An Integrated Analysis of Maternal-Infant Sleep, Breastfeeding, and Sudden Infant Death Syndrome Research Supporting a Balanced Discourse

Breastfeeding and the place of sleep for the mother and the infant have been controversial internationally due to reported concerns regarding infant deaths despite the known benefits of exclusive and prolonged breastfeeding, which are increased by breastfeeding at night. The aims of this integrated analysis were to (a) review breastfeeding and maternal and infant sleep research literature via historical, epidemiological, anthropological, and methodological lenses; (b) use this information to determine where we are currently in safeguarding both infant lives and breastfeeding; and (c) postulate the direction that research might take from this point forward to improve our knowledge and inform our policy and practice. Despite well-meaning but unsuccessful campaigns in some countries to dissuade parents from sleeping with their babies, many breastfeeding mothers and caregivers do sleep with their infants whether intentionally or unintentionally. Taking cultural contexts and socio-ecological circumstances into consideration, data supports policies to counsel parents and caregivers on safe sleep practices, including bed-sharing in non-hazardous circumstances, particularly in the absence of parental smoking, recent parental alcohol consumption, or sleeping next to an adult on a sofa. Further research with appropriate methodology is needed to drill down on actual rates of infant deaths, paying close attention to the definitions of deaths, the circumstances of the deaths, and confounding factors, in order to ensure we have the best information with which to derive public health policy. Introduction and use of the concept of “breastsleeping” is a plausible way to remove the negative connotations of “co-sleeping” and redirect ongoing data-driven discussions and education of best practices of breastfeeding and sleep

Dynamic clonal progression in xenografts of acute lymphoblastic leukemia with intrachromosomal amplification of chromosome 21

Intrachromosomal amplification of chromosome 21 is a heterogeneous chromosomal rearrangement occurring in 2% of childhood precursor B-cell acute lymphoblastic leukemia. There are no cell lines with iAMP21 and these abnormalities are too complex to faithfully engineer in animal models. As a resource for future functional and pre-clinical studies, we have created xenografts from intrachromosomal amplification of chromosome 21 leukemia patient blasts and characterised them by in-vivo and ex-vivo luminescent imaging, FLOW immunophenotyping, and histological and ultrastructural analysis of bone marrow and the central nervous system. Investigation of up to three generations of xenografts revealed phenotypic evolution, branching genomic architecture and, compared with other B-cell acute lymphoblastic leukemia genetic subtypes, greater clonal diversity of leukemia initiating cells. In support of intrachromosomal amplification of chromosome 21 as a primary genetic abnormality, it was always retained through generations of xenografts, although we also observed the first example of structural evolution of this rearrangement. Clonal segregation in xenografts revealed convergent evolution of different secondary genomic abnormalities implicating several known tumour suppressor genes and a region, containing the B-cell adaptor, PIK3AP1, and nuclear receptor co-repressor, LCOR, in the progression of B-ALL. Tracking of mutations in patients and derived xenografts provided evidence for co-operation between abnormalities activating the RAS pathway in B-ALL and for their aggressive clonal expansion in the xeno-environment. Bi-allelic loss of the CDKN2A/B locus was recurrently maintained or emergent in xenografts and also strongly selected as RNA sequencing demonstrated a complete absence of reads for genes associated with the deletions

Evc2 is a positive modulator of Hedgehog signalling that interacts with Evc at the cilia membrane and is also found in the nucleus

<p>Abstract</p> <p>Background</p> <p>Evc is essential for Indian Hedgehog (Hh) signalling in the cartilage growth plate. The gene encoding Evc2 is in close proximity in divergent orientation to <it>Evc </it>and mutations in both human genes lead to the chondrodysplasia Ellis-van Creveld syndrome.</p> <p>Results</p> <p>Bioinformatic analysis reveals that the <it>Evc </it>and <it>Evc2 </it>genes arose through a duplication event early in metazoan evolution and were subsequently lost in arthropods and nematodes. Here we demonstrate that Evc2 is essential for Hh pathway activation in response to the Smo agonist purmorphamine. A yeast two-hybrid screen using Evc as bait identified Evc2 as an Evc binding partner and we confirmed the interaction by immunoprecipitation. We developed anti-Evc2 antibodies and show that Evc2 and Evc co-localize at the basal body and also on primary cilia. In transfected cells, basal body and cilia localization is observed when Evc and Evc2 constructs are co-transfected but not when either construct is transfected individually. We show that Evc and Evc2 are cilia transmembrane proteins, the C-terminus for both being intracellular and Evc2, but not Evc, having an extracellular portion. Furthermore, Evc is absent at the basal body in Evc2 null cells. Using Western blots of cytoplasmic and nuclear protein, we also demonstrate that full length Evc2 but not Evc, is located in the nucleus.</p> <p>Conclusions</p> <p>We demonstrate for the first time that Evc2 is a positive regulator of the Hh signalling pathway and that it is located at the basal body of primary cilia. We show that the presence of Evc and Evc2 at the basal body and cilia membrane is co-dependent. In addition, Evc2, but not Evc, is present in the cell nucleus suggesting movement of Evc2 between the cilium and nucleus.</p

Statistical analysis plan for the Urodynamics for Prostate Surgery Trial; Randomised Evaluation of Assessment Methods (UPSTREAM)

Abstract Background Current management for men with lower urinary tract symptoms (LUTS) is a pathway that results in prostate surgery in a significant proportion. While helpful in relieving benign prostatic obstruction (BPO), surgery may be ineffective for men suffering from difficulties not relating to BPO. The UPSTREAM trial started recruitment in October 2014 with the aim of establishing whether a care pathway including urodynamics (a diagnostic tool for BPO and thus an indication of whether surgery is needed) is no worse for men, in terms of symptomatic outcome, than one without (routine care). Methods/design This analysis plan outlines the main outcomes of the study and specific design choices, such as non-inferiority margins. The trial is currently recruiting in 26 hospitals across the UK, randomising men to either urodynamics or routine care, with recruitment set to end on the 31 December 2016. All outcomes will be measured 18 months after randomisation to allow sufficient time for surgical procedures and recovery. The primary outcome is based on a non-inferiority design with a margin of 1 point on the International Prostate Symptom Score (IPSS) scale. The key secondary outcome for this trial is surgery rate per arm, which is estimated to be at least 18% lower in the urodynamics arm. Surgery rates, adverse events, flow rate, urinary symptoms and sexual symptoms are secondary outcomes to be assessed for superiority. This is an update to the UPSTREAM protocol, which has already been published in this journal. Discussion This a priori statistical analysis plan aims to reduce reporting bias by allowing access to the trial’s objectives and plans in advance of recruitment end. The results of the trial are expected to be published soon after the trial end date of 30 September 2018. Trial registration ISRCTN registry, ISRCTN56164274 . Registered on 8 April 2014

Bedsharing and Breastfeeding: The Academy of Breastfeeding Medicine Protocol #6, Revision 2019

A central goal of the Academy of Breastfeeding Medicine is the development of clinical protocols for managing common medical problems that may impact breastfeeding success. These protocols serve only as guidelines for the care of breastfeeding mothers and infants and do not delineate an exclusive course of treatment or serve as standards of medical care. Variations in treatment may be appropriate according to the needs of an individual patient

Expression of homologous RND efflux pump genes is dependent upon AcrB expression:implications for efflux and virulence inhibitor design

OBJECTIVES: Enterobacteriaceae have multiple efflux pumps that confer intrinsic resistance to antibiotics. AcrB mediates clinically relevant multidrug resistance and is required for virulence and biofilm formation, making it an attractive target for the design of inhibitors. The aim of this study was to assess the viability of single transporters as a target for efflux inhibition using Salmonella Typhimurium as the model pathogen. METHODS: The expression of resistance–nodulation–division (RND) efflux pump genes in response to the inactivation of single or multiple homologues was measured using real-time RT–PCR. Phenotypes of mutants were characterized by measuring antimicrobial susceptibility, dye accumulation and the ability to cause infection in vitro. RESULTS: The expression of all RND efflux pump genes was increased when single or multiple acr genes were inactivated, suggesting a feedback mechanism that activates the transcription of homologous efflux pump genes. When two or three acr genes were inactivated, the mutants had further reduced efflux, altered susceptibility to antimicrobials (including increased susceptibility to some, but conversely and counterintuitively, decreased susceptibility to some others) and were more attenuated in the tissue culture model than mutants lacking single pumps were. CONCLUSIONS: These data indicate that it is critical to understand which pumps an inhibitor is active against and the effect of this on the expression of homologous systems. For some antimicrobials, an inhibitor with activity against multiple pumps will have a greater impact on susceptibility, but an unintended consequence of this may be decreased susceptibility to other drugs, such as aminoglycosides

Risk of Parkinson disease in carriers of parkin mutations : estimation using the kin-cohort method

Objective: To estimate the risk of Parkinson disease (PD) in individuals with mutations in the Parkin gene. Design: We assessed point mutations and exon deletions and duplications in the Parkin gene in 247 probands with PD (age at onset 50 years) and 104 control probands enrolled in the Genetic Epidemiology of Parkinson's Disease (GEPD) study. For each first-degree relative, a consensus diagnosis of PD was established. The probability that each relative carried a mutation was estimated from the proband's Parkin carrier status using Mendelian principles and from the relationship of the relative to the proband. Setting: Tertiary care movement disorders center. Patients: Cases, controls, and their first-degree relatives were enrolled in the GEPD study. Main Outcome Measures: Estimated age-specific penetrance in first-degree relatives. Results: Parkin mutations were identified in 25 probands with PD (10.1%), 18 (72.0%) of whom were heterozygotes. One Parkin homozygote was reported in 2 siblings with PD. The cumulative incidence of PD to age 65 years in carrier relatives (age-specific penetrance) was estimated to be 7.0% (95% confidence interval, 0.4%-71.9%), compared with 1.7% (95% confidence interval, 0.8%-3.4%) in noncarrier relatives of the cases (P = .59) and 1.1% (95% confidence interval, 0.3%-3.4%) in relatives of the controls (compared with noncarrier relatives, P = .52). Conclusions: The cumulative risk of PD to age 65 years in a noncarrier relative of a case with an age at onset of 50 years or younger is not significantly greater than the general population risk among controls. Age-specific penetrance among Parkin carriers, in particular heterozygotes, deserves further study. Mutations in the Parkin gene (PARK2; GenBank AB009973) are associated primarily with early-onset Parkinson disease (PD), defined as age at onset (AAO) ranging from 45 years or younger to 55 years or younger, but have also been described in PD cases with an AAO older than 70 years. In PD cases with an AAO of 45 years or younger with a mode of inheritance consistent with autosomal recessive transmission, the frequency of Parkin mutations may be as high as 49%, whereas in cases without a family history of PD the range is 15% to 18%. Age at onset is inversely correlated with the frequency of Parkin mutations in both familial and sporadic cases. Several studies have compared the AAO of PD in heterozygous, compound heterozygous, and homozygous Parkin mutation carriers and found that heterozygous cases, both familial and sporadic, have an older AAO. Heterozygous Parkin mutation carriers are more frequently reported among sporadic than familial cases. Information on the risk of PD in individuals who carry Parkin mutations in either the homozygous, compound heterozygous, or heterozygous state (or penetrance) is essential for genetic counseling. The penetrance of Parkin mutations has only been reported for isolated families. Most of the previous study designs sampled PD cases based on family history of PD, which would bias penetrance estimates upwards. To obtain an unbiased estimate of risk, a population-based random sample would be desirable, but Parkin mutations are so rare in the population that such a sample would have to be extremely large to obtain sufficient precision in penetrance estimates. To obtain unbiased estimates of the risk of PD in Parkin carriers despite the low population frequency of Parkin mutations, we used a kin-cohort study design applied to participants in the Genetic Epidemiology of Parkinson's Disease (GEPD) study. The kin-cohort design is highly efficient for estimating penetrance because the relatives' mutation status is not required for the analyses, thus reducing costs for genetic analysis