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This review of the literature was conducted to define avoidant restrictive food intake disorder (ARFID) and provide the current evidence-based treatment modalities and implications for Nurse Practitioners. A specific case is used to illustrate the daily struggles of a pediatric patient with ARFID that include bullying, self-doubt, and anxiety related to eating. There is a need for increased awareness of the disorder to increase identification of the disorder, enhance the research on treatment modalities for the disorder, and most importantly, to increase the quality of life for those with the disorder and their family members.

Objective:Healthcare personnel (HCP) were recruited to provide serum samples, which were tested for antibodies against Ebola or Lassa virus to evaluate for asymptomatic seroconversion.Setting:From 2014 to 2016, 4 patients with Ebola virus disease (EVD) and 1 patient with Lassa fever (LF) were treated in the Serious Communicable Diseases Unit (SCDU) at Emory University Hospital. Strict infection control and clinical biosafety practices were implemented to prevent nosocomial transmission of EVD or LF to HCP.Participants:All personnel who entered the SCDU who were required to measure their temperatures and complete a symptom questionnaire twice daily were eligible.Results:No employee developed symptomatic EVD or LF. EVD and LF antibody studies were performed on sera samples from 42 HCP. The 6 participants who had received investigational vaccination with a chimpanzee adenovirus type 3 vectored Ebola glycoprotein vaccine had high antibody titers to Ebola glycoprotein, but none had a response to Ebola nucleoprotein or VP40, or a response to LF antigens.Conclusions:Patients infected with filoviruses and arenaviruses can be managed successfully without causing occupation-related symptomatic or asymptomatic infections. Meticulous attention to infection control and clinical biosafety practices by highly motivated, trained staff is critical to the safe care of patients with an infection from a special pathogen.

The output of the retina is organized into many detector grids, called 'mosaics', that signal different features of visual scenes to the brain1-4. Each mosaic comprises a single type of retinal ganglion cell (RGC), whose receptive fields tile visual space. Many mosaics arise as pairs, signalling increments (ON) and decrements (OFF), respectively, of a particular visual feature5. Here we use a model of efficient coding6 to determine how such mosaic pairs should be arranged to optimize the encoding of natural scenes. We find that information is maximized when these mosaic pairs are anti-aligned, meaning that the distances between the receptive field centres across mosaics are greater than expected by chance. We tested this prediction across multiple receptive field mosaics acquired using large-scale measurements of the light responses of rat and primate RGCs. ON and OFF RGC pairs with similar feature selectivity had anti-aligned receptive field mosaics, consistent with this prediction. ON and OFF RGC types that encode distinct features have independent mosaics. These results extend efficient coding theory beyond individual cells to predict how populations of diverse types of RGC are spatially arranged.

Complementary food hygiene is important to reduce infant exposures to enteric pathogens; however, interventions to improve food hygiene in low- and middle-income countries often ignore the larger context in which childcare occurs. In this study, we explore on observational and qualitative information regarding childcare in an informal community in Kenya. Our findings demonstrate that behaviors associated with food contamination, such as hand feeding and storing food for extended periods, are determined largely by the larger social and economic realities of primary caretakers. Data also show how caregiving within an informal settlement is highly dynamic and involves multiple individuals and locations throughout the day. Findings from this study will help inform the development and implementation of food hygiene interventions in informal urban communities.

Missense DNA variants have variable effects upon protein function. Consequently, interpreting their pathogenicity is challenging, especially when they are associated with disease variability. To determine the degree to which functional assays inform interpretation, we analyzed 48 CFTR missense variants associated with variable expressivity of cystic fibrosis (CF). We assessed function in a native isogenic context by evaluating CFTR mutants that were stably expressed in the genome of a human airway cell line devoid of endogenous CFTR expression. 21 of 29 variants associated with full expressivity of the CF phenotype generated 25% WT-CFTR function; two were higher than 75% WT-CFTR. As expected, 14 of 19 variants associated with partial expressivity of CF had >25% WT-CFTR function; however, four had minimal to no effect on CFTR function (>75% WT-CFTR). Thus, 6 of 48 (13%) missense variants believed to be disease causing did not alter CFTR function. Functional studies substantially refined pathogenicity assignment with expert annotation and criteria from the American College of Medical Genetics and Genomics and Association for Molecular Pathology. However, four algorithms (CADD, REVEL, SIFT, and PolyPhen-2) could not differentiate between variants that caused severe, moderate, or minimal reduction in function. In the setting of variable expressivity, these results indicate that functional assays are essential for accurate interpretation of missense variants and that current prediction tools should be used with caution.

Nursing education is continuously evolving to meet Nursing and Midwifery Council (NMC) requirements for registered nurses. NMC standards state that all registered nurses are responsible for the student learning experience. However, newly qualified nurses can feel underprepared to support pre-registration student learning in the clinical area as the university setting does not facilitate formal peer support. This article will discuss the implementation of a peer facilitation scheme for pre-registration nursing students undertaking the BSc (Hons) and PGDip programmes in a higher education institution in London. The scheme trained second-year nursing students to be peer facilitators for first-year clinical skills sessions. This article will also consider the benefits of the scheme for both first and second-year student nurses.

We developed a variant-annotation method that combines sequence-based machine-learning classification with a context-dependent algorithm for selecting splice variants. Our approach is distinctive in that it compares the splice potential of a sequence bearing a variant with the splice potential of the reference sequence. After training, classification accurately identified 168 of 180 (93.3%) canonical splice sites of five genes. The combined method, CryptSplice, identified and correctly predicted the effect of 18 of 21 (86%) known splice-altering variants in CFTR, a well-studied gene whose loss-of-function variants cause cystic fibrosis (CF). Among 1,423 unannotated CFTR disease-associated variants, the method identified 32 potential exonic cryptic splice variants, two of which were experimentally evaluated and confirmed. After complete CFTR sequencing, the method found three cryptic intronic splice variants (one known and two experimentally verified) that completed the molecular diagnosis of CF in 6 of 14 individuals. CryptSplice interrogation of sequence data from six individuals with X-linked dyskeratosis congenita caused by an unknown disease-causing variant in DKC1 identified two splice-altering variants that were experimentally verified. To assess the extent to which disease-associated variants might activate cryptic splicing, we selected 458 pathogenic variants and 348 variants of uncertain significance (VUSs) classified as high confidence from ClinVar. Splice-site activation was predicted for 129 (28%) of the pathogenic variants and 75 (22%) of the VUSs. Our findings suggest that cryptic splice-site activation is more common than previously thought and should be routinely considered for all variants within the transcribed regions of genes.

Growth hormone (GH) and the GH receptor (GHR) are expressed in a wide range of malignant tumors including melanoma. However, the effect of GH/insulin-like growth factor (IGF) on melanoma in vivo has not yet been elucidated. Here we assessed the physical and molecular effects of GH on mouse melanoma B16-F10 and human melanoma SK-MEL-30 cells in vitro. We then corroborated these observations with syngeneic B16-F10 tumors in two mouse lines with different levels of GH/IGF: bovine GH transgenic mice (bGH, high GH, high IGF-1) and GHR gene-disrupted or knockout mice (GHRKO, high GH, low IGF-1). In vitro, GH treatment enhanced mouse and human melanoma cell growth, drug retention and cell invasion. While the in vivo tumor size was unaffected in both bGH and GHRKO mouse lines, multiple drug-efflux pumps were up regulated. This intrinsic capacity of therapy resistance appears to be GH dependent. Additionally, epithelial-to-mesenchymal transition (EMT) gene transcription markers were significantly upregulated in vivo supporting our current and recent in vitro observations. These syngeneic mouse melanoma models of differential GH/IGF action can be valuable tools in screening for therapeutic options where lowering GH/IGF-1 action is important.

CFTR modulators have revolutionized the treatment of individuals with cystic fibrosis (CF) by improving the function of existing protein. Unfortunately, almost half of the disease-causing variants in CFTR are predicted to introduce premature termination codons (PTC) thereby causing absence of full-length CFTR protein. We hypothesized that a subset of nonsense and frameshift variants in CFTR allow expression of truncated protein that might respond to FDA-approved CFTR modulators. To address this concept, we selected 26 PTC-generating variants from four regions of CFTR and determined their consequences on CFTR mRNA, protein and function using intron-containing minigenes expressed in 3 cell lines (HEK293, MDCK and CFBE41o-) and patient-derived conditionally reprogrammed primary nasal epithelial cells. The PTC-generating variants fell into five groups based on RNA and protein effects. Group A (reduced mRNA, immature (core glycosylated) protein, function 1% (n = 5)), Group D (reduced mRNA, mature protein, function >1% (n = 5)) and Group E (aberrant RNA splicing, mature protein, function > 1% (n = 1)) variants responded to modulators. Increasing mRNA level by inhibition of NMD led to a significant amplification of modulator effect upon a Group D variant while response of a Group A variant was unaltered. Our work shows that PTC-generating variants should not be generalized as genetic ‘nulls’ as some may allow generation of protein that can be targeted to achieve clinical benefit., Author summary The development of variant specific modulators that correct dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) protein is an excellent example of precision medicine. Currently there is no molecular treatment available for individuals with cystic fibrosis (CF) carrying nonsense or frameshift variants because such variants introduce a premature termination codon (PTC), and are not expected to produce CFTR protein. We have performed a systematic study of nonsense and frameshift variants located in four regions of CFTR that we postulated should have varying effects on mRNA stability, protein production, and/or function. Using primary nasal cells and three different cell line models stably expressing CFTR expression mini-genes (EMGs), we report molecular consequences of 26 PTC-generating variants in CFTR, and identify which variants allow generation of CFTR protein that is responsive to currently available modulator therapies and which require alternative therapeutic approaches.

Background Community health workers play an important role in health service delivery and are increasingly involved in behaviour change interventions, including for hygiene-related behaviour change. However, their role and capacity to deliver behaviour change interventions, particularly in high-density urban settlements, remain under-researched. This study examines the behaviour change-related activities of community health volunteers (CHVs)—community health workers affiliated with the Kenyan Ministry of Health—in a peri-urban settlement in Kenya, in order to assess their capabilities, opportunities to work effectively, and sources of motivation. Methods This mixed-methods study included a census of 16 CHVs who work in the study area. All CHVs participated in structured observations of their daily duties, structured questionnaires, in-depth interviews, and two focus group discussions. Structured data were analysed descriptively. Thematic content analysis was followed for qualitative data. Results were synthesized and interpreted using the capability, opportunity, motivation for behaviour change framework, COM-B. Results In addition to their responsibilities with the Ministry of Health, CHVs partnered with a range of non-governmental organizations engaged in health and development programming, often receiving small stipends from these organizations. CHVs reported employing a limited number of behaviour change techniques when interacting with community members at the household level. Capability: While supervision and support from the MOH was robust, CHV training was inconsistent and inadequate with regard to behaviour change and CHVs often lacked material resources necessary for their work. Opportunity: CHVs spent very little time with the households in their allocated catchment area. The number of households contacted per day was insufficient to reach all assigned households within a given month as required and the brief time spent with households limited the quality of engagement. Motivation: Lack of compensation was noted as a demotivating factor for CHVs. This was compounded by the challenging social environment and CHVs’ low motivation to encourage behaviour change in local communities. Conclusions In a complex urban environment, CHVs faced challenges that limited their capacity to be involved in behaviour change interventions. More resources, better coordination, and additional training in modern behaviour change approaches are needed to ensure their optimal performance in implementing health programmes.

Treatment of individuals with cystic fibrosis (CF) has been transformed by small molecule therapies that target select pathogenic variants in the CF transmembrane conductance regulator (CFTR). To expand treatment eligibility, we stably expressed 43 rare missense CFTR variants associated with moderate CF from a single site in the genome of human CF bronchial epithelial (CFBE41o-) cells. The magnitude of drug response was highly correlated with residual CFTR function for the potentiator ivacaftor, the corrector lumacaftor, and ivacaftor-lumacaftor combination therapy. Response of a second set of 16 variants expressed stably in Fischer rat thyroid (FRT) cells showed nearly identical correlations. Subsets of variants were identified that demonstrated statistically significantly higher responses to specific treatments. Furthermore, nearly all variants studied in CFBE cells (40 of 43) and FRT cells (13 of 16) demonstrated greater response to ivacaftor-lumacaftor combination therapy than either modulator alone. Together, these variants represent 87% of individuals in the CFTR2 database with at least 1 missense variant. Thus, our results indicate that most individuals with CF carrying missense variants are (a) likely to respond modestly to currently available modulator therapy, while a small fraction will have pronounced responses, and (b) likely to derive the greatest benefit from combination therapy.

Childhood diarrhea is one of the leading causes of morbidity and mortality in children under five in low and middle-income countries, second only to respiratory illness. The mouthing behavior that is common in children exposes them to fecal-orally transmitted pathogens that can result in diarrhea; however, there is a need for further evidence on specific exposure routes. This study describes the frequency and diversity of two important routes of enteric pathogen exposure among infants 3-9 months of age: infant oral contact behavior and caregiver handwashing behavior. Data were collected through structured observations of 25 index infants for the oral contact data and 25 households for the caregiver handwashing data in a peri-urban setting in Kisumu (Obunga), Kenya. Breast was the most common type of oral contact event with an average of 3.00 per observation period and 0.5 events per hour. This was followed by a range of physical objects with an average of 2.49 per observation and 0.4 events per hour. The "infant's own hands" was the third most common oral contact, with an average of 2.16 events per hour, and 0.4 oral contact events per hour. Food and liquids were the 4th and 5th most common oral contact events with an average of 1.64 food contacts and 0.52 liquid oral contact events per observation period. Feeding events, including breastfeeding, were the most commonly observed key juncture-71% of total junctures observed were caregivers feeding children. This was followed by child cleaning (23%), caregiver toilet uses at (4%), and lastly food preparation at 2%. HWWS was observed only once before a feeding event (1%), twice after cleaning a child (9%), and twice after caregiver toilet use (40%). The combined implication of data from observing oral contact behavior in children and hand hygiene of caregivers suggests that caregiver hand hygiene prior to feeding events and after cleaning a child are priority interventions.

To gain a better understanding of the evolution of animal cognition, it is necessary to test and compare the cognitive abilities of a broad array of taxa. Meaningful inter-species comparisons are best achieved by employing universal paradigms that standardize testing among species. Many cognitive paradigms, however, have been tested in only a few taxa, mostly birds and primates. One such example, known as the Aesop’s Fable paradigm, is designed to assess causal understanding in animals using water displacement. To evaluate the universal effectiveness of the Aesop’s Fable paradigm, we applied this paradigm to a previously untested taxon, the raccoon (Procyon lotor). We first trained captive raccoons to drop stones into a tube of water to retrieve a floating food reward. Next, we presented successful raccoons with objects that differed in the amount of water they displaced to determine whether raccoons could select the most functional option. Raccoons performed differently than corvids and human children did in previous studies of Aesop’s Fable, and we found raccoons to be innovative in many aspects of this task. We suggest that raccoon performance in this paradigm reflected differences in tangential factors, such as behavior, morphology, and testing procedures, rather than cognitive deficiencies. We also present insight into previously undocumented challenges that should better inform future Aesop’s Fable studies incorporating more diverse taxa.

Growth hormone (GH) facilitates therapy resistance in the cancers of breast, colon, endometrium, and melanoma. The GH-stimulated pathways responsible for this resistance were identified as suppression of apoptosis, induction of epithelial-to-mesenchymal transition (EMT), and upregulated drug efflux by increased expression of ATP-binding cassette containing multidrug efflux pumps (ABC-transporters). In extremely drug-resistant melanoma, ABC-transporters have also been reported to mediate drug sequestration in intracellular melanosomes, thereby reducing drug efficacy. Melanocyte-inducing transcription factor (MITF) is the master regulator of melanocyte and melanoma cell fate as well as the melanosomal machinery. MITF targets such as the oncogene MET, as well as MITF-mediated processes such as resistance to radiation therapy, are both known to be upregulated by GH. Therefore, we chose to query the direct effects of GH on MITF expression and activity towards conferring chemoresistance in melanoma. Here, we demonstrate that GH significantly upregulates MITF as well as the MITF target genes following treatment with multiple anticancer drug treatments such as chemotherapy, BRAF-inhibitors, as well as tyrosine-kinase inhibitors. GH action also upregulated MITF-regulated processes such as melanogenesis and tyrosinase activity. Significant elevation in MITF and MITF target gene expression was also observed in mouse B16F10 melanoma cells and xenografts in bovine GH transgenic (bGH) mice compared to wild-type littermates. Through pathway inhibitor analysis we identified that both the JAK2-STAT5 and SRC activities were critical for the observed effects. Additionally, a retrospective analysis of gene expression data from GTEx, NCI60, CCLE, and TCGA databases corroborated our observed correlation of MITF function and GH action. Therefore, we present in vitro, in vivo, and in silico evidence which strongly implicates the GH&ndash, GHR axis in inducing chemoresistance in human melanoma by driving MITF-regulated and ABC-transporter-mediated drug clearance pathways.

The development of cystic fibrosis transmembrane conductance regulator (CFTR) targeted therapy for cystic fibrosis has generated interest in maximizing membrane residence of mutant forms of CFTR by manipulating interactions with scaffold proteins, such as sodium/hydrogen exchange regulatory factor-1 (NHERF1). In this study, we explored whether COOH-terminal sequences in CFTR beyond the PDZ-binding motif influence its interaction with NHERF1. NHERF1 displayed minimal self-association in blot overlays (NHERF1, Kd= 1,382 ± 61.1 nM) at concentrations well above physiological levels, estimated at 240 nM from RNA-sequencing and 260 nM by liquid chromatography tandem mass spectrometry in sweat gland, a key site of CFTR function in vivo. However, NHERF1 oligomerized at considerably lower concentrations (10 nM) in the presence of the last 111 amino acids of CFTR (20 nM) in blot overlays and cross-linking assays and in coimmunoprecipitations using differently tagged versions of NHERF1. Deletion and alanine mutagenesis revealed that a six-amino acid sequence1417EENKVR1422and the terminal1478TRL1480(PDZ-binding motif) in the COOH-terminus were essential for the enhanced oligomerization of NHERF1. Full-length CFTR stably expressed in Madin-Darby canine kidney epithelial cells fostered NHERF1 oligomerization that was substantially reduced (∼5-fold) on alanine substitution of EEN, KVR, or EENKVR residues or deletion of the TRL motif. Confocal fluorescent microscopy revealed that the EENKVR and TRL sequences contribute to preferential localization of CFTR to the apical membrane. Together, these results indicate that COOH-terminal sequences mediate enhanced NHERF1 interaction and facilitate the localization of CFTR, a property that could be manipulated to stabilize mutant forms of CFTR at the apical surface to maximize the effect of CFTR-targeted therapeutics.

A nanopore DNA sequencer is used for real-time genomic surveillance of the Ebola virus epidemic in the field in Guinea; the authors demonstrate that it is possible to pack a genomic surveillance laboratory in a suitcase and transport it to the field for on-site virus sequencing, generating results within 24 hours of sample collection. This paper reports the use of nanopore DNA sequencers (known as MinIONs) for real-time genomic surveillance of the Ebola virus epidemic, in the field in Guinea. The authors demonstrate that it is possible to pack a genomic surveillance laboratory in a suitcase and transport it to the field for on-site virus sequencing, generating results within 24 hours of sample collection. The Ebola virus disease epidemic in West Africa is the largest on record, responsible for over 28,599 cases and more than 11,299 deaths1. Genome sequencing in viral outbreaks is desirable to characterize the infectious agent and determine its evolutionary rate. Genome sequencing also allows the identification of signatures of host adaptation, identification and monitoring of diagnostic targets, and characterization of responses to vaccines and treatments. The Ebola virus (EBOV) genome substitution rate in the Makona strain has been estimated at between 0.87 × 10−3 and 1.42 × 10−3 mutations per site per year. This is equivalent to 16–27 mutations in each genome, meaning that sequences diverge rapidly enough to identify distinct sub-lineages during a prolonged epidemic2,3,4,5,6,7. Genome sequencing provides a high-resolution view of pathogen evolution and is increasingly sought after for outbreak surveillance. Sequence data may be used to guide control measures, but only if the results are generated quickly enough to inform interventions8. Genomic surveillance during the epidemic has been sporadic owing to a lack of local sequencing capacity coupled with practical difficulties transporting samples to remote sequencing facilities9. To address this problem, here we devise a genomic surveillance system that utilizes a novel nanopore DNA sequencing instrument. In April 2015 this system was transported in standard airline luggage to Guinea and used for real-time genomic surveillance of the ongoing epidemic. We present sequence data and analysis of 142 EBOV samples collected during the period March to October 2015. We were able to generate results less than 24 h after receiving an Ebola-positive sample, with the sequencing process taking as little as 15–60 min. We show that real-time genomic surveillance is possible in resource-limited settings and can be established rapidly to monitor outbreaks.

Introduction Ventolin Nebules® (reference product; GlaxoSmithKline) was the first licensed nebulizer solution containing the rapid-onset, short-acting β2-agonist salbutamol. Salbutamol Steri-Neb™ (comparator; Teva Pharmaceuticals, Inc.) has the same chemical composition as the reference product. This study evaluated whether the effectiveness of the comparator is non-inferior to the reference product alongside concomitant medications during real-life clinical management of COPD exacerbations. Safety in terms of adverse events (AEs) was also examined. Methods This matched (1:1) historical cohort study evaluated data from 2 UK primary care databases on patients prescribed the salbutamol comparator or reference. The study included a 1-year baseline period, starting 1 year before the index prescription date, and 1-year outcome period. Cohorts were matched for baseline COPD respiratory medications. The primary outcome was analysis of non-inferiority for the comparator versus reference product for the rate of moderate and severe COPD exacerbations. Non-inferiority was satisfied if the 95% confidence interval (CI) upper limit for mean differences in proportions between treatments was

Prescribing patterns in chronic obstructive pulmonary disease (COPD) are often inconsistent with published guidelines. This retrospective, observational study utilised data from the Optimum Patient Care Research Database to examine the changes in COPD prescribing patterns over time and to identify predictors of physician treatment choice for patients newly diagnosed with COPD. Initial therapy was defined as the treatment(s) prescribed at or within 1 year before COPD diagnosis. Changes over time were assessed in three cohorts based on the date of diagnosis: (1) 1997–2001; (2) 2002–2006; and (3) 2007–2010. Factors affecting the odds of being prescribed any initial therapy or any initial maintenance therapy were identified by univariable and multivariable logistic regression. The analysis included 20,154 patients, 45% of whom were prescribed an initial regimen containing an inhaled corticosteroid (ICS), whereas 28% received no initial pharmacological treatment. Prescribing of ICS monotherapy decreased over time, as did the proportion of patients receiving no therapy at or within 1 year before diagnosis. Comorbid asthma, a high exacerbation rate, increased symptoms and poor lung function each increased the likelihood of being prescribed any initial therapy or initial maintenance therapy; comorbid asthma and an annual rate of ⩾3 exacerbations were the strongest predictors. In conclusion, our analyses revealed major differences between actual prescribing behaviour and guideline recommendations for patients with newly diagnosed COPD, with many patients receiving no treatment and large numbers of patients receiving ICS-containing regimens. Predictors of initial therapy were identified.

We introduce NetKet, a comprehensive open source framework for the study of many-body quantum systems using machine learning techniques. The framework is built around a general and flexible implementation of neural-network quantum states, which are used as a variational ansatz for quantum wavefunctions. NetKet provides algorithms for several key tasks in quantum many-body physics and quantum technology, namely quantum state tomography, supervised learning from wavefunction data, and ground state searches for a wide range of customizable lattice models. Our aim is to provide a common platform for open research and to stimulate the collaborative development of computational methods at the interface of machine learning and many-body physics., SoftwareX, 10, ISSN:2352-7110