Development of a Core Outcome Set and Minimum Reporting Set for intervention studies in growth restriction in the NEwbOrN (COSNEON): study protocol for a Delphi study.

BACKGROUND: Growth restriction in the newborn (GRN) can predispose to severe complications including hypoglycemia, sepsis, and necrotizing enterocolitis. Different interventions and treatments, such as feeding strategies, for GRN have specific benefits and risks. Comparing results from studies investigating intervention studies in GRN is challenging due to the use of different baseline and study characteristics and differences in reported study outcomes. In order to be able to compare study results and to allow pooling of data, uniform reporting of study characteristics (minimum reporting set [MRS]) and outcomes (core outcome set [COS]) are needed. We aim to develop both an MRS and a COS for interventional and treatment studies in GRN. METHODS/DESIGN: The MRS and COS will be developed according to Delphi methodology. First, a scoping literature search will be performed to identify study characteristics and outcomes in research focused on interventions/treatments in the GRN. An international group of stakeholders, including experts (clinicians working with GRN, and researchers who focus on GRN) and lay experts ([future] parents of babies with GRN), will be questioned to rate the importance of the study characteristics and outcomes in three rounds. After three rounds there will be two consensus meetings: a face-to-face meeting and an electronic meeting. During the consensus meetings multiple representatives of stakeholder groups will reach agreement upon which study characteristics and outcomes will be included into the COS and MRS. The second electronic consensus meeting will be used to test if an electronic meeting is as effective as a face-to-face meeting. DISCUSSION: In our opinion a COS alone is not sufficient to compare and aggregate trial data. Hence, to ensure optimum comparison we also will develop an MRS. Interventions in GRN infants are often complicated by coexisting preterm birth. A COS already has been developed for preterm birth. The majority of GRN infants are born at term, however, and we therefore chose to develop a separate COS for interventions in GRN, which can be combined (with expected overlap) in intervention studies enrolling preterm GRN babies. TRIAL REGISTRATION: Not applicable. This study is registered in the Core Outcome Measures for Effectiveness ( COMET ) database. Registered on 30 June 2017

Dextral and sinistral Amphidromus inversus (Gastropoda: Pulmonata: Camaenidae) produce dextral sperm

Coiling direction in pulmonate gastropods is determined by a single gene via a maternal effect, which causes cytoskeletal dynamics in the early embryo of dextral gastropods to be the mirror image of the same in sinistral ones. We note that pulmonate gastropod spermatids also go through a helical twisting during their maturation. Moreover, we suspect that the coiling direction of the helical elements of the spermatozoa may affect their behaviour in the female reproductive tract, giving rise to the possibility that sperm chirality plays a role in the maintenance of whole-body chiral dimorphism in the tropical arboreal gastropod Amphidromus inversus (Müller, 1774). For these reasons, we investigated whether there is a relationship between a gastropod’s body chirality and the chirality of the spermatozoa it produces. We found that spermatozoa in A. inversus are always dextrally coiled, regardless of the coiling direction of the animal itself. However, a partial review of the literature on sperm morphology in the Pulmonata revealed that chiral dimorphism does exist in certain species, apparently without any relationship with the coiling direction of the body. Though our study shows that body and sperm chirality follows independent developmental pathways, it gives rise to several questions that may be relevant to the understanding of the chirality of spermatid ultrastructure and spermatozoan motility and sexual selection

Building capacity for HIV/AIDS program leadership and management in Uganda through mentored Fellowships

Background: Around the world, health professionals and program managers are leading and managing public and private health organizations with little or no formal management and leadership training and experience. Objective: To describe an innovative 2-year, long-term apprenticeship Fellowship training program implemented by Makerere University School of Public Health (MakSPH) to strengthen capacity for leadership and management of HIV/AIDS programs in Uganda. Implementation process: The program, which began in 2002, is a 2-year, full-time, non-degree Fellowship. It is open to Ugandan nationals with postgraduate training in health-related disciplines. Enrolled Fellows are attached to host institutions implementing HIV/AIDS programs and placed under the supervision of host institution and academic mentors. Fellows spend 75% of their apprenticeship at the host institutions while the remaining 25% is dedicated to didactic short courses conducted at MakSPH to enhance their knowledge base. Achievements: Overall, 77 Fellows have been enrolled since 2002. Of the 57 Fellows who were admitted between 2002 and 2008, 94.7% (54) completed the Fellowship successfully and 50 (92.3%) are employed in senior leadership and management positions in Uganda and internationally. Eighty-eight percent of those employed (44/54) work in institutions registered in Uganda, indicating a high level of in-country retention. Nineteen of the 20 Fellows who were admitted between 2009 and 2010 are still undergoing training. A total of 67 institutions have hosted Fellows since 2002. The host institutions have benefited through staff training and technical expertise from the Fellows as well as through grant support to Fellows to develop and implement innovative pilot projects. The success of the program hinges on support from mentors, stakeholder involvement, and the hands-on approach employed in training. Conclusion: The Fellowship Program offers a unique opportunity for hands-on training in HIV/AIDS program leadership and management for both Fellows and host institutions

The INeS study: prevention of multiple pregnancies: a randomised controlled trial comparing IUI COH versus IVF e SET versus MNC IVF in couples with unexplained or mild male subfertility

BACKGROUND Multiple pregnancies are high risk pregnancies with higher chances of maternal and neonatal mortality and morbidity. In the past decades the number of multiple pregnancies has increased. This trend is partly due to the fact that women start family planning at an increased age, but also due to the increased use of ART. Couples with unexplained or mild male subfertility generally receive intrauterine insemination IUI with controlled hormonal stimulation (IUI COH). The cumulative pregnancy rate is 40%, with a 10% multiple pregnancy rate. This study aims to reveal whether alternative treatments such as IVF elective Single Embryo Transfer (IVF e SET) or Modified Natural Cycle IVF (MNC IVF) can reduce the number of multiple pregnancy rates, but uphold similar pregnancy rates as IUI COH in couples with mild male or unexplained subfertility. Secondly, the aim is to perform a cost effective analyses and assess treatment preference of these couples. METHODS/DESIGN We plan a multicentre randomised controlled clinical trial in the Netherlands comparing six cycles of intra-uterine insemination with controlled ovarian hyperstimulation or six cycles of Modified Natural Cycle (MNC) IVF or three cycles with IVF-elective Single Embryo Transfer (eSET) plus cryo-cycles within a time frame of 12 months. Couples with unexplained subfertility or mild male subfertility and a poor prognosis for treatment independent pregnancy will be included. Women with anovulatory cycles, severe endometriosis, double sided tubal pathology or serious endocrine illness will be excluded. Our primary outcome is the birth of a healthy singleton. Secondary outcomes are multiple pregnancy, treatment costs, and patient experiences in each treatment arm. The analysis will be performed according tot the intention to treat principle. We will test for non-inferiority of the three arms with respect to live birth. As we accept a 12.5% loss in pregnancy rate in one of the two IVF arms to prevent multiple pregnancies, we need 200 couples per arm (600 couples in total). DISCUSSION Determining the safest and most cost-effective treatment will ensure optimal chances of pregnancy for subfertile couples with substantially diminished perinatal and maternal complications. Should patients find the most cost-effective treatment acceptable or even preferable, this could imply the need for a world wide shift in the primary treatment. TRIAL REGISTRATION Current Controlled Trials ISRCTN 52843371Alexandra J Bensdorp, Els Slappendel, Carolien Koks, Jur Oosterhuis, Annemieke Hoek, Peter Hompes, Frank Broekmans, Harold Verhoeve, Jan Peter de Bruin, Janne Meije van Weert, Maaike Traas, Jacques Maas, Nicole Beckers, Sjoerd Repping, Ben W Mol, Fulco van der Veen and Madelon van Wel

Utilizing direct skin feeding assays for development of vaccines that interrupt malaria transmission: A systematic review of methods and case study.

Shifting the malaria priorities from a paradigm of control and elimination to a goal of global eradication calls for renewed attention to the interruption of malaria transmission. Sustained progress toward eradication will require both improved understanding of infectious reservoirs and efficient development of novel transmission-blocking interventions, such as rapidly acting and highly efficacious therapeutics and vaccines. Here, we review the direct skin feeding assay (DSF), which has been proposed as a valuable tool for measuring the in natura transmission of malaria parasites from human hosts to mosquito vectors across heterogeneous populations. To capture the methodological breadth of this assay's use, we first systematically review and qualitatively synthesize previously published investigations using DSFs to study malaria transmission in humans. Then, using a recent Phase 1 trial in Mali of the Pfs25H-EPA/Alhydrogel® vaccine candidate (NCT01867463) designed to interrupt Plasmodium falciparum transmission as a case study, we describe the potential opportunities and current limitations of utilizing the endpoints measured by DSF in making early clinical decisions for individually randomized transmission-interrupting intervention candidates. Using simulations based on the data collected in the clinical trial, we demonstrate that the capacity of the DSF to serve as an evaluative tool is limited by the statistical power constraints of the "effective sample size" (i.e. the number of subjects that are capable of transmitting at the time of feeding). Altogether, our findings suggest DSFs have great potential utility for assessing the public health impacts of emerging antimalarial tools, but additional research is needed to address issues of scalability and to establish correlation with community-wide clinical endpoints as well as complementary in vitro measures, such as standard membrane feeding assays

Possible bite-induced abscess and osteomyelitis in Lufengosaurus (Dinosauria: sauropodomorph) from the Lower Jurassic of the Yimen Basin, China

We report an osseous abnormality on a specimen of the sauropod dinosaur Lufengosaurus huenei from the Fengjiahe Formation in Yuxi Basin, China. A gross pathological defect occurs on the right third rib, which was subjected to micro-computed tomographic imaging as an aid in diagnosis. The analysis of pathological characteristics and the shape of the abnormality is incompatible with impact or healed trauma, such as a common rib fracture, and instead suggests focal penetration of the rib, possibly due to a failed predator attack. The identification of characteristics based on gross morphology and internal micro-morphology presented by the specimen, suggests an abscess with osteomyelitis as the most parsimonious explanation. Osteomyelitis is a severe infection originating in the bone marrow, usually resulting from the introduction of pyogenic (pus-producing) bacteria into the bone. Micro-tomographic imaging of the lesion suggests a degree of healing and bone remodelling following post-traumatic wound infection with evidence of sclerotic bone formation at the site of pathological focus, indicating that L. huenei survived the initial trauma. However, as osteomyelitis can express through widespread systemic effects, including a lowering of immune response and overall condition, this disease may have been a contributing factor to the eventual death of the individual

Objective and Self-Rated Sedentary Time and Indicators of Metabolic Health in Dutch and Hungarian 10–12 Year Olds: The ENERGY-Project

Background: The association between objectively assessed sedentary time and metabolic risk factors in childhood have rarely been studied. Therefore, we examined the independent relationship between objectively assessed and self-rated sedentary time and indicators of metabolic health in Dutch and Hungarian 10–12 year olds. Methodology/Principal Findings: We performed a cross-sectional survey in primary schools. Participants were Dutch and Hungarian girls (n = 73, aged 12.260.6 years, 18 % overweight/obese) and boys (n = 69, aged 12.260.7 years, 38% overweight/obese). Sedentary time and physical activity were assessed by the Actigraph accelerometer. TV and PC time were assessed by self-report. Adiposity indicators included body weight, height, and waist circumference (WC). Fasting plasma glucose, C-peptide, total cholesterol, low density lipoprotein cholesterol, high density lipoprotein cholesterol, and triglycerides were determined in capillary blood and summed into a metabolic risk score. Linear regression analyses were adjusted for physical activity, number of sedentary bouts and WC. Children spent on average 7.6 hours of their daily waking time in sedentary behavior and self-reported 116664 min/day watching TV and 85657 min/day using the computer. Comparing the 1 st and 4 th quartile of objectively assessed sedentary time, C-Peptide levels, WC and BMI were significantly higher in the most sedentary quartile, while the difference in metabolic risk score was borderline significant (p = 0.09). Comparing the 1 st and 4 th quartile of TV time, BMI was significantly higher in the most sedentary quartile, while th

Core Outcome Set for GROwth restriction: deVeloping Endpoints (COSGROVE).

BACKGROUND: Foetal growth restriction (FGR) refers to a foetus that does not reach its genetically predetermined growth potential. It is well recognised that growth-restricted foetuses are at increased risk of stillbirth, foetal compromise, early neonatal death and neonatal morbidity. Later in life, they are prone to health problems, including increased risk of cardiovascular diseases and neurodevelopmental disorders. Interventions for preventing and treating FGR have been studied in many trials, but evidence is often difficult to synthesise and compare because of differences in the selection and definition of outcomes. To enable future trials to measure similar, meaningful outcomes, we are developing two core outcome sets (COS) - one for prevention and the other for treatment of FGR. METHODS: We will review the literature to identify previously reported outcomes. An international panel of relevant stakeholders who have experience of FGR (parent or carer of a baby that was growth restricted, health professional involved in the care of mothers and babies affected by FGR, a person with expertise in FGR research) will rate the importance of each of those outcomes in a series of three sequential online rounds of a Delphi study. Participants will be able to add items to the proposed list in round 1. A final face-to-face consensus meeting will be held with representatives of each stakeholder group at which a final list of outcomes for inclusion in the COS will be agreed. DISCUSSION: The development of COSs in FGR will ensure the collection and reporting of a minimum dataset agreed by stakeholder consensus and will reduce inconsistencies in the reporting of outcomes across relevant trials. Such standardisation in the reporting of outcomes will improve synthesis of evidence and generalisability of knowledge in the future by reducing heterogeneity in outcomes between trials and thus improve the results of systematic reviews and meta-analyses. Ultimately, we hope that the COSs will lead to an improvement in the quality of evidence-based clinical practice, enhance patient care, and improve the quality and consistency of research. TRIAL REGISTRATION: Not applicable. This study is registered in the Core Outcome Measures for Effectiveness (COMET) database