SPOM is a new approach to IVM, mimicing some characteristics of oocyte maturation in vivo and substantially improving oocyte developmental outcomes. Adaption of SPOM for clinical application should have significant implications for infertility management and bring important benefits to patients.

BackgroundLifestyle factors have been associated mostly with individual chronic diseases. We investigated the relationship between lifestyle factors (individual and combined) and the co-occurrence of multiple chronic diseases.MethodsCross-sectional analysis of results from the Program of Research on the Evolution of a Cohort Investigating Health System Effects (PRECISE) in Quebec, Canada. Subjects aged 45 years and older. A randomly-selected cohort in the general population recruited by telephone. Multimorbidity (3 or more chronic diseases) was measured by a simple count of self-reported chronic diseases from a list of 14. Five lifestyle factors (LFs) were evaluated: 1) smoking habit, 2) alcohol consumption, 3) fruit and vegetable consumption, 4) physical activity, and 5) body mass index (BMI). Each LF was given a score of 1 (unhealthy) if recommended behavioural targets were not achieved and 0 otherwise. The combined effect of unhealthy LFs (ULFs) was evaluated using the total sum of scores.ResultsA total of 1,196 subjects were analyzed. Mean number of ULFs was 2.6 ± 1.1 SD. When ULFs were considered separately, there was an increased likelihood of multimorbidity with low or high BMI [Odd ratio (95% Confidence Interval): men, 1.96 (1.11-3.46); women, 2.57 (1.65-4.00)], and present or past smoker [men, 3.16 (1.74-5.73)]. When combined, in men, 4-5 ULFs increased the likelihood of multimorbidity [5.23 (1.70-16.1)]; in women, starting from a threshold of 2 ULFs [1.95 (1.05-3.62)], accumulating more ULFs progressively increased the likelihood of multimorbidity.ConclusionsThe present study provides support to the association of lifestyle factors and multimorbidity.

PURPOSE We aimed to develop a consensus-based set of core outcomes specifically for studies in multimorbidity. METHODSWe undertook a consensus study following the COS-STAR (Core Outcome Set-STAndards for Reporting) guidelines for the design and reporting of core outcome sets. A Delphi panel of experts completed a web-based survey with 2 rounds. Panelists were presented with a range of outcomes that had been identified in previous workshops and a related systematic review. They indicated their level of agreement on whether each outcome should be included in the core set using a 5-point Likert scale, and outcomes reaching a prespecified consensus level were included. RESULTSOf 30 individuals invited to be panelists, 26 from 13 countries agreed. All 26 completed both rounds of the survey. The Delphi panel reached consensus on 17 outcomes for inclusion in a core outcome set for multimorbidity (COSmm). The highest-ranked outcomes were health-related quality of life, mental health outcomes, and mortality. Other outcomes were grouped into overarching themes of patient-reported impacts and behaviors (treatment burden, self-rated health, self-management behavior, self-efficacy, adherence); physical activity and function (activities of daily living, physical function, physical activity); consultation related (communication, shared decision making, prioritization); and health systems (health care use, costs, quality of health care). CONCLUSIONSThis consensus study involved a wide range of international experts who identified a large number of outcomes for multimorbidity intervention studies. Our results suggest that quality of life, mental health outcomes, and mortality should be regarded as essential core outcomes. Researchers should, however, also consider the full range of outcomes when designing studies to capture important domains in multimorbidity depending on individual study aims and interventions.

The phosphodiesterase (PDE) family is a group of enzymes that catalyzes the transformation of cyclic nucleotides into 5' nucleotides. Based on rodents, the current mammalian model of PDE distribution in the ovarian follicle predicts Pde3a in the oocyte and Pde4d in the somatic cells. Using bovine as an experimental model, the present results showed that PDE3 was the predominant PDE activity in oocytes. However, cumulus cell cAMP-PDE activity was predominantly resistant to inhibition by 3-isobutyl-methylxantine, indicating PDE8 activity (60% of total PDE activity) and a minor role for PDE4 (<5%). A total of 20% of total oocyte PDE activity was also attributed to PDE8. The PDE activity measurements in mural granulosa cells from 2 to 6 mm in diameter suggest the presence of PDE4 and PDE8. In granulosa cells from follicles >10 mm, total PDE and PDE8 activities along with PDE8A protein level were increased compared with smaller follicles. The RT-PCR experiments showed that cumulus cells expressed PDE8A, PDE8B, and PDE10A. Western blot experiments showed PDE8A, PDE8B, and PDE4D proteins in mural granulosa cells and cumulus-oocyte complexes. PDE8 inhibition using dipyridamole in a dose-dependent manner increased cAMP levels in the cumulus-oocyte complexes and delayed oocyte nuclear maturation. These results are the first to demonstrate the functional presence of PDE8 in the mammalian ovarian follicle. This challenges the recently described cell-specific expression of cAMP-PDEs in the ovarian follicle and the notion that PDE4 is the predominant granulosa/cumulus cell PDE. These findings have implications for our understanding of hormonal regulation of folliculogenesis and the potential application of PDE inhibitors as novel contraceptives.

Prevalence, symptoms, and treatment of depression suggest that major depressive disorders (MDD) present sex differences. Social stress-induced neurovascular pathology is associated with depressive symptoms in male mice; however, this association is unclear in females. Here, we report that chronic social and subchronic variable stress promotes blood-brain barrier (BBB) alterations in mood-related brain regions of female mice. Targeted disruption of the BBB in the female prefrontal cortex (PFC) induces anxiety- and depression-like behaviours. By comparing the endothelium cell-specific transcriptomic profiling of the mouse male and female PFC, we identify several pathways and genes involved in maladaptive stress responses and resilience to stress. Furthermore, we confirm that the BBB in the PFC of stressed female mice is leaky. Then, we identify circulating vascular biomarkers of chronic stress, such as soluble E-selectin. Similar changes in circulating soluble E-selectin, BBB gene expression and morphology can be found in blood serum and postmortem brain samples from women diagnosed with MDD. Altogether, we propose that BBB dysfunction plays an important role in modulating stress responses in female mice and possibly MDD.

Gap-junctional communication (GJC) plays a central role in oocyte growth. However, little is known about the regulation of connexin 43 (Cx43)-based gap-junction channels in cumulus-oocyte complexes (COCs) during in vitro maturation. We show that rupture of COCs from mural granulosa cells up-regulates Cx43-mediated GJC and that gonadotropins signal GJC breakdown by recruiting Cx43 to lipid rafts when oocyte meiosis resumes. Oocyte calcein uptake through gap junctions increases during early in vitro oocyte maturation and remains high until 18 h, when it falls simultaneously with the oocyte germinal vesicle breakdown. Immunodetection of Cx43 and fluorescence recovery after photobleaching assays revealed that the increase of GJC is independent of gonadotropins but requires RNA transcription, RNA polyadenylation, and translation. GJC rupture, in contrast, is achieved by a gonadotropin-dependent mechanism involving recruitment of Cx43 to clustered lipid rafts. These results show that GJC up-regulation in COCs in in vitro culture is independent of gonadotropins and transcriptionally regulated. However, GJC breakdown is gonadotropin dependent and mediated by the clustering of Cx43 in lipid raft microdomains. In conclusion, this study supports a functional role of lipid raft clustering of Cx43 in GJC breakdown in the COCs during in vitro maturation.

C hronic conditions are the most common problems in health care and the leading causes of death globally. 1 Acute communicable diseases have given way to chronic conditions such as arthritis, diabetes, and cardiovascular and respiratory diseases that will impose an even greater burden in the future. 2 The needs of patients with these diseases are usually complex and are challenging to manage. For this reason, many chronic disease prevention and management (CDPM) programs have been designed with the aim of improving outcomes in these patients. CDPM programs targeting diabetes, 3-7 asthma, 8,9 heart diseases, [10][11][12] costs, adherence to medication, disease control, use of health services, quality of life and mortality. However, these studies were conducted in different settings and were based on single diseases.Interventions oriented toward single diseases take little account of the multiple morbidities experienced by most patients in primary care. To date, the appropriateness of using Background: Chronic disease prevention and management programs are usually single-disease oriented. Our objective was to evaluate an intervention that targeted multiple chronic conditions and risk factors. Methods:We conducted a pragmatic randomized controlled trial involving patients aged 18-75 years with at least 1 of the targeted chronic conditions or risk factors from 8 primary care practices in the Saguenay region of Quebec, Canada, to evaluate an intervention that included self-management support and patient-centred motivational approaches. Self-management (primary outcome) was evaluated using the Health Education Impact Questionnaire (heiQ). Secondary outcomes included self-efficacy, health-related quality of life, psychological distress and health behaviours.Results: Three hundred thirty-two patients were recruited and randomly assigned (n = 166 for both intervention and control groups) and evaluated after 3 months. The intervention group showed improvement in 6 of the 8 heiQ domains: health-directed behaviour (relative risk [RR] 1.71, 95% confidence interval [CI] 1.13 to 2.59), emotional well-being (RR 1.73, 95% CI 1.07 to 2.79), self-monitoring and insight (RR 2.40, 95% CI 1.19 to 4.86), constructive attitudes and approaches (RR 2.40, 95% CI 1.37 to 4.21), skill and technique acquisition (RR 1.70, 95% CI 1.14 to 2.53), and health service navigation (RR 1.93, 95% CI 1.08 to 3.47). Improvement was also observed in the Physical Component Summary (p = 0.017) and the Single Index (p = 0.041) of the 12-Item Short Form Health Survey (version 2). The intervention group improved in fruit and vegetable consumption (odds ratio [OR] 2.36, 95% CI 1.41 to 3.95) and physical activity (OR 3.81, 95% CI 1.65 to 8.76). One-year improvement was maintained in the intervention group for several outcomes.Interpretation: It is possible to implement an intervention integrating chronic disease prevention and management services into primary care settings. We obtained positive and promising results using this intervention.

The purpose of this study was to examine the effects of an activator of AMPK (5-aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside (AICAR)) on bovine oocyte nuclear maturation in vitro. After 7 hr of culture, AICAR (1 mM) significantly increased the percentages of cumulus-enclosed oocytes (CEO) and denuded oocytes (DO) remaining at the germinal vesicle stage. After 22 hr of culture, AICAR significantly reduced the percentage of CEO reaching metaphase II (MII). AICAR at 1.0 mM also increased the inhibitory effect of the adenylate cyclase activator forskolin in CEO; however, at 0.05 mM, AICAR increased the percentage of oocytes at MII after 22 hr of culture compared to forskolin alone. The adenosine kinase inhibitor 5'-aminodeoxyadenosine reversed the effect of AICAR in CEO and DO showing that phosphorylation of AICAR by adenosine kinase is required for its inhibitory activity. GMP, but not AMP, inhibited meiosis in CEO and DO; however, inhibition of guanyl and adenyl nucleotides synthesis did not reverse the effect of AICAR suggesting that the inhibitory effect of AICAR is not due to increased synthesis of these nucleotides. Metformin, another activator of AMPK, also inhibited GVBD in CEO and DO. The alpha-1 isoform of the catalytic subunit of AMPK was detected in oocytes and cumulus cells, and reverse transcription-polymerase chain reaction experiments showed the presence of transcripts for alpha-1, alpha-2, beta-1, and gamma-3 isoforms of the regulatory subunits in cumulus cells and oocytes. These data show that the AMPK activator AICAR is inhibitory to nuclear maturation in bovine oocytes due to activation of AMPK.