Ontogenic effects of early feeding of sea bass (Dicentrarchus labrax) larvae with a range of dietary n-3 HUFA levels on the functioning of PUFA desaturation pathways

Four replicated groups of sea bass (Dicentrarchus labrax) larvae were fed diets containing an extra-high level of highly unsaturated fatty acids (HUFA) (XH; 3·7% EPA + DHA), a high level of HUFA (HH; 1·7 %), a low level of HUFA (LH; 0·7%) or an extra-low level of HUFA (XLH; 0·5%) from day 6 to day 45 (experiment 1; XH1, HH1, LH1, XLH1). After a subsequent 1-month period feeding a commercial diet (2·7% EPA + DHA), the capacity of the four initial groups to adapt to an n-3 HUFA-restricted diet (0·3% EPA + DHA; R-groups: XH2R, HH2R, LH2R, XLH2R) was tested for 35 d. Larval dietary treatments had no effect on larval and juvenile survival rates. The wet weight of day 45 larvae was higher in XH1 and HH1 (P < 0·001), but the R-juvenile mass gains were similar in all treatments. D-6-desaturase (D6D) mRNA level was higher in LH1 and XLH1 at day 45 (

Chalcogenide Glass Optical Waveguides for Infrared Biosensing

Due to the remarkable properties of chalcogenide (Chg) glasses, Chg optical waveguides should play a significant role in the development of optical biosensors. This paper describes the fabrication and properties of chalcogenide fibres and planar waveguides. Using optical fibre transparent in the mid-infrared spectral range we have developed a biosensor that can collect information on whole metabolism alterations, rapidly and in situ. Thanks to this sensor it is possible to collect infrared spectra by remote spectroscopy, by simple contact with the sample. In this way, we tried to determine spectral modifications due, on the one hand, to cerebral metabolism alterations caused by a transient focal ischemia in the rat brain and, in the other hand, starvation in the mouse liver. We also applied a microdialysis method, a well known technique for in vivo brain metabolism studies, as reference. In the field of integrated microsensors, reactive ion etching was used to pattern rib waveguides between 2 and 300 μm wide. This technique was used to fabricate Y optical junctions for optical interconnections on chalcogenide amorphous films, which can potentially increase the sensitivity and stability of an optical micro-sensor. The first tests were also carried out to functionalise the Chg planar waveguides with the aim of using them as (bio)sensors

Nurse staffing, medical staffing and mortality in intensive care: an observational study

Objectives: To investigate whether the size of the workforce (nurses, doctors and support staff) has an impact of the survival chances of critically ill patients both in the intensive care unit (ICU) and in the hospital. Background: Investigations of intensive care outcomes suggest that some of the variation in patient survival rates might be related to staffing levels and workload, but the evidence is still equivocal. Data: Information about patients, including the outcome of care (whether the patient lived or died) came from the Intensive Care National Audit & Research Centre (ICNARC) Case Mix Programme. An Audit Commission survey of ICUs conducted in 1998 gave information about staffing levels. The merged dataset had information on 65 ICUs and 38,168 patients. This is currently the best available dataset for testing the relationship between staffing and outcomes in UK ICUs Design: A cross-sectional, retrospective, risk adjusted observational study. Methods: Multivariable, multilevel logistic regression. Outcome Measures: ICU and in-hospital mortality. Results: After controlling for patient characteristics and workload we found that higher numbers of nurses per bed and higher numbers of consultants were associated with higher survival rates. Further exploration revealed that the number of nurses had the greatest impact on patients at high risk of death whereas the effect of medical staffing was across the range of patient acuity. No relationship between patient outcomes and the number of support staff was found. Distinguishing between direct care and supernumerary nurses and restricting the analysis to patients who had been in the unit for more than 8 hours made little difference to the results. Separate analysis of in-unit and in-hospital survival showed that the clinical workforce in intensive care had a greater impact on ICU mortality than on hospital mortality which gives the study additional credibility. Conclusion: This study supports claims that the availability of medical and nursing staff is associated with the survival of critically ill patients and suggests that future studies should focus on the resources of the health care team. The results emphasise the urgent need for a prospective study of staffing levels and the organisation of care in ICUs

Feasibility and Effectiveness of Basic Lymphedema Management in Leogane, Haiti, an Area Endemic for Bancroftian Filariasis

Lymphatic filariasis is a parasitic disease that is spread by mosquitoes. In tropical countries where lymphatic filariasis occurs, approximately 14 million people suffer from chronic swelling of the leg, known as lymphedema. Repeated episodes of bacterial skin infection (acute attacks) cause lymphedema to progress to its disfiguring form, elephantiasis. To help achieve the goal of eliminating lymphatic filariasis globally, the World Health Organization recommends basic lymphedema management, which emphasizes hygiene, skin care, exercise, and leg elevation. Its effectiveness in reducing acute attack frequency, as well as the role of compressive bandaging, have not been adequately evaluated in filariasis-endemic areas. Between 1995 and 1998, we studied 175 people with lymphedema of the leg in Leogane, Haiti. During Phase I of the study, when compression bandaging was used to reduce leg volume, the average acute attack rate was 1.56 episodes per year; it was greater in people who were illiterate and those who used compression bandages. After March 1997, when hygiene and skin care were emphasized and bandaging discouraged, acute attack frequency significantly decreased to 0.48 episodes per year. This study highlights the effectiveness of hygiene and skin care, as well as limitations of compressive bandaging, in managing lymphedema in filariasis-endemic areas

Uncertainties and controversies in axillary management of patients with breast cancer

The aims of this Oncoplastic Breast Consortium and European Breast Cancer Research Association of Surgical Trialists initiative were to identify uncertainties and controversies in axillary management of early breast cancer and to recommend appropriate strategies to address them. By use of Delphi methods, 15 questions were prioritized by more than 250 breast surgeons, patient advocates and radiation oncologists from 60 countries. Subsequently, a global virtual consensus panel considered available data, ongoing studies and resource utilization. It agreed that research should no longer be prioritized for standardization of axillary imaging, de-escalation of axillary surgery in node-positive cancer and risk evaluation of modern surgery and radiotherapy. Instead, expert consensus recommendations for clinical practice should be based on current evidence and updated once results from ongoing studies become available. Research on de-escalation of radiotherapy and identification of the most relevant endpoints in axillary management should encompass a meta-analysis to identify knowledge gaps, followed by a Delphi process to prioritize and a consensus conference to refine recommendations for specific trial designs. Finally, treatment of residual nodal disease after surgery was recommended to be assessed in a prospective register

Neurodevelopmental and Epilepsy Phenotypes in Individuals With Missense Variants in the Voltage-Sensing and Pore Domains of KCNH5

Background and Objectives KCNH5 encodes the voltage-gated potassium channel EAG2/Kv10.2. We aimed to delineate the neurodevelopmental and epilepsy phenotypic spectrum associated with de novo KCNH5 variants.Methods We screened 893 individuals with developmental and epileptic encephalopathies for KCNH5 variants using targeted or exome sequencing. Additional individuals with KCNH5 variants were identified through an international collaboration. Clinical history, EEG, and imaging data were analyzed; seizure types and epilepsy syndromes were classified. We included 3 previously published individuals including additional phenotypic details.Results We report a cohort of 17 patients, including 9 with a recurrent de novo missense variant p.Arg327His, 4 with a recurrent missense variant p.Arg333His, and 4 additional novel missense variants. All variants were located in or near the functionally critical voltage-sensing or pore domains, absent in the general population, and classified as pathogenic or likely pathogenic using the American College of Medical Genetics and Genomics criteria. All individuals presented with epilepsy with a median seizure onset at 6 months. They had a wide range of seizure types, including focal and generalized seizures. Cognitive outcomes ranged from normal intellect to profound impairment. Individuals with the recurrent p.Arg333His variant had a self-limited drug-responsive focal or generalized epilepsy and normal intellect, whereas the recurrent p.Arg327His variant was associated with infantile-onset DEE. Two individuals with variants in the pore domain were more severely affected, with a neonatal-onset movement disorder, early-infantile DEE, profound disability, and childhood death.Discussion We describe a cohort of 17 individuals with pathogenic or likely pathogenic missense variants in the voltage-sensing and pore domains of Kv10.2, including 14 previously unreported individuals. We present evidence for a putative emerging genotype-phenotype correlation with a spectrum of epilepsy and cognitive outcomes. Overall, we expand the role of EAG proteins in human disease and establish KCNH5 as implicated in a spectrum of neurodevelopmental disorders and epilepsy.</p

Oncoplastic breast consortium recommendations for mastectomy and whole breast reconstruction in the setting of post-mastectomy radiation therapy

Aim: Demand for nipple-and skin-sparing mastectomy (NSM/SSM) with immediate breast reconstruction (BR) has increased at the same time as indications for post-mastectomy radiation therapy (PMRT) have broadened. The aim of the Oncoplastic Breast Consortium initiative was to address relevant questions arising with this clinically challenging scenario. Methods: A large global panel of oncologic, oncoplastic and reconstructive breast surgeons, patient advocates and radiation oncologists developed recommendations for clinical practice in an iterative process based on the principles of Delphi methodology. Results: The panel agreed that surgical technique for NSM/SSM should not be formally modified when PMRT is planned with preference for autologous over implant-based BR due to lower risk of long-term complications and support for immediate and delayed-immediate reconstructive approaches. Nevertheless, it was strongly believed that PMRT is not an absolute contraindication for implant-based or other types of BR, but no specific recom-mendations regarding implant positioning, use of mesh or timing were made due to absence of high-quality evidence. The panel endorsed use of patient-reported outcomes in clinical practice. It was acknowledged that the shape and size of reconstructed breasts can hinder radiotherapy planning and attention to details of PMRT techniques is important in determining aesthetic outcomes after immediate BR. Conclusions: The panel endorsed the need for prospective, ideally randomised phase III studies and for surgical and radiation oncology teams to work together for determination of optimal sequencing and techniques for PMRT for each patient in the context of BRPeer reviewe

Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice.

Pathogenic variants in KMT5B, a lysine methyltransferase, are associated with global developmental delay, macrocephaly, autism, and congenital anomalies (OMIM# 617788). Given the relatively recent discovery of this disorder, it has not been fully characterized. Deep phenotyping of the largest (n = 43) patient cohort to date identified that hypotonia and congenital heart defects are prominent features that were previously not associated with this syndrome. Both missense variants and putative loss-of-function variants resulted in slow growth in patient-derived cell lines. KMT5B homozygous knockout mice were smaller in size than their wild-type littermates but did not have significantly smaller brains, suggesting relative macrocephaly, also noted as a prominent clinical feature. RNA sequencing of patient lymphoblasts and Kmt5b haploinsufficient mouse brains identified differentially expressed pathways associated with nervous system development and function including axon guidance signaling. Overall, we identified additional pathogenic variants and clinical features in KMT5B-related neurodevelopmental disorder and provide insights into the molecular mechanisms of the disorder using multiple model systems

Reducing disease burden and health inequalities arising from chronic disease among indigenous children: an early childhood caries intervention in Aotearoa/New Zealand

BACKGROUND Maaori are the Indigenous people of New Zealand and do not enjoy the same oral health status as the non-Indigenous majority. To overcome oral health disparities, the life course approach affords a valid foundation on which to develop a process that will contribute to the protection of the oral health of young infants. The key to this process is the support that could be provided to the parents or care givers of Maaori infants during the pregnancy of the mother and the early years of the child. This study seeks to determine whether implementing a kaupapa Maaori (Maaori philosophical viewpoint) in an early childhood caries (ECC) intervention reduces dental disease burden among Maaori children. The intervention consists of four approaches to prevent early childhood caries: dental care provided during pregnancy, fluoride varnish application to the teeth of children, motivational interviewing, and anticipatory guidance. METHODS/DESIGN The participants are Maaori women who are expecting a child and who reside within the Maaori tribal area of Waikato-Tainui. This randomised-control trial will be undertaken utilising the principles of kaupapa Maaori research, which encompasses Maaori leadership, Maaori relationships, Maaori customary practices, etiquette and protocol. Participants will be monitored through clinical and self-reported information collected throughout the ECC intervention. Self-report information will be collected in a baseline questionnaire during pregnancy and when children are aged 24 and 36 months. Clinical oral health data will be collected during standardised examinations at ages 24 and 36 months by calibrated dental professionals. All participants receive the ECC intervention benefits, with the intervention delayed by 24 months for participants who are randomised to the control-delayed arm. Discussion The development and evaluation of oral health interventions may produce evidence that supports the application of the principles of kaupapa Maaori research in the research processes. This study will assess an ECC intervention which could provide a meaningful approach for Maaori for the protection and maintenance of oral health for Maaori children and their family, thus reducing oral health disparities. TRIAL REGISTRATION Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12611000111976.John R Broughton, Joyce Te H Maipi, Marie Person, W Murray Thomson, Kate C Morgaine, Sarah-Jane Tiakiwai, Jonathan Kilgour, Kay Berryman, Herenia P Lawrence, Lisa M Jamieso

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms