Psychosocial family-level mediators in the intergenerational transmission of trauma: Protocol for a systematic review and meta-analysis.

INTRODUCTION: Family-level psychosocial factors appear to play a critical role in mediating the intergenerational transmission of trauma; however, no review article has quantitatively synthesized causal mechanisms across a diversity of trauma types. This study aims to systematically consolidate the epidemiological research on family-level psychosocial mediators and moderators to ultimately produce causal diagram(s) of the intergenerational transmission of trauma. METHODS: We will identify epidemiological peer-reviewed publications, dissertations, and conference abstracts that measure the impact of at least one psychosocial family-level factor mediating or moderating the relationship between parental trauma exposure and a child mental health outcome. English, French, Kinyarwanda, and Spanish articles will be eligible. We will search MEDLINE, PsycINFO, PTSDpubs, Scopus, and ProQuest Dissertations and Theses and will conduct forward citation chaining of included documents. Two reviewers will perform screening independently. We will extract reported mediators, moderators, and relevant study characteristics for included studies. Findings will be presented using narrative syntheses, descriptive analyses, mediation meta-analyses, moderating meta-analyses, and causal diagram(s), where possible. We will perform a risk of bias assessment and will assess for publication bias. DISCUSSION: The development of evidence-based causal diagram(s) would provide more detailed understanding of the paths by which the psychological impacts of trauma can be transmitted intergenerationally at the family-level. This review could provide evidence to better support interventions that interrupt the cycle of intergenerational trauma. TRIAL REGISTRATION: Systematic review registration: PROSPERO registration ID #CRD42021251053.

Vitamin D Levels and the Risk of Posttransplant Diabetes Mellitus After Kidney Transplantation.

INTRODUCTION: Given the burden of posttransplant diabetes mellitus and the high prevalence of low vitamin D levels in kidney transplant recipients, it is reasonable to consider vitamin D as a novel and potentially modifiable risk factor in this patient population. RESEARCH QUESTION: To determine the association between 25- hydroxyvitamin D (25(OH)D) level and posttransplant diabetes among kidney transplant recipients. Design: In a multi-center cohort study of 442 patients who received a kidney transplant between January 1, 2005 and December 31, 2010, serum samples within one-year before transplant were analyzed for 25(OH)D levels. The association between 25(OH)D and posttransplant diabetes were examined in Cox proportional hazard models. RESULTS: The median 25(OH)D level was 66 nmol/L. The cumulative probability of diabetes at 12-months by quartiles of 25(OH)D (< 42, 42 to 64.9, 65 to 94.9, and > 95 nmol/L) were 23.4%, 26.9%, 21.4%, and 15.6%, respectively. Compared to the highest 25(OH)D quartile, hazard ratios (95% CI) for the risk were 1.85 (1.03, 3.32), 2.01 (1.12, 3.60), 1.77 (0.96, 3.25) across the first to third quartiles, respectively. The associations were accentuated in a model restricted to patients on tacrolimus. When modeled as a continuous variable, 25(OH)D levels were significantly associated with a higher risk of diabetes (hazard ratio 1.06, 95% CI: 1.01, 1.13 per 10 nmol/L decrease). DISCUSSION: Serum 25(OH)D was an independent predictor of posttransplant diabetes in kidney transplant recipients. These results may inform the design of trials using vitamin D to reduce the risk in kidney transplant recipients.

Rapid network meta-analysis using data from Food and Drug Administration approval packages is feasible but with limitations.

OBJECTIVE: To test rapid approaches that use Drugs@FDA (a public database of approved drugs) and ClinicalTrials.gov to identify trials and to compare these two sources with bibliographic databases as an evidence base for a systematic review and network meta-analysis (NMA). STUDY DESIGN AND SETTING: We searched bibliographic databases, Drugs@FDA, and ClinicalTrials.gov for eligible trials on first-line glaucoma medications. We extracted data, assessed risk of bias, and examined the completeness and consistency of information provided by different sources. We fitted random-effects NMA models separately for trials identified from each source and for all unique trials from three sources. RESULTS: We identified 138 unique trials including 29,394 participants on 15 first-line glaucoma medications. For a given trial, information reported was sometimes inconsistent across data sources. Journal articles provided the most information needed for a systematic review; trial registrations provided the least. Compared to an NMA including all unique trials, we were able to generate reasonably precise effect estimates and similar relative rankings for available interventions using trials from Drugs@FDA alone (but not ClinicalTrials.gov). CONCLUSIONS: A rapid NMA approach using data from Drugs@FDA is feasible but has its own limitations. Reporting of trial design and results can be improved in both the drug approval packages and on ClinicalTrials.gov.

Sperm DNA fragmentation index does not correlate with blastocyst aneuploidy or morphological grading.

High DNA fragmentation index (DFI) may be associated with poor outcome after IVF. Our aim was to determine whether DFI impacts blastocyst quality or clinical outcome. This retrospective study included 134 couples who underwent 177 IVF-ICSI and pre-implantation genetic screening (PGS) cycles during January 1st, 2014-March 31st, 2016 and had documented previous DFI. Group 1 (DFI>30%) encompassed 25 couples who underwent 36 cycles; Group 2 (DFI 15-30%) included 45 couples and 57 cycles; group 3 (DFI<15%) included 64 couples and 83 cycles. Male partners within group 1 were older (45.1 compared to 40.6 and 38.3 years, respectively, p<0.05), had higher BMI (32.4 compared to 26.6 and 25.8 respectively, p<0.05) and lower sperm count and motility (46*106/ml and 35.5%, respectively) compared to groups 2 (61.8*106/ml and 46.6%, respectively) and 3 (75.8*106/ml and 55.1%, respectively, p<0.05). Female parameters including ovarian reserve and response and embryo development were similar. Total numbers of biopsied blastocysts were 116, 175 and 259 in groups 1, 2 and 3, respectively. PGS for 24 chromosomes revealed comparable euploidy rate of 46-50.4%, with a similar morphological classification. No significant differences were found regarding pregnancy rates or pregnancy loss. It seems that DFI doesn't correlate with blastocyst aneuploidy or morphological grading.

Lower complication rates with office-based D&C under ultrasound guidance for missed abortion.

BACKGROUND: Missed abortion (MA) can be managed expectantly, medically or surgically. Surgical management has been performed safely in the office setting by suction dilation and curettage (D&C). Prior studies suggest that intraoperative ultrasound guidance (USG) may reduce complications for first-trimester therapeutic abortion. The aim of this study was to evaluate the safety of office D&C for MA using real-time USG. METHODS: This retrospective cohort study included 255 patients who underwent office D&C under USG for first trimester MA at a single university-affiliated fertility clinic during January 2011-December 2013. Transabdominal USG was utilized during the procedure and was immediately followed by a transvaginal ultrasound examination to confirm full evacuation. Intra- and postoperative complication rates were compared to previously published data. RESULTS: There were no intraoperative complications, including excessive blood loss or uterine perforation. Two of the 255 patients (0.87%) were diagnosed with RPOCs requiring uterine re-evacuation. This rate of RPOCs was superior to rates previously reported for D&Cs without USG (2.6-4.9%, P=0.046). There were no other post procedure complications identified. CONCLUSIONS: We observed very low complications rate in Office-based D&C under USG, lower than those reported in the literature with unguided D&C.

The Safety and Efficacy of Mineralocorticoid Receptor Antagonists in Patients Who Require Dialysis: A Systematic Review and Meta-analysis.

BACKGROUND: Patients who require dialysis are at high risk for cardiovascular mortality, which may be improved by mineralocorticoid receptor antagonists (MRAs). STUDY DESIGN: Systematic review and meta-analysis of randomized controlled trials. SETTING & POPULATION: Adults undergoing long-term hemodialysis or peritoneal dialysis with or without heart failure. SELECTION CRITERIA FOR STUDIES: Randomized controlled trials evaluating an MRA in dialysis and reported at least one outcome of interest. INTERVENTION: Spironolactone (8 trials) or eplerenone (1 trial) compared to placebo (7 trials) or standard of care (2 trials). OUTCOMES: Cardiovascular and all-cause mortality, hyperkalemia, serum potassium level, hypotension, change in blood pressure, and gynecomastia. RESULTS: We identified 9 trials including 829 patients. The overall quality of evidence was low due to methodologic limitations in most of the included trials. The relative risk (RR) for cardiovascular mortality was 0.34 (95% CI, 0.15-0.75) for MRA-treated compared with control patients. The RR for all-cause mortality was 0.40 (95% CI, 0.23-0.69). The RR for hyperkalemia for MRA treatment was 3.05 (95% CI, 1.21-7.70). Sensitivity analyses demonstrated wide variability in RRs for cardiovascular mortality, all-cause mortality, and hyperkalemia, suggesting further uncertainty in the confidence of the primary results. LIMITATIONS: Trial quality and size insufficient to robustly and precisely identify a treatment effect. CONCLUSIONS: Given the uncertainty of both the benefits and harms of MRAs in dialysis, large high-quality trials are required.

Outcomes of Kidney Transplantation Abroad: A Single-Center Canadian Cohort Study.

CONTEXT: An increasing demand for kidney transplantation has enticed some patients with end-stage renal disease (ESRD) to venture outside their country of residence, but their posttransplant outcomes may be suboptimal. OBJECTIVE: We compared the risks and clinical outcomes among tourists, or patients who pursue a kidney transplant abroad, versus patients who received a transplant at the Toronto General Hospital (TGH). METHODS: A single-center, 1:3 matched (based on age at transplant, time on dialysis, and year of transplant) cohort study was conducted. Forty-five tourists were matched with 135 domestic transplant recipients between January 1, 2000, and December 31, 2011. Multivariable Cox proportional hazards models were fitted to assess graft and patient outcomes. RESULTS: Among the 45 tourists, the majority (38 of 45) traveled to the Middle East or Far East Asia, and most received living donor kidney transplants (35 of 45). Multivariable Cox proportional hazards models showed that tourists had a higher risk for the composite outcome of acute rejection, death-censored graft failure, or death with graft function (DWGF; hazard ratio [HR] 2.08, 95% confidence interval [CI]: 1.06-4.07). Tourists also showed a higher risk for the individual end points of acute rejection, DWGF, and posttransplant hospitalizations. CONCLUSION: Patients going abroad for kidney transplantation may have inferior outcomes compared to domestic patients receiving kidney transplants. Patients who are contemplating an overseas transplant need to be aware of the increased risk of adverse posttransplant outcomes and should be appropriately counseled by transplant professionals during the pretransplant evaluation process.

The continuum of high ovarian response: a rational approach to the management of high responder patient subgroups.

Ovarian follicular responsiveness to controlled ovarian hyperstimulation (COH) with gonadotropins is extremely variable between individual patients, and even from cycle to cycle for the same patient. High responder patients are characterized by an exaggerated response to gonadotropin administration, accompanied by a higher risk for ovarian hyperstimulation syndrome (OHSS). In spite of its importance, the literature regarding high responders is characterized by heterogeneous classification methodologies. A clear separation should be drawn between risk factors for a high ovarian response and the actual response exhibited by a patient to stimulation. Similarly, it is important to distinguish between high ovarian response and development of clinically significant OHSS. In this article we: (1) review recent publications pertaining to the identification and clinical management of high responders, (2) propose an integrated clinical model to differentiate sub-groups within this population based on this review, and (3) suggest specific protocols for each sub-group. The model is based on a chronological patient assessment in an effort to target treatment based on the specific clinical circumstances. It is our hope that the algorithm we have developed will assist clinicians to supply targeted and precise treatments in order to achieve a favorable reproductive outcome with minimum complications for each patient.

Pseudomonas aeruginosa-induced bleb-niche formation in epithelial cells is independent of actinomyosin contraction and enhanced by loss of cystic fibrosis transmembrane-conductance regulator osmoregulatory function.

UNLABELLED: The opportunistic pathogen Pseudomonas aeruginosa can infect almost any site in the body but most often targets epithelial cell-lined tissues such as the airways, skin, and the cornea of the eye. A common predisposing factor is cystic fibrosis (CF), caused by defects in the cystic fibrosis transmembrane-conductance regulator (CFTR). Previously, we showed that when P. aeruginosa enters epithelial cells it replicates intracellularly and occupies plasma membrane blebs. This phenotype is dependent on the type 3 secretion system (T3SS) effector ExoS, shown by others to induce host cell apoptosis. Here, we examined mechanisms for P. aeruginosa-induced bleb formation, focusing on its relationship to apoptosis and the CFTR. The data showed that P. aeruginosa-induced blebbing in epithelial cells is independent of actin contraction and is inhibited by hyperosmotic media (400 to 600 mOsM), distinguishing bacterially induced blebs from apoptotic blebs. Cells with defective CFTR displayed enhanced bleb formation upon infection, as demonstrated using bronchial epithelial cells from a patient with cystic fibrosis and a CFTR inhibitor, CFTR(Inh)-172. The defect was found to be correctable either by incubation in hyperosmotic media or by complementation with CFTR (pGFP-CFTR), suggesting that the osmoregulatory function of CFTR counters P. aeruginosa-induced bleb-niche formation. Accordingly, and despite their reduced capacity for bacterial internalization, CFTR-deficient cells showed greater bacterial occupation of blebs and enhanced intracellular replication. Together, these data suggest that P. aeruginosa bleb niches are distinct from apoptotic blebs, are driven by osmotic forces countered by CFTR, and could provide a novel mechanism for bacterial persistence in the host. IMPORTANCE: Pseudomonas aeruginosa is an opportunistic pathogen problematic in hospitalized patients and those with cystic fibrosis (CF). Previously, we showed that P. aeruginosa can enter epithelial cells and replicate within them and traffics to the membrane blebs that it induces. This "bleb-niche" formation requires ExoS, previously shown to cause apoptosis. Here, we show that the driving force for bleb-niche formation is osmotic pressure, differentiating P. aeruginosa-induced blebs from apoptotic blebs. Either CFTR inhibition or CFTR mutation (as seen in people with CF) causes P. aeruginosa to make more bleb niches and provides an osmotic driving force for blebbing. CFTR inhibition also enhances bacterial occupation of blebs and intracellular replication. Since CFTR is targeted for removal from the plasma membrane when P. aeruginosa invades a healthy cell, these findings could relate to pathogenesis in both CF and healthy patient populations.

Herpes simplex virus protein kinases US3 and UL13 modulate VP11/12 phosphorylation, virion packaging, and phosphatidylinositol 3-kinase/Akt signaling activity.

UNLABELLED: The phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway plays key roles in diverse cellular activities and promotes cell growth and survival. It is therefore unsurprising that most viruses modify this pathway in order to facilitate their replication and spread. Previous work has suggested that the herpes simplex virus 1 (HSV-1) tegument proteins VP11/12 and US3 protein kinase modulate the PI3K/Akt pathway, albeit in opposing ways: VP11/12 binds and activates Src family kinases (SFKs), is tyrosine phosphorylated, recruits PI3K in an SFK-dependent fashion, and is required for HSV-induced phosphorylation of Akt on its activating residues; in contrast, US3 inhibits Akt activation and directly phosphorylates downstream Akt targets. We examined if US3 negatively regulates Akt by dampening the signaling activity of VP11/12. Consistent with this hypothesis, the enhanced Akt activation that occurs during US3-null infection requires VP11/12 and correlates with an increase in SFK-dependent VP11/12 tyrosine phosphorylation. In addition, deleting US3 leads to a striking increase in the relative abundances of several VP11/12 species that migrate with reduced mobility during SDS-PAGE. These forms arise through phosphorylation, strictly require the viral UL13 protein kinase, and are excluded from virions. Taken in combination, these data indicate that US3 dampens SFK-dependent tyrosine and UL13-dependent serine/threonine phosphorylation of VP11/12, thereby inhibiting VP11/12 signaling and promoting virion packaging of VP11/12. These results illustrate that protein phosphorylation events mediated by viral protein kinases serve to coordinate the roles of VP11/12 as a virion component and intracellular signaling molecule. IMPORTANCE: Herpesvirus tegument proteins play dual roles during the viral life cycle, serving both as structural components of the virus particle and as modulators of cellular and viral functions in infected cells. How these two roles are coordinated during infection and virion assembly is a fundamental and largely unanswered question. Here we addressed this issue with herpes simplex virus VP11/12, a tegument protein that activates the cellular PI3K/Akt signaling pathway. We showed that protein phosphorylation mediated by the viral US3 and UL13 kinases serves to orchestrate its functions: UL13 appears to inhibit VP11/12 virion packaging, while US3 antagonizes UL13 action and independently dampens VP11/12 signaling activity.

Comparison of IVF Outcomes between Minimal Stimulation and High-Dose Stimulation for Patients with Poor Ovarian Reserve.

We examined whether treatment with minimum-dose stimulation (MS) protocol enhances clinical pregnancy rates compared to high-dose stimulation (HS) protocol. A retrospective cohort study was performed comparing IVF and pregnancy outcomes between MS and HS gonadotropin-antagonist protocol for patients with poor ovarian reserve (POR). Inclusion criteria included patients with an anti-Müllerian hormone (AMH) ≤8 pmol/L and/or antral follicle count (AFC) ≤5 on days 2-3 of the cycle. Patients from 2008 exclusively had a HS protocol treatment, while patients in 2010 had treatment with a MS protocol exclusively. The MS protocol involved letrozole at 2.5 mg over 5 days, starting from day 2, overlapping with gonadotropins, starting from the third day of letrozole at 150 units daily. GnRH antagonist was introduced once one or more follicles reached 14 mm or larger. The HS group received gonadotropins (≥300 IU/day) throughout their antagonist cycle. Clinical pregnancy rate was significantly higher in the MS protocol compared to the HS protocol (P = 0.007). Furthermore, the live birth rate was significantly higher in the MS group compare to the HS group (P = 0.034). In conclusion, the MS IVF protocol is less expensive (lower gonadotropin dosage) and resulted in a higher clinical pregnancy rate and live birth rate than a HS protocol for poor responders.