The risk of cardiovascular diseases after miscarriage, stillbirth, and induced abortion: a systematic review and meta-analysis.

Aims: Miscarriage and stillbirth have been included in cardiovascular disease (CVD) risk guidelines, however heterogeneity in exposures and outcomes and the absence of reviews assessing induced abortion, prevented comprehensive assessment. We aimed to perform a systematic review and meta-analysis of the risk of cardiovascular diseases for women with prior pregnancy loss (miscarriage, stillbirth, and induced abortion). Methods and results: Observational studies reporting risk of CVD, coronary heart disease (CHD), and stroke in women with pregnancy loss were selected after searching MEDLINE, Scopus, CINAHL, Web of Knowledge, and Cochrane Library (to January 2020). Data were extracted, and study quality were assessed using the Newcastle-Ottawa Scale. Pooled relative risk (RR) and 95% confidence intervals (CIs) were calculated using inverse variance weighted random-effects meta-analysis.Twenty-two studies involving 4 337 683 women were identified. Seven studies were good quality, seven were fair and eight were poor. Recurrent miscarriage was associated with a higher CHD risk (RR = 1.37, 95% CI: 1.12-1.66). One or more stillbirths was associated with a higher CVD (RR = 1.41, 95% CI: 1.09-1.82), CHD (RR = 1.51, 95% CI: 1.04-1.29), and stroke risk (RR = 1.33, 95% CI: 1.03-1.71). Recurrent stillbirth was associated with a higher CHD risk (RR = 1.28, 95% CI: 1.18-1.39). One or more abortions was associated with a higher CVD (RR = 1.04, 95% CI: 1.02-1.07), as was recurrent abortion (RR = 1.09, 95% CI: 1.05-1.13). Conclusion: Women with previous pregnancy loss are at a higher CVD, CHD, and stroke risk. Early identification and risk factor management is recommended. Further research is needed to understand CVD risk after abortion.

Defining Terms Used for Animals Working in Support Roles for People with Support Needs.

The nomenclature used to describe animals working in roles supporting people can be confusing. The same term may be used to describe different roles, or two terms may mean the same thing. This confusion is evident among researchers, practitioners, and end users. Because certain animal roles are provided with legal protections and/or government-funding support in some jurisdictions, it is necessary to clearly define the existing terms to avoid confusion. The aim of this paper is to provide operationalized definitions for nine terms, which would be useful in many world regions: "assistance animal", "companion animal", "educational/school support animal", "emotional support animal", "facility animal", "service animal", "skilled companion animal", "therapy animal", and "visiting/visitation animal". At the International Society for Anthrozoology (ISAZ) conferences in 2018 and 2020, over 100 delegates participated in workshops to define these terms, many of whom co-authored this paper. Through an iterative process, we have defined the nine terms and explained how they differ from each other. We recommend phasing out two terms (i.e., "skilled companion animal" and "service animal") due to overlap with other terms that could potentially exacerbate confusion. The implications for several regions of the world are discussed.

Advancing a Human Rights-Based Approach to Access to Medicines: Lessons Learned from the Constitutional Court of Peru.

Access to medicines and the right to health continues to be widely discussed in academic literature. United Nations human rights bodies have done much work to elaborate on the normative content of the right to health and the obligations of states to uphold this right, although translating this into tangible benefits to the public at national level remains a challenge. This paper explores the case of Peru to evaluate prominent decisions of the Constitutional Court that have been instructive in clarifying the state's obligations in relation to health. I argue that the court's rights-based approach offers lessons that other states can draw on to meet their obligations to ensure the right to health by securing access to essential medicines.

The risk of cardiovascular disease in women after miscarriage, stillbirth, and therapeutic abortion: a protocol for a systematic review and meta-analysis.

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death in women, responsible for approximately a third of all female deaths. Pregnancy complications are known to be associated with a greater risk of incident CVD in mothers. However, the relationships between pregnancy loss due to miscarriage, stillbirth, or therapeutic abortion, and future maternal cardiovascular health are under-researched. This study seeks to provide an up-to-date systematic review and meta-analysis of the relationship between these three forms of pregnancy loss and the subsequent development of CVD. METHODS: This systematic review will follow the Preferred Reporting Items for Systematic Review and Meta-Analysis checklist (PRISMA) and the Meta-analyses Of Observational Studies in Epidemiology (MOOSE) Checklist. A systematic search will be undertaken using publications identified in MEDLINE (PubMed), Scopus, Web of Knowledge, the CINAHL Nursing Database, and the Cochrane Library. The eligibility of each publication will be determined by predefined selection criteria. The quality of the included studies will be rated using the Newcastle-Ottawa Scale. Pooled measures of association will be computed using random-effects model meta-analyses. Between-study heterogeneity will be assessed using the I2 statistic and the Cochrane χ2 statistic. Small study effects will be evaluated for meta-analyses with sufficient studies through the use of funnel plots and Egger's test. DISCUSSION: The results of this systematic review will discuss the long-term risks of multiple types of cardiovascular disease in women who have experienced miscarriage, stillbirth, and/or therapeutic abortion. It will contribute to the growing field of cardio-obstetrics as the first to consider the full breadth of literature regarding the association between all forms of pregnancy loss and future maternal cardiovascular disease. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration number [CRD42020167587].

From words to actions: systematic review of interventions to promote sexual and reproductive health of persons with disabilities in low- and middle-income countries.

INTRODUCTION: Persons with disabilities have the same sexual and reproductive health and rights (SRHR) as non-disabled persons. Yet they face numerous barriers in their access to sexual and reproductive health services and their rights are often not met. Evidence on SRHR for persons with disabilities is sparse, particularly evaluations of interventions demonstrating 'what works.' This systematic review assessed interventions to promote SRHR for persons with disabilities in low- and middle-income countries. METHODS: We searched for qualitative, quantitative or mixed method observational studies representing primary research, published between 2010 and 2019, using MEDLINE, Embase, PubMed, Global Health and CINAHL Plus. Search strings were compiled for different elements of SRHR and for all forms of disability. 24,919 records were screened, leading to over 380 relevant papers, most of which were descriptive, focussing on needs and barriers to SRHR needs being fulfilled. Of the 33 full-text articles assessed for eligibility, 18 were included in the synthesis. All included studies were assessed for bias and quality of evidence, using STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) and RATS (relevance, appropriateness, transparency andsoundness) tools. Among the 16 interventions (from 18 articles), 25% had low risk of bias, 31% had moderate risk of bias and 44% had high risk of bias. Data analysis used narrative synthesis; a method suited for systematic reviews with heterogeneous studies. We used Levesque healthcare access model to analyse the focus of interventions. RESULTS: 11 interventions were from upper middle-income settings; two from lower-income settings; only one operated in rural areas. Interventions addressed intellectual impairment (6), visual impairment (6), hearing impairment (4), mental health conditions (2) and physical impairments (2). Most interventions (15/16) focus on information provision and awareness raising. We could not identify any intervention promoting access to maternal health, family planning and contraception, or safe abortion for people with disabilities. CONCLUSION: This systematic review has highlighted stark gaps in evidence. More rigorous evaluations are needed.

Interaction with caveolin-1 modulates vascular ATP-sensitive potassium (KATP) channel activity.

ATP-sensitive potassium channels (K(ATP) channels) of arterial smooth muscle are important regulators of arterial tone, and hence blood flow, in response to vasoactive transmitters. Recent biochemical and electron microscopic evidence suggests that these channels localise to small vesicular invaginations of the plasma membrane, known as caveolae, and interact with the caveolae-associated protein, caveolin. Here we report that interaction with caveolin functionally regulates the activity of the vascular subtype of K(ATP) channel, Kir6.1/SUR2B. Pinacidil-evoked recombinant whole-cell Kir6.1/SUR2B currents recorded in HEK293 cells stably expressing caveolin-1 (69.6 +/- 8.3 pA pF(1), n = 8) were found to be significantly smaller than currents recorded in caveolin-null cells (179.7 +/- 35.9 pA pF(1), n = 6; P < 0.05) indicating that interaction with caveolin may inhibit channel activity. Inclusion in the pipette-filling solution of a peptide corresponding to the scaffolding domain of caveolin-1 had a similar inhibitory effect on whole-cell Kir6.1/SUR2B currents as co-expression with full-length caveolin-1, while a scrambled version of the same peptide had no effect. Interestingly, intracellular dialysis of vascular smooth muscle cells with the caveolin-1 scaffolding domain peptide (SDP) also caused inhibition of pinacidil-evoked native whole-cell K(ATP) currents, indicating that a significant proportion of vascular K(ATP) channels are susceptible to block by exogenously applied SDP. In cell-attached recordings of Kir6.1/SUR2B single channel activity, the presence of caveolin-1 significantly reduced channel open probability (from 0.05 +/- 0.01 to 0.005 +/- 0.001; P < 0.05) and the amount of time spent in a relatively long-lived open state. These changes in kinetic behaviour can be explained by a caveolin-induced shift in the channel's sensitivity to its physiological regulator MgADP. Our findings thus suggest that interaction with caveolin-1 suppresses vascular-type K(ATP) channel activity. Since caveolin expression is regulated by cellular free cholesterol and plasma levels of low-density lipoprotein (LDL), this interaction may have implications in both the physiological and pathophysiological control of vascular function.

Significance of the Fanconi anemia FANCD2 protein in sporadic and metastatic human breast cancer.

FANCD2, a pivotal protein in the Fanconi anemia and BRCA pathway/network, is monoubiquitylated in the nucleus in response to DNA damage. This study examines the subcellular location and relationship with prognostic factors and patient survival of FANCD2 in breast cancer. Antibodies to FANCD2 were used to immunocytochemically stain 16 benign and 20 malignant breast specimens as well as 314 primary breast carcinomas to assess its association with subcellular compartment and prognostic factors using Fisher's Exact test or with patient survival over 20 years using Wilcoxon-Gehan statistics. Immunoreactive FANCD2 was found in the nucleus and cytoplasm of all 16 benign tissues, but nuclear staining was lost from a significant 19/20 malignant carcinomas (P < 0.0001). Antibodies to FANCD2 stained the cytoplasm of 196 primary carcinomas, leaving 118 as negatively stained. Negative cytoplasmic staining was significantly associated with positive staining for the metastasis-inducing proteins S100A4, S100P, osteopontin, and AGR2 (P < or = 0.002). Survival of patients with FANCD2-negative carcinomas was significantly worse (P < 0.0001) than those with positively stained carcinomas, and only 4% were alive at the census date. Multivariate regression analysis identified negative staining for cytoplasmic FANCD2 as the most significant indicator of patient death (P = 0.001). Thus FANCD2's cytoplasmic loss in the primary carcinomas may allow the selection of cells overexpressing proteins that can induce metastases before surgery.

Exchange protein activated by cAMP (Epac) mediates cAMP-dependent but protein kinase A-insensitive modulation of vascular ATP-sensitive potassium channels.

Exchange proteins directly activated by cyclic AMP (Epacs or cAMP-GEF) represent a family of novel cAMP-binding effector proteins. The identification of Epacs and the recent development of pharmacological tools that discriminate between cAMP-mediated pathways have revealed previously unrecognized roles for cAMP that are independent of its traditional target cAMP-dependent protein kinase (PKA). Here we show that Epac exists in a complex with vascular ATP-sensitive potassium (KATP) channel subunits and that cAMP-mediated activation of Epac modulates KATP channel activity via a Ca2+-dependent mechanism involving the activation of Ca2+-sensitive protein phosphatase 2B (PP-2B, calcineurin). Application of the Epac-specific cAMP analogue 8-pCPT-2'-O-Me-cAMP, at concentrations that activate Epac but not PKA, caused a 41.6 +/- 4.7% inhibition (mean +/- S.E.M.; n = 7) of pinacidil-evoked whole-cell KATP currents recorded in isolated rat aortic smooth muscle cells. Importantly, similar results were obtained when cAMP was elevated by addition of the adenylyl cyclase activator forskolin in the presence of the structurally distinct PKA inhibitors, Rp-cAMPS or KT5720. Activation of Epac by 8-pCPT-2'-O-Me-cAMP caused a transient 171.0 +/- 18.0 nM (n = 5) increase in intracellular Ca2+ in Fura-2-loaded aortic myocytes, which persisted in the absence of extracellular Ca2+. Inclusion of the Ca2+-specific chelator BAPTA in the pipette-filling solution or preincubation with the calcineurin inhibitors, cyclosporin A or ascomycin, significantly reduced the ability of 8-pCPT-2'-O-Me-cAMP to inhibit whole-cell KATP currents. These results highlight a previously undescribed cAMP-dependent regulatory mechanism that may be essential for understanding the physiological and pathophysiological roles ascribed to arterial KATP channels in the control of vascular tone and blood flow.

Angiotensin II-activated protein kinase C targets caveolae to inhibit aortic ATP-sensitive potassium channels.

OBJECTIVE: The vasoconstrictor angiotensin II (Ang II) acts at G(q/11)-coupled receptors to suppress ATP-sensitive potassium (K(ATP)) channel activity via activation of protein kinase C (PKC). The aim of this study was to determine the PKC isoforms involved in the Ang II-induced inhibition of aortic K(ATP) channel activity and to investigate potential mechanisms by which these isoforms specifically target these ion channels. METHODS AND RESULTS: We show that the inhibitory effect of Ang II on pinacidil-evoked whole-cell rat aortic K(ATP) currents persists in the presence of Gö6976, an inhibitor of the conventional PKC isoforms, but is abolished by intracellular dialysis of a selective PKCepsilon translocation inhibitor peptide. This suggests that PKC-dependent inhibition of aortic K(ATP) channels by Ang II arises exclusively from the activation and translocation of PKCepsilon. Using discontinuous sucrose density gradients and Western blot analysis, we show that Ang II induces the translocation of PKCepsilon to cholesterol-enriched rat aortic smooth muscle membrane fractions containing both caveolin, a protein found exclusively in caveolae, and Kir6.1, the pore-forming subunit of the vascular K(ATP) channel. Immunogold electron microscopy of rat aortic smooth muscle plasma membrane sheets confirms both the presence of Kir6.1 in morphologically identifiable regions of the membrane rich in caveolin and Ang II-evoked migration of PKCepsilon to these membrane compartments. CONCLUSIONS: Ang II induces the recruitment of the novel PKC isoform, PKCepsilon, to arterial smooth muscle caveolae. This translocation allows PKCepsilon access to K(ATP) channels compartmentalized within these specialized membrane microdomains and highlights a potential role for caveolae in targeting PKC isozymes to an ion channel effector.