Exploring the experiences of people with urogynaecology conditions in the UK: a reflexive thematic analysis and conceptual model.

BACKGROUND: Urogynaecological conditions, such as pelvic organ prolapse, urinary incontinence, and urinary tract infection, can have a profound impact on people's lives. The Independent Medicines and Medical Devices Safety Review highlights missed opportunities to prevent harm when patient voices are not incorporated into healthcare policy and practice. This resonates with the Women's Health Strategy for England. The National Institute for Health and Care Research (NIHR) Policy Research Programme funded this in-depth qualitative exploration of people's experiences of living with urogynaecological conditions, and of seeking healthcare treatment, to inform health and social care improvements in the UK. METHODS: We conducted in-depth interviews online or by telephone (April 2021-December 2021) and used reflexive thematic analysis to develop themes that cut across urogynaecological conditions. RESULTS: We spoke to seventy-four adults aged 22-84 across a range of backgrounds and lived experiences of urogynaecological conditions, including pelvic organ prolapse, urinary incontinence and persistent or recurring urinary tract infection. Eight themes were developed: [1] I get no respite from my own body; [2] I feel confined and separated; [3] I can no longer be 'me'; [4] I am constrained by stigma, shame and silence; [5] I feel fragmented and lost in the healthcare system; [6] I need to be heard, believed, and valued; [7] I need respect as an equal partner in healthcare; and [8] (Re)connected to a more open community. CONCLUSIONS: High quality care focuses on the whole person rather than their body parts. Openness and candour support a shared decision-making model of care. A culture of shame can have a negative impact on access to health care and recovery.

Customized birth-weight centiles and placenta-related fetal growth restriction.

OBJECTIVE: The value of using customized birth-weight centiles to improve the diagnostic accuracy for fetal growth restriction (FGR), in comparison with using population-based charts, remains a matter of debate. One potential explanation for the conflicting data is that most studies used measures of perinatal mortality and morbidity as proxies for placenta-mediated FGR, many of which are not specific and may be confounded by other factors such as prematurity. The aim of this study was to compare the diagnostic accuracy of small-for-gestational age (SGA) at birth, defined according to customized vs population-based charts, for associated abnormal placental pathology. METHODS: This was a secondary analysis of data from a prospective cohort study on risk factors for placenta-mediated complications and abnormal placental pathology in low-risk nulliparous women. All placentae were sent for detailed histopathological examination by two perinatal pathologists. The primary exposure was SGA, defined as birth weight < 10th centile for gestational age using either a customized (SGAcust ) or a population-based (SGApop ) birth-weight reference. The outcomes of interest were one of three types of abnormal placental pathology associated with FGR: maternal vascular malperfusion (MVM), chronic villitis and fetal vascular malperfusion (FVM). Adjusted relative risks (aRR) with 95% CIs were estimated using modified Poisson regression analysis, with adjustment for smoking, body mass index and aspirin treatment. RESULTS: A total of 857 nulliparous women met the study criteria. The proportions of infants identified as SGA based on the customized and population-based charts were 12.6% (108/857) and 11.4% (98/857), respectively. A diagnosis of SGA using either customized or population-based charts was associated with an increased risk of any placental pathology (aRR, 3.04 (95% CI, 2.29-4.04) and 1.60 (95% CI, 1.10-2.31), respectively) and MVM pathology (aRR, 12.33 (95% CI, 6.60-23.03) and 5.29 (95% CI, 2.87-9.76), respectively). SGAcust , but not SGApop , was also associated with an increased risk for chronic villitis (aRR, 1.85 (95% CI, 1.07-3.18)) and FVM pathology (aRR, 2.48 (95% CI, 1.25-4.93)). SGAcust had a higher detection rate for any placental pathology (30.3% vs 17.1%; P < 0.001), MVM pathology (63.2% vs 39.5%; P = 0.003) and chronic villitis (20.8% vs 8.3%; P = 0.007) than did SGApop , for a similar false-positive rate. This was mainly the result of a higher detection rate for abnormal pathology in the white and East-Asian subgroups and a lower false-positive rate for abnormal pathology in the South-Asian subgroup by SGAcust than by SGApop . In addition, pregnancies in the SGAcust group, but not those in the SGApop group, were more likely to be complicated by preterm birth and a low 5-min Apgar score than were the corresponding non-SGA group. CONCLUSION: These findings suggest that customized birth-weight centiles may be superior to population-based birth-weight centiles in detecting FGR that is due to underlying placental disease. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Open education resources to support the WHO nurse educator core competencies.

AIM: This paper describes an innovative approach to tackling the shortage of qualified nurse educators, which is a major constraining factor or 'bottle-neck' to improve the global supply of nurses, especially in low- and middle-income countries. BACKGROUND: The World Health Organization commissioned experts to develop Nurse Educator Core Competencies that describe expectations for this cadre of workers. In their deliberations, the WHO experts cited the challenges affecting the adoption of these competencies, particularly the lack of resources available for implementation. To address this specific challenge, a USA-based non-government organiization, Nurses International, has developed Open Education Resources (NI-OER) to support nurse educators with freely accessible curriculum materials and remote mentoring support. METHODS: This paper applies item analysis to consider how the NI-OER could assist higher education institutes and individual faculty members in meeting each of the WHO Nurse Educator Core Competencies. FINDINGS: The NI-OER is a good fit with six of the Nurse Educator Core Competencies and a partial fit with the other two. DISCUSSION: Congruence with the WHO Nurse Educator Core Competencies is an important validity check for the NI-OER. The ultimate goal of the NI-OER is to promote sustainable development through intermediate goals related to supporting faculty as they prepare nurses for current and future service needs. Technological solutions like the NI-OER cannot solve all aspects of a complex problem like the global nursing shortage but are an important tool. IMPLICATIONS FOR NURSING AND HEALTH POLICY: This resource has significant implications for nursing and health policy because it tackles several constraints to the global goal of increasing production and capacity of nurses. Combined with the organization's remote mentoring and communities of practice, the NI-OER appears to have the potential to support novice nurse educators with accessible, adaptable resources.

Integration of a recent infection testing algorithm into HIV surveillance in Ireland: improving HIV knowledge to target prevention.

Recent infection testing algorithms (RITA) for HIV combine serological assays with epidemiological data to determine likely recent infections, indicators of ongoing transmission. In 2016, we integrated RITA into national HIV surveillance in Ireland to better inform HIV prevention interventions. We determined the avidity index (AI) of new HIV diagnoses and linked the results with data captured in the national infectious disease reporting system. RITA classified a diagnosis as recent based on an AI < 1.5, unless epidemiological criteria (CD4 count <200 cells/mm3; viral load <400 copies/ml; the presence of AIDS-defining illness; prior antiretroviral therapy use) indicated a potential false-recent result. Of 508 diagnoses in 2016, we linked 448 (88.1%) to an avidity test result. RITA classified 12.5% of diagnoses as recent, with the highest proportion (26.3%) amongst people who inject drugs. On multivariable logistic regression recent infection was more likely with a concurrent sexually transmitted infection (aOR 2.59; 95% CI 1.04-6.45). Data were incomplete for at least one RITA criterion in 48% of cases. The study demonstrated the feasibility of integrating RITA into routine surveillance and showed some ongoing HIV transmission. To improve the interpretation of RITA, further efforts are required to improve completeness of the required epidemiological data.

HDAC inhibitors modulate innate immune responses to micro-organisms relevant to chronic mucocutaneous candidiasis.

Signal transducer and activator of transcription 1 (STAT-1) gain-of-function (GOF) mutations cause chronic mucocutaneous candidiasis (CMC), a disease associated with Candida albicans and Staphylococcus aureus infection. Patients suffer from dysegulated immune responses due to aberrant cell programming and function. We investigated the effect of inhibitory molecules targeting histone deacetylases (HDACi) on the immune responses of peripheral blood mononuclear cells (PBMCs) of healthy controls and patients with CMC towards microbes relevant for CMC. PBMCs cells were pretreated with HDACi and challenged with C. albicans or S. aureus. Innate and adaptive cytokines were measured in cell culture supernatants by enzyme-linked immunosorbent assay (ELISA). We assessed the effect of HDAC inhibitors on T helper type 1 (Th1) and Th17 cells and measured STAT-1 and STAT-3 phosphorylation using flow cytometry. Panobinostat, a pan-HDAC inhibitor, strongly inhibits innate and adaptive cytokines upon challenge with C. albicans or S. aureus. Specific inhibitors (entinostat or RGFP966) also had a tendency to lower production of most innate cytokines in CMC patient cells. Entinostat and RGFP966 increased the production of interleukin (IL)-22 specifically after S. aureus challenge in patient cells. In healthy and control cells, entinostat and RGFP966 treatment down-regulated STAT-1 phosphorylation while pSTAT-3 levels remained stable. HDACi modulate cytokine production in response to C. albicans and S. aureus. Pan-inhibitors lower overall cytokine production, whereas specific inhibitors confer a selective effect. Entinostat and RGFP966 are promising therapeutic candidates to treat STAT-1 GOF due to their capacity to restore IL-22 production and decrease STAT-1 phosphorylation; however, their inhibition of innate cytokines poses a possible risk to secondary infections.

Moving towards a reliable HIV incidence test - current status, resources available, future directions and challenges ahead.

In 2011 the Incidence Assay Critical Path Working Group reviewed the current state of HIV incidence assays and helped to determine a critical path to the introduction of an HIV incidence assay. At that time the Consortium for Evaluation and Performance of HIV Incidence Assays (CEPHIA) was formed to spur progress and raise standards among assay developers, scientists and laboratories involved in HIV incidence measurement and to structure and conduct a direct independent comparative evaluation of the performance of 10 existing HIV incidence assays, to be considered singly and in combinations as recent infection test algorithms. In this paper we report on a new framework for HIV incidence assay evaluation that has emerged from this effort over the past 5 years, which includes a preliminary target product profile for an incidence assay, a consensus around key performance metrics along with analytical tools and deployment of a standardized approach for incidence assay evaluation. The specimen panels for this evaluation have been collected in large volumes, characterized using a novel approach for infection dating rules and assembled into panels designed to assess the impact of important sources of measurement error with incidence assays such as viral subtype, elite host control of viraemia and antiretroviral treatment. We present the specific rationale for several of these innovations, and discuss important resources for assay developers and researchers that have recently become available. Finally, we summarize the key remaining steps on the path to development and implementation of reliable assays for monitoring HIV incidence at a population level.

Increased frequencies of the killer immunoglobulin-like receptor genes KIR2DL2 and KIR2DS2 are associated with neuroblastoma.

Neuroblastoma is the most common extra-cranial solid tumour in children. Natural killer (NK) cells are innate lymphocytes that are known to mediate the direct cytotoxicity of neuroblastoma tumour cells. Natural variation in the highly polymorphic killer immunoglobulin-like receptors (KIR) and their cognate human leukocyte antigen (HLA) class I ligands results in considerable diversity in NK cell function. As the early onset of neuroblastoma suggests the contribution of genetic factors, we investigated if individual KIR genes, combined KIR gene haplotypes or compound KIR-HLA ligand genotypes could influence susceptibility to neuroblastoma. Genotype analysis of the KIR genes as well as their three major HLA class I ligand groups, HLA-C1, HLA-C2 and HLA-Bw4, was carried out in a cohort of 201 neuroblastoma patients compared with 240 healthy control subjects using polymerase chain reaction with sequence-specific primers. We found a significant increase in the frequency of KIR2DL2 (P = 0.019) as well as KIR2DS2 (P = 0.008) in patients with neuroblastoma compared with the healthy control group. While the incidence of the least inhibitory compound KIR-HLA-C genotype, KIR2DL3 in the presence of HLA-C1 was slightly reduced in neuroblastoma patients, this did not reach statistical significance (P = 0.069). In summary, while KIR-HLA compound genotypes have previously been implicated in predicting treatment outcomes in neuroblastoma, here we show that the presence of the individual KIR genes, KIR2DL2 and KIR2DS2, irrespective of HLA-C genotype is associated with the onset of this embryonal malignancy.

Fetal skeletal dysplasias in a tertiary care center: radiology, pathology, and molecular analysis of 112 cases.

Fetal skeletal dysplasias are a heterogeneous group of rare genetic disorders, affecting approximately 2.4-4.5 of 10,000 births. We performed a retrospective review of the perinatal autopsies conducted between the years 2002-2011 at our center. The study population consisted of fetuses diagnosed with skeletal dysplasia with subsequent termination, stillbirth and live-born who died shortly after birth. Of the 2002 autopsies performed, 112 (5.6%) were diagnosed with skeletal dysplasia. These 112 cases encompassed 17 of 40 groups of Nosology 2010. The two most common Nosology groups were osteogenesis imperfecta [OI, 27/112 (24%)] and the fibroblast growth factor receptor type 3 (FGFR3) chondrodysplasias [27/112 (24%)]. The most common specific diagnoses were thanatophoric dysplasia (TD) type 1 [20 (17.9%)], and OI type 2 [20 (17.9%)]. The combined radiology, pathology, and genetic investigations and grouping the cases using Nosology 2010 resulted in a specific diagnosis in 96 of 112 cases.

Temporal lobe dysplasia: a characteristic sonographic finding in thanatophoric dysplasia.

OBJECTIVE: To determine the incidence of temporal lobe dysplasia (TLD) detected on prenatal ultrasound in thanatophoric dysplasia (TD) over an 11-year period in a tertiary referral center. METHODS: An 11-year retrospective review of perinatal autopsies from 2002 to 2013 was performed to identify cases of TD. The ultrasound images and corresponding reports of all TD cases were examined for the presence of TLD. The same set of images subsequently underwent a retrospective review by a perinatal radiologist with knowledge of the features of TLD to determine whether they could be identified. RESULTS: Thirty-one cases of TD underwent perinatal autopsy, and prenatal ultrasound imaging was available for review in 24 (77%). Mean gestational age at diagnosis of TD was 21.3 (range, 18-36) weeks. TLD was identified and reported in 6/24 (25%) cases; all six cases occurred after 2007. Retrospective interpretation of the ultrasound images identified features of TLD in 10 additional cases. In total, 16/24 (67%) cases displayed sonographic evidence of TLD. Temporal trends showed that TLD features were present in 50% (5/10) of all TD cases between 2002 and 2006 and in 79% (11/14) of those detected between 2007 and 2013. CONCLUSIONS: At present, the detection rate of TLD by ultrasound is low but may be increased by modified brain images that enhance visualization of the temporal lobes. Prenatal identification of TLD may help in the prenatal diagnosis of TD and thus provide more accurate prenatal counseling and guide molecular investigations to confirm the specific diagnosis of TD.

The accuracy of prehospital triage decisions in English trauma networks - a case-cohort study.

BACKGROUND: Care for injured patients in England is provided by inclusive regional trauma networks. Ambulance services use triage tools to identify patients with major trauma who would benefit from expedited Major Trauma Centre (MTC) care. However, there has been no investigation of triage performance, despite its role in ensuring effective and efficient MTC care. This study aimed to investigate the accuracy of prehospital major trauma triage in representative English trauma networks. METHODS: A diagnostic case-cohort study was performed between November 2019 and February 2020 in 4 English regional trauma networks as part of the Major Trauma Triage Study (MATTS). Consecutive patients with acute injury presenting to participating ambulance services were included, together with all reference standard positive cases, and matched to data from the English national major trauma database. The index test was prehospital provider triage decision making, with a positive result defined as patient transport with a pre-alert call to the MTC. The primary reference standard was a consensus definition of serious injury that would benefit from expedited major trauma centre care. Secondary analyses explored different reference standards and compared theoretical triage tool accuracy to real-life triage decisions. RESULTS: The complete-case case-cohort sample consisted of 2,757 patients, including 959 primary reference standard positive patients. The prevalence of major trauma meeting the primary reference standard definition was 3.1% (n=54/1,722, 95% CI 2.3 - 4.0). Observed prehospital provider triage decisions demonstrated overall sensitivity of 46.7% (n=446/959, 95% CI 43.5-49.9) and specificity of 94.5% (n=1,703/1,798, 95% CI 93.4-95.6) for the primary reference standard. There was a clear trend of decreasing sensitivity and increasing specificity from younger to older age groups. Prehospital provider triage decisions commonly differed from the theoretical triage tool result, with ambulance service clinician judgement resulting in higher specificity. CONCLUSIONS: Prehospital decision making for injured patients in English trauma networks demonstrated high specificity and low sensitivity, consistent with the targets for cost-effective triage defined in previous economic evaluations. Actual triage decisions differed from theoretical triage tool results, with a decreasing sensitivity and increasing specificity from younger to older ages.

Leptin is differentially expressed and epigenetically regulated across monochorionic twin placenta with discordant fetal growth.

Severely growth-discordant monochorionic (MC) twins offer a unique opportunity to study fetal and placental growth based on a similar genetic background and maternal host environment where the healthy twin serves as an ideal control. Differences in development of MC twins may therefore be due to differential epigenetic regulation of genes involved in placental development and function. Growth-discordant twins are known for abnormal angio-architecture in the placenta of the smaller twin. Since the reasons for this phenotype are mostly unknown this study was aimed to investigate the expression and regulation of genes known to be involved in angiogenesis. We studied 10 severely growth-discordant MC twin placentas (birthweight difference ≥20%) without twin-twin-transfusion syndrome and 5 growth-concordant MC twin placentas. Growth-discordant twin placentas were phenotyped by histology. Placental mRNA expression of 88 angiogenesis-related genes was measured by PCR array. ELISA assay and immunohistochemistry were used to confirm PCR results. EpiTYPTER for DNA methylation was used to determine if methylation ratios were responsible for differential gene expression. The PCR array analysis showed significant mRNA up-regulation in the placental share of the smaller twin for several genes. These included leptin (24.6-fold, P = 0.017), fms-like tyrosine kinase 1 (Flt1, 2.4-fold, P = 0.016) and Endoglin (Eng, 1.86-fold, P = 0.078). None of the other 84 angiogenesis-related genes showed significant differences. ELISA confirmed significantly increased leptin protein expression (49.22 versus 11.03 pg/ml, P = 0.049) in the smaller twin of the discordant growth cohort. Leptin expression in smaller twins' placentas was associated with elevated DNA methylation of the leptin promotor region suggesting the inhibition of binding of a transcriptional activator/inhibitor in that region. We attempted to overcome the limitation of sample size by careful patient selection. We minimized any bias in placental sampling by random sampling from two different sites and by avoiding sampling from areas with grossly visible abnormalities using a standardized sampling protocol. In conclusion, the smaller twin's placenta is characterized by differentially increased gene expressions for Flt1 and Eng mRNA that may be causally associated with the villous pathology driven by abnormal feto-placental angiogenesis. The substantial up-regulation of leptin mRNA may be epigenetically conferred and relevant to the post-natal risk of metabolic syndrome in intrauterine growth restriction offspring with placental pathology. Growth-discordant MC twins offer unique insights into the epigenetic basis of perinatal programming.

Epigenetic changes in diabetes.

Diabetes is a multifactorial disease with numerous pathways influencing its progression and recent observations suggest that the complexity of the disease cannot be entirely accounted for by genetic predisposition. A compelling argument for an epigenetic component is rapidly emerging. Epigenetic processes at the chromatin template significantly sensitize transcriptional and phenotypic outcomes to environmental signaling information including metabolic state, nutritional requirements and history. Epigenetic mechanisms impact gene expression that could predispose individuals to the diabetic phenotype during intrauterine and early postnatal development, as well as throughout adult life. Furthermore, epigenetic changes could account for the accelerated rates of chronic and persistent microvascular and macrovascular complications associated with diabetes. Epidemiological and experimental animal studies identified poor glycemic control as a major contributor to the development of diabetic complications and highlight the requirement for early intervention. Early exposure to hyperglycemia can drive the development of complications that manifest late in the progression of the disease and persist despite improved glycemic control, indicating a memory of the metabolic insult. Understanding the molecular events that underlie these transcriptional changes will significantly contribute to novel therapeutic interventions to prevent, reverse or retard the deleterious effects of the diabetic milieu.

Placental hyperinflation and the risk of adverse perinatal outcome.

OBJECTIVES: To determine the pathological basis and clinical associations of excessively thick placentae observed at second-trimester ultrasound examination. METHODS: In a retrospective cohort of 19 singleton high-risk second-trimester pregnancies noted to have a placental length-to-maximum thickness ratio ≤ 2.0, maximum sonographic placental thickness was correlated with clinical outcome, maximum placental thickness after delivery and placental pathological findings. Results were compared with those of an intermediate group of 21 high-risk pregnancies with normal placental dimensions and a control group of 18 low-risk pregnancies also with normal placental dimensions. Increased maximum placental thickness (> 28 mm) and abnormal placental deflation following delivery (pathology - sonography difference in maximum placental thickness < -2 mm) were defined by the upper and lower quartile values, respectively, in the control group. RESULTS: The study group exhibited significantly more adverse outcomes and gross pathological placental features compared with both intermediate and control groups. Despite increased sonographic maximum placental thickness in the study group (median, 55 (range, 40-75) mm compared with both the intermediate group (median, 27 (range, 22-41) mm, P < 0.0001) and the control group (median 26 (range, 23-36) mm, P < 0.0001)), all three groups had similar maximal placental thickness following delivery (study group: median, 24 (range, 10-50) mm vs intermediate group: median, 27 (range, 15-40) mm, P = 0.82 and vs control group: median, 28.5 (range, 18-44), P = 0.42). Pathology-sonography difference in maximum placental thickness in the study group (median, -30 (range, -42 to 0) mm) was significantly greater than that in either the intermediate (median, -2 (range, -11 to 9) mm, P < 0.0001) or the control (median, 1.5 (range, -10 to 18) mm, P < 0.0001) group and was significantly associated with abnormal development of the gas-exchanging placental villi (distal villous hypoplasia) (P = 0.0001). CONCLUSIONS: Increased second-trimester sonographic maximum placental thickness represents a pathological finding associated with severe adverse perinatal outcome. This observation is due to overinflation of the intervillous space by maternal blood rather than to adaptive formation of functional placental tissue.

Minimally invasive fetal therapy for hydropic lung masses: three different approaches and review of the literature.

OBJECTIVE: To report three different antenatal therapeutic approaches for fetal lung masses associated with hydrops. METHODS: Three prospectively followed cases are described, and all 30 previously published minimally invasive cases of fetal therapy for hydropic lung masses are reviewed. RESULTS: Three hydropic fetuses with large intrathoracic lung masses presented at 17, 25 and 21 weeks of gestation, respectively. An aortic feeding vessel was identified in each case and thus a bronchopulmonary sequestration (BPS) was suspected. Under ultrasound guidance, the feeding vessel was successfully occluded with interstitial laser (Case 1), radiofrequency ablation (RFA) (Case 2) and thrombogenic coil embolization (Case 3). Complete (Cases 1 and 2) or partial (Case 3) resolution of the lung mass and hydrops was observed. A healthy infant was born at term after laser therapy (Case 1), and the involved lung lobe was resected on day 2 of postnatal life. In Case 2, hydrops resolved completely following RFA, but an iatrogenic congenital diaphragmatic hernia and abdominal wall defect became apparent 4 weeks later. The neonate died from sepsis following spontaneous preterm labor at 33 weeks. In Case 3, despite technical success in complete vascular occlusion with coils, a stillbirth ensued 2 days after embolization. CONCLUSIONS: The prognosis of large microcystic or echogenic fetal chest masses associated with hydrops is dismal. This has prompted attempts at treatment by open fetal surgery, with mixed results, high risk of premature labor and consequences for future pregnancies. We have demonstrated the possibility of improved outcome following ultrasound-guided laser ablation of the systemic arterial supply. Despite technical success, RFA and coil embolization led to procedure-related complications and need further evaluation.

Systolic function in dogs with pulmonic stenosis of different severities and the effect of balloon valvuloplasty.

INTRODUCTION/OBJECTIVES: Pulmonic stenosis (PS) is one of the most common congenital heart diseases in dogs leading to right ventricular (RV) pressure overload, myocardial remodeling, and potential RV dysfunction. Our objectives were to investigate the extent of RV systolic dysfunction in canine PS and to examine the immediate influence of balloon valvuloplasty (BV) on systolic function. ANIMALS, MATERIALS AND METHODS: This prospective study evaluated 72 dogs with PS and 86 healthy dogs. Echocardiographic parameters of systolic function included normalized tricuspid annular plane systolic excursion (N-TAPSE), normalized systolic myocardial tissue Doppler velocity of the lateral tricuspid annulus (N-RVFW-S'), fractional area change, and speckle-tracking longitudinal endocardial RV strain. Forty-four dogs underwent BV and were re-examined after surgery. RESULTS: Systolic function at the basal segment of the RV was significantly lower in the PS group when compared to healthy dogs (mean N-TAPSE 4.29 ± standard deviation 1.18 mm/kg0.285 vs. 5.60 ± 1.29 mm/kg0.285; median N-RVFW-S' 5.28 [lower-upper 25% quantile 4.35-6.43 cm/s/kg0.186] vs. 7.82 [6.73-8.79 cm/s/kg0.186]; all P<0.001). Global longitudinal RV endocardial strain showed no significant difference between the two groups (-28.50 ± 6.23% vs. 28.61 ± 4.64%; P=0.886), but segmental strain analyses revealed basal hypo- and potential compensatory hyperkinesis of the apical RVFW. Furthermore, BV affected most parameters of systolic function, but not the segmental strain values and N-TAPSE. CONCLUSIONS: Right ventricular basal longitudinal systolic function is decreased in dogs with PS in comparison to a healthy cohort. Regional and global function does not necessarily coincide.

Effects of exercise intensity on gut microbiome composition and function in people with type 2 diabetes.

Exercise is positively associated with higher microbial diversity, but there is limited information on exercise intensity's effect on gut microbiome composition and function in clinical populations. This study examines whether different intensities of exercise exert differential effects on gut microbiome composition and function in low active people with type 2 diabetes. This is a sub-study of the Exercise for Type 2 Diabetes Study, a single centre, prospective, randomised controlled trial. Participants (n = 12) completed 8-weeks of combined aerobic and resistance moderate intensity continuous training (C-MICT) or combined aerobic and resistance high-intensity interval training (C-HIIT). Faecal samples were collected before and after intervention to measure gut microbiome composition and metabolic pathways (metagenome shotgun sequencing) and short-chain fatty acids. Post-exercise α-diversity was different between groups as was the relative abundance of specific taxa was (p < .05). Post-exercise relative abundance of Bifidobacterium, A. municiphila, and butyrate-producers Lachnospira eligens, Enterococcus spp., and Clostridium Cluster IV were higher at lower exercise intensity. Other butyrate-producers (from Eryspelothrichales and Oscillospirales), and methane producer Methanobrevibacter smithii were higher at higher exercise intensity. Pyruvate metabolism (ko00620),COG "Cell wall membrane envelope biogenesis" and "Unknown function" pathways were significantly different between groups and higher in C-MICT post-exercise. Differential abundance analysis on KO showed higher expression of Two-component system in C-HIIT. Transcription factors and "unknown metabolism" related pathways decreased in both groups. There were no significant between group changes in faecal short chain fatty acids. Exercise intensity had a distinct effect on gut microbiome abundance and metabolic function, without impacting short-chain fatty acid output.HighlightsEvidence of exercise effect on gut microbiome outcomes is limited to healthy and athletic populationsIn low active people with type 2 diabetes, different exercise intensities increased specific health promoting and butyrate producers species, and showed differentially abundant gut microbiome metabolic pathways.Further investigation is warranted, and if this supports the present findings, then specific exercise intensities may be promoted to target specific species and optimise gut health.

Adenosine inhibits glutamatergic input to basal forebrain cholinergic neurons.

Adenosine has been proposed as an endogenous homeostatic sleep factor that accumulates during waking and inhibits wake-active neurons to promote sleep. It has been specifically hypothesized that adenosine decreases wakefulness and promotes sleep recovery by directly inhibiting wake-active neurons of the basal forebrain (BF), particularly BF cholinergic neurons. We previously showed that adenosine directly inhibits BF cholinergic neurons. Here, we investigated 1) how adenosine modulates glutamatergic input to BF cholinergic neurons and 2) how adenosine uptake and adenosine metabolism are involved in regulating extracellular levels of adenosine. Our experiments were conducted using whole cell patch-clamp recordings in mouse brain slices. We found that in BF cholinergic neurons, adenosine reduced the amplitude of AMPA-mediated evoked glutamatergic excitatory postsynaptic currents (EPSCs) and decreased the frequency of spontaneous and miniature EPSCs through presynaptic A(1) receptors. Thus we have demonstrated that in addition to directly inhibiting BF cholinergic neurons, adenosine depresses excitatory inputs to these neurons. It is therefore possible that both direct and indirect inhibition may synergistically contribute to the sleep-promoting effects of adenosine in the BF. We also found that blocking the influx of adenosine through the equilibrative nucleoside transporters or inhibiting adenosine kinase and adenosine deaminase increased endogenous adenosine inhibitory tone, suggesting a possible mechanism through which adenosine extracellular levels in the basal forebrain are regulated.

Congenital megalourethra: prenatal diagnosis and postnatal/autopsy findings in 10 cases.

OBJECTIVE: Congenital megalourethra is a rare urogenital malformation characterized by dilation and elongation of the penile urethra associated with absence or hypoplasia of the corpora spongiosa and cavernosa. Postnatal complications include voiding and erectile dysfunction as well as renal insufficiency and pulmonary hypoplasia. To date, only a few prenatally diagnosed cases have been reported. We report on 10 cases diagnosed prenatally and their postnatal/autopsy findings. METHODS: The study involved retrospective chart review of all cases diagnosed antenatally in three tertiary care centers over 5 years. Antenatal ultrasound images and medical records from obstetrics, genetics, urology and nephrology were reviewed. RESULTS: Ten fetuses with megalourethra were identified at a median gestational age of 19 (range, 13-24) weeks and all were confirmed postnatally or at autopsy. Three pregnancies were terminated and seven continued. All cases presented with a distended bladder and megalourethra and all cases had normal karyotype. Of seven liveborn babies, one died neonatally of pulmonary hypoplasia. All six infants alive at the time of writing had a dysfunctional urethra and three suffered from impaired or end-stage renal disease. Associated anomalies were found in half of the cases. CONCLUSION: Congenital megalourethra is caused by abnormal development or hypoplasia of the penile erectile tissue, secondary to distal urethral obstruction. When the amniotic fluid volume is normal, survival is possible. However, all liveborn infants have voiding and renal dysfunction and sexual dysfunction is expected. Megalourethra should be considered in all male fetuses presenting prenatally with megacystis and detailed fetal ultrasonography should look for an elongated and/or distended phallic structure as well as any associated anomalies.

Urate-induced epigenetic modifications in myeloid cells.

OBJECTIVES: Hyperuricemia is a metabolic condition central to gout pathogenesis. Urate exposure primes human monocytes towards a higher capacity to produce and release IL-1ß. In this study, we assessed the epigenetic processes associated to urate-mediated hyper-responsiveness. METHODS: Freshly isolated human peripheral blood mononuclear cells or enriched monocytes were pre-treated with solubilized urate and stimulated with LPS with or without monosodium urate (MSU) crystals. Cytokine production was determined by ELISA. Histone epigenetic marks were assessed by sequencing immunoprecipitated chromatin. Mice were injected intraarticularly with MSU crystals and palmitate after inhibition of uricase and urate administration in the presence or absence of methylthioadenosine. DNA methylation was assessed by methylation array in whole blood of 76 participants with normouricemia or hyperuricemia. RESULTS: High concentrations of urate enhanced the inflammatory response in vitro in human cells and in vivo in mice, and broad-spectrum methylation inhibitors reversed this effect. Assessment of histone 3 lysine 4 trimethylation (H3K4me3) and histone 3 lysine 27 acetylation (H3K27ac) revealed differences in urate-primed monocytes compared to controls. Differentially methylated regions (e.g. HLA-G, IFITM3, PRKAB2) were found in people with hyperuricemia compared to normouricemia in genes relevant for inflammatory cytokine signaling. CONCLUSION: Urate alters the epigenetic landscape in selected human monocytes or whole blood of people with hyperuricemia compared to normouricemia. Both histone modifications and DNA methylation show differences depending on urate exposure. Subject to replication and validation, epigenetic changes in myeloid cells may be a therapeutic target in gout.

HER1 signaling mediates extravillous trophoblast differentiation in humans.

This study examines the role of HER1 signaling in the differentiation of proliferative extravillous trophoblast (EVT) into invasive EVT. Using the JAR choriocarcinoma cell line and placental villous explants as experimental models and immunohistochemical assessment of protein markers of EVT differentiation (downregulation of HER1 and Cx40 and upregulation of HER2 and alpha1 integrin), we show that the ability of decidual conditioned medium (DCM) to induce HER1/2 switching was abrogated in the presence of the HER1 antagonist, AG1478. Similarly, epidermal growth factor (EGF) treatment resulted in the downregulation of HER1 and an upregulation of HER2 expression, whereas co-incubation of EGF with AG1478 inhibited this response. However, EGF did not downregulate Cx40 or induce migration of EVT. In contrast, heparin-binding epidermal-like growth factor (HBEGF) stimulated dose-dependent JAR cell migration, which was inhibited by both AG1478 and AG825 (HER2 antagonist). Western blot analysis of HER1 activation demonstrated that HBEGF-mediated phosphorylation of the HER1 Tyr992 and Tyr1068 sites, while EGF activated the Tyr1045 site. Moreover, HBEGF induced a stronger and more sustained activation of both the mitogen-activated protein kinase and phosphoinositol 3 kinase (PIK3) signaling pathways. Migration assays using a panel of signaling pathway inhibitors demonstrated that the HBEGF-mediated migration was dependent on the PIK3 pathway. These results demonstrate that HBEGF-mediated HER1 signaling through PIK3 is an important component of EVT invasion.