A Critical Reappraisal of the Bleeding Time.

Seminars in Thrombosis and Hemostasis (STH) celebrates 50 years of publishing in 2024. To celebrate this landmark event, STH is republishing some archival material. This manuscript represents the second most highly cited paper ever published in STH. The manuscript published without an abstract, and essentially represented a State of the Art Review on the bleeding time, a relatively invasive procedure that required an incision on the skin or earlobe of a patient, and timing how long it took for the incision to stop bleeding. The bleeding time test was first described in 1901 by the French physician Milian, who presented three studies of bleeding from stab wounds made in the fingertips of healthy and diseased subjects. In 1910, Duke observed the duration of bleeding from small incisions of the ear lobe, and pointed out that the duration of bleeding was increased in instances of reduced platelet counts. The test was subsequently repeatedly modified, and numerous variants of the test, including semiautomated methods, were described by several workers. The most frequently utilised test reflected one described by Ivy and coworkers, who shifted the location of the incision to the volar aspect of the forearm and applied a blood pressure cuff to the arm to maintain a standard venous pressure. The bleeding time has been proposed for use as a diagnostic test for platelet-related bleeding disorders, a measure of efficacy in various forms of therapy, and as a prognosticator of abnormal bleeding. The authors to the current review reevaluated the bleeding time literature using methods to assess the performance of the test in 1990, locating 862 printed documents that discussed the bleeding time, the majority in peer-reviewed professional journals. As this is a republication of archival material, transformed into a modern format, we apologise in advance for any errors introduced during this transformation.

Experiences of Users with an Online Self-Guided Mental Health Training Program Using Gamification.

Young adulthood is a period of high risk for the development of mental health concerns. Increasing well-being among young adults is important to prevent mental health concerns and their consequences. Self-compassion has been identified as a modifiable trait with the potential to protect against mental health concerns. An online self-guided mental health training program using gamification was developed and the user experience was evaluated in a 6-week experimental design. During this period, 294 participants were allocated to use the online training program via a website. User experience was assessed via self-report questionnaires, and interaction data for the training program were also collected. Results showed that those who completed the intervention (n= 47) visited the website on average 3.2 days a week, with a mean of 45.8 interactions during the 6 weeks. Participants report positive user experiences of the online training, on average a System Usability Scale Brooke (1) score of 79.1 (out of 100) at the end-point. Participants showed positive engagement with story elements of the training, based on an average score of 4.1 (out of 5) in the evaluation of the story at the end-point. This study found the online self-compassion intervention for youth to be acceptable, although some features seem preferred by users as compared to others. Gamification in the form of a guiding story and a reward structure seemed to be a promising element for successfully motivating participants and serving as a guiding metaphor for self-compassion.

Circulating cell-free endometrial DNA level is unaltered during menstruation and in endometriosis.

STUDY QUESTION: Is circulating cell-free DNA (cirDNA) from the endometrium elevated during menstruation and in endometriosis? SUMMARY ANSWER: Endometrial cirDNA does not increase during menstruation and is not elevated in endometriosis. WHAT IS KNOWN ALREADY: Changes in cirDNA associated with common benign conditions are a potential source of false positives in cancer diagnostic applications, but also present an opportunity for biomarker development for diseases such as endometriosis. Elevated cirDNA has been reported in endometriosis patients compared to healthy community controls, but no difference in total or endometrial cirDNA has been found between patients with endometriosis and patients with other gynaecological conditions. Likewise, menstruation is a potential driver of changes in cirDNA levels and tissue profile, but total and endothelial cirDNA do not increase during menstruation. STUDY DESIGN, SIZE, DURATION: For endometriosis comparisons, 59 participants with surgically confirmed endometriosis and 27 laparoscopic patients without endometriosis (hospital controls) were prospectively recruited, while 25 healthy community participants (healthy controls) were recruited in a university setting. Total and endometrial cirDNA and cirDNA fragmentation were measured across the three groups. For menstrual comparisons, 36 matched non-menstruating and menstruating samples were collected from healthy women recruited within a university setting, and the endometrial cirDNA was compared between the two groups. PARTICIPANTS/MATERIALS, SETTING, METHODS: cirDNA was extracted from venous blood plasma then quantitated by quantitative PCR of ALU repetitive element (115 bp) and TP53 gene sequence (105 bp) for total concentration. cirDNA derived from the endometrium was quantitated by methylation-specific droplet digital PCR of a FAM101A region (69 bp) after bisulfite conversion of the DNA. A cirDNA size fragmentation ratio was obtained by quantifying a long segment of ALU repetitive element (247 bp) and expressing the amount relative to the 115 bp ALU target. MAIN RESULTS AND THE ROLE OF CHANCE: No differences in cirDNA level were found in any comparison populations in this study. Mean total cirDNA was unchanged between healthy controls (ALU-115-3.31 ng/ml; TP53-2.73 ng/ml), hospital controls (ALU-115-3.47 ng/ml; TP53-2.83 ng/ml) and endometriosis patients (ALU-115-3.35 ng/ml; TP53-2.66 ng/ml). Likewise, endometrial cirDNA was unchanged between healthy controls (18.3 copies/ml), hospital controls (20.6 copies/ml) and endometriosis patients (22 copies/ml). Endometrial cirDNA did not change during menstruation (non-menstruating: 38 copies/ml; menstruating: 33 copies/ml). Irrespective of endometriosis diagnosis, blood from patients undergoing laparoscopy (hospital controls: 0.77; endometriosis patients: 0.79), had a significantly higher cirDNA size ratio than community-recruited healthy controls (0.64), indicating increased abundance of long cirDNA fragments. LIMITATIONS, REASONS FOR CAUTION: It was not possible to completely match the age, BMI and parity between the three cohorts investigated, however of these, only age has been shown to influence circulating DNA levels and not within the age range of our cohort. Blood from community-recruited healthy women and women undergoing laparoscopy was collected via antecubital vein venepuncture (processed within 3 h) and with either peripheral cannula or venepuncture (processed within 6 h), respectively, which could potentially impact the size distribution of circulating DNA fragments. For the collection of non-menstruating phase blood samples, we did not differentiate between follicular phase, ovulation and luteal phase. Thus, only the mensturating samples were collected at a consistent phase, and any fluctuations in cirDNA that occur at the other phases may have obscured small changes during menstruation. WIDER IMPLICATIONS OF THE FINDINGS: There is no evidence that cirDNA has potential as a diagnostic biomarker for endometriosis. Endometriosis, representing a common benign gynaecological condition, and menstruation, representing a normal physiological occurrence in women, should not affect methylation-based diagnostics in other disease areas, including oncology. STUDY FUNDING/COMPETING INTEREST(S): N.L.Y.: Australian Government Research Training Program (RTP) Stipend through The University of New South Wales, Translational Cancer Research Network PhD Scholarship Top-Up Award via the Cancer Institute NSW, Beth Yarrow Memorial Award in Medical Science, UNSW Completion Scholarship; C.E.H.: Gynaecological Oncology Fund of the Royal Hospital for Women; K.W.: Ovarian Cancer Research Foundation and CAMILLA AND MARC. C.E.F.: UNSW Women's Wellbeing Academy and the Australian Human Rights Institute. We declare the following competing interest: K.W. holds stock in Guardant Health, Exact Sciences and Epigenomics AG. No other authors have competing interests. TRIAL REGISTRATION NUMBER: N/A.

Supplementation of rangeland primiparous Bos indicus x Bos taurus beef heifers during lactation. 1. Effects on dam milk production and liveweight, bull calf growth, live carcass characteristics and metabolic hormone concentrations.

The practice of feeding replacement-breeding bulls on high energy diets after weaning to meet liveweight (LW) and carcass expectations between 18 and 24 months of age negatively affects reproductive potential. This experiment reports upon the effects of an alternative management strategy aimed at improving calfhood nutrition in rangeland-reared bulls to enhance LW and live carcass characteristics at 2 years. Following artificial insemination (AI cohort; n = 26), or natural mating, subsequent to the addition of bulls at 39 d post-AI (NM cohort; n = 36), primiparous Santa Gertrudis heifers grazing rangeland pastures with bull calf progeny were allocated at parturition to receive either nil supplement (control; CON) or provided with unrestricted access to a pelleted vegetable protein meal-based supplement containing 35% CP (SUPP) until weaning at 199 ± (SD) 26 d. The mean estimated pellet consumption by SUPP heifers during lactation was 2.6 ± (SEM) 0.5 kg DM daily. Grazing diet quality measurements indicated nutritional restriction of CON heifers until at least 115 d of lactation. This was confirmed by lower blood urea nitrogen concentrations at 88 d (P < 0.001) and greater mean NEFA (P < 0.001) concentrations. Rainfall during mid-lactation subsequently improved grazing diet quality; thus the CON heifers experienced moderate nutritional restriction across lactation, but sufficient to reduce milk yield by 1.6 kg/d (P < 0.001) and maternal LW at weaning by 18.4 kg (P < 0.001). Bulls reared by SUPP heifers were 17.5 kg heavier at weaning (P = 0.001) and had elevated IGF-I and leptin concentrations between 4 and 4.5 months of age (P < 0.05). Effects on metabolic hormones during calfhood were cohort specific, with greater concentrations of IGF-I confined to AISUPP bulls and NMSUPP bulls demonstrating greater concentrations of leptin. Bulls were amalgamated at weaning and grazed common pastures without supplementation until the experiment concluded at 675 d. Pre-weaning plane of nutrition did not affect the LW, carcass fat depth, IGF-I or leptin concentrations of bulls after weaning. Mean eye muscle area (EMA) was greater in SUPP compared to CON bulls (68.5 ± 0.9 cm2vs 65.2 ± 0.9 cm2; P < 0.05) and AISUPP bulls tended to have greater EMA (P = 0.06) than AICON bulls from 495 d of age. Thus when primiparous heifers experience moderate nutritional restriction during lactation, supplementation may have persistent effects upon increasing carcass muscle characteristics of bull progeny.

Supplementation of rangeland primiparous Bos indicus x Bos taurus beef heifers during lactation. 2. Effects upon the reproductive development of bull calf progeny.

This experiment evaluated the effect of pre-weaning plane of nutrition of dams upon reproductive development in Bos indicus x Bos taurus bull offspring reared under extensively managed conditions in the northern Australia rangelands. Following artificial insemination (AI cohort; n = 26), or natural mating (NM cohort; n = 36), grazing primiparous heifers received either nil supplement (Control; CON), thereby experiencing a moderate nutritional restriction, or were provided a protein supplement (SUPP) between parturition and weaning at mean age 199 ± (SD) 26 d. Bull progeny grazed rangeland pastures without supplementation from weaning until the experiment concluded at 675 d. At 120 ± 3 d and 140 d ± 10 d age, within the AI and NM cohort, respectively, bull calves were subjected to a GnRH challenge (1.5 µg/kg of body weight i.m.). Jugular blood samples collected immediately before and at 60 min after administration of GnRH were analysed for LH, FSH, testosterone and inhibin concentrations. Overall mean concentrations of testosterone in SUPP bulls were greater in both the AI cohort (P = 0.05) and the NM cohort (P = 0.06). At 60 d intervals during the post-weaning period, scrotal circumference (SC) was measured and semen collected to assess concentration, progressive motility and morphology of sperm. Bulls reared by SUPP heifers had greater (P = 0.05) SC at 375 d and tended to have greater (P = 0.09) mean percentage of morphologically normal sperm (PNS). Within the NM cohort, NMSUPP bulls had greater (P = 0.04) overall mean SC and tended (P = 0.07) to demonstrate both greater progressive motility and PNS. A greater incidence of sperm morphological abnormalities, associated with sexual immaturity, were observed in CON bulls. Consequently, NMCON bulls demonstrated delayed (P = 0.03) age of sexual maturity as compared to NMSUPP bulls. In summary, improving the plane of nutrition supplied to Bos indicus x Bos taurus bulls between parturition and weaning via moderate supplementation of grazing dams reduces age at sexual maturity with consequent economic advantages to the producer.

Characterizing a body positive online forum: Resistance and pursuit of appearance-ideals.

The body positive movement emerged in response to pressure to pursue the unattainable thin ideal, and promotes a more accepting stance towards the body. To date, however, little is known regarding the nature of online body positive content. Using publicly available data from a large online discussion platform (Reddit), all the forums to which commenters on a body acceptance forum (N = 1262) had also contributed were identified. For each pairing of 50 representative forums (i.e., a large number and proportion of body acceptance commenters), the commenter-overlap between the two forums was used to compute a network model, to detect communities of body acceptance commenters. By manually reviewing the topics of each community's forums, the shared interests of these commenters were identified. The majority of commenters (86 %) contributed to forums relating to women, feminism, relationships and support, and mental health. Large proportions of the commenters also revealed an interest in topics including body weight/shape, eating, exercise, and cosmetics. These findings confirm that original feminist tenets of body positivity remain present. However, our findings also suggest the existence of a sizeable subgroup interacting with topics related to the thin ideal, perhaps illustrating a gradual absorption of the body positive movement into mainstream culture.

Pre-positioned Outbreak Research: The Joint Medical Emerging Diseases Intervention Clinical Capability Experience in Uganda.

The West Africa Ebola virus disease outbreak of 2014-2016 demonstrated that responses to viral hemorrhagic fever epidemics must go beyond emergency stopgap measures and should incorporate high-quality medical care and clinical research. Optimal patient management is essential to improving outcomes, and it must be implemented regardless of geographical location or patient socioeconomic status. Coupling clinical research with improved care has a significant added benefit: Improved data quality and management can guide the development of more effective supportive care algorithms and can support regulatory approvals of investigational medical countermeasures (MCMs), which can alter the cycle of emergency response to reemerging pathogens. However, executing clinical research during outbreaks of high-consequence pathogens is complicated and comes with ethical and research regulatory challenges. Aggressive care and excellent quality control must be balanced by the requirements of an appropriate infection prevention and control posture for healthcare workers and by overcoming the resource limitations inherent in many outbreak settings. The Joint Mobile Emerging Disease Intervention Clinical Capability was established in 2015 to develop a high-quality clinical trial capability in Uganda to support rigorous evaluation of MCMs targeting high-consequence pathogens like Ebola virus. This capability assembles clinicians, laboratorians, clinical researchers, logisticians, and regulatory professionals trained in infection prevention and control and in good clinical and good clinical laboratory practices. The resulting team is prepared to provide high-quality medical care and clinical research during high-consequence outbreaks.

Exercise and insulin resistance in PCOS: muscle insulin signalling and fibrosis.

OBJECTIVE: Mechanisms of insulin resistance in polycystic ovary syndrome (PCOS) remain ill defined, contributing to sub-optimal therapies. Recognising skeletal muscle plays a key role in glucose homeostasis we investigated early insulin signalling, its association with aberrant transforming growth factor ß (TGFß)-regulated tissue fibrosis. We also explored the impact of aerobic exercise on these molecular pathways. METHODS: A secondary analysis from a cross-sectional study was undertaken in women with (n = 30) or without (n = 29) PCOS across lean and overweight BMIs. A subset of participants with (n = 8) or without (n = 8) PCOS who were overweight completed 12 weeks of aerobic exercise training. Muscle was sampled before and 30 min into a euglycaemic-hyperinsulinaemic clamp pre and post training. RESULTS: We found reduced signalling in PCOS of mechanistic target of rapamycin (mTOR). Exercise training augmented but did not completely rescue this signalling defect in women with PCOS. Genes in the TGFß signalling network were upregulated in skeletal muscle in the overweight women with PCOS but were unresponsive to exercise training except for genes encoding LOX, collagen 1 and 3. CONCLUSIONS: We provide new insights into defects in early insulin signalling, tissue fibrosis, and hyperandrogenism in PCOS-specific insulin resistance in lean and overweight women. PCOS-specific insulin signalling defects were isolated to mTOR, while gene expression implicated TGFß ligand regulating a fibrosis in the PCOS-obesity synergy in insulin resistance and altered responses to exercise. Interestingly, there was little evidence for hyperandrogenism as a mechanism for insulin resistance.

Quantification of viable granulosa cells in murine ovarian follicles.

Ovarian follicle growth and oocyte maturation depend on the viability of granulosa cells (GC). We quantified GC in whole mouse follicles. Single follicles were isolated from adult mouse ovaries and stained with DAPI or Live-Dead stain before fixation. An objective image analysis protocol for counting fluorescent labeled GC was developed that used Image J software to measure GC cytoplasmic and nuclear areas. These data were compared to the number of GC obtained by disaggregating 96 follicles with enzymes to produce a suspension of GC, which then was stained with trypan blue and assessed using a hemocytometer. We found a linear relation between GC/follicle and follicle diameter. Viability of GC/follicle ranged from 40 ± 11 to 72 ± 7%. The coefficient of variation for image analysis of DAPI stained GC by different assessors was 4%, but the number of GC obtained from image analysis was approximately 50% less than from disaggregated follicles. The number of GC in intact mouse follicles was greater than the number reported earlier for fixed ovarian sections. We found that the number of GC was less in fluorescence labeled follicles; it is possible that the three-dimensional structure of the intact follicles obscured the fluorescent signal. Direct quantification of viable GC isolated from follicles appears to be the most accurate method.

Maternal periconceptional and first trimester protein restriction in beef heifers: effects on placental parameters and fetal and neonatal calf development.

Few studies have investigated the effects of nutrition during the periconception and early gestation periods on fetal and placental development in cattle. In this study, nulliparous yearling heifers (n=360) were individually fed a diet high or low in protein (HPeri and LPeri) beginning 60 days before conception. From 24 to 98 days after conception, half of each treatment group was changed to the alternative high- or low-protein diet (HPost and LPost) yielding four groups in a 2×2 factorial design. A subset of heifers (n=46) was necropsied at 98 days after conception and fetoplacental development assessed. Placentome number and volume decreased in response to LPeri and LPost diets respectively. Absolute lung, pancreas, septum and ventricle weights decreased in LPost versus HPost fetuses, whereas the post-conception diet altered absolute and relative liver and brain weights depending on sex. Similarly, changes in fetal hepatic gene expression of factors regulating growth, glucose output and lipid metabolism were induced by protein restriction in a sex-specific manner. At term, neonatal calf and placental measures were not different. Protein restriction of heifers during the periconception and early gestation periods alters fetoplacental development and hepatic gene expression. These changes may contribute to functional consequences for progeny, but this may not be apparent from gross morphometry at birth.

Evidence summaries and recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome: assessment and treatment of infertility.

STUDY QUESTION: What is the recommended assessment and management of infertile women with polycystic ovary syndrome (PCOS), based on the best available evidence, clinical expertize and consumer preference? SUMMARY ANSWER: International evidence-based guidelines, including 44 recommendations and practice points, addressed prioritized questions to promote consistent, evidence-based care and improve the experience and health outcomes of infertile women with PCOS. WHAT IS KNOWN ALREADY: Previous guidelines on PCOS lacked rigorous evidence-based processes, failed to engage consumer and multidisciplinary perspectives or were outdated. The assessment and management of infertile women with PCOS are inconsistent. The needs of women with PCOS are not being adequately met and evidence practice gaps persist. PARTICIPANTS/MATERIALS SETTING METHODS: Governance included a six continent international advisory and a project board, a multidisciplinary international guideline development group (GDG), consumer and translation committees. Extensive health professional and consumer engagement informed the guideline scope and priorities. The engaged international society-nominated panel included endocrinology, gynaecology, reproductive endocrinology, obstetrics, public health and other experts, alongside consumers, project management, evidence synthesis and translation experts. Thirty-seven societies and organizations covering 71 countries engaged in the process. Extensive online communication and two face-to-face meetings over 15 months addressed 19 prioritized clinical questions involving nine evidence-based reviews and 10 narrative reviews. Evidence-based recommendations (EBRs) were formulated prior to consensus voting within the guideline panel. STUDY DESIGN SIZE DURATION: International evidence-based guideline development engaged professional societies and consumer organizations with multidisciplinary experts and women with PCOS directly involved at all stages. A (AGREE) II-compliant processes were followed, with extensive evidence synthesis. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework was applied across evidence quality, desirable and undesirable consequences, feasibility, acceptability, cost, implementation and ultimately recommendation strength. The guideline was peer-reviewed by special interest groups across our partner and collaborating societies and consumer organizations, was independently assessed against AGREE II criteria and underwent methodological review. This guideline was approved by all members of the GDG and has been approved by the NHMRC. MAIN RESULTS AND THE ROLE OF CHANCE: The quality of evidence (QOE) for the EBRs in the assessment and management of infertility in PCOS included very low (n = 1), low (n = 9) and moderate (n = 4) quality with no EBRs based on high-quality evidence. The guideline provides 14 EBRs, 10 clinical consensus recommendations (CCRs) and 20 clinical practice points on the assessment and management of infertility in PCOS. Key changes in this guideline include emphasizing evidence-based fertility therapy, including cheaper and safer fertility management. LIMITATIONS REASONS FOR CAUTION: Overall evidence is generally of low to moderate quality, requiring significantly greater research in this neglected, yet common condition. Regional health systems vary and a process for adaptation of this guideline is provided. WIDER IMPLICATIONS OF THE FINDINGS: The international guideline for the assessment and management of infertility in PCOS provides clinicians with clear advice on best practice based on the best available evidence, expert multidisciplinary input and consumer preferences. Research recommendations have been generated and a comprehensive multifaceted dissemination and translation program supports the guideline with an integrated evaluation program. STUDY FUNDING/COMPETING INTERESTS: The guideline was primarily funded by the Australian National Health and Medical Research Council of Australia (NHMRC) supported by a partnership with ESHRE and the American Society for Reproductive Medicine (ASRM). GDG members did not receive payment. Travel expenses were covered by the sponsoring organizations. Disclosures of conflicts of interest were declared at the outset and updated throughout the guideline process, aligned with NHMRC guideline processes. Dr Costello has declared shares in Virtus Health and past sponsorship from Merck Serono for conference presentations. Prof. Norman has declared a minor shareholder interest in the IVF unit Fertility SA, travel support from Merck and grants from Ferring. Prof. Norman also has scientific advisory board duties for Ferring. The remaining authors have no conflicts of interest to declare.This article was not externally peer-reviewed by Human Reproduction Open.

The within-subject application of diffusion tensor MRI and CLARITY reveals brain structural changes in Nrxn2 deletion mice.

Background: Of the many genetic mutations known to increase the risk of autism spectrum disorder, a large proportion cluster upon synaptic proteins. One such family of presynaptic proteins are the neurexins (NRXN), and recent genetic and mouse evidence has suggested a causative role for NRXN2 in generating altered social behaviours. Autism has been conceptualised as a disorder of atypical connectivity, yet how single-gene mutations affect such connectivity remains under-explored. To attempt to address this, we have developed a quantitative analysis of microstructure and structural connectivity leveraging diffusion tensor MRI (DTI) with high-resolution 3D imaging in optically cleared (CLARITY) brain tissue in the same mouse, applied here to the Nrxn2α knockout (KO) model. Methods: Fixed brains of Nrxn2α KO mice underwent DTI using 9.4 T MRI, and diffusion properties of socially relevant brain regions were quantified. The same tissue was then subjected to CLARITY to immunolabel axons and cell bodies, which were also quantified. Results: DTI revealed increases in fractional anisotropy in the amygdala (including the basolateral nuclei), the anterior cingulate cortex, the orbitofrontal cortex and the hippocampus. Axial diffusivity of the anterior cingulate cortex and orbitofrontal cortex was significantly increased in Nrxn2α KO mice, as were tracts between the amygdala and the orbitofrontal cortex. Using CLARITY, we find significantly altered axonal orientation in the amygdala, orbitofrontal cortex and the anterior cingulate cortex, which was unrelated to cell density. Conclusions: Our findings demonstrate that deleting a single neurexin gene (Nrxn2α) induces atypical structural connectivity within socially relevant brain regions. More generally, our combined within-subject DTI and CLARITY approach presents a new, more sensitive method of revealing hitherto undetectable differences in the autistic brain.

Morphometric and gene expression analyses of stromal expansion during development of the bovine fetal ovary.

During ovarian development stroma from the mesonephros penetrates and expands into the ovarian primordium and thus appears to be involved, at least physically, in the formation of ovigerous cords, follicles and surface epithelium. Cortical stromal development during gestation in bovine fetal ovaries (n=27) was characterised by immunohistochemistry and by mRNA analyses. Stroma was identified by immunostaining of stromal matrix collagen type I and proliferating cells were identified by Ki67 expression. The cortical and medullar volume expanded across gestation, with the rate of cortical expansion slowing over time. During gestation, the proportion of stroma in the cortex and total volume in the cortex significantly increased (P<0.05). The proliferation index and numerical density of proliferating cells in the stroma significantly decreased (P<0.05), whereas the numerical density of cells in the stroma did not change (P>0.05). The expression levels of 12 genes out of 18 examined, including osteoglycin (OGN) and lumican (LUM), were significantly increased later in development (P<0.05) and the expression of many genes was positively correlated with other genes and with gestational age. Thus, the rate of cortical stromal expansion peaked in early gestation due to cell proliferation, whilst late in development expression of extracellular matrix genes increased.

Peri-conception and first trimester diet modifies reproductive development in bulls.

Nutritional perturbation during gestation alters male reproductive development in rodents and sheep. In cattle both the developmental trajectory of the feto-placental unit and its response to dietary perturbations is dissimilar to that of these species. This study examined the effects of dietary protein perturbation during the peri-conception and first trimester periods upon reproductive development in bulls. Nulliparous heifers (n=360) were individually fed a high- or low-protein diet (HPeri and LPeri) from 60 days before conception. From 24 until 98 days post conception, half of each treatment group changed to the alternative post-conception high- or low-protein diet (HPost and LPost) yielding four treatment groups in a 2×2 factorial design. A subset of male fetuses (n=25) was excised at 98 days post conception and fetal testis development was assessed. Reproductive development of singleton male progeny (n=40) was assessed until slaughter at 598 days of age, when adult testicular cytology was evaluated. Low peri-conception diet delayed reproductive development: sperm quality was lowered during pubertal development with a concomitant delay in reaching puberty. These effects were subsequent to lower FSH concentrations at 330 and 438 days of age. In the fetus, the low peri-conception diet increased the proportion of seminiferous tubules and decreased blood vessel area in the testis, whereas low first trimester diet increased blood vessel number in the adult testis. We conclude that maternal dietary protein perturbation during conception and early gestation may alter male testis development and delay puberty in bulls.

Complications of external cephalic version: a retrospective analysis of 1121 patients at a tertiary hospital in Sydney.

OBJECTIVE: To report the complication rate associated with external cephalic version (ECV) at term. DESIGN: Single-centre retrospective study. SETTING: A major tertiary hospital in Sydney, Australia. POPULATION OR SAMPLE: All women who underwent an ECV at Royal Prince Alfred Hospital from 1995-2013 were included. METHODS: ECV was attempted on all consenting women with a breech presentation at term in the absence of contraindications. Complications were classified as minor (transient cardiotocography abnormalities, ruptured membranes, small antepartum haemorrhage) or serious (fetal death, placental abruption, fetal distress requiring emergency caesarean section, fetal bone injury, cord prolapse). ECV success rates and rate of reversion to breech were recorded. MAIN OUTCOME MEASURES: The primary outcome was the incidence of serious complications. Secondary outcome measures were the rate of minor complications and reversion to breech. RESULTS: Of 1121 patients that underwent ECV, five (0.45%) experienced a serious complication. There was one placental abruption, one emergency caesarean section for fetal distress and two cord prolapses. There was one fetal death attributable to a successful ECV. Forty-eight women (4.28%) experienced a minor complication. Reversion to the breech occurred in sixteen patients (3.32%). CONCLUSION: ECV at term is associated with a low rate of serious complications. TWEETABLE ABSTRACT: Study of 1121 consecutive ECV attempts shows low rate of complications although one fetal death reported.

Bench to bedside in appetite research: Lost in translation?

Despite substantial progress in our understanding of the complex bio-machinery involved in the regulation of appetite and energy homeostasis, few weight loss drugs are currently government-approved in the USA or Europe. While acknowledging novel drug monotherapies (such as Belviq® & Saxenda®), this review focuses on the various drug polytherapies that are currently attracting so much research interest. Unfortunately, however, the dependent variables in these new studies remain firmly rooted in outcome measures i.e. reduced food intake and bodyweight. Such evidence is clearly essential, as are physiological data bearing upon potential 'off-target' effects of any new treatment. However, as emphasised by many authors, this profiling has to be matched by sophisticated behavioural analysis addressing fundamental 'process' questions such as how such reductions in intake and/or bodyweight have been achieved. The value of behavioural analysis is exemplified, and it is argued that such a process-led approach should optimise the translation from preclinical to clinical development of candidate drugs, and avoid yet further expensive blind alleys.

Subacute ruminal acidosis reduces sperm quality in beef bulls.

Breeding bulls are commonly fed high-energy diets, which may induce subacute ruminal acidosis (SARA). In this experiment, 8 Santa Gertrudis bulls (age 20 ± 6 mo) were used to evaluate the extent and duration of effects of SARA on semen quality and the associated changes in circulating hormones and metabolites. The bulls were relocated and fed in yards with unrestricted access to hay and daily individual concentrate feeding for 125 d before SARA challenge. Semen was collected and assessed at 14-d intervals before the challenge to ensure acclimatization and the attainment of a stable spermiogram. The challenge treatments consisted of either a single oral dose of oligofructose (OFF; 6.5 g/kg BW) or an equivalent sham dose of water (Control). Locomotion, behavior, respiratory rate, and cardiovascular and gastrointestinal function were intensively monitored during the 24-h challenge period. Rumen fluid samples were retained for VFA, ammonia, and lactate analysis. After the challenge, semen was then collected every third day for a period of 7 wk and then once weekly until 12 wk, with associated blood collection for FSH, testosterone, inhibin, and cortisol assay. Percent normal sperm decreased in bulls dosed with OFF after the challenge period ( < 0.05) and continued to remain lower on completion of the study at 88 d after challenge. There was a corresponding increase in sperm defects commencing from 16 d after challenge. These included proximal cytoplasmic droplets ( < 0.001), distal reflex midpieces ( = 0.01), and vacuole and teratoid heads ( < 0.001). Changes in semen quality after challenge were associated with lower serum testosterone ( < 0.001) and FSH ( < 0.05). Serum cortisol in OFF bulls tended to be greater ( = 0.07) at 7 d after challenge. This study shows that SARA challenge causes a reduction in sperm quality sufficient to preclude bulls from sale as single sire breeding animals 3 mo after the event occurred.

[Problematic Internet use, time spent online and personality traits]. / Utilisation problématique d'Internet, temps passé en ligne et traits de personnalité.

BACKGROUND: Internet addiction or problematic Internet use is a recent and increasingly recognized disorder which has been consistently associated with many psychiatric disorders, adding to the documented negative consequences of problematic Internet use. However, very few studies have examined the relationship between problematic Internet use and personality traits and none in a French sample. Moreover, those which have evaluated this relationship have mainly been conducted on small samples. OBJECTIVE: The main goal of our study was to explore the relationship between problematic Internet use, time spent online and personality traits in a French sample, taking into account the presence of depressive symptoms, and gender. METHODS: A sample of 276 participants aged from 18 to 50 (M=28; SD=8.9) completed a questionnaire assessing problematic Internet use, time spent online, the presence of ten personality traits and depressive symptoms. RESULTS: Our results revealed significant differences between genders. Among men, problematic Internet use was associated with personality clusters A and B while in women no cluster or personality traits were associated. Time spent online was predicted by schizoid personality traits among men and avoidant personality traits among women. DISCUSSION: Our results indicate that cluster A (schizoid and schizotypal) and cluster B traits (borderline and antisocial) play a more important role in problematic Internet use than cluster C traits among men. Differences between men and women regarding the relationships between personality traits, time online and problematic Internet use may be related to differences in the activities engaged in by men and women online. We observed that communication websites use was more prevalent among women while erotic, gambling and shopping websites use was more prevalent among men suggesting that the characteristics of problematic Internet use may vary according to gender. CONCLUSION: Few studies have examined the relationship between problematic Internet use, time spent online and personality traits, and none among a French sample. These results suggest the importance of assessing the impact of personality traits on Internet use, particularly on time spent online, by differentiating results in terms of gender and online activities.