Curcumin abrogates cobalt-induced neuroinflammation by suppressing proinflammatory cytokines release, inhibiting microgliosis and modulation of ERK/MAPK signaling pathway.

Curcumin, a bioactive polyphenol derived from turmeric, has been reported to have anti-inflammatory properties. The current study investigated the anti-inflammatory effect of curcumin in the hippocampal subfields (CA1 and CA3) after exposure to cobalt (Co) and the impact of ERK protein. Twenty-eight albino Wistar rats were divided into four groups, each with seven randomly selected rats as follows: Control (distilled water), Cobalt (Co) only (40 mg/kg), 120 mg/kg or 240 mg/kg curcumin + Co (40 mg/kg). Treatment was via oral gavage for 28 days. We performed a biochemical investigation to determine the levels of proinflammatory cytokines (TNFα and IL-1ß). Furthermore, we conducted an immunohistochemical evaluation to assess the expression of IBA1 by microglial cells and the immunoexpression of ERK protein in the hippocampus. Results revealed a significant (p<0.05) elevation in the tissue level of TNFα and IL-1ß, an increase in the number of IBA1-positive microglia, and upregulation of ERK protein in the hippocampal subfields of the rats after exposure to cobalt-only. Nevertheless, pretreatment with curcumin restored these parameters to levels comparable to control. In conclusion, our results showed that curcumin abrogated the Co-induced neuroinflammation by suppressing the release of proinflammatory biomarkers, reducing microgliosis, and modulating the ERK/MAPK pathway.

Frequency and reporting of complications after Dupuytren's contracture interventions: A systematic review and meta-analysis.

INTRODUCTION: Numerous complications are reported following interventions for Dupuytren's contracture; however, their incidence, management, and outcomes remain poorly reported. The aims of this review were to report the proportions of complications, compare likelihood of complications between interventions, and evaluate reporting of complications, including assessment, grading, management, and subsequent reporting of their impact on patient outcomes. METHODS: Extracted data included patient demographics, intervention details, complications, their management, and final outcomes. Analysis of descriptive data enabled review of complications reporting. Meta-analysis(MA) of non-comparative datasets enabled estimation of proportions of patients experiencing complications. Network meta-analysis(NMA) of comparative studies estimated the relative occurrence of complications between interventions. Risk of bias analysis was performed. RESULTS: 26 studies, comprising 10,831 patients, were included. Interventions included collagenase injection, percutaneous needle fasciotomy(PNF), limited fasciectomy(LF), open fasciotomy(OF), and dermofasciectomy(DF). Overall quality and consistency of outcomes reporting was poor. MA enabled estimates of probabilities for three common complications(infection, nerve injury, complex regional pain syndrome(CRPS)) across all interventions; the reported rates for LF were 4.5% for infection, 3% for nerve injury, and 3.3% for CRPS. As the commonest intervention, LF was used as the reference intervention for comparison of the commonest complications via NMA, including haematoma [OF OR 0.450(0.277, 0.695); PNF OR 0.245(0.114, 0.457)], infection [PNF OR 0.2(0.0287, 0.690); DF OR 2.02(1.02, 3.74)], and neuropraxia [PNF OR 0.0926(0.00553, 0.737)]. We noted that the complication incidence was higher the more invasive the intervention. CONCLUSIONS: There was limited reporting of complication occurrence, management, and outcomes following interventions, contributing to a gap in information for informed patient consent. MA was possible for reporting of proportions for infection, nerve injury, and CRPS across interventions. NMA enabled direct comparison of the six commonest complications between interventions. These findings can guide intervention selection. Improving consistency and quality in complications reporting is essential to aid counselling of patients regarding the true rates and consequences of the risks of interventions. TYPE OF STUDY/LEVEL OF EVIDENCE: 2.

Intraoperative computed tomography for orbital reconstruction: a systematic review.

Orbital reconstruction is a common procedure with inherent challenges and important consequences. Intraoperative use of computed tomography (CT) is an emerging application that facilitates accurate intraoperative evaluation to improve clinical outcomes. This review aims to investigate the intraoperative and postoperative outcomes of intraoperative CT use in orbital reconstruction. PubMed and Scopus databases were systematically searched. Inclusion criteria were: clinical studies investigating intraoperative CT use in orbital reconstruction. Exclusion criteria were: duplicates; non-English publications; non-full-text publications; studies with insufficient data. Of the 1022 articles identified, seven eligible articles representing 256 cases were included. The mean age was 39 years. Most cases were male (69.9%). With regards to intraoperative outcomes, the mean revision rate was 34.1%, with plate repositioning being the most common type (51.1%). Intraoperative time was variably reported. With regards to postoperative outcomes, there were no revisions, and only one case that had a complication (transient exophthalmos). Mean volumetric difference between the repaired and contralateral orbits was reported in two studies. The findings of this review present an updated evidence-based summary of the intraoperative and postoperative outcomes of intraoperative CT use in orbital reconstruction. Robust longitudinal comparisons of clinical outcomes between intraoperative and non-intraoperative CT cases are required.

Barriers and enablers of vigorous intermittent lifestyle physical activity (VILPA) in physically inactive adults: a focus group study.

BACKGROUND: Vigorous Intermittent Lifestyle Physical Activity (VILPA) refers to brief bouts of vigorous intensity physical activity performed as part of daily living. VILPA has been proposed as a novel concept to expand physical activity options among the least active. As a nascent area of research, factors which impede or encourage VILPA in physically inactive adults are yet to be explored. Such information is pertinent in the design of future interventions. We examined the barriers and enablers of VILPA among physically inactive adults using the Capability, Opportunity, Motivation, Behavior (COM-B) model as a conceptual framework. METHODS: We recruited a sample of self-identified physically inactive middle-aged and older adults (N = 78) based in Australia to take part in 19 online focus groups across three age groups: young-middle (age 35-44), middle (age 45-59) and old (age 60-76). We analyzed interviews using a critical realist approach to thematic analysis. Identified barriers and enablers were subsequently mapped onto the COM-B model components. RESULTS: The data generated 6 barriers and 10 enablers of VILPA that corresponded to COM-B concepts. Barriers included physical limitations (physical capability), perceptions of aging, need for knowledge (psychological capability), environmental constraints (physical opportunity), perceptions of effort and energy, and fear (automatic motivation). Enablers included convenience, reframing physical activity as purposeful movement, use of prompts and reminders (physical opportunity), normalization of taking the active option, gamification (social opportunity), sense of achievement, health improvements, personally salient rewards (reflective motivation), identity fit, and changing from effortful deliberation to habitual action (automatic motivation). CONCLUSION: The barriers and enablers of VILPA span capability, opportunity, and motivation beliefs. Promoting the time-efficient nature and simplicity of VILPA requiring no equipment or special gym sessions, the use of prompts and reminders at opportune times, and habit formation strategies could capitalize on the enablers. Addressing the suitability of the small bouts, the development of specific guidelines, addressing safety concerns, and explicating the potential benefits of, and opportunities to do, VILPA could ameliorate some of the barriers identified. Future VILPA interventions may require limited age customization, speaking to the potential for such interventions to be delivered at scale.

[Transition, fertility and options for preservation of fertility]. / Transition, fertilité et options de préservation de fertilité.

Oftentimes ignored or infrequently expressed, some transgender persons harbor a desire for parenthood. Given the evolution of medical techniques and the enacting of legislative reforms, it is henceforth possible to propose fertility preservation strategies in the overall context of gender transidentity. During the "female to male" (FtM) transition pathway, androgen therapy has an impact on gonadic function, generally inducing blockage of the ovarian function, with amenorrhea. Even though these events may be reversed on cessation of treatment, the possible long-term effects on future fertility and on the health of children yet to be born are little known. Moreover, transition surgeries definitively compromise the possibility of pregnancy insofar as they involve bilateral adnexectomy and/or hysterectomy. Options for fertility preservation in the framework of FtM transition are premised on cryopreservation of oocytes and/or ovarian tissue. In a comparable manner, even though relevant documentation is lacking, hormonal treatments for persons transitioning from male to female (MtF) can have an impact on future fertility. In the event of surgery involving bilateral orchidectomy in which spermatozoid cryopreservation has not been carried out, fertility is definitively impossible. In both cases and under present-day legislation, numerous legal and regulatory barriers render highly problematic the reutilization of cryopreserved gametes. Given these different constraints, it is indispensable to closely supervise these types of treatment by proposing psychological support.

Dihydroartemisinin-induced ferroptosis in acute myeloid leukemia: links to iron metabolism and metallothionein.

Artemisinin is an anti-malarial drug that has shown anticancer properties. Recently, ferroptosis was reported to be induced by dihydroartemisinin (DHA) and linked to iron increase. In the current study, we determined the effect of DHA in leukemic cell lines on ferroptosis induction and iron metabolism and the cytoprotective effect triggered in leukemic cells. We found that treatment of DHA induces early ferroptosis by promoting ferritinophagy and subsequent iron increase. Furthermore, our study demonstrated that DHA activated zinc metabolism signaling, especially the upregulation of metallothionein (MT). Supportingly, we showed that inhibition MT2A and MT1M isoforms enhanced DHA-induced ferroptosis. Finally, we demonstrated that DHA-induced ferroptosis alters glutathione pool, which is highly dependent on MTs-driven antioxidant response. Taken together, our study indicated that DHA activates ferritinophagy and subsequent ferroptosis in AML and that MTs are involved in glutathione regenerating and antioxidant response.

Modulatory Role of Curcumin on Cobalt-Induced Memory Deficit, Hippocampal Oxidative Damage, Astrocytosis, and Nrf2 Expression.

Chemical overexposure is a growing environmental risk factor for many medical issues. Cobalt toxicity from environmental, industrial, and medical exposure has previously been linked to neurological impairment. Hence, the current study looked into the neuroprotective potential of curcumin, a natural polyphenol contained in the spice turmeric, against cobalt-induced neurotoxicity. Adult rats were randomly divided into six groups as follows: control, 40 mg/kg cobalt chloride (CoCl2) only, 240 mg/kg curcumin only, 120 mg/kg or 240 mg/kg curcumin, or 100 mg/kg vitamin C co-administered with CoCl2. The administration was via oral route daily for 4 weeks. After that, neurobehavioral tests were undertaken to evaluate short-term spatial memory. Biochemical investigation was performed to determine the hippocampal levels of status via measures of SOD, CAT, GST, and LPO. Furthermore, immunohistochemical assessment of the expression of GFAP and Nrf2 in the hippocampus was carried out. In the CoCl2 group, the results showed altered behavioral responses, a decrease in antioxidant activities, increased expression of GFAP and the number of activated astrocytes, and decreased immunoexpression of Nrf2. These effects were mitigated in the curcumin- and vitamin C-treated groups. These results collectively imply that curcumin enhances memory functions in rats exposed to cobalt possibly by attenuating oxidative responses, mitigating astrocytosis, and modulating Nrf2 signaling.

Stark differences in cancer epidemiological data between GLOBOCAN and GBD: Emphasis on oral cancer and wider implications.

Background: GLOBOCAN 2020 and Global Burden of Disease (GBD) 2019 are the two most established global online cancer databases. It is important to examine the differences between the two platforms, to attempt to explain these differences, and to appraise the quality of the data. There are stark differences for lip and oral cancers (LOC) and we attempt to explain these by detailed analysis of ten countries at the extremes of differences. Methods: Age-standardised incidence rates (ASIR) of LOC were obtained from GLOBOCAN 2020 and GBD 2019. Five countries with the greatest and smallest fold differences were selected. A systematic search of PubMed and Embase electronic databases was then performed to identify publications reporting the incidence of LOC in the selected countries between 2015 and 2022. Specifically, data sources of the articles were examined and evaluated. Findings: For LOC, greatest differences were found in Papua New Guinea, Vietnam, China, Pakistan, and Indonesia (group A). In contrast, the United States of America (USA), Brazil, France, Germany, and India (group B) had the least differences between the two databases. Interpretation: It is not surprising that when GLOBOCAN and GBD could not obtain high-quality or accessible LOC data from national or local cancer registries, as in group A, discrepancies would be seen between the two online databases. In contrast, where only minor differences were seen between GLOBOCAN and GBD, as in group B, presumptively due to those countries having well-established cancer registries and healthcare administrative systems, the literature is more consistent. Moreover, many studies have grouped lip and oral cavity with pharynx and categorised outputs as "oral and oropharyngeal cancer" or "oral cavity and pharynx cancer". Those categorisations lacked subsite accuracy and failed to realise that oral cancer and oropharyngeal cancer have completely different etiological factors, pathogeneses, prognosis, and treatment outcomes. Funding: This research received no specific grant or funding from any funding agency in the public, commercial, or not-for-profit sectors, and the authors received no financial support for the research, authorship, and/or publication of this article.

Traumatic maxillofacial and brain injuries: a systematic review.

Concomitant traumatic brain injury (TBI) and maxillofacial fractures carry the risk of significant morbidity and mortality. The aim of this review was to explore the demographics, types of injury, and complications of traumatic maxillofacial and brain injuries, in order to contribute to comprehensive health strategies. The PubMed and Scopus databases were systematically searched. Inclusion criteria were clinical studies investigating combined traumatic maxillofacial and brain injuries. Exclusion criteria were duplicates, non-English publications, non-full-text publications, publication date before 1990, and studies with insufficient data. Of the 754 articles identified, 15 eligible articles representing 1421 cases were included. The mean age was 38.3 years. Most cases were male (79%). The most common mechanism of injury was traffic accidents (53.4%). The most common fracture pattern was middle third fractures (52.4%). Seven studies had an explicit definition for TBI, using the Glasgow Coma Score (GCS), radiological evidence, and/or specific symptoms. There were 147 complications reported in 62 of 253 cases (24.5%), with the most common being infection (n=54, 36.7%). Significant risk factors for complications included delayed surgical repair, low GCS, and upper third fractures. Robust longitudinal evaluations with clear definitions of TBI are required. Gaps in knowledge include risk factors for complications and fracture pattern-GCS correlations.

Frontal sinus fracture management: a systematic review and meta-analysis.

A systematic review of the frontal sinus fracture management literature was undertaken to document measurable outcomes, with emphasis on complications associated with the various treatment strategies. A comprehensive electronic search was undertaken in October 2018. Randomized controlled trials (RCT), controlled clinical trials, retrospective and prospective studies describing the management of frontal sinus fractures and complications were included. Twenty-four publications were included: one reporting a prospective RCT and 23 reporting consecutive case series studies (four prospective, 19 retrospective). These included 2388 patients (84.1% male, average age 23-43 years); 50.7% of cases were due to motor vehicle accidents and 61.8% had a concomitant intracranial injury. There were six categories for anterior table reconstruction, three endoscopic surgery categories, 11 for obliteration, and six for cranialization. Forest plots demonstrating complications based on the Clavien-Dindo classification of 1 ('low') and >3 ('high') were determined for total, early, and late complications, with heterogeneous effect sizes. Fractures with a nasofrontal outflow tract (NFOT) injury without obstruction can be treated with reconstruction if displaced, or managed conservatively if undisplaced. Obliteration and cranialization should be considered when there is obstruction of the NFOT. A computed tomography scan should be performed at 6 months to evaluate re-ventilation of the sinus. Endoscopic sinus surgery is a reasonable salvage re-ventilation procedure.

Top 10 priorities for future infertility research: an international consensus development study.

STUDY QUESTION: Can the priorities for future research in infertility be identified? SUMMARY ANSWER: The top 10 research priorities for the four areas of male infertility, female and unexplained infertility, medically assisted reproduction, and ethics, access, and organization of care for people with fertility problems were identified. WHAT IS KNOWN ALREADY: Many fundamental questions regarding the prevention, management, and consequences of infertility remain unanswered. This is a barrier to improving the care received by those people with fertility problems. STUDY DESIGN, SIZE, DURATION: Potential research questions were collated from an initial international survey, a systematic review of clinical practice guidelines, and Cochrane systematic reviews. A rationalized list of confirmed research uncertainties was prioritized in an interim international survey. Prioritized research uncertainties were discussed during a consensus development meeting. Using a formal consensus development method, the modified nominal group technique, diverse stakeholders identified the top 10 research priorities for each of the categories male infertility, female and unexplained infertility, medically assisted reproduction, and ethics, access, and organization of care. PARTICIPANTS/MATERIALS, SETTING, METHODS: Healthcare professionals, people with fertility problems, and others (healthcare funders, healthcare providers, healthcare regulators, research funding bodies and researchers) were brought together in an open and transparent process using formal consensus methods advocated by the James Lind Alliance. MAIN RESULTS AND THE ROLE OF CHANCE: The initial survey was completed by 388 participants from 40 countries, and 423 potential research questions were submitted. Fourteen clinical practice guidelines and 162 Cochrane systematic reviews identified a further 236 potential research questions. A rationalized list of 231 confirmed research uncertainties were entered into an interim prioritization survey completed by 317 respondents from 43 countries. The top 10 research priorities for each of the four categories male infertility, female and unexplained infertility (including age-related infertility, ovarian cysts, uterine cavity abnormalities, and tubal factor infertility), medically assisted reproduction (including ovarian stimulation, IUI, and IVF), and ethics, access, and organization of care, were identified during a consensus development meeting involving 41 participants from 11 countries. These research priorities were diverse and seek answers to questions regarding prevention, treatment, and the longer-term impact of infertility. They highlight the importance of pursuing research which has often been overlooked, including addressing the emotional and psychological impact of infertility, improving access to fertility treatment, particularly in lower resource settings, and securing appropriate regulation. Addressing these priorities will require diverse research methodologies, including laboratory-based science, qualitative and quantitative research, and population science. LIMITATIONS, REASONS FOR CAUTION: We used consensus development methods, which have inherent limitations, including the representativeness of the participant sample, methodological decisions informed by professional judgement, and arbitrary consensus definitions. WIDER IMPLICATIONS OF THE FINDINGS: We anticipate that identified research priorities, developed to specifically highlight the most pressing clinical needs as perceived by healthcare professionals, people with fertility problems, and others, will help research funding organizations and researchers to develop their future research agenda. STUDY FUNDING/ COMPETING INTEREST(S): The study was funded by the Auckland Medical Research Foundation, Catalyst Fund, Royal Society of New Zealand, and Maurice and Phyllis Paykel Trust. Geoffrey Adamson reports research sponsorship from Abbott, personal fees from Abbott and LabCorp, a financial interest in Advanced Reproductive Care, committee membership of the FIGO Committee on Reproductive Medicine, International Committee for Monitoring Assisted Reproductive Technologies, International Federation of Fertility Societies, and World Endometriosis Research Foundation, and research sponsorship of the International Committee for Monitoring Assisted Reproductive Technologies from Abbott and Ferring. Siladitya Bhattacharya reports being the Editor-in-Chief of Human Reproduction Open and editor for the Cochrane Gynaecology and Fertility Group. Hans Evers reports being the Editor Emeritus of Human Reproduction. Andrew Horne reports research sponsorship from the Chief Scientist's Office, Ferring, Medical Research Council, National Institute for Health Research, and Wellbeing of Women and consultancy fees from Abbvie, Ferring, Nordic Pharma, and Roche Diagnostics. M. Louise Hull reports grants from Merck, grants from Myovant, grants from Bayer, outside the submitted work and ownership in Embrace Fertility, a private fertility company. Neil Johnson reports research sponsorship from Abb-Vie and Myovant Sciences and consultancy fees from Guerbet, Myovant Sciences, Roche Diagnostics, and Vifor Pharma. José Knijnenburg reports research sponsorship from Ferring and Theramex. Richard Legro reports consultancy fees from Abbvie, Bayer, Ferring, Fractyl, Insud Pharma and Kindex and research sponsorship from Guerbet and Hass Avocado Board. Ben Mol reports consultancy fees from Guerbet, iGenomix, Merck, Merck KGaA and ObsEva. Ernest Ng reports research sponsorship from Merck. Craig Niederberger reports being the Co Editor-in-Chief of Fertility and Sterility and Section Editor of the Journal of Urology, research sponsorship from Ferring, and retains a financial interest in NexHand. Jane Stewart reports being employed by a National Health Service fertility clinic, consultancy fees from Merck for educational events, sponsorship to attend a fertility conference from Ferring, and being a clinical subeditor of Human Fertility. Annika Strandell reports consultancy fees from Guerbet. Jack Wilkinson reports being a statistical editor for the Cochrane Gynaecology and Fertility Group. Andy Vail reports that he is a Statistical Editor of the Cochrane Gynaecology & Fertility Review Group and of the journal Reproduction. His employing institution has received payment from HFEA for his advice on review of research evidence to inform their 'traffic light' system for infertility treatment 'add-ons'. Lan Vuong reports consultancy and conference fees from Ferring, Merck and Merck Sharp and Dohme. The remaining authors declare no competing interests in relation to the present work. All authors have completed the disclosure form. TRIAL REGISTRATION NUMBER: Not applicable.

Top 10 priorities for future infertility research: an international consensus development study† ‡.

STUDY QUESTION: Can the priorities for future research in infertility be identified? SUMMARY ANSWER: The top 10 research priorities for the four areas of male infertility, female and unexplained infertility, medically assisted reproduction and ethics, access and organization of care for people with fertility problems were identified. WHAT IS KNOWN ALREADY: Many fundamental questions regarding the prevention, management and consequences of infertility remain unanswered. This is a barrier to improving the care received by those people with fertility problems. STUDY DESIGN, SIZE, DURATION: Potential research questions were collated from an initial international survey, a systematic review of clinical practice guidelines and Cochrane systematic reviews. A rationalized list of confirmed research uncertainties was prioritized in an interim international survey. Prioritized research uncertainties were discussed during a consensus development meeting. Using a formal consensus development method, the modified nominal group technique, diverse stakeholders identified the top 10 research priorities for each of the categories male infertility, female and unexplained infertility, medically assisted reproduction and ethics, access and organization of care. PARTICIPANTS/MATERIALS, SETTING, METHODS: Healthcare professionals, people with fertility problems and others (healthcare funders, healthcare providers, healthcare regulators, research funding bodies and researchers) were brought together in an open and transparent process using formal consensus methods advocated by the James Lind Alliance. MAIN RESULTS AND THE ROLE OF CHANCE: The initial survey was completed by 388 participants from 40 countries, and 423 potential research questions were submitted. Fourteen clinical practice guidelines and 162 Cochrane systematic reviews identified a further 236 potential research questions. A rationalized list of 231 confirmed research uncertainties was entered into an interim prioritization survey completed by 317 respondents from 43 countries. The top 10 research priorities for each of the four categories male infertility, female and unexplained infertility (including age-related infertility, ovarian cysts, uterine cavity abnormalities and tubal factor infertility), medically assisted reproduction (including ovarian stimulation, IUI and IVF) and ethics, access and organization of care were identified during a consensus development meeting involving 41 participants from 11 countries. These research priorities were diverse and seek answers to questions regarding prevention, treatment and the longer-term impact of infertility. They highlight the importance of pursuing research which has often been overlooked, including addressing the emotional and psychological impact of infertility, improving access to fertility treatment, particularly in lower resource settings and securing appropriate regulation. Addressing these priorities will require diverse research methodologies, including laboratory-based science, qualitative and quantitative research and population science. LIMITATIONS, REASONS FOR CAUTION: We used consensus development methods, which have inherent limitations, including the representativeness of the participant sample, methodological decisions informed by professional judgment and arbitrary consensus definitions. WIDER IMPLICATIONS OF THE FINDINGS: We anticipate that identified research priorities, developed to specifically highlight the most pressing clinical needs as perceived by healthcare professionals, people with fertility problems and others, will help research funding organizations and researchers to develop their future research agenda. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by the Auckland Medical Research Foundation, Catalyst Fund, Royal Society of New Zealand and Maurice and Phyllis Paykel Trust. G.D.A. reports research sponsorship from Abbott, personal fees from Abbott and LabCorp, a financial interest in Advanced Reproductive Care, committee membership of the FIGO Committee on Reproductive Medicine, International Committee for Monitoring Assisted Reproductive Technologies, International Federation of Fertility Societies and World Endometriosis Research Foundation, and research sponsorship of the International Committee for Monitoring Assisted Reproductive Technologies from Abbott and Ferring. Siladitya Bhattacharya reports being the Editor-in-Chief of Human Reproduction Open and editor for the Cochrane Gynaecology and Fertility Group. J.L.H.E. reports being the Editor Emeritus of Human Reproduction. A.W.H. reports research sponsorship from the Chief Scientist's Office, Ferring, Medical Research Council, National Institute for Health Research and Wellbeing of Women and consultancy fees from AbbVie, Ferring, Nordic Pharma and Roche Diagnostics. M.L.H. reports grants from Merck, grants from Myovant, grants from Bayer, outside the submitted work and ownership in Embrace Fertility, a private fertility company. N.P.J. reports research sponsorship from AbbVie and Myovant Sciences and consultancy fees from Guerbet, Myovant Sciences, Roche Diagnostics and Vifor Pharma. J.M.L.K. reports research sponsorship from Ferring and Theramex. R.S.L. reports consultancy fees from AbbVie, Bayer, Ferring, Fractyl, Insud Pharma and Kindex and research sponsorship from Guerbet and Hass Avocado Board. B.W.M. reports consultancy fees from Guerbet, iGenomix, Merck, Merck KGaA and ObsEva. E.H.Y.N. reports research sponsorship from Merck. C.N. reports being the Co Editor-in-Chief of Fertility and Sterility and Section Editor of the Journal of Urology, research sponsorship from Ferring and retains a financial interest in NexHand. J.S. reports being employed by a National Health Service fertility clinic, consultancy fees from Merck for educational events, sponsorship to attend a fertility conference from Ferring and being a clinical subeditor of Human Fertility. A.S. reports consultancy fees from Guerbet. J.W. reports being a statistical editor for the Cochrane Gynaecology and Fertility Group. A.V. reports that he is a Statistical Editor of the Cochrane Gynaecology & Fertility Review Group and the journal Reproduction. His employing institution has received payment from Human Fertilisation and Embryology Authority for his advice on review of research evidence to inform their 'traffic light' system for infertility treatment 'add-ons'. N.L.V. reports consultancy and conference fees from Ferring, Merck and Merck Sharp and Dohme. The remaining authors declare no competing interests in relation to the present work. All authors have completed the disclosure form. TRIAL REGISTRATION NUMBER: N/A.

Brca1 mutations in the coiled-coil domain impede Rad51 loading on DNA and mouse development.

We recently developed a Brca1 coiled-coil mutant mouse model (Brca1CC ). Brca1CC/CC results in embryonic lethality, with a fraction of mice reaching birth but with defects that parallel Fanconi anemia. Brca1CC/CC cells lacked Rad51 foci and were PARP inhibitor sensitive. Strikingly, inter-crossing with Brca1Δ11 generated Brca1 CC/Δ11 mice that were developmentally normal.

Investigation of the safety and feasibility of AAV1/SERCA2a gene transfer in patients with chronic heart failure supported with a left ventricular assist device - the SERCA-LVAD TRIAL.

The SERCA-LVAD trial was a phase 2a trial assessing the safety and feasibility of delivering an adeno-associated vector 1 carrying the cardiac isoform of the sarcoplasmic reticulum calcium ATPase (AAV1/SERCA2a) to adult chronic heart failure patients implanted with a left ventricular assist device. The SERCA-LVAD trial was one of a program of AAV1/SERCA2a cardiac gene therapy trials including CUPID1, CUPID 2 and AGENT trials. Enroled subjects were randomised to receive a single intracoronary infusion of 1 × 1013 DNase-resistant AAV1/SERCA2a particles or a placebo solution in a double-blinded design, stratified by presence of neutralising antibodies to AAV. Elective endomyocardial biopsy was performed at 6 months unless the subject had undergone cardiac transplantation, with myocardial samples assessed for the presence of exogenous viral DNA from the treatment vector. Safety assessments including ELISPOT were serially performed. Although designed as a 24 subject trial, recruitment was stopped after five subjects had been randomised and received infusion due to the neutral result from the CUPID 2 trial. Here we describe the results from the 5 patients at 3 years follow up, which confirmed that viral DNA was delivered to the failing human heart in 2 patients receiving gene therapy with vector detectable at follow up endomyocardial biopsy or cardiac transplantation. Absolute levels of detectable transgene DNA were low, and no functional benefit was observed. There were no safety concerns in this small cohort. This trial identified some of the challenges of performing gene therapy trials in this LVAD patient cohort which may help guide future trial design.

Riparian forest fragments in rice fields under different management: differences on hymenopteran parasitoids diversity / Fragmentos de floresta riparia em áreas de cultivo de arroz sob diferentes manejos: diferenças através diversidade de himenópteros parasitoides

Abstract Hymenopteran parasitoids are important biological control agents in agroecosystems, and their diversity can be increased with habitat heterogeneity. Thus, the purpose of the study is to evaluate the influence of distance of rice-growing areas from natural fragment, type of crop management (organic and conventional) and crop stages (vegetative and reproductive stages) on parasitoids family diversity. The work took place in two irrigated rice crops, one with organic management (O.M.) and another one with conventional management (C.M.), in the municipality of Nova Santa Rita, RS, Brazil, during the 2013/2014 and 2014/2015 seasons. The parasitoids were collected with Malaise trap arranged at different distances in relation to the native vegetation surrounding the rice crop in both places. Specimens were collected twice a month from seeding until the rice harvest. Average abundance between management, distances and rice development were compared. The most abundant families were Platygastridae, Mymaridae, Encyrtidae, Eulophidae and Trichogrammatidae. Parasitoid average abundance was significantly higher on OM only in the second season. There was a negative correlation between distance from native vegetation and parasitoid abundance in C.M. areas. There were differences in the composition of the parasitoid assembly between the phenological stages of rice.

Resumo Os himenópteros parasitoides são importantes agentes de controle biológico em agroecossistemas com sua diversidade variando de acordo com a heterogeneidade de habitat. Nesse sentido, o objetivo deste trabalho foi avaliar a influência da distância de áreas com fragmentos de vegetação natural das áreas de cultivo de arroz, o tipo de manejo (orgânico ou convencional) e os estágios da cultura (vegetativo e reprodutivo) na diversidade de famílias de parasitoides. O trabalho foi conduzido em duas áreas com plantio de arroz irrigado, uma com manejo orgânico (MO) e outra com manejo convencional (CM), no município de Nova Santa Rita, RS, Brasil, durante a safra 2013/2014 e 2014/2015. Os parasitoides foram coletados com armadilha Malaise colocadas sob diferentes distâncias em relação a vegetação nativa circundante ao cultivo em ambas as áreas. Os espécimes foram coletados duas vezes ao mês da semeadura até a colheita. Foram comparadas a abundância média entre os manejos, distâncias e estágio de desenvolvimento do arroz. As famílias mais abundantes foram Platygastridae, Mymaridae, Encyrtidae, Eulophidae e Trichogrammatidae com suas abundâncias variando ao longo da safra. A abundância média de parasitoides foi significativamente maior no MO somente na segunda safra. Houve uma correlação negativa entre a distância da vegetação nativa e a abundância de parasitoides. Houve diferença na composição da assembleia de parasitoides entre os estágios fenológicos do arroz.

Pelvic fat volume reduction with preoperative very low energy diet (VLED): implications for rectal cancer surgery in the obese.

BACKGROUND: Obese patients have higher complication rates after pelvic surgery. Laparoscopic rectal surgery may not be possible in the obese individual due to mesorectal, total pelvic and general visceral fat volumes. Very low energy diets reduce visceral fat but the changes within the pelvis and mesorectum are unknown. The aim of the present study was to quantify the proportion of fat lost from total pelvic and mesorectal fat with a very low energy diet (VLED) and define simple, accessible measurements that correlate with expected volume reduction. METHODS: A study was conducted on proportion change in mesorectal and intrapelvic fat volumes in patients on a VLED prior to bariatric surgery at the Alfred Hospital in Melbourne. The VLED was a standardized 4-week meal replacement. Proportion change in mesorectal and intrapelvic fat volumes were measured. Patients had standardized pre-diet and post-diet magnetic resonance imaging (MRI) of the pelvis. Body mass index, weight and girth measures were obtained. Adipose quantification analysis was performed using Q-Fat. RESULTS: Nine patients were included in this study, who were preparing for bariatric (not colorectal) surgery (5 females, median age 42 years, range 27-59 years) pre-protocol body mass index was 55.8 (range 39.5-60.6 kg/m2); median weight was 163 kg. Median mesorectal fat reduction was 29.9% (range 11.6-66.6%). Linear regression showed a relationship between the amount of mesorectal fat reduction and two variables: patient height and the distance from S1 to the posterior aspect of the rectum on MRI. The relationship predicted response to the diet (R2 67%, p = 0.040). CONCLUSIONS: Very low energy diets result in a clinically significant reduction in mesorectal fat with a lesser change in total pelvic fat, suggesting that very low energy diets may be useful for preparation for pelvic surgery in the obese. The distance from S1 to the posterior rectum correlates well with mesorectal reduction, making this a valuable clinical tool when volumetric analysis is not possible. This analysis is limited to the quantification of the effect of the diet and cannot comment on the safety of this approach before pelvic cancer surgery.

Correction to: Pelvic fat volume reduction with preoperative very low energy diet (VLED): implications for rectal cancer surgery in the obese.

Due to substantial contributions by Dr. Phillip Malouf and Dr. Stephen Bell.

High Prevalence of Lifestyle Factors Attributable for Oral Cancer, and of Oral Potentially Malignant Disorders in Rural Sri Lanka

Background: Oral Cancer is a major public health problem in most of the South East Asian countries including Sri Lanka. Use of tobacco in the form of smokeless tobacco and smoking, use of alcohol and betel quid chewing are the major contributory factors for causation oral cancer. The aim of this study was to investigate the prevalence of lifestyle factors responsible for causation of oral cancer and Oral Potentially Malignant Disorders (OPMD) in the Sabaragamuwa province of Sri Lanka. Methods: A cross-sectional community based study was conducted in Sabaragamuwa province by interviewing, then conducting an oral examination, on 1029 subjects over 30 years of age, over a one year period from November 2006. The study protocol included an interviewer-administered questionnaire to gather socio-demographic factors, recording of habits that included areca/betel chewing, smoking, and alcohol consumption. A three-day food diary was obtained, particularly to assess the consumption of tea, fruits and vegetables. The weight and height of residents was taken for calculation of Body Mass Index (BMI). Results: One hundred and two individuals with one or more OPMD were detected among these 1029 subjects. The prevalence of OPMD, weighted according to the estate sector and gender, was estimated as 11.3%. The prevalence of daily betel quid chewing in this study was 53.8%: 15.7% without tobacco and 47.4% with tobacco. The prevalence of individuals who reported consumption of alcohol at least weekly was 13.4%. A significant minority, 31.7%, were under nourished, with a BMI < 18.5. Forty six percent of the males practiced combined habits of betel quid chewing, smoking and regular use of alcohol. Conclusions: This study discloses high prevalence of OPMD and of lifestyle factors for oral cancer in these communities. There is an urgent need for a comprehensive strategy to control the use of tobacco, betel quid chewing and alcohol for prevention of oral cancer.