The genotype-phenotype correlation of this disorder has been widely described. Here, we present two affected siblings, whose fetal phenotypes were discordant. A 31-year-old Japanese woman, G0P0, was referred to our institution because of fetal micromelia. After obstetric counseling, the pregnancy was terminated at 21 weeks' gestation. Post-mortem radiographs demonstrated severely defective mineralization of the skeleton. The calvarial, spinal, and tubular bones were mostly missing. Only the occipital bones, mandible, clavicles, ribs, one thoracic vertebra, ilia, and tibia were relatively well ossified. The radiological findings suggested lethal HPP. Genetic testing for genomic DNA extracted from the umbilical cord identified compound heterozygous mutations in the ALPL gene (c.532T>C, p.Y178H; c.1559delT, p.Leu520Argfs*86). c.532T>C was a novel variant showing no residual activity of the protein by the functional analysis. The parents were heterozygous carriers. In the next pregnancy, biometric values on fetal ultrasonography at 20 and 26 weeks' gestation were normal. At 34 weeks, however, a small chest and shortening of distal long bones came to attention. The neonate delivered at 41 weeks showed serum ALP of <5U/L. Radiological examination showed only mild thoracic hypoplasia and metaphyseal mineralization defects of the long bones. ALP replacement therapy was introduced shortly after birth, and the neonate was discharged at day 22 without respiratory distress. Awareness of discordant fetal phenotypes in siblings with HPP precludes a diagnostic error, and enables early medical intervention to mildly affected neonates.

http://ift.tt/2iDbM3q

Less common underlying genetic diagnoses found in a cohort of 139 individuals surgically corrected for craniosynostosis

http://ift.tt/2AYisji

Response to: “In reply to: ‘Mast Cell Disorders in Ehlers–Danlos Syndrome’ (Jaime Vengoechea, Department of Human Genetics, Emory University)”

http://ift.tt/2iBPZsQ

Parental education accounts for variability in the IQs of probands with Down syndrome: A longitudinal study

Recent work has demonstrated that variability in probands' phenotypes, including physical features, cognitive abilities, social functioning, and other developmental domains, is influenced by parental traits. Here we examine the role of parental education as a factor contributing to the variability of intelligence quotient (IQ) of offspring with trisomy 21. Participants were 43 probands with trisomy 21, aged 4–21 years of age, and their parents. Data were collected on parental education, and a bi-parental mean education score (BMES) was calculated. Probands' cognitive abilities were assessed by the Stanford-Binet 4th edition at baseline (T1), and again 24 months later (T2). Probands were placed into one of two age groups: 4–12 years and 13–21 years. Results indicated higher parent-proband correlations in Age Group 2 (mean r = .47) relative to Age Group 1 (mean r = .33) and increasing parent-proband correlations across time, with mean correlations of Age Group 1, T1: r = .26, T2: 39; Age Group 2 T1: r = .49, T2: r = 46. Despite the expected IQ deficits observed in trisomy 21 probands, parental education may still contribute to the variability of probands' cognitive abilities. These findings are consistent with the literature noting increasing heritability of IQ with development.

http://ift.tt/2AYzcqM

Tarsal-carpal coalition syndrome: Report of a novel missense mutation in NOG gene and phenotypic delineation

We report a family of Indian origin presenting with Tarsal-carpal coalition syndrome (TCC), which is a rare genetic disorder of skeletal abnormalities, inherited in autosomal dominant manner. In this family, three individuals (mother and two children) were found to be similarly affected with slight intrafamilial individual variability in the phenotype. Sanger sequencing revealed a novel heterozygous missense mutation in NOG gene (NM_005450.4:c.611G>A) in all the affected individuals of the family. Until now only six mutations have been reported in different families affected with TCC syndrome worldwide. This report further delineates the phenotypic spectrum of this rare disorder with the addition of a new variant to the mutation spectrum.

http://ift.tt/2iDadCS

Orthopaedic manifestations within the 22q11.2 Deletion syndrome: A systematic review

The 22q11.2 Deletion Syndrome (22q11.2DS) is the most common microdeletion syndrome with an estimated prevalence of 1:4,000 live births. 22q11.2DS is known to have wide phenotypic variability, including orthopaedic manifestations. The purpose of this systematic review is to increase the awareness of orthopaedic manifestations associated with 22q11.2DS. This systematic review was performed according to the PRISMA Guidelines. Original epidemiological studies on the prevalence of orthopaedic manifestations within 22q11.2DS were systematically searched for in PubMed and EMBASE. The included articles were scored according to a risk-of-bias tool, a best-evidence synthesis was performed and the prevalence data was extracted. Sixty-nine published manuscripts described 58 orthopaedic manifestations in a total of 6,055 patients. The prevalence of at least one cervical or occipital anomaly is 90.5–100% (strong evidence). Fourteen studies (n = 2,264) revealed moderate evidence for a wide scoliosis prevalence of 0.6–60%. Two studies demonstrated that 5–6.4% of all 22q11.2DS patients required surgical scoliosis correction. Fifteen studies (n = 2,115) reported a 1.1–13.3% prevalence of clubfoot with moderate evidence. Other reported orthopaedic manifestations are patellar dislocation (10–20%), juvenile rheumatic arthritis (3.75%), impaired growth and skeletal anomalies like polydactyly (1.0–3.7%), syndactyly (11–11.8%), butterfly vertebrae (11.1%) and 13 ribs (2–19%). Orthopaedic findings are important manifestations of the 22q11.2DS, both in bringing patients to diagnostic attention and in requiring surveillance and appropriate intervention. Data on these manifestations are scattered and incomprehensive. Routinely screening for cervical anomalies, scoliosis, and upper and lower limb malformations is recommended in this vulnerable group of patients.

http://ift.tt/2AYsHED

Summary of the first inaugural joint meeting of the International Consortium for scoliosis genetics and the International Consortium for vertebral anomalies and scoliosis, March 16–18, 2017, Dallas, Texas

Scoliosis represents the most common musculoskeletal disorder in children and affects approximately 3% of the world population. Scoliosis is separated into two major phenotypic classifications: congenital and idiopathic. Idiopathic scoliosis is defined as a curvature of the spine of 10° or greater visualized on plane radiograph and does not have associated vertebral malformations (VM). "Congenital" scoliosis (CS) due to malformations in vertebrae is frequently associated with other birth defects. Recently, significant advances have been made in understanding the genetic basis of both conditions. There is evidence that both conditions are etiologically related. A 2-day conference entitled "Genomic Approaches to Understanding and Treating Scoliosis" was held at Scottish Rite Hospital for Children in Dallas, Texas, to synergize research in this field. This first combined, multidisciplinary conference featured international scoliosis researchers in basic and clinical sciences. A major outcome of the conference advancing scoliosis research was the proposal and subsequent vote in favor of merging the International Consortium for Vertebral Anomalies and Scoliosis (ICVAS) and International Consortium for Scoliosis Genetics (ICSG) into a single entity called International Consortium for Spinal Genetics, Development, and Disease (ICSGDD). The ICSGDD is proposed to meet annually as a forum to synergize multidisciplinary spine deformity research.

http://ift.tt/2iDa4iO

Marked yield of re-evaluating phenotype and exome/target sequencing data in 33 individuals with intellectual disabilities

The diagnosis of intellectual disability/developmental delay (ID/DD) benefits from the clinical application of target/exome sequencing. The yield in Mendelian diseases varies from 25% to 68%. The aim of the present study was to identify the genetic causes of 33 ID/DD patients using target/exome sequencing. Recent studies have demonstrated that reanalyzing undiagnosed exomes could yield additional diagnosis. Therefore, in addition to the normal data analysis, in this study, re-evaluation was performed prior to manuscript preparation after updating OMIM annotations, calling copy number variations (CNVs) and reviewing the current literature. Molecular diagnosis was obtained for 19/33 patients in the first round of analysis. Notably, five patients were diagnosed during the re-evaluation of the geno/phenotypic data. This study confirmed the utility of exome sequencing in the diagnosis of ID/DD. Furthermore, re-evaluation leads to a 15% improvement in diagnostic yield. Thus, to maximize the diagnostic yield of next-generation sequencing (NGS), periodical re-evaluation of the geno/phenotypic data of undiagnosed individuals is recommended by updating the OMIM annotation, applying new algorithms, reviewing the literature, sharing pheno/genotypic data, and re-contacting patients.

http://ift.tt/2AYsC3N

Maternal inheritance of BDNF deletion, with phenotype of obesity and developmental delay in mother and child

Childhood obesity is a significant world health problem. Understanding the genetic and environmental factors contributing to the development of obesity in childhood is important for the rational design of strategies for obesity prevention and treatment. Brain-derived neurotrophic factor (BDNF) plays an important role in the growth and development of the central nervous system, there is also an evidence that BDNF plays a role in regulation of appetite. Disruption of the expression of this gene in a child has been previously reported to result in a phenotype of severe obesity, hyperphagia, impaired cognitive function, and hyperactivity. We report a mother and child, both with micro-deletions encompassing the BDNF gene locus, who both have obesity and developmental delay, although without hyperactivity. This report highlights the maternal inheritance of a rare genetic cause of childhood obesity.

http://ift.tt/2iBOv1X

Relationship between socioeconomic status and HIV infection: findings from a survey in the Free State and Western Cape Provinces of South Africa

Background

Studies have shown a mixed association between socioeconomic status (SES) and prevalent HIV infection across and within settings in sub-Saharan Africa. In general, the relationship between years of formal education and HIV infection changed from a positive to a negative association with maturity of the HIV epidemic. Our objective was to determine the association between SES and HIV in women of reproductive age in the Free State (FSP) and Western Cape Provinces (WCP) of South Africa (SA).

Study design

Cross-sectional.

Setting

SA.

Methods

We conducted secondary analysis on 1906 women of reproductive age from a 2007 to 2008 survey that evaluated effectiveness of Prevention of Mother-to-Child HIV Transmission Programmes. SES was measured by household wealth quintiles, years of formal education and employment status. Our analysis principally used logistic regression for survey data.

Results

There was a significant negative trend between prevalent HIV infection and wealth quintile in WCP (P<0.001) and FSP (P=0.025). In adjusted analysis, every additional year of formal education was associated with a 10% (adjusted OR (aOR) 0.90 (95% CI 0.85 to 0.96)) significant reduction in risk of prevalent HIV infection in WCP but no significant association was observed in FSP (aOR 0.99; 95% CI 0.89 to 1.11). There was no significant association between employment and prevalent HIV in each province: (aOR 1.54; 95% CI 0.84 to 2.84) in WCP and (aOR 0.96; 95% CI 0.71 to 1.30) in FSP.

Conclusion

The association between HIV infection and SES differed by province and by measure of SES and underscores the disproportionately higher burden of prevalent HIV infection among poorer and lowly educated women. Our findings suggest the need for re-evaluation of whether current HIV prevention efforts meet needs of the least educated (in WCP) and the poorest women (both WCP and FSP), and point to the need to investigate additional or tailored strategies for these women.

http://ift.tt/2zm6Gmy

Sensitivity analysis for mistakenly adjusting for mediators in estimating total effect in observational studies

Objectives

In observational studies, epidemiologists often attempt to estimate the total effect of an exposure on an outcome of interest. However, when the underlying diagram is unknown and limited knowledge is available, dissecting bias performances is essential to estimating the total effect of an exposure on an outcome when mistakenly adjusting for mediators under logistic regression. Through simulation, we focused on six causal diagrams concerning different roles of mediators. Sensitivity analysis was conducted to assess the bias performances of varying across exposure-mediator effects and mediator-outcome effects when adjusting for the mediator.

Setting

Based on the causal relationships in the real world, we compared the biases of varying across the effects of exposure-mediator with those of varying across the effects of mediator-outcome when adjusting for the mediator. The magnitude of the bias was defined by the difference between the estimated effect (using logistic regression) and the total effect of the exposure on the outcome.

Results

In four scenarios (a single mediator, two series mediators, two independent parallel mediators or two correlated parallel mediators), the biases of varying across the effects of exposure-mediator were greater than those of varying across the effects of mediator-outcome when adjusting for the mediator. In contrast, in two other scenarios (a single mediator or two independent parallel mediators in the presence of unobserved confounders), the biases of varying across the effects of exposure-mediator were less than those of varying across the effects of mediator-outcome when adjusting for the mediator.

Conclusions

The biases were more sensitive to the variation of effects of exposure-mediator than the effects of mediator-outcome when adjusting for the mediator in the absence of unobserved confounders, while the biases were more sensitive to the variation of effects of mediator-outcome than those of exposure-mediator in the presence of an unobserved confounder.

http://ift.tt/2mNryxl

Classroom Promotion of Oral Language (CPOL): protocol for a cluster randomised controlled trial of a school-based intervention to improve childrens literacy outcomes at grade 3, oral language and mental health

Introduction

Oral language and literacy competence are major influences on children's developmental pathways and life success. Children who do not develop the necessary language and literacy skills in the early years of school then go on to face long-term difficulties. Improving teacher effectiveness may be a critical step in lifting oral language and literacy outcomes. The Classroom Promotion of Oral Language trial aims to determine whether a specifically designed teacher professional learning programme focusing on promoting oral language can lead to improved teacher knowledge and practice, and advance outcomes in oral language and literacy for early years school children, compared with usual practice.

Methods and analysis

This is a two-arm cluster multisite randomised controlled trial conducted within Catholic and Government primary schools across Victoria, Australia. The intervention comprises 4 days of face-to-face professional learning for teachers and ongoing implementation support via a specific worker. The primary outcome is reading ability of the students at grade 3, and the secondary outcomes are teacher knowledge and practice, student mental health, reading comprehension and language ability at grade 1; and literacy, writing and numeracy at grade 3. Economic evaluation will compare the incremental costs of the intervention to the measured primary and secondary outcomes.

Ethics and dissemination

This trial was approved by the Monash University Human Research Ethics Committee #CF13/2634-2013001403 and later transferred to the University of Melbourne #1545540. The investigators (including Government and Catholic partners) will communicate trial results to stakeholders, collaborators and participating schools and teachers via appropriate presentations and publications.

Trial registration number

ISRCTN77681972; Pre-results.

http://ift.tt/2mNmYPu

Data quality and 30-day survival for out-of-hospital cardiac arrest in the UK out-of-hospital cardiac arrest registry: a data linkage study

Objectives

The Out-of-Hospital Cardiac Arrest Outcomes (OHCAO) project aims to understand the epidemiology and outcomes of out-of-hospital cardiac arrest (OHCA) across the UK. This data linkage study is a subproject of OHCAO. The aim was to establish the feasibility of linking OHCAO data to National Health Service (NHS) patient demographic data and Office for National Statistics (ONS) date of death data held on the NHS Personal Demographics Service (PDS) database to improve OHCAO demographic data quality and enable analysis of 30-day survival from OHCA.

Design and setting

Data were collected from 1 January 2014 to 31 December 2014 as part of a prospective, observational study of OHCA attended by 10 English NHS Ambulance Services. 28 729 OHCA cases had resuscitation attempted by Emergency Medical Services and were included in the study. Data linkage was carried out using a data linkage service provided by NHS Digital, a national provider of health-related data. To assess data linkage feasibility a random sample of 3120 cases was selected. The sample was securely transferred to NHS Digital to be matched using OHCAO patient demographic data to return previously missing demographic data and provide ONS date of death data.

Results

A total of 2513 (80.5%) OHCAO cases were matched to patients in the NHS PDS database. Using the linkage process, missing demographic data were retrieved for 1636 (72.7%) out of 2249 OHCAO cases that had previously incomplete demographic data. Returned ONS date of death data allowed analysis of 30-day survival status. The results showed a 30-day survival rate of 9.3%, reducing unknown survival status from 46.1% to 8.5%.

Conclusions

In this sample, data linkage between the OHCAO registry and NHS PDS database was shown to be feasible, improving demographic data quality and allowing analysis of 30-day survival status.

http://ift.tt/2mNr76b

Protocol: a cluster randomised control trial study exploring stigmatisation and recovery-based perspectives regarding mental illness and substance use problems among primary healthcare providers across Toronto, Ontario

Introduction

Primary care settings are often the first and only point of contact for persons with mental health and/or substance use problems. However, staff experience and training in this area are often limited. These factors as well as a multitude of other components such as structural and systemic stigma experienced by staff can lead to clients being stigmatised, leading to poorer outcomes. By developing a comprehensive intervention for primary care staff working at community health centres (CHCs) aimed at reducing stigma towards people with mental health and substance use problems (MHSUP), we sought to test an innovative and contact-based intervention consisting of staff training, raising awareness, a recovery-focused art programme and an analysis of internal policies and procedures. All of these components can inform and support staff so they can provide better care for people who are experiencing MHSUP. CHC staff members and clients will be included in this project as active participants.

Methods and analysis

This mixed-methods project will consist of repeated surveys of staff and clients, as well as in-depth, semistructured interviews with a sample of clients and staff. A cluster randomised control trial design will test the effectiveness of an antistigma intervention for CHCs in Toronto, Canada. Six CHCs—three receiving the intervention and three controls—will be included in the study. Using a variety of measures, including the Opening Minds Scale for Health Care Providers (OMS-HC), Mental Illness: Clinicians Attitudes (MICA) Scale, Modified Bogardus Social Distance Scale, Perceived Devaluation-Discrimination Scale, Discrimination Experience subscale of the Internalized Stigma of Mental Illness (ISMI) Scale and the Recovery Assessment Scale (RAS), we hope to gain a thorough understanding of staff members' attitudes and beliefs and clients' perceptions of staff beliefs and behaviours. In-depth interviews will reveal important themes related to clients' experiences of stigma both within and outside the healthcare setting.

Ethics and dissemination

If demonstrated to be successful, this intervention can be used as a model for future initiatives aimed at reducing MHSUP-related stigma among healthcare providers in an organisational context. Adapting this work in other settings is a key strategic goal of this project. The project will also advance knowledge about stigma reduction and the experience of encountering stigma within a healthcare setting.

Trial registration

NCT03043417; Post-results.

http://ift.tt/2zlx93B

Functional visual fields: a cross-sectional UK study to determine which visual field paradigms best reflect difficulty with mobility function

Objectives

To develop an appropriate method of assessing visual field (VF) loss which reflects its functional consequences, this study aims to determine which method(s) of assessing VF best reflect mobility difficulty.

Setting

This cross-sectional observational study took place within a single primary care setting. Participants attended a single session at a University Eye Clinic, Cambridge, UK, with data collected by a single researcher (HS), a qualified optometrist.

Participants

50 adult participants with peripheral field impairment were recruited for this study. Individuals with conditions not primarily affecting peripheral visual function, such as macular degeneration, were excluded from the study.

Primary and secondary outcome measures

Participants undertook three custom and one standard binocular VF tests assessing VF to 60°, and also integrated monocular threshold 24–2 visual fields (IVF). Primary VF outcomes were average mean threshold, percentage of stimuli seen and VF area. VF outcomes were compared with self-reported mobility function assessed with the Independent Mobility Questionnaire, and time taken and patient acceptability were also considered. Receiver operating characteristic (ROC) curves determined which tests best predicted difficulty with mobility tasks.

Results

Greater VF loss was associated with greater self-reported mobility difficulty with all field paradigms (R²0.38–0.48, all P<0.001). All four binocular tests were better than the IVF at predicting difficulty with at least three mobility tasks in ROC analysis. Mean duration of the tests ranged from 1 min 26 s (±9 s) for kinetic assessment to 9 min 23 s (±24 s) for IVF.

Conclusions

The binocular VF tests extending to 60° eccentricity all relate similarly to self-reported mobility function, and slightly better than integrated monocular VFs. A kinetic assessment of VF area is quicker than and as effective at predicting mobility function as static threshold assessment.

http://ift.tt/2mMNWa4

Patient and practice characteristics predicting attendance and completion at a specialist weight management service in the UK: a cross-sectional study

Objective

To determine the association between patient and referring practice characteristics and attendance and completion at a specialist health service weight management service (WMS).

Design

Cross-sectional study.

Setting

Regional specialist WMS located in the West of Scotland.

Participants

9677 adults with obesity referred between 2012 and 2014; 3250 attending service and 2252 completing.

Primary and secondary outcome measures

Primary outcome measure was attendance at the WMS; secondary outcome was completion, defined as attending four or more sessions.

Analysis

Multilevel binary logistic regression models constructed to determine the association between patient and practice characteristics and attendance and completion.

Results

Approximately one-third of the 9677 obese adults referred attended at least one session (n=3250, 33.6%); only 2252 (23%) completed by attending four or more sessions. Practice referrals ranged from 1 to 257. Patient-level characteristics were strongest predictors of attendance; odds of attendance increased with age (OR 4.14, 95% CI 3.27 to 5.26 for adults aged 65+ compared with those aged 18–24), body mass index (BMI) category (OR 1.83, 95% CI 1.56 to 2.15 for BMI 45+ compared with BMI 30–35) and increasing affluence (OR 1.96, 95% CI 1.17 to 3.28). Practice-level characteristics most strongly associated with attendance were being a non-training practice, having a larger list size and not being located in the most deprived areas.

Conclusions

There was wide variation in referral rates across general practice, suggesting that there is still much to do to improve engagement with weight management by primary care practitioners. The high attrition rate from referral to attendance and from attendance to completion suggests ongoing barriers for patients, particularly those from the most socioeconomically deprived areas. Patient and practice-level characteristics can help us understand the observed variation in attendance at specialist WMS following general practitioner (GP) referral and the underlying explanations for these differences merit further investigation.

http://ift.tt/2zm0lYr

“Economies of Experience”—Disambiguation of Degraded Stimuli Leads to a Decreased Dispersion of Eye-Movement Patterns

Abstract

We demonstrate "economies of experience" in eye-movement patterns—that is, optimization of eye-movement patterns aimed at more efficient and less costly visual processing, similar to the priming-induced formation of sparser cortical representations or reduced reaction times. Participants looked at Mooney-type, degraded stimuli that were difficult to recognize without prior experience, but easily recognizable after exposure to their undegraded versions. As predicted, eye-movement dispersion, velocity, and the number of fixations decreased with each stimulus presentation. Further analyses showed that this effect was contingent on recognition, and the selection of information from the stimulus could be informed by the identity of the presented object. Finally, our study demonstrates that after exposure to the undegraded version of the stimulus, eye-movement patterns associated with its degraded and undegraded versions become more similar. This suggests that eye-movement patterns can evolve to facilitate the optimal processing of a given stimulus via experience-driven perceptual learning.

http://ift.tt/2zmHA7k

Context Effects and Spoken Word Recognition of Chinese: An Eye-Tracking Study

Abstract

This study examined the time-course of context effects on spoken word recognition during Chinese sentence processing. We recruited 60 native Mandarin listeners to participate in an eye-tracking experiment. In this eye-tracking experiment, listeners were told to listen to a sentence carefully, which ended with a Chinese homophone, and look at different visual probes (Chinese characters or different line-drawing pictures) presented concurrently on the computer screen naturally. Different types of context and probe types were manipulated in the experiment. The results showed that (1) preceding sentence context had an early effect on spoken word recognition processes and (2) phonological information of the distracters had only a negligible effect on the spoken word recognition processes. Finally, the patterns of eye-tracking results seemed to favor an interactive approach in spoken word recognition.

http://ift.tt/2mJVryq

Treatment of Richter’s Syndrome

Opinion statement

Based on the available literature, mostly derived from retrospective or non-randomized phase I or II studies, it is difficult to define an optimized treatment approach for patients developing Richter's syndrome (RS). Early recognition of chronic lymphocytic leukemia (CLL) patients presenting clinical features suspected for a transformation is useful to avoid exposing them to multiple lines of therapy that, being targeted to CLL progression, have poor efficacy against RS. Because of the low specificity (~ 50–60%) of clinical signs of RS (such as rapid and discordant bulky localized lymphadenopathies, elevated LDH levels, emergent physical deterioration, and/or fever in the absence of infection), a ¹⁸FDG PET/CT and a biopsy are recommended to confirm RS. A ¹⁸FDG PET/CT showing low uptake is helpful to rule out RS and avoid unnecessary risks and costs of performing a biopsy. A ¹⁸FDG PET/CT showing a high uptake is not diagnostic of RS but may help in the choice of the site where the biopsy is to be performed. In the setting of the diffuse large B-cell lymphoma (DLBCL) variant of RS, the definition of a clonal relationship between RS and the underlying CLL may guide the choice of treatment. If a clonal relationship is confirmed (the most common situation), rituximab-CHOP-like treatment does not guarantee long-lasting remissions, and should be used as induction therapy followed by consolidation with a stem cell transplant in physically fit patients. If the CLL and RS are clonally unrelated (the less common situation), the management should be that of a de novo DLBCL. In the setting of the rare Hodgkin lymphoma variant of RS, which is usually clonally unrelated to the CLL, ABVD with or without radiotherapy may be curative of the aggressive lymphoma.

http://ift.tt/2izD4ba

Severe Fertility Effects of sheepish Sperm Caused by Failure To Enter Female Sperm Storage Organs in Drosophila melanogaster

In Drosophila, mature sperm are transferred from males to females during copulation, stored in the sperm storage organs of females, and then utilized for fertilization. Here, we report a gene named sheepish (shps) of D. melanogaster that is essential for sperm storage in females. shps mutant males, although producing morphologically normal and motile sperm that are effectively transferred to females, produce very few offspring. Direct counts of sperm indicated that the primary defect was correlated to failure of shps sperm to migrate into the female sperm storage organs. Increased sperm motion parameters were seen in the control after transfer to females, whereas sperm from shps males have characteristics of the motion parameters different from the control. The few sperm that occasionally entered the female sperm storage organs showed no obvious defects in fertilization and early embryo development. The female post-mating responses after copulation with shps males appeared normal at least with respect to conformational changes of uterus, mating plug formation and female remating rates. The shps gene encodes a protein with homology to amine oxidases, including as observed in mammals, with a transmembrane region at the C-terminal end. The shps mutation was characterized by a nonsense replacement in the third exon of CG13611 and shps was rescued by transformants of the wild-type copy of CG13611. Thus, shps may define a new class of gene responsible for sperm storage.

http://ift.tt/2jGDJux

Global Transcriptome Sequencing Reveals Molecular Profiles of Summer Diapause Induction Stage of Onion Maggot, Delia antiqua (Diptera: Anthomyiidae)

The onion maggot, Delia antiqua, is a worldwide subterranean pest and can enter diapause during summer and winter seasons. The molecular regulation of the ontogenesis transition remains largely unknown. Here we used high-throughput RNA-Seq to identify candidate genes and processes linked to summer diapause induction by comparing the transcriptome differences between the most sensitive larval developmental stage of summer-diapause (SD) and non-diapause (ND). Nine pair-wise comparisons were performed and significantly differentially regulated transcripts were identified. Several functional terms related to lipid, carbohydrate and energy metabolism, environmental adaption, immune response and aging were enriched during the most sensitive SD induction period. A subset of genes, including circadian clock genes was expressed differentially under diapause induction conditions, and there was much more variation in the most sensitive period of ND than SD-destined larvae. These expression variations probably resulted in a deep restructuring of metabolic pathways. Potential regulatory elements of summer diapause induction including genes related to lipid, carbohydrate, energy metabolism and environmental adaption. Collectively, our results suggest circadian clock is one of the key drivers for integrating environmental signals into the SD induction. Our transcriptome analysis provides insight into the fundamental role the circadian clock plays in summer diapause induction in this important model insect species, and contributes to the in-depth elucidation of the molecular regulating mechanism of insect diapause induction.

http://ift.tt/2jKdFi5

A Single Residue Mutation in the G{alpha}q Subunit of the G Protein Complex Causes Blindness in Drosophila

Heterotrimeric G proteins play central roles in many signaling pathways, including the phototransduction cascade in animals. However, the degree of involvement of the G protein subunit Gα_q is not clear since animals with strong loss of function mutations previously reported remain responsive to light stimuli. We recovered a new allele of Gα_q in Drosophila that abolishes light response in a conventional ERG assay, and reduces sensitivity in whole-cell recordings of dissociated cells by at least 5 orders of magnitude. In addition, mutant eyes demonstrate a rapid rate of degeneration in the presence of light. Our new allele is likely the strongest hypomorph described to date. Interestingly, the mutant protein is produced in the eyes but carries a single amino acid change of a conserved hydrophobic residue that has been assigned to the interface of interaction between Gα_q and its downstream effector PLC. Our study thus uncovered possibly the first point mutation that specifically affects this interaction in vivo.

http://ift.tt/2hPSkU9

Genome-Wide Mapping of Decay Factor-mRNA Interactions in Yeast Identifies Nutrient Responsive Transcripts as Targets of the Deadenylase Ccr4

The Ccr4-Not complex is a major regulator of stress responses that controls gene expression at multiple levels, from transcription to mRNA decay. Ccr4, a core subunit of the complex, is the main cytoplasmic deadenylase in Saccharomyces cerevisiae, however its mRNA targets have not been mapped on a genome-wide scale. Here we describe a genome-wide approach, RNA immunoprecipitation-high throughput sequencing (RIP-seq), to identify the RNAs bound to Ccr4, and two proteins that associate with it, Dhh1 and Puf5. All three proteins were preferentially bound to lowly abundant mRNAs, most often at the 3' end of the transcript. Furthermore, Ccr4, Dhh1 and Puf5 are recruited to mRNAs that are targeted by other RNA-binding proteins that promote decay, mRNA transport and inhibit translation.  Although Ccr4-Not regulates mRNA transcription and decay, Ccr4 recruitment to mRNAs correlates better with decay rates, suggesting it imparts greater control over transcript abundance through decay.  Ccr4-enriched mRNAs are refractory to control by the other deadenylase complex in yeast, Pan2/3, suggesting a division of labor between these deadenylation complexes. Finally, Ccr4 and Dhh1 associate with mRNAs whose abundance increases during nutrient starvation and those that fluctuate during metabolic and oxygen consumption cycles, which explains the known genetic connections between these factors and nutrient utilization and stress pathways.

http://ift.tt/2jGKPiN

A Deconvolution Protocol for ChIP-Seq Reveals Analogous Enhancer Structures on the Mouse and Human Ribosomal RNA Genes

The combination of Chromatin Immunoprecipitation and Massively Parallel Sequencing, or ChIP-Seq, has greatly advanced our genome-wide understanding of chromatin and enhancer structures. However, its resolution at any given genetic locus is limited by several factors. In applying ChIP-Seq to the study of the ribosomal RNA genes, we found that a major limitation to resolution was imposed by the underlying variability in sequence coverage that very often dominates the protein-DNA interaction profiles. Here we describe a simple numerical deconvolution approach that in large part corrects for this variability and significantly improves both the resolution and quantitation of protein-DNA interaction maps deduced from ChIP-Seq data. This approach has allowed us to determine the in vivo organization of the RNA Polymerase I preinitiation complexes that form at the promoters and enhancers of the mouse (Mus musculus) and human (Homo sapiens) ribosomal RNA genes, and to reveal a phased binding of the HMG-box factor UBF across the rDNA. The data identify and map a "Spacer Promoter" and associated stalled polymerase in the Intergenic Spacer of the human ribosomal RNA genes, and reveal a very similar Enhancer structure to that found in rodents and lower vertebrates.

http://ift.tt/2hRrdb3

Sequential occurrence of small cell and non-small lung cancer in a male patient: Is it a transformation?

.


http://ift.tt/2AXXXDn

Inactivation of miR-100 combined with arsenic treatment enhances the malignant transformation of BEAS-2B cells via stimulating epithelial -mesenchymal transition

.


http://ift.tt/2AY6mHh

Risk factors for mortality among tuberculosis patients co-infected with HIV

.


http://ift.tt/2zXA53J

Combination antibiotic exposure selectively alters the development of vancomycin intermediate resistance in Staphylococcus aureus [PublishAheadOfPrint]

Invasive methicillin-resistant Staphylococcus aureus (MRSA) treated with vancomycin (VAN) is associated with reduced VAN susceptibility and treatment failure. VAN combination therapy is one strategy to improve response, but comprehensive assessments of combinations to prevent resistance are limited. This study identifies optimal combinations to prevent the emergence of VAN-intermediate Staphylococcus aureus (VISA). Two standard MRSA and two heterogeneous VISA (hVISA) strains were exposed for 28 days in vitro to VAN alone, VAN with cefazolin (CFZ), fosfomycin (FOF), gentamicin (GEN), meropenem (MEM), rifampin (RIF), piperacillin-tazobactam (TZP) or trimethoprim-sulfamethoxazole (SXT). In addition to VAN susceptibility testing, cell wall thickness (CWT), carotenoid content, and membrane fluidity were determined for Mu3. VAN plus any β-lactam limited the VAN MIC increase to 1-4 mg/L throughout the 28-day exposure, with CFZ and TZP as the most effective agents (VAN MIC=1-2 mg/L). Similar MIC trends occurred with the lipo-/glyco-peptide agents daptomycin and telavancin, where β-lactam combinations with VAN prevented MIC increases to these agents as well. Combinations with non β-lactams were ineffective in preventing VAN MIC increases with VAN MICs of 4-16 mg/L emerging during weeks 2-4 of treatment. VAN plus β-lactam decreased CWT significantly whereas VAN plus other antibiotics significantly increased the CWT. No correlation was observed between carotenoid content or membrane fluidity and antibiotic exposure. Only the combination exposures of VAN plus β-lactam suppress the development of VISA. Rational selection of VAN plus β-lactam should be further explored as a long-term combination treatment of MRSA infections due to their ability to suppress VAN resistance.

http://ift.tt/2zWJvyb

Fluconazole Resistant Candida auris is Susceptible to Salivary Histatin 5 Killing and to Intrinsic Host Defenses [PublishAheadOfPrint]

Candida auris is a newly identified species causing invasive candidemia and candidiasis, and has broad multidrug resistance (MDR) not observed for other pathogenic Candida species. Histatin 5 (Hst 5) is a well-studied salivary cationic peptide with significant antifungal activity against C. albicans, and is an attractive candidate to treat MDR fungi since antimicrobial peptides induce minimal drug resistance. We investigated the susceptibility of C. auris to Hst 5 and neutrophils, two first-line innate defenses in the human host. The majority of C. auris clinical isolates, including fluconazole resistant strains, were highly sensitive to Hst 5 with 55-90% of cells being killed using 7.5 μM Hst 5. Hst 5 was translocated to the cytosol and vacuole in C. auris cells, which are requirements for Hst 5 killing of C. albicans. The inverse relationship between fluconazole resistance and Hst 5 killing suggests different cellular targets for Hst 5 than for fluconazole. C. auris showed higher tolerance to oxidative stress compared to C. albicans, and higher survival within neutrophils which correlated with resistance to oxidative stress in vitro. Thus, ROS resistance is likely one, though not the only, important factor in neutrophil killing of C. auris. Hst 5 has a broad and potent candidacidal activity to effectively combat MDR C. auris strains.

http://ift.tt/2hEoONo

Seventy-five years of research on protein binding - do we ever understand? [PublishAheadOfPrint]

This review summarizes evidence that the impact of protein binding of the activity of antibiotics is multifacetted and more complex than indicated by the numerical value of protein binding alone. A plethora of studies has proven that protein binding of antibiotics matters – the free fraction only is antibacterially active and governs pharamcokinetics. Several studies have indicated that independent from protein binding immunoglobulin G, albumin, α-1-acid-glycoprotein, and pulmonary surfactant acted synergistically with antibacterial agents, thus suggesting that some intrinsic properties of serum proteins may have mediated serum antibiotic synergisms. It has been demonstrated that IgG and albumin permeabilized Gram-negative and Gram-positive bacteria and facilitated uptake of poorly penetrating antibiotics. Alpha-1-acid-glycoprotein and pulmonary surfactant exerted a permeabilizing activity, too, but proof that this property results in a sensitizing effect is missing. The permeabilizing effect of serum proteins may explain why serum antibiotic synergisms do not represent a general phenomenon but are limited to specific drug-bug associations only. Although evidence has been generated supporting the hypothesis that native serum proteins interact synergistically with antibiotics, systematic and well controlled studies have to be performed to substantiate this phenomenon. The interactions between serum proteins and bacterial surfaces are driven by physicochemical forces. However, preparative techniques, storage conditions, and incubation methods have a significant impact on the intrinsic activities of these serum proteins affecting serum antibiotic synergisms, so that these techniques have to be standadized as otherwise contradictory data or even artifacts will be generated.

http://ift.tt/2hHwcY6

The comparative in vitro activity of relebactam, imipenem and the combination of the two, plus six comparator antimicrobial agents against 432 strains of anaerobic organisms including imipenem-resistant strains. [PublishAheadOfPrint]

Relebactam is an important beta-lactamase inhibitor for certain aerobic organisms but alone it has no anti-anaerobic activity, with most anaerobes having MICs ≥32 μg/ml with the exception of a very few strains. There was no enhancement or antagonism of imipenem activity with the addition of relebactam, including activity against imipenem resistant strains. The relebactam-imipenem combination had excellent overall activity against the anaerobes tested.

http://ift.tt/2zVFDh4

High-dose daptomycin is effective as an antibiotic-lock therapy in a rabbit model of Staphylococcus epidermidis catheter-related infection [PublishAheadOfPrint]

Long-term catheter-related bloodstream infections (CRBSI) involving coagulase-negative Staphylococci are associated with poor patient outcomes, increased hospitalization and high treatment costs. The use of vancomycin-lock therapy has been an important step forward to treat these biofilms although failures appear in 20% of patients. In this study, we report that a high dose of daptomycin-lock therapy may offer a therapeutic advantage for these CRBSI in just 24 h of treatment.

http://ift.tt/2hEoIW2

In Vitro Activity of the Siderophore Cephalosporin, Cefiderocol, Against Carbapenem-Non-Susceptible and Multidrug-Resistant Isolates of Gram-Negative Bacilli Collected Worldwide in 2014-2016 [PublishAheadOfPrint]

The in vitro activity of the investigational siderophore cephalosporin, cefiderocol (formerly S-649266), was determined against a 2014-2016, 52-country, worldwide collection of clinical isolates of carbapenem-non-susceptible Enterobacteriaceae (n=1,022), multidrug-resistant (MDR) Acinetobacter baumannii (n=368), MDR Pseudomonas aeruginosa (n=262), Stenotrophomonas maltophilia (n=217), and Burkholderia cepacia (n=4) using the Clinical and Laboratory Standards Institute (CLSI) standard broth microdilution method. Iron-depleted cation-adjusted Mueller-Hinton broth (ID-CAMHB), prepared following the recently approved (2017), but not yet published, CLSI protocol, was used to test cefiderocol; all other antimicrobial agents were tested using CAMHB. The concentration of cefiderocol inhibiting 90% of isolates of carbapenem-non-susceptible Enterobacteriaceae (MIC₉₀) was 4 μg/ml; cefiderocol MICs ranged from 0.004 to 32 μg/ml and 97.0% (991/1,022) of isolates demonstrated cefiderocol MICs ≤4 μg/ml. The MIC₉₀s for cefiderocol for MDR A. baumannii, MDR P. aeruginosa, and S. maltophilia were 8, 1, and 0.25 μg/ml, respectively, with 89.7% (330/368), 99.2% (260/262), and 100% (217/217) of isolates demonstrating cefiderocol MICs ≤4 μg/ml. Cefiderocol MICs for B. cepacia ranged from 0.004-8 μg/ml. We conclude that cefiderocol demonstrated potent in vitro activity against a 2014-2016, worldwide collection of clinical isolates of carbapenem non-susceptible Enterobacteriaceae, MDR A. baumannii, MDR P. aeruginosa, S. maltophilia, and B. cepacia as 96.2% of all (1,801/1,873) isolates tested had cefiderocol MICs ≤4 μg/ml.

http://ift.tt/2zVFABU

Anti-Pseudomonal activity of phage PEV20 in a dry powder formulation -- A proof-of-principle study in a murine lung infection model [PublishAheadOfPrint]

Bacteriophage therapy is a promising alternative treatment to antibiotics as it has been documented to be efficacious against multi-drug resistant bacteria with minimal side effects. Several groups have demonstrated the efficacy of phage suspension in vivo to treat lung infections using intranasal delivery; however, phage dry powder administration to the lungs has not yet been explored. Powder formulations provide potential advantages over liquid formulation, including easy storage, transport and administration. The purpose of this study is to assess the bactericidal activities of phage dry powder formulations against MDR strain Pseudomonas aeruginosa FADDI-PA001 in a mouse lung infection model. Phage PEV20 spray dried with lactose and leucine produced inhalable powder at a concentration of 2 x 10⁷ PFU/mg. P. aeruginosa lung infection was established by intratracheal administration of bacterial suspension to neutropenic mice. At 2 h post-bacterial challenge, the infected mice were treated with 2 mg of the phage powder using a dry powder insufflator. At 24 h post-phage treatment, bacterial load in the lung was decreased by 5.3-log₁₀ (p < 0.0005) in the phage-treated group when compared with the non-treated group. Additionally, the phage concentration in the lung was increased by 1-log₁₀ at 24 h in the treated group. These results demonstrate the feasibility of pulmonary delivery of phage PEV20 dry powder formulation for the treatment of lung infection caused by antibiotic-resistant P. aeruginosa.

http://ift.tt/2hEoGNU

Evaluation of the in vitro activity of ceftaroline and comparators against S. pneumoniae isolates from U.S. hospitals: Results from 7 years of the AWARE Surveillance Program (2010-2016) [PublishAheadOfPrint]

We evaluated trends in Streptococcus pneumoniae antimicrobial susceptibility in United States hospitals in the 2010--2016 period. A total of 8,768 clinical isolates from 47 medical centers were tested for susceptibility by broth microdilution methods. Multidrug-resistant (MDR) and extensively drug-resistant (XDR) rates decreased from 25.7/12.4% (MDR/XDR) in 2010 to 17.7%/3.6% in 2016. Susceptibility to most comparator antimicrobial agents increased, whereas susceptibility to ceftaroline, levofloxacin, linezolid, and tigecycline remained stable. Ceftaroline retained potent activity against S. pneumoniae (>99.9%) with no marked variations.

http://ift.tt/2zW916Q

Characterization of Plasmodium Atg3-Atg8 interaction inhibitors identifies novel alternative mechanisms of action in Toxoplasma gondii [PublishAheadOfPrint]

Protozoan parasites, including the apicomplexan pathogens Plasmodium falciparum (malaria) and Toxoplasma gondii (toxoplasmosis) infect millions of people world-wide and represent a major human disease burden. Despite their prevalence, therapeutic strategies to treat these infections remain limited and are threatened by the emergence of drug resistance, highlighting the need for the identification of novel drug targets. Recently, homologues of the core autophagy proteins, including Atg8 and Atg3, were identified in many protozoan parasites. Importantly, components of the Atg8 conjugation system that facilitate the lipidation of Atg8 are required for both canonical and parasite-specific functions, and are essential for parasite viability. Structural characterization of the P. falciparum Atg3-Atg8 interaction has led to the identification of compounds that block this interaction. Additionally, many of these compounds inhibit P. falciparum growth in vitro, demonstrating the viability of this pathway as a drug target. Given the essential role of the Atg8 lipidation pathway in Toxoplasma, we sought to determine whether three PfAtg3-Atg8 interaction inhibitors identified in the Medicines for Malaria Venture Malaria Box exerted a similar inhibitory effect in Toxoplasma. While all three inhibitors blocked Toxoplasma replication in vitro at sub-micromolar concentrations, they did not inhibit TgAtg8 lipidation. Rather, high concentrations of two of these compounds induced TgAtg8 lipidation and fragmentation of the parasite mitochondrion, similar to the effects seen following starvation and monensin-induced autophagy. Additionally, we report that one of the PfAtg3-Atg8 interaction inhibitors induces Toxoplasma egress, and provide evidence that this is mediated by an increase in intracellular calcium in response to drug treatment.

http://ift.tt/2hEoFcO

A Simplified Derivative of Human Defensin 5 with Potent Efficiency against Multidrug-resistant Acinetobacter baumannii [PublishAheadOfPrint]

The increasing incidence of multidrug-resistant Acinetobacter baumannii (MDRAb) infections worldwide has necessitated the development of novel antibiotics. Human defensin 5 (HD5) is an endogenous peptide with a complex architecture and antibacterial activity against MDRAb. In the present study, we attempted to simplify the structure of HD5 by removing disulfide bonds. We found that the Cys2-4 bond was most indispensable for HD5 to inactivate MDRAb, although the antibacterial activity of the derivative was significantly attenuated. We then replaced the non-cationic and non-hydrophobic residues with electropositive Arg to increase the antibacterial activity of HD5 derivative that contains a Cys2-4 bond, obtaining another derivative termed HD5d5. The in vitro antibacterial assay and Irradiation-Wound-Infection animal experiment both showed that HD5d5 was much more effective than HD5 at eliminating MDRAb. Further investigations revealed that HD5d5 efficiently bound to outer membrane lipid A and penetrated membranes, leading to bacterial collapse and peptide translocation. Compared with HD5, more HD5d5 molecules were located in the cytoplasm of MDRAb, and HD5d5 was more efficient at reducing the activities of superoxide dismutase and catalase, causing the accumulation of reactive oxygen species that are detrimental to microbes. Additionally, HD5 failed to suppress the pathogenic outer membrane protein A of Acinetobacter baumannii (AbOmpA) at concentrations up to 50 μg/ml, whereas HD5d5 strongly bound to AbOmpA and exhibited a dramatic toxin-neutralizing ability, thus expanding the repertoire of drugs that is available to treat MRDAb infections.

http://ift.tt/2zW8UrW

KKL-35 exhibits potent antibiotic activity against Legionella species independently of trans-translation inhibition [PublishAheadOfPrint]

Trans-translation is a ribosome rescue system that is ubiquitous in bacteria. Small molecules defining a new family of oxadiazole compounds that inhibit trans-translation have been found to have broad-spectrum antibiotic activity. We sought to determine the activity of KKL-35, a potent member of the oxadiazole family, against the human pathogen Legionella pneumophila and other related species that can also cause Legionnaires disease (LD). Consistent with the essential nature of trans-translation in L. pneumophila, KKL-35 inhibits growth of all tested strains at sub-micromolar concentrations. KKL-35 is also active against other LD-causing Legionella species. KKL-35 remains equally active against L. pneumophila mutants that have evolved resistance to macrolides. KKL-35 inhibits multiplication of L. pneumophila in human macrophages at several stages of infection. No resistant mutants could be obtained, even during extended and chronic exposure. Surprisingly, KKL-35 is not synergistic with other ribosome-targeting antibiotics and does not induce the filamentation phenotype observed in cells defective for trans-translation. Importantly, KKL-35 remains active against L. pneumophila mutants expressing an alternate ribosome-rescue system and lacking tmRNA, the essential component of trans-translation. These results indicate that the antibiotic activity of KKL-35 is not related to the specific inhibition of trans-translation and its mode of action remains to be identified. In conclusion, KKL-35 is an effective antibacterial agent against the intracellular pathogen L. pneumophila and with no detectable resistance. However, further studies are needed to better understand its mechanism of action and to assess further the potential of oxadiazoles in treatment.

http://ift.tt/2hFIsIT

Antimicrobial octapeptin C4 analogues active against Cryptococcus species [PublishAheadOfPrint]

Resistance to antimicrobials is a growing problem in both developed and developing countries. In nations where AIDS is most prevalent, the human fungal pathogen Cryptococcus neoformans is a significant contributor to mortality, and its growing resistance to current antifungals an ever-expanding threat. We investigated octapeptin C4, from the cationic cyclic lipopeptide class of antimicrobials, as a potential new antifungal. Octapeptin C4 was a potent, selective inhibitor of this fungal pathogen with minimum inhibitory concentration of 1.56 μg/mL. Further testing of octapeptin C4 against 40 clinical isolates of C. neoformans var. grubii or neoformans showed MIC 1.56-3.13 μg/mL while 20 clinical isolates of C. neoformans var. gattii had MIC 0.78-12.5 μg/mL. In each case MIC values for octapeptin C4 were equivalent to, or better than, current antifungal drugs fluconazole and amphotericin B. The negatively charged polysaccharide capsule of C. neoformans influences the pathogens sensitivity to octapeptin C4 while degree of melanisation had little effect. Testing synthetic octapeptin C4 derivatives provided insight into the structure activity relationships, revealing that the lipophilic amino acid moieties are more important to the activity than the cationic diaminobutyric acid groups. Octapeptins have promising potential for development as anticryptococcal therapeutic agents.

http://ift.tt/2zW8PEE

Revisiting activation of and the mechanism of resistance to the compound IQG-607 in Mycobacterium tuberculosis [PublishAheadOfPrint]

IQG-607 is a metal complex previously reported as a promising anti-TB drug against isoniazid (INH)-resistant strains of M. tuberculosis. Unexpectedly, we found that INH-resistant clinical isolates were resistant to IQG-607. Spontaneous mutants resistant to IQG-607 were subjected to whole-genome sequencing and all sequenced colonies carried alterations in the katG gene. The katG(S315T) mutation was sufficient to confer resistance to IQG-607 in both MIC assays and inside macrophages. Moreover, overexpressing the InhA(S94A) protein caused IQG-607's resistance.

http://ift.tt/2hEouya

Neoantigen Quality Predicts Immune Response, Survival [News in Brief]

MHC binding affinity and T cell recognition potential shape the "fitness" of neoantigens.

http://ift.tt/2mOxmqo

The glucocorticoid receptor is a key player for prostate cancer cell survival and a target for improved anti-androgen therapy.

Purpose: The major obstacle in the management of advanced prostate cancer (PCa) is the occurrence of resistance to endocrine-therapy. Although the androgen receptor (AR) has been linked to therapy failure, the underlying escape mechanisms have not been fully clarified. Being closely related to the AR, the glucocorticoid receptor (GR) has been suggested to play a role in enzalutamide and docetaxel resistance. Given that glucocorticoids are frequently applied to PCa patients, it is essential to unravel the exact role of the GR in PCa progression. Experimental Design: Assessment of GR expression and functional significance in tissues from 177 PCa patients, including 14 lymph-node metastases, as well as in several human PCa models including androgen-dependent, androgen-independent, and long-term anti-androgen-treated cell lines. Results: While GR expression is reduced in primary PCa tissue, it is restored in metastatic lesions. Relapse patients with high GR experience shortened progression-free survival. GR is significantly increased upon long-term abiraterone or enzalutamide treatment in the majority of preclinical models, thus identifying GR upregulation as an underlying mechanism for cells to bypass AR-blockade. Importantly, GR inhibition by RNA-interference or chemical blockade results in impaired proliferation and 3D-spheroid formation in all tested cell lines. Conclusions: upregulation seems to be a common mechanism during anti-androgen treatment and supports the notion that targeting the GR pathway combined with anti-androgen medication may further improve PCa therapy.

http://ift.tt/2mKO2ip

CAR-T cell Therapies in Glioblastoma: a first look

Glioblastoma is an aggressive malignancy with a poor prognosis. The current standard of care for newly diagnosed glioblastoma patients includes surgery to the extent, temozolomide combined with radiotherapy, and alternating electric fields therapy. After recurrence, there is no standard therapy and survival is less than 9 months. Recurrent glioblastoma offers a unique opportunity to investigate new treatment approaches in a malignancy known for remarkable genetic heterogeneity, immunosuppressive microenvironment and partially permissive anatomical blood brain barrier (BBB). Results from three first-in-man CAR-T cell trials targeting IL13Rα2, Her2/CMV and EGFRvIII have recently been reported. Each one of these trials addresses important questions, such as T cell trafficking to CNS, engraftment and persistence, tumor microenvironment (TME) remodeling, and monitoring of glioma response to chimeric antigen receptor (CAR) T cells. Objective radiological responses have been reported. Here, we discuss and summarize the results of these trials and suggest opportunities for the field.

http://ift.tt/2znafsU

Follicular large cleaved cell (centrocytic) lymphoma: An unrecognized variant of follicular lymphoma

The World Health Organization (WHO) classification of lymphoma recommends the subdivision of follicular lymphoma (FL) into three grades (FL1–3) based on the average number of centroblasts per high-power field (HPF) in the neoplastic follicles, but does not recognize a form of FL characterized by a predominance of large cleaved cells (centrocytes) without enough centroblasts to meet the WHO criteria for FL3. We have classified such cases as follicular large cleaved cell lymphoma (FLC) and, herein, describe the pathologic and clinical features of 72 cases of this entity.

http://ift.tt/2AYoO2b

Towards a fully-fledged integration of spiritual care and medical care

In this article we aim to set out current problems that hinder a fully-fledged integration of spiritual and medical care that address these obstacles. We discuss the following five statements: 1. Spiritual care requires a clear and inclusive definition of spirituality; 2. Empirical evidence for spiritual care interventions should be improved; 3. Understanding patients' experiences of contingency is paramount to deliver effective spiritual care; 4. Attention to spiritual needs of patients is a task for every health care practitioner; 5.

http://ift.tt/2AZ3MQX

Immunoresolvents signaling molecules at intersection between the brain and immune system

Jesmond Dalli | Charles N Serhan

http://ift.tt/2iCLlLx

Serum activity of macrophage-derived adenosine deaminase 2 is associated with liver fibrosis in nonalcoholic fatty liver disease

http://ift.tt/2znipkQ

Evaluation of a Low Risk Mild Traumatic Brain Injury and Intracranial Hemorrhage Emergency Department Observation Protocol

Abstract

Objectives

Among emergency physicians, there is wide variation in admitting practices for patients who suffered a mild traumatic brain injury (TBI) with an intracranial hemorrhage (ICH). The purpose of this study was to evaluate the effects of implementing a protocol in the emergency department (ED) observation unit for patients with mild TBI and ICH.

Methods

This retrospective cohort study was approved by the Institutional Review Board. Study subjects were patients ≥18 years of age with an International Classification of Diseases (ICD) code corresponding to a traumatic IC, and admitted to an ED observation unit (EDOU) of an urban, academic level 1 trauma center between February 1, 2015 and January 31, 2017. Patient data and discharge disposition were abstracted from the electronic health record; imaging data from the final neuroradiologist report. To measure kappa, two abstractors independently collected data for presence of neuro deficit from a 10% random sample of the medical charts. Using a multivariable logistic regression model with a propensity score of the probability of placement in the EDOU pre-post protocol implementation as a covariate, we sought to determine the pre-post effects of implementing a protocol on the composite outcome of admission to the floor, intensive care unit (ICU), or operating room (OR) from the EDOU, and the proportion of patients with worsening findings on repeat CT head scan in the EDOU.

Results

A total of 379 patients were identified during the study period; 83 were excluded as they were found to have no ICH on chart review. Interrater reliability kappa statistic was 0.63 for 30 charts. Among the 296 patients who remained eligible and comprised the study population, 143 were in the pre-protocol period; 153 post-protocol. The EDOU protocol was associated with an independently statistically significant decreased odds ratio (OR) for admission or worsening ICH on repeat CT scan (OR 0.45, 95% confidence interval [CI] 0.25, 0.82, p=0.009) in the observation unit. After a stay in the EDOU, 26% (37/143) of patients required an inpatient admission pre-implementation of the protocol and 13% (20/153) of patients required an inpatient admission post-protocol implementation. There was no statistically significant difference in log transformed EDOU length of stay (LOS) between the groups after adjusting for propensity score (p=0.34).

Conclusions

While there was no difference in EDOU LOS, implementing a low risk mild traumatic brain injury and intracranial hemorrhage protocol in the EDOU may decrease the rate of inpatient admissions from the EDOU. A protocol driven observation unit may help physicians by standardizing eligibility criteria and by providing guidance on management. As the propensity score method limits our ability to create a straightforward predictive model, a future larger study should validate the results.

This article is protected by copyright. All rights reserved.

http://ift.tt/2mMt6rk

A Randomized Double Blind Trial of Needle-free Injected Lidocaine Versus Topical Anesthesia for Infant Lumbar Puncture

Abstract

Objectives

Lumbar punctures (LPs) are commonly performed in febrile infants to evaluate for meningitis, and local anesthesia increases the likelihood of LP success. Traditional methods of local anesthesia require injection which may be painful or topical application which is not effective immediately. Recent advances in needle-free jet injection may offer a rapid alternative to these modalities. We compared a needle-free jet-injection system (J-Tip^™) with 1% buffered lidocaine to topical anesthetic (TA) cream for local anesthesia in infant LPs.

Methods

Single center randomized double-blind trial of J-Tip versus TA for infant LPs in an urban tertiary care Children's Hospital Emergency Department. A computer randomization model was used to allocate patients to either intervention. Patients aged 0-4 months were randomized to J-Tip syringe containing 1% lidocaine and a placebo topical anesthetic cream, or J-Tip syringe containing saline and TA. The primary outcome was the difference between the neonatal faces coding scale (NFCS) pre-procedure and during LP needle insertion. Secondary outcomes included changes in heart rate (HR) and NFCS throughout the procedure, difficulty with LP, number of LP attempts, provider impression of pain control, additional use of lidocaine, skin changes at LP site, and LP success.

Results

We enrolled 66 subjects, 32 were randomized to J-Tip with lidocaine and 34 to EMLA. 6 participants were excluded from the final analysis due to age greater than 4 months, and the remaining 58 were analyzed in their respective groups (32 J-Tip, 34 TA). There was no difference detected in NFCS between the two treatment groups pre-procedure and during needle insertion for the LP (p=0.58, p=0.37). Neither HR nor NCFS differed among the groups throughout the procedure. Median perception of pain control by the provider and the need for additional lidocaine were comparable across groups. LPs performed with a J-Tip were twice as likely to be successful as compared to those performed using TA (RR 2.0; 95% CI 1.01, 3.93; p=0.04) with no difference in level of training or number of prior LPs performed by providers.

Conclusions

In a randomized controlled trial of two modalities for local anesthesia in infant lumbar punctures, J-Tip is not superior to topical anesthetic cream as measured by pain control or physiologic changes. Infant LPs performed with J-Tip were twice as likely to be successful.

This article is protected by copyright. All rights reserved.

http://ift.tt/2zkZ43L

Synaptic phosphorylated α-synuclein in dementia with Lewy bodies

Abstract

Dementia with Lewy bodies is characterized by the accumulation of Lewy bodies and Lewy neurites in the CNS, both of which are composed mainly of aggregated α-synuclein phosphorylated at Ser129. Although phosphorylated α-synuclein is believed to exert toxic effects at the synapse in dementia with Lewy bodies and other α-synucleinopathies, direct evidence for the precise synaptic localization has been difficult to achieve due to the lack of adequate optical microscopic resolution to study human synapses. In the present study we applied array tomography, a microscopy technique that combines ultrathin sectioning of tissue with immunofluorescence allowing precise identification of small structures, to quantitatively investigate the synaptic phosphorylated α-synuclein pathology in dementia with Lewy bodies. We performed array tomography on human brain samples from five patients with dementia with Lewy bodies, five patients with Alzheimer's disease and five healthy control subjects to analyse the presence of phosphorylated α-synuclein immunoreactivity at the synapse and their relationship with synapse size. Main analyses were performed in blocks from cingulate cortex and confirmed in blocks from the striatum of cases with dementia with Lewy bodies. A total of 1 318 700 single pre- or postsynaptic terminals were analysed. We found that phosphorylated α-synuclein is present exclusively in dementia with Lewy bodies cases, where it can be identified in the form of Lewy bodies, Lewy neurites and small aggregates (<0.16 µm³). Between 19% and 25% of phosphorylated α-synuclein deposits were found in presynaptic terminals mainly in the form of small aggregates. Synaptic terminals that co-localized with small aggregates of phosphorylated α-synuclein were significantly larger than those that did not. Finally, a gradient of phosphorylated α-synuclein aggregation in synapses (pre > pre + post > postsynaptic) was observed. These results indicate that phosphorylated α-synuclein is found at the presynaptic terminals of dementia with Lewy bodies cases mainly in the form of small phosphorylated α-synuclein aggregates that are associated with changes in synaptic morphology. Overall, our data support the notion that pathological phosphorylated α-synuclein may disrupt the structure and function of the synapse in dementia with Lewy bodies.

http://ift.tt/2jaLhSz

CLIPPERS, a possible symptomatic lymphohistiocytic immune reaction

Sir,

http://ift.tt/2zXtd6f

Reply: CLIPPERS, a possible symptomatic lymphohistiocytic immune reaction

Sir,

http://ift.tt/2j9DdRO

Normal tissue complication probability (NTCP) modelling of pulmonary toxicity after stereotactic and hypo-fractionated radiotherapy for central lung tumors

We scored grade ≥3 clinical and radiographic bronchial toxicity in patients with central lung tumors treated using ≤12 fractions. All analyzed dosimetric parameters were significantly correlated with clinical and lobar bronchial radiographic toxicity, and V130Gy,EQD had the highest odds ratio for both. NTCP modelling showed a volume dependency for both toxicities. On multivariate analyses, significant predictors for clinical toxicity were a planning target volume overlapping the trachea/main stem bronchus, COPD, and the total V130Gy,EQD.

http://ift.tt/2zTeqvv

Clinical Variables for Prediction of the Therapeutic Effects of Bevacizumab Monotherapy in Nasopharyngeal Carcinoma Patients with Radiation-induced Brain Necrosis

We underwent this retrospective study to identify the predictive and prognostic factors for brain edema decrease or recurrence after bevacizumab monotherapy in patients who developed radiation-induced brain necrosis (RN) after nasopharyngeal carcinoma. We have developed prediction models for the therapeutic effect of bevacizumab in RN patients by using random forests. Bevacizumab might be more effective in patients with lower maximum radiation dose of the temporal lobe.

http://ift.tt/2hGeLHp

Symptomatic benign distal biliary stricture in setting of anomalous pancreaticobiliary junction treated with metal biliary and temporary plastic pancreatic stents

http://ift.tt/2zVmvjt

Successful Repair of Duodenal Perforation With Endoscopic Vacuum Therapy

http://ift.tt/2hIu4zF

Spiral valves of Heister as per direct cystic ductoscopy

http://ift.tt/2zTLBPE

Sensation, mechanoreceptor and nerve fiber function after nerve regeneration

Abstract

Objective: Sensation is essential for recovery after peripheral nerve injury. However, the relationship between sensory modalities and function of regenerated fibers is uncertain. We have investigated the relationships between touch threshold, tactile gnosis and mechanoreceptor and sensory fiber function after nerve regeneration.

Methods: Twenty-one median or ulnar nerve lesions were repaired by a collagen nerve conduit or direct suture. Quantitative sensory hand function and sensory conduction studies by near-nerve technique including tactile stimulation of mechanoreceptors were followed for 2 years, and results were compared to non-injured hands.

Results: At both repair methods, touch thresholds at the finger tips recovered to 81±3% and tactile gnosis only to 20±4% (P<0.001) of control. The sensory action potentials (SNAPs) remained dispersed and areas recovered to 23±2% and the amplitudes only to 7±1% (P<0.001). The areas of SNAPs after tactile stimulation recovered to 61±11% and remained slowed. Touch sensation correlated with SNAP areas (P<0.005) and was negatively related to the prolongation of tactile latencies (P<0.01); tactile gnosis was not related to electrophysiological parameters.

Interpretation: The recovered function of regenerated peripheral nerve fibers and reinnervated mechanoreceptors may differentially influence recovery of sensory modalities. Touch was affected by the number and function of regenerated fibers and mechanoreceptors. In contrast, tactile gnosis depends on the input and plasticity of the CNS, which may explain the absence of a direct relation between electrophysiological parameters and poor recovery. Dispersed maturation of sensory nerve fibers with desynchronized inputs to the CNS also contributes to the poor recovery of tactile gnosis. This article is protected by copyright. All rights reserved.

http://ift.tt/2B80Tyc

Do emotions related to alcohol consumption differ by alcohol type? An international cross-sectional survey of emotions associated with alcohol consumption and influence on drink choice in different settings

Objectives

To examine the emotions associated with drinking different types of alcohol, explore whether these emotions differ by sociodemographics and alcohol dependency and whether the emotions associated with different drink types influence people's choice of drinks in different settings.

Design

International cross-sectional opportunistic survey (Global Drug Survey) using an online anonymous questionnaire in 11 languages promoted through newspapers, magazines and social media from November 2015 to January 2016.

Study population

Individuals aged 18–34 years who reported consumption of beer, spirits, red and white wine in the previous 12 months and were resident in countries with more than 200 respondents (n=21 countries; 29 836 respondents).

Main outcome measures

Positive and negative emotions associated with consumption of different alcoholic beverages (energised, relaxed, sexy, confident, tired, aggressive, ill, restless and tearful) over the past 12 months in different settings.

Results

Alcoholic beverages vary in the types of emotions individuals report they elicit, with spirits more frequently eliciting emotional changes of all types. Overall 29.8% of respondents reported feeling aggressive when drinking spirits, compared with only 7.1% when drinking red wine (p<0.001). Women more frequently reported feeling all emotions when drinking alcohol, apart from feelings of aggression. Respondents' level of alcohol dependency was strongly associated with feeling all emotions, with the likelihood of aggression being significantly higher in possible dependent versus low risk drinkers (adjusted OR 6.4; 95% CI 5.79 to 7.09; p<0.001). The odds of feeling the majority of positive and negative emotions also remained highest among dependent drinkers irrespective of setting.

Conclusion

Understanding emotions associated with alcohol consumption is imperative to addressing alcohol misuse, providing insight into what emotions influence drink choice between different groups in the population. The differences identified between sociodemographic groups and influences on drink choice within different settings will aid future public health practice to further comprehend individuals' drinking patterns and influence behaviour change.

http://ift.tt/2mQY2a7

Upregulation of Mitf by Phenolic Compounds-Rich Cymbopogon schoenanthus Treatment Promotes Melanogenesis in B16 Melanoma Cells and Human Epidermal Melanocytes

Melanin provides inherent protection against skin cancer by absorbing broad-spectrum radiant energy of UV radiation. Cutaneous malignant melanoma incidence has recently been observed to increase and the frequency is closely associated with the skin color, highlighting the importance of skin pigmentation. Here, we showed how melanin biosynthesis is enhanced by treatment with phenolic compounds-rich Cymbopogon schoenanthus (CYM) in B16 murine melanoma cells and human epidermal melanocytes (HEM). CYM increased the melanin content of the cells by upregulating the expression of tyrosinase (TYR), tyrosinase-related protein 1 (TRP1), and dopachrome tautomerase (DCT) at the protein and mRNA levels, comparable to the effect of α-melanocyte-stimulating hormone (MSH), in both B16 cells and HEM. Moreover, global gene expression analysis showed that at least 44 pigmentation-associated genes were modulated, including the microphthalmia-associated transcription factor (Mitf) and its transcriptional regulators (Sox10, Pax3, and Lef1). Upregulation of copper transport-associated gene Atp7b indicates that CYM also promotes tyrosinase activity. CYM upregulated Mitf and possibly activates tyrosinase enzyme, providing evidence for its possible use to promote melanogenesis and as a therapeutic agent against hypopigmentation disorders.

http://ift.tt/2zn1EGF

Red Cell Distribution Width Is Associated with All-Cause and Cardiovascular Mortality in Patients with Diabetes

Background and Methods. Red cell distribution width (RDW) has emerged as a prognostic marker in patients with cardiovascular diseases. We investigated mortality in patients with diabetes included in the National Health and Nutrition Examination Survey, in relation to baseline RDW. RDW was divided into 4 quartiles (Q1: ≤12.4%, Q2: 12.5%–12.9%, Q3: 13.0%–13.7%, and Q4: >13.7%). Results. A total of 3,061 patients were included: mean age years, 50% male, 39% White. Mean RDW was . Compared with first quartile (Q1) of RDW, patients in Q4 were more likely to be older, female, and African-American, have had history of stroke, myocardial infarction, and heart failure, and have chronic kidney disease. After a median follow-up of 6 years, 628 patient died (29% of cardiovascular disease). Compared with Q1, patients in Q4 were at increased risk for all-cause mortality (HR 3.44 [2.74–4.32], ) and cardiovascular mortality (HR 3.34 [2.16–5.17], ). After adjusting for 17 covariates, RDW in Q4 remained significantly associated with all-cause mortality (HR 2.39 [1.30–4.38], ) and cardiovascular mortality (HR 1.99 [1.17–3.37], ). Conclusion. RDW is a powerful and an independent marker for prediction of all-cause mortality and cardiovascular mortality in patients with diabetes.

http://ift.tt/2mKSJsv

Relationship between Physical Activity and Physical Fitness in Preschool Children: A Cross-Sectional Study

Purpose. To evaluate the relationships between objectively measured physical activity and physical fitness among preschool children. Methods. A total of 346 participants (201 boys and 145 girls) aged 3.5–5.5 years ( yr, SD = 0.47) from Shanghai, China, completed physical fitness assessments, including triceps skinfold thickness (TSFT), grip strength, tennis throwing, sit and reach test, standing long jump, balance beam, 10mSRT, and 20mSRT. Physical activity was objectively measured by ActiGraphGT3X+ accelerometer. Multiple linear regression models were used to explore the cross-sectional associations between PA and physical fitness after adjusting for age, gender, BMI, and valid wearing time. Results. Positive associations were observed between stand long jump (), tennis throwing (), laps in 20mSRT (), and MVPA. However, TSFT (), time in 10mSRT (), and balance beam () were negatively associated with MVPA. Furthermore, positive associations were found between stand long jump (), tennis throwing (), and MVPA only in boys. Negative associations were found between time on balance beam () and MVPA only in girls. Conclusions. MVPA appears to be an effective and reliable predictor of preschoolers' physical fitness. Boys' body composition, muscular strength, explosive strength, agility, aerobic fitness, girls' agility, aerobic fitness, and balance could improve as MVPA increases.

http://ift.tt/2zne2Xe

Measuring Patient Safety in Real Time: An Essential Method for Effectively Improving the Safety of Care

The continuing evidence of preventable deaths due to medical error has led to recent calls to improve measurement of safety in hospitals. In this opinion piece, the authors discuss the ways that electronic health records can be harnessed to measure harm and better guide and monitor the real effect of patient safety efforts.

http://ift.tt/2zYcRKO

Hepatitis B Vaccination, Screening, and Linkage to Care

http://ift.tt/2jdtMRk

Characteristics of U.S. Physician Marriages, 2000–2015: An Analysis of Data From a U.S. Census Survey

http://ift.tt/2A08wqw

Novel Stool-Based Protein Biomarkers for Improved Colorectal Cancer Screening A Case–Control Study

Background:

The fecal immunochemical test (FIT) for detecting hemoglobin is used widely for noninvasive colorectal cancer (CRC) screening, but its sensitivity leaves room for improvement.

Objective:

To identify novel protein biomarkers in stool that outperform or complement hemoglobin in detecting CRC and advanced adenomas.

Design:

Case–control study.

Setting:

Colonoscopy-controlled referral population from several centers.

Participants:

315 stool samples from one series of 12 patients with CRC and 10 persons without colorectal neoplasia (control samples) and a second series of 81 patients with CRC, 40 with advanced adenomas, and 43 with nonadvanced adenomas, as well as 129 persons without colorectal neoplasia (control samples); 72 FIT samples from a third independent series of 14 patients with CRC, 16 with advanced adenomas, and 18 with nonadvanced adenomas, as well as 24 persons without colorectal neoplasia (control samples).

Measurements:

Stool samples were analyzed by mass spectrometry. Classification and regression tree (CART) analysis and logistic regression analyses were performed to identify protein combinations that differentiated CRC or advanced adenoma from control samples. Antibody-based assays for 4 selected proteins were done on FIT samples.

Results:

In total, 834 human proteins were identified, 29 of which were statistically significantly enriched in CRC versus control stool samples in both series. Combinations of 4 proteins reached sensitivities of 80% and 45% for detecting CRC and advanced adenomas, respectively, at 95% specificity, which was higher than that of hemoglobin alone (P < 0.001 and P = 0.003, respectively). Selected proteins could be measured in small sample volumes used in FIT-based screening programs and discriminated between CRC and control samples (P < 0.001).

Limitation:

Lack of availability of antibodies prohibited validation of the top protein combinations in FIT samples.

Conclusion:

Mass spectrometry of stool samples identified novel candidate protein biomarkers for CRC screening. Several protein combinations outperformed hemoglobin in discriminating CRC or advanced adenoma from control samples. Proof of concept that such proteins can be detected with antibody-based assays in small sample volumes indicates the potential of these biomarkers to be applied in population screening.

Primary Funding Source:

Center for Translational Molecular Medicine, International Translational Cancer Research Dream Team, Stand Up to Cancer (American Association for Cancer Research and the Dutch Cancer Society), Dutch Digestive Foundation, and VU University Medical Center.

http://ift.tt/2j9hj1l

Cost-Effectiveness of Publicly Funded Treatment of Opioid Use Disorder in California

Background:

Only 1 in 5 of the nearly 2.4 million Americans with an opioid use disorder received treatment in 2015. Fewer than half of Californians who received treatment in 2014 received opioid agonist treatment (OAT), and regulations for admission to OAT in California are more stringent than federal regulations.

Objective:

To determine the cost-effectiveness of OAT for all treatment recipients compared with the observed standard of care for patients presenting with opioid use disorder to California's publicly funded treatment facilities.

Design:

Model-based cost-effectiveness analysis.

Data Sources:

Linked population-level administrative databases capturing treatment and criminal justice records for California (2006 to 2010); published literature.

Target Population:

Persons initially presenting for publicly funded treatment of opioid use disorder.

Time Horizon:

Lifetime.

Perspective:

Societal.

Intervention:

Immediate access to OAT with methadone for all treatment recipients compared with the observed standard of care (54.3% initiate opioid use disorder treatment with medically managed withdrawal).

Outcome Measures:

Discounted quality-adjusted life-years (QALYs) and discounted costs.

Results of Base-Case Analysis:

Immediate access to OAT for all treatment recipients costs less (by $78 257), with patients accumulating more QALYs (by 0.42) than with the observed standard of care. In a hypothetical scenario where all Californians starting treatment of opioid use disorder in 2014 had immediate access to OAT, total lifetime savings for this cohort could be as high as $3.8 billion.

Results of Sensitivity Analysis:

99.6% of the 2000 simulations resulted in lower costs and more QALYs.

Limitation:

Nonrandomized delivery of OAT or medically managed withdrawal.

Conclusion:

The value of publicly funded treatment of opioid use disorder in California is maximized when OAT is delivered to all patients presenting for treatment, providing greater health benefits and cost savings than the observed standard of care.

Primary Funding Source:

National Institute on Drug Abuse.

http://ift.tt/2zZMWSS

More Beds or More Chairs? Using a Science-Based Approach to Address the Opioid Epidemic

Krebs and colleagues report an analysis showing that immediate access to opioid agonist treatment (OAT) for all patients with opioid use disorder seeking treatment in California's publicly funded treatment programs is cost-effective compared with the current state-level standard of time-limited medically supervised withdrawal. The editorialists discuss the findings and conclude that it is vital that we use less health care resources on medically supervised withdrawal "beds" and more on outpatient "chairs" for OAT.

http://ift.tt/2jbPMwd

Hepatitis B Vaccination, Screening, and Linkage to Care: Best Practice Advice From the American College of Physicians and the Centers for Disease Control and Prevention

Background:

Vaccination, screening, and linkage to care can reduce the burden of chronic hepatitis B virus (HBV) infection. However, recommendations vary among organizations, and their implementation has been suboptimal. The American College of Physicians' High Value Care Task Force and the Centers for Disease Control and Prevention developed this article to present best practice statements for hepatitis B vaccination, screening, and linkage to care.

Methods:

A narrative literature review of clinical guidelines, systematic reviews, randomized trials, and intervention studies on hepatitis B vaccination, screening, and linkage to care published between January 2005 and June 2017 was conducted.

Best Practice Advice 1:

Clinicians should vaccinate against hepatitis B virus (HBV) in all unvaccinated adults (including pregnant women) at risk for infection due to sexual, percutaneous, or mucosal exposure; health care and public safety workers at risk for blood exposure; adults with chronic liver disease, end-stage renal disease (including hemodialysis patients), or HIV infection; travelers to HBV-endemic regions; and adults seeking protection from HBV infection.

Best Practice Advice 2:

Clinicians should screen (hepatitis B surface antigen, antibody to hepatitis B core antigen, and antibody to hepatitis B surface antigen) for HBV in high-risk persons, including persons born in countries with 2% or higher HBV prevalence, men who have sex with men, persons who inject drugs, HIV-positive persons, household and sexual contacts of HBV-infected persons, persons requiring immunosuppressive therapy, persons with end-stage renal disease (including hemodialysis patients), blood and tissue donors, persons infected with hepatitis C virus, persons with elevated alanine aminotransferase levels (≥19 IU/L for women and ≥30 IU/L for men), incarcerated persons, pregnant women, and infants born to HBV-infected mothers.

Best Practice Advice 3:

Clinicians should provide or refer all patients identified with HBV (HBsAg-positive) for posttest counseling and hepatitis B–directed care.

http://ift.tt/2zYeMPt

Annals for Hospitalists - 21 November 2017

http://ift.tt/2hHyEhs

Review: In adults with sleep apnea, positive airway pressure does not reduce cardiovascular events or death

http://ift.tt/2zUby1f

Predicting 30-Day Mortality for Patients With Acute Heart Failure in the Emergency Department A Cohort Study

Background:

Physicians in the emergency department (ED) need additional tools to stratify patients with acute heart failure (AHF) according to risk.

Objective:

To predict mortality using data that are readily available at ED admission.

Design:

Prospective cohort study.

Setting:

34 Spanish EDs.

Participants:

The derivation cohort included 4867 consecutive ED patients admitted during 2009 to 2011. The validation cohort comprised 3229 patients admitted in 2014.

Measurements:

88 candidate risk factors and 30-day mortality.

Results:

Thirteen independent risk factors were identified in the derivation cohort and were combined into an overall score, the MEESSI-AHF (Multiple Estimation of risk based on the Emergency department Spanish Score In patients with AHF) score. This score predicted 30-day mortality with excellent discrimination (c-statistic, 0.836) and calibration (Hosmer–Lemeshow P = 0.99) and provided a steep gradient in 30-day mortality across risk groups (<2% for patients in the 2 lowest risk quintiles and 45% in the highest risk decile). These characteristics were confirmed in the validation cohort (c-statistic, 0.828). Multiple sensitivity analyses did not find important amounts of confounding or bias.

Limitations:

The study was confined to a single country. Participating EDs were not selected randomly. Many patients had missing data. Measurement of some risk factors was subjective.

Conclusion:

This tool has excellent discrimination and calibration and was validated in a different cohort from the one that was used to develop it. Physicians can consider using this tool to inform clinical decisions as further studies are done to determine whether the tool enhances physician decision making and improves patient outcomes.

Primary Funding Source:

Instituto de Salud Carlos III, Spanish Ministry of Health; Fundació La Marató de TV3; and Catalonia Govern.

http://ift.tt/2yl0zhC

Guideline: Recommendations for THA or TKA perioperative antirheumatic drugs in patients with rheumatic diseases

http://ift.tt/2zTtZ6l

Concentration of Potentially Preventable Spending Among High-Cost Medicare Subpopulations An Observational Study

Background:

Little is known about whether potentially preventable spending is concentrated among a subset of high-cost Medicare beneficiaries.

Objective:

To determine the proportion of total spending that is potentially preventable across distinct subpopulations of high-cost Medicare beneficiaries.

Design:

Beneficiaries in the highest 10% of total standardized individual spending were defined as "high-cost" patients, using a 20% sample of Medicare fee-for-service claims from 2012. The following 6 subpopulations were defined using a claims-based algorithm: nonelderly disabled, frail elderly, major complex chronic, minor complex chronic, simple chronic, and relatively healthy. Potentially preventable spending was calculated by summing costs for avoidable emergency department visits using the Billings algorithm plus inpatient and associated 30-day postacute costs for ambulatory care–sensitive conditions (ACSCs). The amount and proportion of potentially preventable spending were then compared across the high-cost subpopulations and by individual ACSCs.

Setting:

Medicare.

Participants:

6 112 450 Medicare beneficiaries.

Measurements:

Proportion of spending deemed potentially preventable.

Results:

In 2012, 4.8% of Medicare spending was potentially preventable, of which 73.8% was incurred by high-cost patients. Despite making up only 4% of the Medicare population, high-cost frail elderly persons accounted for 43.9% of total potentially preventable spending ($6593 per person). High-cost nonelderly disabled persons accounted for 14.8% of potentially preventable spending ($3421 per person) and the major complex chronic group for 11.2% ($3327 per person). Frail elderly persons accounted for most spending related to admissions for urinary tract infections, dehydration, heart failure, and bacterial pneumonia.

Limitation:

Potential misclassification in the identification of preventable spending and lack of detailed clinical data in administrative claims.

Conclusion:

Potentially preventable spending varied across Medicare subpopulations, with the majority concentrated among frail elderly persons.

Primary Funding Source:

The Commonwealth Fund.

http://ift.tt/2xQxje0

In patients with proteinuric IgA nephropathy, benefits of methylprednisolone were offset by harms

http://ift.tt/2zTtWYd

Oral Human Papillomavirus Infection: Differences in Prevalence Between Sexes and Concordance With Genital Human Papillomavirus Infection, NHANES 2011 to 2014

Background:

The burden of human papillomavirus (HPV)–positive oropharyngeal squamous cell carcinoma (OPSCC) is disproportionately high among men, yet empirical evidence regarding the difference in prevalence of oral HPV infection between men and women is limited. Concordance of oral and genital HPV infection among men is unknown.

Objective:

To determine the prevalence of oral HPV infection, as well as the concordance of oral and genital HPV infection, among U.S. men and women.

Design:

Nationally representative survey.

Setting:

Civilian noninstitutionalized population.

Participants:

Adults aged 18 to 69 years from NHANES (National Health and Nutrition Examination Survey), 2011 to 2014.

Measurements:

Oral rinse, penile swab, and vaginal swab specimens were evaluated by polymerase chain reaction followed by type-specific hybridization.

Results:

The overall prevalence of oral HPV infection was 11.5% (95% CI, 9.8% to 13.1%) in men and 3.2% (CI, 2.7% to 3.8%) in women (equating to 11 million men and 3.2 million women nationwide). High-risk oral HPV infection was more prevalent among men (7.3% [CI, 6.0% to 8.6%]) than women (1.4% [CI, 1.0% to 1.8%]). Oral HPV 16 was 6 times more common in men (1.8% [CI, 1.3% to 2.2%]) than women (0.3% [CI, 0.1% to 0.5%]) (1.7 million men vs. 0.27 million women). Among men and women who reported having same-sex partners, the prevalence of high-risk HPV infection was 12.7% (CI, 7.0% to 18.4%) and 3.6% (CI, 1.4% to 5.9%), respectively. Among men who reported having 2 or more same-sex oral sex partners, the prevalence of high-risk HPV infection was 22.2% (CI, 9.6% to 34.8%). Oral HPV prevalence among men with concurrent genital HPV infection was 4-fold greater (19.3%) than among those without it (4.4%). Men had 5.4% (CI, 5.1% to 5.8%) greater predicted probability of high-risk oral HPV infection than women. The predicted probability of high-risk oral HPV infection was greatest among black participants, those who smoked more than 20 cigarettes daily, current marijuana users, and those who reported 16 or more lifetime vaginal or oral sex partners.

Limitation:

Sexual behaviors were self-reported.

Conclusion:

Oral HPV infection is common among U.S. men. This study's findings provide several policy implications to guide future OPSCC prevention efforts to combat this disease.

Primary Funding Source:

National Cancer Institute.

http://ift.tt/2xK6hK6

Self-administered Versus Directly Observed Once-Weekly Isoniazid and Rifapentine Treatment of Latent Tuberculosis Infection A Randomized Trial

Background:

Expanding latent tuberculosis treatment is important to decrease active disease globally. Once-weekly isoniazid and rifapentine for 12 doses is effective but limited by requiring direct observation.

Objective:

To compare treatment completion and safety of once-weekly isoniazid and rifapentine by self-administration versus direct observation.

Design:

An open-label, phase 4 randomized clinical trial designed as a noninferiority study with a 15% margin. Seventy-five percent or more of study patients were enrolled from the United States for a prespecified subgroup analysis. (ClinicalTrials.gov: NCT01582711)

Setting:

Outpatient tuberculosis clinics in the United States, Spain, Hong Kong, and South Africa.

Participants:

1002 adults (aged ≥18 years) recommended for treatment of latent tuberculosis infection.

Intervention:

Participants received once-weekly isoniazid and rifapentine by direct observation, self-administration with monthly monitoring, or self-administration with weekly text message reminders and monthly monitoring.

Measurements:

The primary outcome was treatment completion, defined as 11 or more doses within 16 weeks and measured using clinical documentation and pill counts for direct observation, and self-reports, pill counts, and medication event–monitoring devices for self-administration. The main secondary outcome was adverse events.

Results:

Median age was 36 years, 48% of participants were women, and 77% were enrolled at the U.S. sites. Treatment completion was 87.2% (95% CI, 83.1% to 90.5%) in the direct-observation group, 74.0% (CI, 68.9% to 78.6%) in the self-administration group, and 76.4% (CI, 71.3% to 80.8%) in the self-administration–with–reminders group. In the United States, treatment completion was 85.4% (CI, 80.4% to 89.4%), 77.9% (CI, 72.7% to 82.6%), and 76.7% (CI, 70.9% to 81.7%), respectively. Self-administered therapy without reminders was noninferior to direct observation in the United States; no other comparisons met noninferiority criteria. A few drug-related adverse events occurred and were similar across groups.

Limitation:

Persons with latent tuberculosis infection enrolled in South Africa would not routinely be treated programmatically.

Conclusion:

These results support using self-administered, once-weekly isoniazid and rifapentine to treat latent tuberculosis infection in the United States, and such treatment could be considered in similar settings when direct observation is not feasible.

Primary Funding Source:

Centers for Disease Control and Prevention.

http://ift.tt/2hhznJu