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Contains fulltext : 287940.pdf (Publisher’s version ) (Open Access) OBJECTIVES: We aimed to describe the variation of hemostasis proteins in children with bacterial infections due to different pathogens ( Neisseria meningitidis, Streptococcus pneumoniae, Staphylococcus aureus , and group A streptococcus [GAS]) and to study hemostasis proteins in relation to mortality. DESIGN: Preplanned analysis in prospective cohort study. SETTING: Hospitals in five European countries (Austria, The Netherlands, Spain, Switzerland, and the United Kingdom). PATIENTS: Admitted children (2012-2016) with community-acquired infections due to meningococci ( n = 83), pneumococci ( n = 64), S. aureus (n = 50), and GAS ( n = 44) with available serum samples collected less than 48 hours after admission. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Fibronectin, plasminogen activator inhibitor type 1 (PAI-1), thrombomodulin, and a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS-13) were measured in serum in 2019-2020. Additionally, von Willebrand factor, protein C, protein S, and factor IX were measured in citrate plasma available from a subset of patients. Outcome measures included in-hospital mortality and disease severity (need for ventilation/inotropes, Pediatric Index of Mortality score).Of 241 children, 21 (8.7%) died and 177 (73.5%) were admitted to PICU. Mortality rate was similar for the pathogen groups. Levels of fibronectin and thrombomodulin differed for the different pathogens ( p < 0.05). Fibronectin levels were lower in GAS infections than in S. pneumoniae and S. aureus infections but did not differ from meningococcal infections. Thrombomodulin levels in meningococcal infections were higher than in S. aureus and pneumococcal infections. Overall, the area under the curve for mortality was 0.81 (95% CI, 0.70-0.92) for thrombomodulin and 0.78 (95% CI, 0.69-0.88) for ADAMTS-13. The association of each hemostasis protein did not vary across pathogens for any of the outcome measures. CONCLUSIONS: Hemostatic disturbances in childhood bacterial infections are not limited to meningococcal sepsis but occur with a comparable severity across nonmeningococcal infections. High thrombomodulin and high ADAMTS-13 had good discriminative ability for mortality. Our results emphasize the importance of hemostatic disturbances in meningococcal and nonmeningococcal pediatric bacterial infections.

Febrile children below 3 months have a higher risk of serious bacterial infections, which often leads to extensive diagnostics and treatment. There is practice variation in management due to differences in guidelines and their usage and adherence. We aimed to assess whether management in febrile children below 3 months attending European Emergency Departments (EDs) was according to the guidelines for fever. This study is part of the MOFICHE study, which is an observational multicenter study including routine data of febrile children (0–18 years) attending twelve EDs in eight European countries. In febrile children below 3 months (excluding bronchiolitis), we analyzed actual management compared to the guidelines for fever. Ten EDs applied the (adapted) NICE guideline, and two EDs applied local guidelines. Management included diagnostic tests, antibiotic treatment, and admission. We included 913 children with a median age of 1.7 months (IQR 1.0–2.3). Management per ED varied as follows: use of diagnostic tests 14–83%, antibiotic treatment 23–54%, admission 34–86%. Adherence to the guideline was 43% (374/868) for blood cultures, 29% (144/491) for lumbar punctures, 55% (270/492) for antibiotic prescriptions, and 67% (573/859) for admission. Full adherence to these four management components occurred in 15% (132/868, range 0–38%), partial adherence occurred in 56% (484/868, range 35–77%).Conclusion: There is large practice variation in management. The guideline adherence was limited, but highest for admission which implies a cautious approach. Future studies should focus on guideline revision including new biomarkers in order to optimize management in young febrile children. What is Known:• Febrile children below 3 months have a higher risk of serious bacterial infections, which often leads to extensive diagnostics and treatment.• There is practice variation in management of young febrile children due to differences in guidelines and their usage and adherence. What is New:• Full guideline adherence is limited, whereas partial guideline adherence is moderate in febrile children below 3 months across Europe.• Guideline revision including new biomarkers is needed to improve management in young febrile children.

RESEARCH QUESTION: Is seminal oxidation-reduction potential (ORP) clinically relevant to reproductive outcome? DESIGN: Prospective observational study including a total of 144 couples who had an intracytoplasmic sperm injection (ICSI) cycle between June 2018 and December 2020. The study included patients undergoing fresh ICSI cycles with autologous gametes. Cycles that had day 3 embryo transfers and cryopreservation cycles were excluded. There was no restriction on patients with severe male infertility; couples with unexplained infertility and unexplained male infertility were included, those with azoospermia were excluded. Semen analysis, seminal ORP as determined by means of the MiOXSYS system, sperm DNA fragmentation (SDF) and reproductive outcomes (fertilization, blastocyst development, clinical pregnancy and live birth) were determined. RESULTS: Seminal ORP was significantly negatively correlated with fertilization rate (r = -0.267; P = 0.0012), blastocyst development rate (r = -0.432; P < 0.0001), implantation/clinical pregnancy (r = -0.305; P = 0.0003) and live birth (r = -0.366; P < 0.0001). Receiver operating characteristic curve analysis showed significant predictive power for ORP for fertilization (≥80%; area under the curve [AUC] 0.652; P = 0.0012), blastocyst development rate (≥60%; AUC 0.794; P < 0.0001), implantation/clinical pregnancy (AUC 0.680; P = 0.0002) and live birth (AUC 0.728; P < 0.0001). Comparable results were obtained for SDF (fertilization: AUC 0.678; blastocyst development: AUC 0.777; implantation/clinical pregnancy: AUC 0.665; live birth: AUC 0.723). Normal sperm morphology showed the lowest predictive power for all reproductive outcome parameters. With male age as confounding factor, ORP (cut-off value of 0.51 mV/106 sperm/ml) has significant (P < 0.04667) effects on odds ratios for all reproductive outcome parameters. Multivariate logistic regression to investigate potential seminal and female confounding factors revealed that seminal ORP significantly (P < 0.0039; P < 0.0130) affects reproductive outcome. CONCLUSION: Seminal ORP is relevant for good fertilization, blastocyst development, implantation, clinical pregnancy and live birth.

Due to advancements in ultrasound techniques, the focus of antenatal ultrasound screening is moving towards the first trimester of pregnancy. The early first trimester however remains in part, a 'black box', due to the size of the developing embryo and the limitations of contemporary scanning techniques. Therefore there is a need for images of early anatomical developmental to improve our understanding of this area. By using new imaging techniques, we can not only obtain better images to further our knowledge of early embryonic development, but clear images of embryonic and fetal development can also be used in training for e.g. sonographers and fetal surgeons, or to educate parents expecting a child with a fetal anomaly. The aim of this review is to provide an overview of the past, present and future techniques used to capture images of the developing human embryo and fetus and provide the reader newest insights in upcoming and promising imaging techniques. The reader is taken from the earliest drawings of da Vinci, along the advancements in the fields of in utero ultrasound and MR imaging techniques towards high-resolution ex utero imaging using Micro-CT and ultra-high field MRI. Finally, a future perspective is given about the use of artificial intelligence in ultrasound and new potential imaging techniques such as synchrotron radiation-based CT to increase our knowledge regarding human development. ispartof: SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY vol:131 pages:78-92 ispartof: location:England status: published

Background: Anaemia in infants is a major public health concern particularly in low and middle-income countries. Delayed cord clamping (DCC) has been advocated as a strategy to decrease iron deficiency anaemia in infants because of the benefits that come with placental transfusion. Despite the documented benefits of delayed cord clamping in preventing anaemia the current practices of delayed cord clamping by midwives and obstetricians across countries and in different contexts is unclear. This narrative review assesses the literature on delayed cord clamping practices published from 2013 to February 2022, in order to examine current practice in birth units globally, and with a focus in low and middle-income countries (LMICs). Method: A search of four bibliographic databases Medline, Scopus (Elsevier), ProQuest, CINAHL and two network and search engines, Wiley and Google Scholar, was undertaken from 2013 to February 2022 using key terms related to delayed cord clamping and immediate cord clamping. A snowball method as well as backward and forward reference checking was also undertaken. Results: The search strategy identified 10 studies on umbilical cord clamping practices by midwives and obstetricians. Only two studies were conducted in low and middle-income countries. Conclusion: Despite the potential benefits of DCC in reducing anaemia, particularly in low and middle-income countries where the burden of anaemia is a public health concern, there is a paucity of literature on current DCC practices by obstetricians and midwives. Research to establish current DCC practices in these countries is needed to address this gap in the literature. Refereed/Peer-reviewed

OBJECTIVE: To assess the association between maternal asthma and adverse perinatal outcomes in an Australian Indigenous population. METHODS: This prospective cohort study included all Indigenous mother and baby dyads for births from 2001 to 2013 in Western Australia (n = 25 484). Data were linked from Western Australia Births, Deaths, Midwives, Hospital, and Emergency Department collections. Maternal asthma was defined as a self-reported diagnosis at an antenatal visit or hospitalization or emergency visit for asthma during pregnancy or less than 3 years before pregnancy. Associations with birth, labor, and pregnancy outcomes were assessed using generalized estimating equations. Asthma exacerbation during pregnancy and stratification by remoteness was also assessed. RESULTS: Maternal asthma was associated with placental abruption (adjusted odds ratio [aOR], 1.59 [95% confidence interval (CI), 1.07-2.35]), threatened preterm labor (aOR, 1.58 [95% CI, 1.39-1.79]), and emergency cesarean sections (aOR, 1.27 [95% CI, 1.13-1.44]). These risks increased further with an asthma exacerbation during pregnancy or if the mother was from a remote area. No associations were found for low birth weight, preterm birth, small for gestational age, or perinatal mortality. CONCLUSION: Maternal asthma in Indigenous women is associated with an increased risk of emergency cesarean sections, placental abruption, and threatened preterm labor. These risks may be mitigated by improved management of asthma exacerbations during pregnancy.

ObjectiveTo develop a clinical prediction model to diagnose neonatal sepsis in low-resource settings.DesignSecondary analysis of data collected by the Neotree digital health system from 01/02/2019 to 31/03/2020. We used multivariable logistic regression with candidate predictors identified from expert opinion and literature review. Missing data were imputed using multivariate imputation and model performance was evaluated in the derivation cohort.SettingA tertiary neonatal unit at Sally Mugabe Central Hospital, Zimbabwe.PatientsWe included 2628 neonates aged +0weeks and birth weight ≥ 1500 grams.InterventionsParticipants received standard care as no specific interventions were dictated by the study protocol.Main outcome measuresClinical early-onset neonatal sepsis (within the first 72 hours of life), defined by the treating consultant neonatologist.ResultsClinical early-onset sepsis was diagnosed in 297 neonates (11.3%). The optimal model included eight predictors: maternal fever, offensive liquor, prolonged rupture of membranes, neonatal temperature, respiratory rate, activity, chest retractions and grunting. Receiver operating characteristic analysis gave an area under the curve of 0.736 (95% confidence interval 0.701-0.772). For a sensitivity of 95% (92-97%), corresponding specificity was 11% (10-13%), positive predictive value 12% (11-13%), negative predictive value 95% (92-97%), positive likelihood ratio 1.1 (95% CI 1.0-1.1), and negative likelihood ratio 0.4 (95% CI 0.3-0.6).ConclusionsOur clinical prediction model achieved high sensitivity with modest specificity, suggesting it may be suited to excluding early-onset sepsis. Future work will validate and refine this model before considering it for clinical use within the Neotree.What is already known on this topicVarious clinical prediction models exist to diagnose neonatal sepsis. However, there is a paucity of literature on models in low-resource settings, particularly sub-Saharan Africa.What this study addsWe developed a clinical prediction model to diagnose clinical early-onset neonatal sepsis with over 2,500 neonates in a lower middle-income, low-resource neonatal unit. Our model is easy to implement, does not require laboratory tests and achieved high sensitivity with modest specificity in the derivation cohort.How this study might affect research, practice or policyOur model could support less experienced healthcare professionals avoid unnecessary antibiotic therapy in the absence of immediate local senior support. Before implementation, this model must be externally validated and its impact on sepsis-related neonatal morbidity and mortality must be assessed in future studies.

Aims/hypothesis The prevalence of type 2 diabetes is increasing worldwide, and previous studies have suggested that it is higher in individuals who are seropositive for herpesviruses. This study examines the prospective association of herpesviruses with (pre)diabetes to evaluate their potential role in diabetes aetiology. Methods Two follow-up examinations of the German population-based KORA cohort (F4 and FF4) were used to identify participants with normal glucose tolerance at baseline, thus being at risk for (pre)diabetes (n = 1257). All participants had repeated OGTTs and antibody measurements for herpes simplex virus (HSV) 1 and 2, varicella-zoster virus, Epstein–Barr virus, cytomegalovirus (CMV) and human herpesvirus 6 and 7. Regression models were used to evaluate the association between serostatus with (pre)diabetes incidence after a 7 year follow-up and HbA1c. Results HSV2 and CMV were associated with (pre)diabetes incidence after adjustment for sex, age, BMI, education, smoking, physical activity, parental diabetes, hypertension, lipid levels, insulin resistance and fasting glucose. Seropositivity of both viruses was also cross-sectionally associated with higher HbA1c at baseline, with the association of HSV2 being independent of confounders, including the prevalence of (pre)diabetes itself. While seropositivity for multiple herpesviruses was associated with a higher incidence of (pre)diabetes, this association was not independent of confounders. Conclusions/interpretation The associations of HSV2 and CMV serostatus with (pre)diabetes incidence indicate that these herpesviruses may contribute to the development of impaired glucose metabolism. Our results highlight the link between viral infection and (pre)diabetes, and the need for more research evaluating viral prevention strategies. Graphical abstract

BACKGROUND: Non-invasive prenatal screening (NIPS) is being increasingly used by expectant parents. Much provision of this test in Australia is occurring in clinical settings where specialised genetic counselling is unavailable, such as general practice. Potential psychosocial consequences from this kind of prenatal genetic screening remain largely unexplored. AIMS: To explore clinicians' experiences with NIPS for aneuploidy, their perspectives of the benefits and harms of NIPS, clinicians' information needs, and their perceptions of the needs of expectant parents. MATERIALS AND METHODS: Qualitative, semi-structured interviews with 17 health professionals (clinical geneticists, obstetricians, genetic counsellors and general practitioners) who request and counsel for NIPS in Australian hospital and private practice settings, conducted between June 2019 and February 2020. RESULTS: Five themes were identified relating to clinicians' perceptions and experiences of NIPS in their practice: perceived benefits of NIPS, perceived harms of NIPS (with two subthemes: clinical harms and psychosocial harms), financial and equity-related concerns, counselling as a protective buffer against perceived harms, and clinicians' unmet education needs. While clinicians view NIPS as a useful and high-quality screening test, especially for detection of common trisomies, many participants had concerns about how NIPS has been implemented in practice, particularly the quality (and often absence) of pre-/post-test counselling and the routinisation of testing for sex chromosome aneuploidies, microdeletion and microduplication syndromes. CONCLUSION: These findings support the need for targeted clinician training around NIPS, and for a shared decision-making approach to support expectant parents' autonomous decisions about NIPS.

BACKGROUND The beneficial effects of hormonal therapy in stimulating spermatogenesis in patients with non-obstructive azoospermia (NOA) and either normal gonadotrophins or hypergonadotropic hypogonadism prior to surgical sperm retrieval (SSR) is controversial. Although the European Association of Urology guidelines state that hormone stimulation is not recommended in routine clinical practice, a significant number of patients undergo empiric therapy prior to SSR. The success rate for SSR from microdissection testicular sperm extraction is only 40–60%, thus hormonal therapy could prove to be an effective adjunctive therapy to increase SSR rates. OBJECTIVE AND RATIONALE The primary aim of this systematic review and meta-analysis was to compare the SSR rates in men with NOA (excluding those with hypogonadotropic hypogonadism) receiving hormone therapy compared to placebo or no treatment. The secondary objective was to compare the effects of hormonal therapy in normogonadotropic and hypergonadotropic NOA men. SEARCH METHODS A literature search was performed using the Medline, Embase, Web of Science and Clinicaltrials.gov databases from 01 January 1946 to 17 September 2020. We included all studies where hormone status was confirmed. We excluded non-English language and animal studies. Heterogeneity was calculated using I2 statistics and risk of bias was assessed using Cochrane tools. We performed a meta-analysis on all the eligible controlled trials to determine whether hormone stimulation (irrespective of class) improved SSR rates and also whether this was affected by baseline hormone status (hypergonadotropic versus normogonadotropic NOA men). Sensitivity analyses were performed when indicated. OUTCOMES A total of 3846 studies were screened and 22 studies were included with 1706 participants. A higher SSR rate in subjects pre-treated with hormonal therapy was observed (odds ratio (OR) 1.96, 95% CI: 1.08–3.56, P = 0.03) and this trend persisted when excluding a study containing only men with Klinefelter syndrome (OR 1.90, 95% CI: 1.03–3.51, P = 0.04). However, the subgroup analysis of baseline hormone status demonstrated a significant improvement only in normogonadotropic men (OR 2.13, 95% CI: 1.10–4.14, P = 0.02) and not in hypergonadotropic patients (OR 1.73, 95% CI: 0.44–6.77, P = 0.43). The literature was at moderate or severe risk of bias. WIDER IMPLICATIONS This meta-analysis demonstrates that hormone therapy is not associated with improved SSR rates in hypergonadotropic hypogonadism. While hormone therapy improved SSR rates in eugonadal men with NOA, the quality of evidence was low with a moderate to high risk of bias. Therefore, hormone therapy should not be routinely used in men with NOA prior to SSR and large scale, prospective randomized controlled trials are needed to validate the meta-analysis findings.

Context The oocyte-secreted factors growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) play essential roles in follicle development and oocyte maturation, and aberrant regulation might contribute to the pathogenesis of polycystic ovary syndrome. Objective Are there measurable differences in concentrations of GDF9, BMP15, and the GDF9/BMP15 heterodimer in small antral follicle fluids from women with and without polycystic ovaries (PCO)? Design and Setting Follicle fluids (n = 356) were collected from 4- to 11-mm follicles in unstimulated ovaries of 87 women undergoing ovarian tissue cryopreservation for fertility preservation. Patients Twenty-seven women with PCO were identified and 60 women without PCO-like characteristics (non-PCO women) were matched according to age and follicle size. Main outcome measures Intrafollicular concentrations of GDF9, BMP15, GDF9/BMP15 heterodimer, anti-Mullerian hormone (AMH), inhibin-A and -B, total inhibin, activin-B and -AB, and follistatin were measured using enzyme-linked immunosorbent assays. Results The detectability of GDF9, BMP15, and the GDF9/BMP15 heterodimer were 100%, 94.4%, and 91.5%, respectively, and concentrations were significantly negatively correlated with increasing follicle size (P Conclusions Intrafollicular concentrations of GDF9 and BMP15 varied inversely in women with PCO reflecting an aberrant endocrine environment. An increased GDF9:BMP15 ratio may be a new biomarker for PCO.

Objectives: Fluid bolus resuscitation in African children is harmful. Little research has evaluated physiologic effects of maintenance-only fluid strategy. Design: We describe the efficacy of fluid-conservative resuscitation of septic shock using case-fatality, hemodynamic, and myocardial function endpoints. Setting: Pediatric wards of Mbale Regional Referral Hospital, Uganda, and Kilifi County Hospital, Kenya, conducted between October 2013 and July 2015. Data were analysed from August 2016 to July 2019. Patients: Children (≥ 60 d to ≤ 12 yr) with severe febrile illness and clinical signs of impaired perfusion. Interventions: IV maintenance fluid (4 mL/kg/hr) unless children had World Health Organization (WHO) defined shock (≥ 3 signs) where they received two fluid boluses (20 mL/kg) and transfusion if shock persisted. Clinical, electrocardiographic, echocardiographic, and laboratory data were collected at presentation, during resuscitation and on day 28. Outcome measures were 48-hour mortality, normalization of hemodynamics, and cardiac biomarkers. Measurement and Main Results: Thirty children (70% males) were recruited, six had WHO shock, all of whom died (6/6) versus three of 24 deaths in the non-WHO shock. Median fluid volume received by survivors and nonsurvivors were similar (13 [interquartile range (IQR), 9–32] vs 30 mL/kg [28–61 mL/kg], z = 1.62, p = 0.23). By 24 hours, we observed increases in median (IQR) stroke volume index (39 mL/m2 [32–42 mL/m2] to 47 mL/m2 [41–49 mL/m2]) and a measure of systolic function: fractional shortening from 30 (27–33) to 34 (31–38) from baseline including children managed with no-bolus. Children with WHO shock had a higher mean level of cardiac troponin (t = 3.58; 95% CI, 1.24–1.43; p = 0.02) and alpha-atrial natriuretic peptide (t = 16.5; 95% CI, 2.80–67.5; p < 0.01) at admission compared with non-WHO shock. Elevated troponin (> 0.1 μg/mL) and hyperlactatemia (> 4 mmol/L) were putative makers predicting outcome. Conclusions: Maintenance-only fluid therapy normalized clinical and myocardial perturbations in shock without compromising cardiac or hemodynamic function whereas fluid-bolus management of WHO shock resulted in high fatality. Troponin and lactate biomarkers of cardiac dysfunction could be promising outcome predictors in pediatric septic shock in resource-limited settings.

Hypogonadism can be present in up to 40% in men who present with couple infertility. Testosterone is the major androgen regulating-spermatogenesis in men; as a result, men with either primary or secondary hypogonadism may be subfertile because of impaired spermatogenesis. The clinical impact of hypogonadism on fertility potential depends on the timing of its onset (fetal, prepubertal, or postpubertal) and effect on semen parameters. Treatment pathways and success rates differ according to the cause of hypogonadism and the time of its onset. When medical therapy fails to induce sufficient sperm, assisted reproductive technologies are considered.

The opinion on the mechanisms underlying the pathogenesis of preeclampsia still divides scientists and clinicians. This common complication of pregnancy has long been viewed as a disorder linked primarily to placental dysfunction, which is caused by abnormal trophoblast invasion, however, evidence from the previous two decades has triggered and supported a major shift in viewing preeclampsia as a condition that is caused by inherent maternal cardiovascular dysfunction, perhaps entirely independent of the placenta. In fact, abnormalities in the arterial and cardiac functions are evident from the early subclinical stages of preeclampsia and even before conception. Moving away from simply observing the peripheral blood pressure changes, studies on the central hemodynamics reveal two different mechanisms of cardiovascular dysfunction thought to be reflective of the early-onset and late-onset phenotypes of preeclampsia. More recent evidence identified that the underlying cardiovascular dysfunction in these phenotypes can be categorized according to the presence of coexisting fetal growth restriction instead of according to the gestational period at onset, the former being far more common at early gestational ages. The purpose of this review is to summarize the hemodynamic research observations for the two phenotypes of preeclampsia. We delineate the physiological hemodynamic changes that occur in normal pregnancy and those that are observed with the pathologic processes associated with preeclampsia. From this, we propose how the two phenotypes of preeclampsia could be managed to mitigate or redress the hemodynamic dysfunction, and we consider the implications for future research based on the current evidence. Maternal hemodynamic modifications throughout pregnancy can be recorded with simple-to-use, noninvasive devices in obstetrical settings, which require only basic training. This review includes a brief overview of the methodologies and techniques used to study hemodynamics and arterial function, specifically the noninvasive techniques that have been utilized in preeclampsia research.

Key content Continuing financial constraints on the UK’s National Health Service means the need for clinicians to provide high-quality care in a cost-effective way has never been greater. While the medical education system equips doctors with skills to provide safe clinical care, it should also provide an understanding of healthcare costs and cost-effectiveness analysis. Value-based care is becoming a key paradigm in women’s health services, where clinicians must employ strategies for delivering value, rationalising costs and capitalising on the use of emerging technologies. The calculation of value of an intervention for providers and service users may differ; care must be taken to ensure this concept is adapted for, and not imposed on healthcare systems. Engaging trainees in systems transformation and embedding the concepts of ‘do no financial harm’ are essential to ensure sustainable healthcare services. Learning Objectives To understand the principles of value-based health care. To highlight the importance of adopting ‘cost-conscious’ care within daily clinical practice. To learn the differences between ‘cost’, ‘charge’, ‘price’ and ‘reimbursement. To encourage developing value-based competencies for future medical workforce through utilising out of programme placements and digital resources. Ethical Issues The ethical obligation of clinicians to consider cost may encompass justice and equity. However, the impact of practicing value-based health care is yet to be evaluated.

Optimal immunogenicity from nucleic acid vaccines requires a balance of antigen expression that effectively engages the host immune system without generating a cellular response that rapidly destroys cells producing the antigen and thereby limiting vaccine antigen expression. We investigated the role of the cellular response on the expression and antigenicity of DNA vaccines using a plasmid DNA construct expressing luciferase. Repeated intramuscular administration led to diminished luciferase expression, suggesting a role for immune-mediated clearance of expression. To investigate the role of cell trafficking, we used the sphingosine 1-phosphate receptor (S1PR) modulator, FTY720 (Fingolimod), which traps lymphocytes within the lymphoid tissues. When lymphocyte trafficking was blocked with FTY720, DNA transgene expression was maintained at a constant level for a significantly extended time period. Both continuous and staggered administration of FTY720 prolonged transgene expression. However, blocking lymphocyte egress during primary transgene administration did not result in an increase of transgene expression during secondary administration. Interestingly, there was a disconnect between transgene expression and immunogenicity, as increasing expression by this approach did not enhance the overall immune response. Furthermore, when FTY720 was administered alongside a DNA vaccine expressing the HIV gp140 envelope antigen, there was a significant reduction in both antigen-specific antibody and T-cell responses. This indicates that the developing antigen-specific cellular response clears DNA vaccine expression but requires access to the site of expression in order to develop an effective immune response.

Children have the right to grow up free from the hazards associated with tobacco smoking. Tobacco smoke exposure can have detrimental effects on children’s health and development, from before birth and beyond. As a result of effective tobacco control policies, European smoking rates are steadily decreasing among adults, as is the proportion of adolescents taking up smoking. Substantial variation however exists between countries, both in terms of smoking rates and regarding implementation, comprehensiveness and enforcement of policies to address smoking and second-hand smoke exposure. This is important because comprehensive tobacco control policies such as smoke-free legislation and tobacco taxation have extensively been shown to carry clear health benefits for both adults and children. Additional policies such as increasing the legal age to buy tobacco, reducing the number of outlets selling tobacco, banning tobacco display and advertising at the point-of-sale, and introducing plain packaging for tobacco products can help reduce smoking initiation by youth. At societal level, health professionals can play an important role in advocating for stronger policy measures, whereas they also clearly have a duty to address smoking and tobacco smoke exposure at the patient level. This includes providing cessation advise and referring to effective cessation services.Conclusion: Framing of tobacco exposure as a child right’s issue and of comprehensive tobacco control as a tool to work towards the ultimate goal of reaching a tobacco-free generation can help accelerate European progress to curb the tobacco epidemic. What is Known:• Tobacco exposure is associated with a range of adverse health effects among babies and children.• Comprehensive tobacco control policies helped bring down smoking rates in Europe and benefit child health. What is New:• Protecting the rights and health of children provides a strong starting point for tobacco control advocacy.• The tobacco-free generation concept helps policy-makers set clear goals for protecting future generations from tobacco-associated harms.

Objective. To describe molecular and clinical characteristics of patients with high-grade recurrent ovarian carcinoma (HGOC) who had long-term responses to the poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib. Methods. This post hoc analysis pooled patients from Study 10 (NCT01482715; Parts 2A and 2B; n = 54) and ARIEL2 (NCT01891344; Parts 1 and 2; n = 491). Patients with investigator-assessed complete or partial response per RECIST were classified based on duration of response (DOR): long (≥1 year), intermediate (6 months to

Background Pregnancy can be a stressful period for most women and their family members, and the mental wellbeing of pregnant women can face serious challenges. Social support can play a role in improving the psychological well-being of pregnant women by enhancing the stress coping ability and alleviating stressful conditions. The current study aimed to assess the mediating effects of social support in the relationship between perceived stress and depressive symptoms as well as anxiety symptoms during pregnancy among Australian women. Methods Of the 8,010 women who completed Survey 6 of the 1973–78 Australian Longitudinal Study on Women’s Health (ALSWH) cohort in 2012, those who reported being pregnant (n = 493) were included in the current analyses. Antenatal depressive and anxiety symptoms were assessed using the 10 item Center for Epidemiological Studies Depression (CES-D-10) scale, and the 9-item Goldberg Anxiety and Depression scale (GADS) respectively. The 19 item-Medical Outcomes Study Social Support index (MOSS) was used to examine social support. A parallel mediation model was used to explore the mediational role of each domain of social support between perceived stress and antenatal depressive and anxiety symptoms. Result The study found that emotional/informational support has a partial mediating effect on the relationship between perceived stress and antenatal depressive symptoms (β = 0.371, 95% CI: 0.067, 0.799) and on the relationship between perceived stress and antenatal anxiety symptoms (β = 0.217, 95% CI: 0.029, 0.462). Affectionate support/positive social interaction and tangible support was found to play no significant mediation role between stress and antenatal depressive and anxiety symptoms. Conclusions Emotional/informational support appears to play a mediating role in the relationship between stress and antenatal depressive as well as between stress and antenatal anxiety symptoms. In order to further protect pregnant women from the effects of stress, policy makers and maternal health professionals are advised to develop community-based social support programs to enhance prenatal psychosocial support and ensure pregnant women have adequate emotional/information support., Plain language summary Social support is a resource or a means that an individual can use to cope with stressful events and improve psychological wellbeing. It improves emotional and physical well-being and promotes health for a successful pregnancy. However, the relationship between domains of social support and antenatal depressive and anxiety symptoms remains understudied in Australia. Therefore, our study intended to examine the mediating role of domains of social support in the linkage between stress and depressive and anxiety symptoms during pregnancy among Australian Women. Data were obtained from Survey 6 of the 1973–78 ALSWH cohort, which was conducted in 2012, and those who reported being pregnant were part of the study (n = 493, aged 34–39 years). Social support provided for a pregnant woman was the outcome variable, assessed using the 19-item Medical Outcomes Study Social Support index (MOS-SSS-19 item). A parallel mediation model was used to explore the mediational role of each domain of social support between perceived stress and antenatal depressive and anxiety symptoms. Emotional/informational support plays a mediating role in the relationship between stress and antenatal depressive as well as between stress and antenatal anxiety symptoms. So, to further protect pregnant women from the effect of stress, policymakers and maternal health professionals are advised to develop community-based social support programs.

Objective Decision aids have been developed to help prospective parents make informed, shared decisions about medical tests, but these options are rapidly changing. This study aimed to identify and evaluate publicly available decision aids written in English for prospective parents seeking prenatal test information. Methods A systematic review process was followed using 3 sources: known decision aid repositories, fetal medicine organisations and Google. The search, screening process, quality assessment, and data extraction was performed by two independent researchers. The quality assessment of the decision aids was based on the International Patient Decision Aids Standards (IPDAS v.4.0). Results We identified 13 decision aids, which varied in the screening and diagnostic tests that they discussed. No decision aid met all the IPDAS v.4.0. criteria and no decision aid reported updated risk of miscarriage for amniocentesis and chorionic villus sampling (CVS). There was a lack of decision aids for some common decisions in the prenatal context. Conclusion We identified outdated content in current prenatal decision aids. The findings will inform healthcare professionals of the quality of current prenatal decision aids, which may facilitate their patients’ informed decision-making about prenatal tests. Innovation Considerations for improving future decision aids are outlined.

Aims/hypothesis Type 2 diabetes mellitus can manifest over a broad clinical range, although there is no clear consensus on the categorisation of disease complexity. We assessed the effects of canagliflozin, compared with placebo, on cardiovascular and kidney outcomes in the CANagliflozin cardioVascular Assessment Study (CANVAS) Program over a range of type 2 diabetes mellitus complexity, defined separately by baseline intensity of treatment, duration of diabetes and glycaemic control. Methods We performed a post hoc analysis of the effects of canagliflozin on major adverse cardiovascular events (MACE) according to baseline glucose-lowering treatments (0 or 1, 2 or 3+ non-insulin glucose-lowering treatments, or insulin-based treatment), duration of diabetes (16 years) and HbA1c (≤53.0 mmol/mol [53.0 to 58.5 mmol/mol [>7.0% to 7.5%], >58.5 to 63.9 mmol/mol [>7.5 to 8.0%], >63.9 to 69.4 mmol/mol [8.0% to 8.5%], >69.4 to 74.9 mmol/mol [>8.5 to 9.0%] or >74.9 mmol/mol [>9.0%]). We analysed additional secondary endpoints for cardiovascular and kidney outcomes, including a combined kidney outcome of sustained 40% decline in eGFR, end-stage kidney disease or death due to kidney disease. We used Cox regression analyses and compared the constancy of HRs across subgroups by fitting an interaction term (p value for significance Results At study initiation, 5095 (50%) CANVAS Program participants were treated with insulin, 2100 (21%) had an HbA1c > 74.9 mmol/mol (9.0%) and the median duration of diabetes was 12.6 years (interquartile interval 8.0–18 years). Canagliflozin reduced MACE (HR 0.86 [95% CI 0.75, 0.97]) with no evidence that the benefit differed between subgroups defined by the number of glucose-lowering treatments, the duration of diabetes or baseline HbA1c (all p-heterogeneity >0.17). Canagliflozin reduced MACE in participants receiving insulin with no evidence that the benefit differed from other participants in the trial (HR 0.85 [95% CI 0.72, 1.00]). Similar results were observed for other cardiovascular outcomes and for the combined kidney outcome (HR for combined kidney outcome 0.60 [95% CI 0.47, 0.77]), with all p-heterogeneity >0.37. Conclusions/interpretation In people with type 2 diabetes mellitus at high cardiovascular risk, there was no evidence that cardiovascular and renal protection with canagliflozin differed across subgroups defined by baseline treatment intensity, duration of diabetes or HbA1c. Graphical abstract

Background We examined the evidence derived from healthcare professionals’ interfacing with women with female genital mutilation (FGM) to comprehend the referral pathways available to these women in Australia. Main body Clinicians encountered FGM-related complications that included ruptured bladder and total urinary incontinence. Midwives and paediatricians indicated a lack of referral pathways for FGM, but used their discretion to refer such cases to social work departments, obstetric/gynaecological units, child protection service providers, psychological counsellors and surgeons. The continuum of care for women with FGM is characterised by inadequate and lack of clear referral pathways. This underscores the need to develop and strengthen referral pathways in response to physical, birthing and psychological complications of women with FGM to improve their care experiences in Australia. Short conclusion Capacity building initiatives on FGM-prevention and care for trainees and practising health providers and community involvement in high burden areas/populations should be implemented to promote uptake and utilization of the referral services. Provision of infrastructural support, including clinical management tools, job aids, posters, referral algorithms and electronic patient records with "drop-down menus" for referral sites for health complications of FGM to reinforce the providers’ efforts are critical.

BACKGROUND Active surveillance for cervical intraepithelial neoplasia 2 (CIN2) would allow time for most cases to regress naturally and in turn avoid potentially unnecessary and harmful treatment. AIM To determine reasons for choosing active surveillance over surgery among women given a hypothetical diagnosis of CIN2. MATERIALS AND METHODS Women residing in Australia aged 25-40 years with no prior diagnosis of cervical cancer, cervical abnormality CIN2 or above, and/or previous hysterectomy, were randomised to one of four identical hypothetical scenarios of testing human papillomavirus (HPV)-positive: high-grade cytology and a diagnosis of CIN2 that used alternate terminology to describe resolution of abnormal cells and/or inclusion of an overtreatment statement. Participants selected active surveillance or surgery after viewing the scenario and free-text reason/s for their choice were thematically analysed. RESULTS Of the 1638 women randomised, 79% (n = 1293) opted for active surveillance. The most common reasons for choosing active surveillance included concerns about surgery and associated risks, preferring to 'wait and see', trusting the doctor's recommendations and having an emotional response toward surgery. For women who chose surgery, being risk-averse, addressing the issue straight away and perceiving surgery to be the better option for them were the most common themes identified. CONCLUSION When presented with balanced information on the benefits and harms of different management options for CIN2 and given a choice, most women in this hypothetical situation chose active surveillance over surgery. Addressing women's concerns about active surveillance may open up the possibility that if deemed safe, it could be an acceptable alternative for women.

Aims/hypothesis The aim of this study was to leverage human genetic data to investigate the cardiometabolic effects of glucose-dependent insulinotropic polypeptide (GIP) signalling. Methods Data were obtained from summary statistics of large-scale genome-wide association studies. We examined whether genetic associations for type 2 diabetes liability in the GIP and GIPR genes co-localised with genetic associations for 11 cardiometabolic outcomes. For those outcomes that showed evidence of co-localisation (posterior probability >0.8), we performed Mendelian randomisation analyses to estimate the association of genetically proxied GIP signalling with risk of cardiometabolic outcomes, and to test whether this exceeded the estimate observed when considering type 2 diabetes liability variants from other regions of the genome. Results Evidence of co-localisation with genetic associations of type 2 diabetes liability at both the GIP and GIPR genes was observed for five outcomes. Mendelian randomisation analyses provided evidence for associations of lower genetically proxied type 2 diabetes liability at the GIP and GIPR genes with lower BMI (estimate in SD units −0.16, 95% CI −0.30, −0.02), C-reactive protein (−0.13, 95% CI −0.19, −0.08) and triacylglycerol levels (−0.17, 95% CI −0.22, −0.12), and higher HDL-cholesterol levels (0.19, 95% CI 0.14, 0.25). For all of these outcomes, the estimates were greater in magnitude than those observed when considering type 2 diabetes liability variants from other regions of the genome. Conclusions/interpretation This study provides genetic evidence to support a beneficial role of sustained GIP signalling on cardiometabolic health greater than that expected from improved glycaemic control alone. Further clinical investigation is warranted. Data availability All data used in this study are publicly available. The scripts for the analysis are available at: https://github.com/vkarhune/GeneticallyProxiedGIP. Graphical abstract

BACKGROUND: Utilization of contraceptives remains low in several countries in sub-Saharan Africa despite evidence of its benefits. Several factors are associated with contraceptive use. However, little is known about the association between women's decision-making capacity and the utilization of contraceptives in Mali. This study sought to determine the effect of women's household decision-making power on contraceptive use in Mali. METHODS: This study involved a cross-sectional analysis of data from the 2018 Mali Demographic and Health Survey. A total of 7893 married women were included in the final analysis. A binary logistic regression analysis was conducted with statistical significance set at p

Objectives To summarise the available data regarding the effect of hormone replacement therapy (HRT) on cognition and mood in women. Background Complaints of impaired cognition and mood are common in the peri-menopausal and menopausal period. There is debate as to whether HRT can ameliorate this phenomenon. Design A literature search of studies using electronic databases was conducted. Both randomised control trials and observational studies were included. Patients Perimenopausal and menopausal women. Results Due to the heterogenicity of results it is challenging to draw firm conclusions. The preparations used in many of the studies are older regimes no longer routinely used clinically. The notion of a ‘critical window’ for HRT is compelling, suggesting HRT has a positive impact on cognition when administered in the peri-menopausal or early postmenopausal period but may have negative effects on cognition in the older, postmenopausal woman. The evidence would seem to suggest importance of hormonal replacement in woman undergoing a surgical menopause, especially when young. It remains unclear for how long they ought to continue HRT though until at least the natural age of the menopause seems reasonable. Evidence for a positive effect of HRT on mood is more convincing, though possibly more efficacious in the younger age group. The effect of HRT on anxiety is less clear. Conclusions Further study, particularly focusing on the more contemporaneous HRT preparations, is warranted before evidence-based conclusions can be drawn.

PURPOSE: Long-acting reversible contraceptives (LARC), such as intrauterine devices (IUD) and implants, are highly effective. However, the uptake of LARC in Australia has been slow and the oral contraceptive pill (OC) remains the best known and most widely used contraceptive. Our aim was to investigate women's preferences for the features of LARC. METHODS: We used a discrete choice experiment (DCE) in which each respondent completed 12 choice tasks. We recruited a general population sample of 621 women in Australia aged 18-49 using an online survey panel. A mixed logit model was used to analyse DCE responses; a latent class model explored preference heterogeneity. RESULTS: Overall, 391 (63%) of women were currently using contraception; 49.3% were using an OC. About 22% of women were using a LARC. Women prefer products that are more effective in preventing pregnancy, have low levels of adverse events (including negative effects on mood), and which their general practitioner (GP) recommends or says is suitable for them. CONCLUSIONS: Women have strong preferences for contraceptive products that are effective, safe, and recommended by their GP. The results indicate which characteristics of LARCs need to be front and centre in information material and in discussions between women and healthcare professionals.

Copyright: © The authors 2022. Objective: Telomeres are DNA–protein complexes that protect chromosome ends from DNA damage and are surrogate biomarkers of cellular aging. Current evidence, almost entirely from cross-sectional observations, supports negative associations between leukocyte telomere length (LTL) and adverse lifestyle factors and cardiometabolic risk factors. Polycystic ovary syndrome (PCOS), the most common gynecological endocrine disorder, is associated with inflammation and oxidative stress, both factors associated with accelerated telomere attrition. We therefore hypothesized that LTL would be shorter and decrease more rapidly in women with PCOS in comparison to a control population. Design: This is a population-based cohort study comprising women of Northern Finland Birth Cohort 1966, with clinical examinations at ages 31 and 46. The sample included self-reported PCOS (age 31, n = 190; age 46, n = 207) and referent women (age 31, n = 1054; age 46, n = 1324) with data on LTL. Methods: The association between LTL and PCOS at ages 31 and 46 was analyzed by linear regression models adjusted for BMI, smoking, alcohol consumption and socioeconomic status at the corresponding age. Results Women with PCOS had similar mean LTL at ages 31 and 46 (P > 0.4 for both). The mean LTL change between ages 31 and 46 did not differ between groups (P = 0.19). However, we observed a significant LTL attrition between ages 31 and 46 in the reference population (P

BACKGROUND: Many women with chronic hypertension are conflicted about antihypertensive medication during pregnancy and some are non-adherent to prescribed medication. OBJECTIVES: Codesign, implement and evaluate a novel shared decision-making (SDM) intervention for use with pregnant women with chronic hypertension. SETTING AND PARTICIPANTS: Pregnant women with chronic hypertension and their principal healthcare professionals (obstetricians, midwives, and physicians), at three National Health Service hospital trusts with different models of care. MAIN OUTCOME MEASURES: The RE-AIM framework guided the evaluation. Primary: Decisional conflict scale, medication intention survey and women's acceptability. Secondary: Healthcare professionals' acceptability and the barriers and facilitators to SDM implementation with pregnant women with chronic hypertension. RESULTS: Fifty women participated. Nearly half (46 %; n = 23) of women were from Black and Asian backgrounds. The SDM intervention was effective at reducing decisional conflict (mean reduction from baseline 42 %, 95 % CI 35-49, p ≤ 0.05). In 36 women (72 %), the reduction was of clinical importance. 24 women (48 %) were uncertain about or planned not to take antihypertensives prior to the SDM intervention, compared to two women (4 %) after the intervention. The intervention was acceptable to women and healthcare professionals. 10 of 14 healthcare professionals felt that the in-consultation aid facilitated SDM in current antenatal contexts, a similar proportion (10/14) felt the length of consultations hindered SDM. CONCLUSION: A novel codesigned SDM intervention reduced decisional conflict and increased women's intention to take antihypertensive agents during pregnancy. This intervention could be adopted into practice for women making pregnancy decisions where there is uncertainty around the medication management option.

IntroductionCongenital cytomegalovirus (cCMV) is the leading cause of neurodevelopmental and hearing impairment from in-utero infection. Late diagnosis results in limited treatment options and may compromise long-term outcome.MethodsA retrospective audit of infants with cCMV referred to a Tertiary Pediatric Infectious Diseases center from 2012–2021. Data collected included timing of diagnostics, treatment initiation and reasons for delays.Results90 infants with confirmed cCMV were included, 46/90 (51%) were symptomatic at birth. Most common reasons for diagnostics in asymptomatic infants were failed newborn hearing screening (17/44, 39%) and antenatal risk-factors (14/44, 32%). Median age at cCMV diagnosis was 3 (range 0–68) and 7 (0–515) days, with median referral age 10 (1–120) and 22 (2–760) days for symptomatic and asymptomatic infants respectively. There was a significant risk of delay in diagnosis (>21 days) for asymptomatic infants [RR 2.93 (1.15–7.45); p = 0.02]. Of asymptomatic infants who received treatment, 13/24 (54%) commenced it within 28 days of life, a significant delay in treatment compared to 30/36 (83%) symptomatic infants [RR 2.75 (1.18–6.43); p = 0.02]. The commonest reason for delayed treatment initiation was delayed first diagnostic test for both symptomatic 4/6 (67%) and asymptomatic infants 9/11 (82%).ConclusionsDelays in diagnosis and treatment for cCMV are unacceptably frequent and significantly higher in asymptomatic infants. Our study highlights the need for increased awareness among healthcare professionals, reconsideration of age-targets for Newborn Hearing Screening, and research that addresses the barriers to implementation of universal screening, which would ultimately facilitate prompt diagnosis and management of all infants with cCMV.

Treatment of gestational diabetes improves maternal and infant health, although diagnostic criteria remain unclear.We randomly assigned women at 24 to 32 weeks' gestation in a 1:1 ratio to be evaluated for gestational diabetes with the use of lower or higher glycemic criteria for diagnosis. The lower glycemic criterion was a fasting plasma glucose level of at least 92 mg per deciliter (≥5.1 mmol per liter), a 1-hour level of at least 180 mg per deciliter (≥10.0 mmol per liter), or a 2-hour level of at least 153 mg per deciliter (≥8.5 mmol per liter). The higher glycemic criterion was a fasting plasma glucose level of at least 99 mg per deciliter (≥5.5 mmol per liter) or a 2-hour level of at least 162 mg per deciliter (≥9.0 mmol per liter). The primary outcome was the birth of an infant who was large for gestational age (defined as a birth weight above the 90th percentile according to Fenton-World Health Organization standards). Secondary outcomes were maternal and infant health.A total of 4061 women underwent randomization. Gestational diabetes was diagnosed in 310 of 2022 women (15.3%) in the lower-glycemic-criteria group and in 124 of 2039 women (6.1%) in the higher-glycemic-criteria group. Among 2019 infants born to women in the lower-glycemic-criteria group, 178 (8.8%) were large for gestational age, and among 2031 infants born to women in the higher-glycemic-criteria group, 181 (8.9%) were large for gestational age (adjusted relative risk, 0.98; 95% confidence interval, 0.80 to 1.19; P = 0.82). Induction of labor, use of health services, use of pharmacologic agents, and neonatal hypoglycemia were more common in the lower-glycemic-criteria group than in the higher-glycemic-criteria group. The results for the other secondary outcomes were similar in the two trial groups, and there were no substantial between-group differences in adverse events. Among the women in both groups who had glucose test results that fell between the lower and higher glycemic criteria, those who were treated for gestational diabetes (195 women), as compared with those who were not (178 women), had maternal and infant health benefits, including fewer large-for-gestational-age infants.The use of lower glycemic criteria for the diagnosis of gestational diabetes did not result in a lower risk of a large-for-gestational-age infant than the use of higher glycemic criteria. (Funded by the Health Research Council of New Zealand and others; GEMS Australian New Zealand Clinical Trials Registry number, ACTRN12615000290594.).