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ObjectiveHuman papillomavirus (HPV) has been associated with adverse pregnancy outcomes but placental HPV infection has been rarely studied. The objective was to determine the proportion of HPV-positive placentas and the associated risk factors among HPV-positive women during pregnancy.MethodsWe analysed data from pregnant women enrolled in HERITAGE cohort study between 2010 and 2016 with positive vaginal HPV infection during the first trimester of pregnancy (n=354). Placental swabs and biopsies were collected. HPV genotyping was performed using Linear Array. The predictors of placental HPV detection were identified by generalised estimating equations models.ResultsHPV was detected in 78 placentas (22.0%) (one among 96 caesarean sections and 77 among 258 vaginal deliveries). Overall, 91% of HPV-positive placentas were positive for a genotype that was detected in vaginal samples during pregnancy. Among women who delivered vaginally, abnormal cytology (adjusted OR (aOR) 1.78 (95% CI 1.02 to 3.10)), other genitourinary infection (aOR 2.41 (95% CI 1.31 to 4.44)), presence of multiple HPV genotypes in the first trimester (aOR 2.69 (95% CI 1.76 to 4.12)) and persistence of high-risk HPV infections during pregnancy (HPV-16/18: aOR 3.94 (95% CI 2.06 to 7.55) and other than HPV-16/18: aOR 2.06 (95% CI 1.05 to 4.02)) were independently associated with placental HPV.ConclusionsHPV was frequently detected in the placenta of women who delivered vaginally and may be associated with host immune response characteristics.

BackgroundThe impact of different therapeutic classes of drugs in antiretroviral therapy (ART) regimens on the CD4/CD8 ratio is not well documented in people treated for HIV. The objective of this study was to analyze the long-term effect of exposure to integrase strand transfer inhibitor (INSTI) on CD4/CD8 ratio compared with nonnucleoside reverse transcriptase inhibitor (NNRTI) or protease inhibitor (PI) among ART-treated persons with HIV (PLHIV).MethodsData from the Quebec HIV Cohort collected from 31 August 2017 were used. Our analysis included all patients in the cohort who received a first or subsequent ART regimen composed of 2 nucleoside reverse transcriptase inhibitors (NRTIs) and a third active drug of a different class (NNRTI, PI, or INSTI) for at least 16 weeks. Marginal structural Cox models were constructed to estimate the effect of different therapeutic classes on the CD4/CD8 ratio outcome.ResultsAmong the 3907 eligible patients, 972 (24.9%), 1996 (51.1%), and 939 (24.0%) were exposed to an ART regimen whose third active agent was an NNRTI, PI, or INSTI, respectively. The total follow-up time was 13 640.24 person-years. The weighted hazard ratio for the association between the third active class and CD4/CD8 ratio ≥1 was .56 (95% confidence interval [CI]: .48–.65) for patients exposed to NNRTI + 2 NRTIs and .41 (95% CI: .35–.47) for those exposed to PI + 2 NRTIs, compared with those exposed INSTI + 2 NRTIs.ConclusionsFor people treated for HIV, INSTI-based ART appears to be associated with a higher CD4/CD8 ratio than NNRTI and PI-based ART.

Background Tricuspid regurgitation (TR) is common among adults with corrected tetralogy of Fallot (TOF) or pulmonary stenosis (PS) referred for pulmonary valve replacement (PVR). Yet, combined valve surgery remains controversial. Objectives This study sought to evaluate the impact of concomitant tricuspid valve intervention (TVI) on post-operative TR, length of hospital stay, and on a composite endpoint consisting of 7 early adverse events (death, reintervention, cardiac electronic device implantation, infection, thromboembolic event, hemodialysis, and readmission). Methods The national Canadian cohort enrolled 542 patients with TOF or PS and mild to severe TR who underwent isolated PVR (66.8%) or PVR+TVI (33.2%). Outcomes were abstracted from charts and compared between groups using multivariable logistic and negative binomial regression. Results Median age at reintervention was 35.3 years. Regardless of surgery type, TR decreased by at least 1 echocardiographic grade in 35.4%, 66.9%, and 92.8% of patients with pre-operative mild, moderate, and severe insufficiency. In multivariable analyses, PVR+TVI was associated with an additional 2.3-fold reduction in TR grade (odds ratio [OR]: 0.44; 95% confidence interval [CI]: 0.25 to 0.77) without an increase in early adverse events (OR: 0.85; 95% CI: 0.46 to 1.57) or hospitalization time (incidence rate ratio: 1.17; 95% CI: 0.93 to 1.46). Pre-operative TR severity and presence of transvalvular leads independently predicted post-operative TR. In contrast, early adverse events were strongly associated with atrial tachyarrhythmia, extracardiac arteriopathy, and a high body mass index. Conclusions In patients with TOF or PS and significant TR, concomitant TVI is safe and results in better early tricuspid valve competence than isolated PVR.

Background Experimental studies provide evidence of the harmful effect of human papillomavirus (HPV) infection on pregnancy, but observational studies are inconclusive. We systematically assessed the association between HPV and adverse pregnancy outcomes. Methods We searched electronic databases up to December 1, 2019. We included observational studies on the association between HPV and adverse pregnancy outcomes. We conducted a random-effect meta-analysis for each outcome and assessed heterogeneity between studies. Results From 3034 citations, we included 38 studies and quantitatively synthesized 36 studies. Human papillomavirus was significantly associated with preterm birth (age-adjusted odds ratio [aOR], 1.50; 95% confidence interval [CI], 1.19–1.88), preterm premature rupture of membranes (aOR, 1.96; 95% CI, 1.11–3.45), premature rupture of membranes (aOR, 1.42; 95% CI, 1.08–1.86), intrauterine growth restriction (aOR, 1.17; 95% CI, 1.01–1.37), low birth weight (aOR, 1.91; 95% CI, 1.33–2.76), and fetal death (aOR, 2.23; 95% CI, 1.14–4.37). No significant association was found for spontaneous abortion (aOR, 1.14; 95% CI, 0.40–3.22) and pregnancy-induced hypertensive disorders (aOR, 1.24; 95% CI, 0.80–1.92). Most of the studies were of moderate or low quality, and substantial between-studies heterogeneity remained unexplained. Conclusions We found a consistent and significant association between HPV and preterm birth and preterm premature rupture of membranes. Human papillomavirus may also be associated with intrauterine growth restriction, low birth weight, and fetal death, but findings are limited by suboptimal control of biases.

Key Points Question Is human papillomavirus (HPV) infection during pregnancy associated with preterm delivery? Findings In this multicenter cohort study of 899 pregnant women, persistent HPV-16/18 infection during pregnancy was significantly associated with preterm birth. Meaning If the identified association between HPV infection during pregnancy and preterm delivery is causal, HPV vaccination may reduce preterm birth and the associated burden., Importance Preterm birth remains a leading cause of perinatal mortality and lifelong morbidity worldwide. The cause of most preterm births is unknown, although several infectious processes have been implicated. Objective To assess whether human papillomavirus (HPV) infection, a frequent infection among women of childbearing age, is associated with preterm birth. Design, Setting, and Participants The prospective HERITAGE cohort study was conducted at 3 academic hospitals in Montreal, Québec, Canada, among 899 pregnant women recruited between November 8, 2010, and October 16, 2016. Follow-up was completed on June 15, 2017. Statistical analysis was conducted from February 6, 2020, to January 21, 2021. Exposures Vaginal HPV DNA detection in the first and third trimesters of pregnancy and placental HPV infection. Main Outcomes and Measures The main outcome was preterm birth (defined as a live birth or stillbirth between 20 weeks and 0 days and 36 weeks and 6 days of gestation). The association between HPV DNA detection and preterm birth was measured using logistic regression. Odds ratios (ORs) and 95% CIs were adjusted by inverse probability of treatment weights of the propensity score. Results The study included 899 women (mean [SD] age, 31.3 [4.6] years [range, 19-47 years]) with singleton pregnancies. A total of 378 women (42.0%) had HPV DNA detected in vaginal samples collected during the first trimester, and it was detected in 91 of 819 placentas (11.1%) at delivery. Fifty-five participants experienced preterm birth (38 spontaneous and 17 medically indicated). Persistent vaginal HPV-16/18 detection was significantly associated with all preterm births (adjusted OR [aOR], 3.72; 95% CI, 1.47-9.39) and spontaneous preterm births (aOR, 3.32; 95% CI, 1.13-9.80), as was placental HPV infection (all preterm births: aOR, 2.53; 95% CI, 1.06-6.03; spontaneous preterm births: aOR, 2.92; 95% CI, 1.09-7.81). Results were similar when restricting the analysis to participants without a history of cervical intraepithelial neoplasia treatment. Conclusions and Relevance The study’s results suggest that persistent HPV-16/18 infection is associated with an increased risk of preterm birth, independent of cervical treatment. Future studies should investigate the association of HPV vaccination and vaccination programs with the risk of preterm birth., This cohort study assesses whether human papillomavirus infection, a frequent infection among women of childbearing age, is associated with preterm birth.

Liver transplantation is associated with major bleeding and red blood cell (RBC) transfusions. No well-designed causal analysis on interventions used to reduce transfusions, such as an intraoperative phlebotomy, has been conducted in this population.We conducted a historical cohort study among liver transplantations performed from July 2008 to January 2021 in a Canadian centre. The exposure was intraoperative phlebotomy. The outcomes were blood loss, perioperative RBC transfusions (intraoperative and up to 48 hr after surgery), intraoperative RBC transfusions, and one-year survival. We estimated marginal multiplicative factors (MFs), risk differences (RDs), and hazard ratios by inverse probability of treatment weighting both among treated patients and the whole population. Estimates are reported with 95% confidence intervals (CIs).We included 679 patients undergoing liver transplantations of which 365 (54%) received an intraoperative phlebotomy. A phlebotomy did not reduce bleeding, transfusion risks, or mortality when estimated among the treated but reduced bleeding and transfusion risks when estimated among the whole population (MF, 0.85; 95% CI, 0.72 to 0.99; perioperative RD, -15.2%; 95% CI, -26.1 to -0.8; intraoperative RD, -14.7%; 95% CI, -23.2 to -2.8). In a subgroup analysis on 584 patients with end-stage liver disease, slightly larger effects were observed on both transfusion risks when estimated among the whole population while beneficial effects were observed on the intraoperative transfusion risk when estimated among the treated population.The use of intraoperative phlebotomy was not consistently associated with better outcomes in all targets of inference but may improve outcomes among the whole population.www.gov (NCT04826666); registered 1 April 2021.RéSUMé: CONTEXTE: La transplantation hépatique est associée à des saignements importants et à de multiples transfusions de globules rouges (GR). Aucune analyse causale bien conçue sur l’effet d’interventions servant à réduire les transfusions, comme une phlébotomie peropératoire, n'a été menée dans cette population. MéTHODE: Nous avons mené une étude de cohorte historique incluant toutes les transplantations hépatiques réalisées dans un centre canadien de juillet 2008 à janvier 2021. L'exposition d’intérêt était une phlébotomie peropératoire. Les critères d’évaluation étaient le saignement peropératoire, les transfusions de GR périopératoires (peropératoires et jusqu'à 48 heures après la chirurgie), les transfusions de globules rouges peropératoires et la survie à un an. Des facteurs multiplicatifs (FM), des différences de risque (DR) et des rapports de risques instantanés marginaux ont été estimés en utilisant une pondération par l’inverse de la probabilité de traitement parmi les patients traités et parmi l'ensemble de la population. Les effets estimés ont été rapportés avec des intervalles de confiance (IC) à 95 %. RéSULTATS: Nous avons inclus 679 transplantations hépatiques dont 365 (54 %) ont bénéficié d'une phlébotomie peropératoire. La phlébotomie n'a pas réduit les saignements, le risque de transfusion ou la mortalité lorsque ses effets ont été estimés parmi les patients traités, mais a réduit les risques de saignement et de transfusion lorsque ses effets ont été estimés parmi l'ensemble de la population (FM = 0,85 (IC 95 %, 0,72 à 0,99); DR périopératoire = −15,2 % (IC 95 %, −26,1 % à −0,8 %); DR peropératoire = −14,7 % (IC 95 %, −23,2 % à −2,8 %)). Dans une analyse de sous-groupe portant sur 584 patients atteints d'une hépatopathie terminale, des effets légèrement plus importants ont été observés sur les deux risques transfusionnels lorsqu’estimés dans l'ensemble de la population, tandis que des effets bénéfiques ont été observés sur le risque transfusionnel peropératoire lorsqu'estimés parmi les patients traités. CONCLUSION: L'utilisation de la phlébotomie peropératoire n'a pas été systématiquement associée à de meilleurs résultats dans toutes les populations cibles, mais semble améliorer les résultats lorsque les effets sont estimés dans l'ensemble de la population. ENREGISTREMENT DE L’éTUDE: www.ClinicalTrials.gov (NCT04826666); enregistrée le 1

Thromboembolic events contribute greatly to morbidity and mortality following Fontan surgery for univentricular hearts.This study sought to evaluate the effect of type of Fontan surgery on thromboembolic risk.A North American multicenter retrospective cohort study enrolled 522 patients with Fontan palliation consisting of an atriopulmonary connection (APC) (21.4%), lateral tunnel (LT) (41.8%), or extracardiac conduit (EC) (36.8%). Thromboembolic complications and new-onset atrial arrhythmia were reviewed and classified by a blinded adjudicating committee. Thromboembolic risk across surgical techniques was assessed by multivariable competing-risk survival regression.Over a median follow-up of 11.6 years, 10- and 20-year freedom from Fontan conversion, transplantation, or death was 94.7% and 78.9%, respectively. New-onset atrial arrhythmias occurred in 4.4, 1.2, and 1.0 cases per 100 person-years with APC, LT, and EC, respectively. APC was associated with a 2.82-fold higher risk of developing atrial arrhythmias (p 0.001), with no difference between LT and EC (p = 0.95). A total of 71 thromboembolic events, 32 systemic and 39 venous, occurred in 12.8% of subjects, for an overall incidence of 1.1%/year. In multivariable analyses, EC was independently associated with a lower risk of systemic (hazard ratio [HR]: 0.20 vs. LT; 95% confidence interval [CI]: 0.04 to 0.97) and combined (HR: 0.34 vs. LT; 95% CI: 0.13 to 0.91) thromboembolic events. A lower incidence of combined thromboembolic events was also observed with antiplatelet agents (HR: 0.54; 95% CI: 0.32 to 0.92) but not anticoagulation (p = 0.53).The EC Fontan was independently associated with a lower thromboembolic risk after controlling for time-varying effects of atrial arrhythmias and thromboprophylaxis.

Purpose: In Sub-Saharan Africa, an important proportion of incident HIV cases occur among heterosexual serodiscordant couples (HSDC) but the majority of HIV negative partners can remain seronegative. These are called HIV-exposed seronegative (HESN). We aimed to compare immune activation (IA) levels between HESN, their HIV infected counterparts (HIV+ partners) and HIV unexposed uninfected individuals (HIV-neg Controls) and to evaluate the association between sexual exposure to HIV (SEHIV) and IA. Methods: We conducted a cross-sectional study in Dakar, Senegal on 148 participants recruited between November 2013 and February 2014: 40 HIV-neg Controls, 54 HESN and 54 HIV+ Partners. SEHIV was evaluated individually using questionnaires. IA level was measured by plasma level of β2-microglobulin (β2m). Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for the different associations. Results: The median levels of β2m were 1.57 mg/l (IQR: 1.37 - 1.77), 2.14 mg/l (IQR: 1.76 - 2.43) and 2.24 mg/l (IQR: 1.80 - 3.17) for HIV-neg Controls, HESN and HIV+ partners, respectively. After adjustment, HESN had similar levels of IA with HIV+ partners but significantly higher than that of HIV-neg Controls (adjusted OR = 6.28; 95% CI: [2.19 - 18.00]). The association between IA and SEHIV was evaluated in the HIV negative individuals. High frequency of SEHIV was associated with a β2m > 2.2 mg/l (OR = 6.56; 95% CI: [1.71 - 25.21]); significantly more than median cut off value of >1.81 mg/l. Conclusions: Our study shows that, despite being uninfected with HIV, HESN individuals show a high level of IA, which was depended on the level of SEHIV.

Background: Epstein–Barr virus (EBV) and cytomegalovirus (CMV) infections can have serious consequences during the period of aplasia and lymphopenia following hematopoietic stem cell transplantation (HSCT). Large pediatric cohort studies examining the effect of antiviral prophylaxis against these viruses are scarce. The present study aimed to analyse the potential effect of antiviral prophylaxis (acyclovir and famciclovir) on active post-transplant EBV and CMV infection in a pediatric cohort of allogeneic HSCT recipients. Methods: We used data from the TREASuRE cohort, consisting of 156 patients who had a first allogeneic HSCT, enrolled in four pediatric centers in Canada between July 2013 and March 2017. Follow-up was performed from the time of transplant up to 100 days post-transplant. Adjusted hazard ratio (HR) with 95% confidence intervals (CI) for the association between antiviral prophylaxis with acyclovir and/or famciclovir and EBV and CMV DNAemia was estimated using multivariate Cox regression models. Results: The post-transplant cumulative incidence of EBV and CMV DNAemia at 100 days of follow-up were, respectively, 34.5% (95% CI: 27.6–42.6) and 19.9% (95% CI: 14.5–27.1). For acyclovir, the adjusted hazard ratio (HR) for CMV and EBV DNAemia was 0.55 (95% CI: 0.24–1.26) and 1.41 (95% CI: 0.63–3.14), respectively. For famciclovir, the adjusted HR were 0.82 (95% CI: 0.30–2.29) and 0.79 (95% CI: 0.36–1.72) for CMV and EBV DNAemia, respectively. Conclusion: The antivirals famciclovir and acyclovir did not reduce the risk of post-transplant CMV and EBV DNAemia among HSCT recipients in our pediatric population.

Background Epstein-Barr virus (EBV) can cause severe disease following hematopoietic stem cell transplant (HSCT), including post-transplant lymphoproliferative disorder (PTLD). The objective was to analyze risk factors associated with post-transplant EBV outcomes among pediatric allogeneic HSCT recipients. Methods We used data from 156 pediatric allogeneic HSCT recipients enrolled in the Canadian multicenter TREASuRE study. Cox and Prentice-Williams-Petersen models were used to analyze risk factors for post-transplant EBV events including occurrence and recurrence of EBV DNAemia, increase in EBV viral load (EBV-VL), and preemptive use of rituximab, an effective therapy against PTLD. Results Females were at higher risk for increasing EBV-VL (adjusted hazard ratio (HR) = 2.83 [95% confidence intervals (CI): 1.33-6.03]) and rituximab use (HR = 3.08 [1.14-8.30]), but had the same EBV DNAemia occurrence (HR = 1.21 [0.74-1.99]) and recurrence risks (HR=1.05 [0.70-1.58]) compared to males. EBV DNAemia was associated with recipient pre-transplant EBV seropositivity (HR = 2.47 [1.17-5.21]) and with graft from an EBV-positive donor (HR = 3.53 [1.95-6.38]). Anti-thymocyte globulin (ATG) was strongly associated with all EBV outcomes, including the use of rituximab (HR = 5.33 [1.47-19.40]). Mycophenolate mofetil (MMF) significantly decreased the risk of all EBV events including the rituximab use (HR = 0.13 [0.03-0.63]). Conclusion This study in pediatric allogeneic HSCT patients reveals a reduced risk of all EBV outcomes with the use of MMF. Risk factors for EBV events such as EBV-VL occurrence and recurrence include EBV positivity in the donor and recipient, and use of ATG, whereas risk factors for the most severe forms of EBV outcome (EBV-VL and the use of rituximab) include female sex and ATG use.

This systematic review was undertaken to identify risk factors associated with post-transplant Epstein–Barr virus (EBV) active infection and post-transplant lymphoproliferative disease (PTLD) in pediatric and adult recipients of hematopoietic stem cell transplants (HSCT). A literature search was conducted in PubMed and EMBASE to identify studies published until 30 June 2020. Descriptive information was extracted for each individual study, and data were compiled for individual risk factors, including, when possible, relative risks with 95% confidence intervals and/or p-values. Meta-analyses were planned when possible. The methodological quality and potential for bias of included studies were also evaluated. Of the 3362 titles retrieved, 77 were included (62 for EBV infection and 22 for PTLD). The overall quality of the studies was strong. Several risk factors were explored in these studies, but few statistically significant associations were identified. The use of anti-thymocyte globulin (ATG) was identified as the most important risk factor positively associated with post-transplant active EBV infection and with PTLD. The pooled relative risks obtained using the random-effect model were 5.26 (95% CI: 2.92–9.45) and 4.17 (95% CI: 2.61–6.68) for the association between ATG and post-transplant EBV infection and PTLD, respectively. Other risk factors for EBV and PTLD were found in the included studies, such as graft-versus-host disease, type of conditioning regimen or type of donor, but results are conflicting. In conclusion, the results of this systematic review indicate that ATG increases the risk of EBV infection and PTLD, but the link with all other factors is either nonexistent or much less convincing.

BackgroundImplementation of the programmes for the Prevention of Mother to Child Transmission (PMTCT) of Human Immunodeficiency Virus (HIV) into antenatal care over the last three decades could inform implementation of interventions for other health challenges such as gestational diabetes mellitus (GDM). This study assessed PMTCT outcomes, and how GDM screening, care, and type 2 diabetes (T2DM) prevention were integrated into PMTCT in Western Cape (WC), South Africa.MethodsA convergent mixed methods and triangulation design were used. Content and thematic analysis of PMTCT-related policy documents and of 30 semi-structured interviews with HIV/PMTCT experts, health care workers and women under PMTC diagnosed with GDM complement quantitative longitudinal analysis of PMTCT implementation indicators across the WC for 2012–2017.ResultsProvincial PMTCT and Post Natal Care (PNC) documents emphasized the importance of PMTCT, but GDM screening and T2DM prevention were not covered. Data on women with both HIV and GDM were not available and GDM screening was not integrated into PMTCT. Women who attended HIV counselling and testing annually increased at 17.8% (95% CI: 12.9% - 22.0%), while women who delivered under PMTCT increased at 3.1% (95% CI: 0.6% - 5.9%) annually in the WC. All 30 respondents favour integrating GDM screening and T2DM prevention initiatives into PMTCT.ConclusionPMTCT programmes have not yet integrated GDM care. However, Western Cape PMTCT integration experience suggests that antenatal GDM screening and post-partum initiatives for preventing or delaying T2DM can be successfully integrated into PMTCT and primary care.

There is uncertainty regarding the potential virologic outcome associated with a change in antiretroviral therapy (ARV) among PLHIV who had previous documented virologic failure or who have been exposure to mono/dual nucleoside reverse transcriptase inhibitors (NRTI) therapy. The objective was to measure the potential impact of exposure to previous virologic failure or mono/dual NRTI regimen on virologic outcome of PLHIV following a switch to dolutegravir with 2 NRTIs from a viremia suppressive ARV therapy. Data from the Quebec HIV Cohort including 10219 PLHIV were collected through routine clinical care at 4 clinical sites in Montreal, Canada. This study includes patients whose ARV therapy was switched to dolutegravir with 2 NRTIs since 2013 with undetectable viral load for ≥6 months before switch. The association between exposure and post-switch virologic outcome was measured by marginal hazard ratio estimated using the Inverse probability weighting Cox model. Among the 1199 eligible PLHIV, 478 (39.9%) previously experienced at least one virologic failure or were exposed to mono/dual therapy before dolutegravir switch. Post-switch virologic failure after 30 months occurred in 4.1% (95% CI 2.1–7.9) of exposed compared to 4.1% (95% CI 2.3–7.4) in unexposed participants. The adjusted hazard ratio for the association between exposure and post-switch virologic failure was 0.84 (95% CI 0.35–2.01). Our findings suggest that switch to dolutegravir with 2 NRTIs from a suppressive therapy is a safe option for PLHIV with documented virologic failure and/or previous exposure to mono/dual NRTI therapy.

Background Switching antiretroviral regimens when human immunodeficiency virus (HIV) viremia is controlled for a new regimen is challenging when there is the potential for prior nucleoside reverse-transcriptase inhibitor (NRTI) resistance. The objective was to study virologic outcomes after switching to dolutegravir compared with remaining on a boosted protease inhibitor (protease inhibitor/ritonavir [PI/r]) regimen in people with HIV (PWH) with prior documented virologic failure and/or exposure to mono/dual NRTIs. Methods We used the Quebec HIV Cohort including 10 219 PWH whose data were collected at 4 sites in Montreal, Canada. We included all PWH with documented virologic failure or exposure to mono/dual NRTI therapy who were virologically suppressed on a PI/r-based regimen for at least 6 months on or after January 1, 2014 (n = 532). A marginal structural Cox model analysis was used to estimate the effect of the switch to dolutegravir on virologic outcome compared with remaining on PI/r. The outcome was defined as 2 consecutive viral loads (VLs) >50 copies/mL or 1 VL >50 copies/mL if it occurred at the last VL available. Results Among 532 eligible participants, 216 (40.6%) had their regimen switched to dolutegravir with 2 NRTIs, whereas 316 (59.4%) remained on the PI/r with 2 NRTIs. The weighted hazard ratio for the effect of dolutegravir switch on virologic failure compared with patients whose regimen remained on PI/r was 0.57 (95% confidence interval, 0.21–1.52). Conclusions We did not find evidence of an increased risk for virologic failure after switching to dolutegravir from PI/r among patients with previous virologic failure or prior exposure to mono/dual NRTI., Therapeutic switches to dolutegravir with 2 NRTIs provide a safe option for patients with a viremia suppressive antiretroviral regimen in the presence of prior documented virologic failure and prior exposure to mono/dual NRTI therapy.

Introduction: Many adults diagnosed with gestational diabetes mellitus (GDM) and type 2 diabetes mellitus (T2DM) also have other known or unknown comorbid conditions. The rising prevalence of GDM and T2DM within a broader context of multimorbidity can best be addressed through an integrated management response, instead of stand-alone programs targeting specific infectious and/or chronic diseases.Aim: To describe GDM and T2DM screening, care and cost-effectiveness outcomes in the context of multimorbidity through integrated interventions in Africa.Methods: A systematic review of all published studies was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Risk Of Bias in Non-randomised Studies of Interventions (ROBINS-I) was used to assess risk of bias. Data synthesis was conducted using narrative synthesis of included studies.Results: A total of 9 out of 13 included studies reported integrated diabetes mellitus (DM) screening, 7 included integrated care and 9 studies addressed cases of newly detected DM who were asymptomatic in pre-diabetes stage. Only 1 study clearly analysed cost-effectiveness in home-based care; another 5 did not evaluate cost-effectiveness but discussed potential cost benefits of an integrated approach to DM screening and care. Compared to partial integration, only 2 fully integrated interventions yielded tangible results regarding DM screening, care and early detection of cases despite many that reported barriers to its sustainability.Conclusion: Though few, integrated interventions for screening and/or care of DM in the context of multimorbidity within available resources in health systems throughout Africa exist and suggest that this approach is possible and could improve health outcomes.

BackgroundIntegrating Prevention of Mother-to-Child Transmission (PMTCT) programmes into routine health services under complex socio-political and health system conditions is a priority and a challenge. The successful rollout of PMTCT in sub-Saharan Africa has decreased Human Immunodeficiency Virus (HIV), reduced child mortality and improved maternal health. In South Africa, PMTCT is now integrated into existing primary health care (PHC) services and this experience could serve as a relevant example for integrating other programmes into comprehensive primary care. This study explored the perspectives of both experts or key informants and frontline health workers (FHCWs) in South Africa on PMTCT integration into PHC in the context of post-AIDS denialism using a Complex Adaptive Systems framework.MethodsA total of 20 in-depth semi-structured interviews were conducted; 10 with experts including national and international health systems and HIV/PMTCT policy makers and researchers, and 10 FHCWs including clinic managers, nurses and midwives. All interviews were conducted in person, audio-recorded and transcribed. Three investigators collaborated in coding transcripts and used an iterative approach for thematic analysis.ResultsExperts and FHCWs agreed on the importance of integrated PMTCT services. Experts reported a slow and partial integration of PMTCT programmes into PHC following its initial rollout as a stand-alone programme in the aftermath of the AIDS denialism period. Experts and FHCWs diverged on the challenges associated with integration of PMTCT. Experts highlighted bureaucracy, HIV stigma and discrimination and a shortage of training for staff as major barriers to PMTCT integration. In comparison, FHCWs emphasized high workloads, staff turnover and infrastructural issues (e.g., lack of rooms, small spaces) as their main challenges to integration. Both experts and FHCWs suggested that working with community health workers, particularly in the post-partum period, helped to address cases of loss to follow-up of women and their babies and to improve linkages to polymerase-chain reaction (PCR) testing and immunisation.ConclusionsDespite organised efforts in South Africa, experts and FHCWs reported multiple barriers for the full integration of PMTCT in PHC, especially postpartum. The results suggest opportunities to address operational challenges towards more integrated PMTCT and other health services in order to improve maternal and child health.

Background Epstein-Barr virus (EBV) is carried in the blood of most adults, and transfusion-related infections have been reported. EBV is particularly deleterious in immunosuppressed transplant patients. The aim was to determine if EBV transmission occurred through leukodepleted blood product transfusion in pediatric recipients of hematopoietic stem cell transplants (HSCT). Study design and methods This prospective Canadian multi-center cohort study includes 156 allogeneic HSCT pediatric recipients. The association between EBV and transfusion was analyzed using Cox regressions. EBV infection, defined by a PCR+ test in the blood of seronegative recipients of an EBV-negative graft, was monitored in order to correlate the recipient EBV strain with that of the blood donors. EBV genotypes were determined by PCR amplification followed by DNA sequencing at two loci (EBNA3b and LMP1). Results No statistically significant associations were found between transfusions and EBV. One case of post-transplant EBV infection was identified among the 21 EBV-seronegative recipients receiving an EBV-negative graft. A total of 22 blood donors were retraced to determine whether the recipient's EBV strain matched that of a donor. One donor strain showed 100% sequence homology at the EBNA3b locus, but differed by one or two point mutations and by a 132-bp deletion at the LMP1 locus. The blood donor in question was alone among the 22 donors to show amplifiable virus in plasma. Blood from this donor readily produced an immortalized lymphoblastoid cell line in culture. Conclusion While considered a rare event, EBV transmission through transfusion may occur in the context of severe immunosuppression.

Background Integrating vertical programmes into routine health services under complex socio-political and health system conditions is a priority and a challenge. The successful rollout of Prevention of Mother-to-Child Transmission programmes (PMTCT) in sub-Saharan Africa has decreased Human Immunodeficiency Virus (HIV), reduced child mortality and improved maternal health. In South Africa, PMTCT is now integrated into existing health services and this experience could serve as a relevant example for integrating other programmes into comprehensive primary care. We explored the perspectives of both experts and frontline health workers (FHCWs) in South Africa on PMTCT integration into primary health care (PHC) in the context of post-AIDS denialism using a Complex Adaptive Systems framework. Methods We conducted a total of 20 in-depth semi-structured interviews; 10 with experts (PMTCT and health system experts, policymakers, researchers and activists) and 10 with FHCWs including clinic managers, nurses and midwives. All interviews were conducted in person, audio-recorded and transcribed. Three investigators collaborated in coding transcripts and used an iterative approach for thematic analysis. Results Experts and FHCWs agreed on the importance of integrated PMTCT services. Experts reported a slow and partial integration of PMTCT programs into PHC following its initial rollout as a stand-alone program in the aftermath of the AIDS denialism period. Experts and FHCWs diverged on the challenges associated with integration of PMTCT. Experts highlighted bureaucracy, HIV stigma and discrimination and a shortage of training for staff as major barriers to PMTCT integration. In comparison, FHCWs emphasized high workloads, staff turnover and infrastructure issues (such as lack of rooms, small spaces, etc.) as their main challenges to integration. Both experts and FHCWs suggested that working with community health workers, particularly in the post-partum period, helped to address cases of loss to follow-up of women and their babies and to improve linkages to protein-chain reaction (PCR) testing and immunisation. Conclusions Despite organised efforts in South Africa, experts and FHCWs reported multiple barriers for the full integration of PMTCT programmes in PHC, especially postpartum. Our results suggest opportunities to address operational challenges towards more integrated PMTCT and other health services in order to improve maternal and child health.

Background Little is known about the association between bisphenol A (BPA) or triclosan (TCS) exposure and hypertension in pregnancy. Objective To investigate potential associations between maternal urinary concentrations of BPA or TCS and gestational hypertension (GH) and preeclampsia. Study Design Among 1,909 pregnant women participating in the maternal-infant research on environmental chemicals (MIREC) study, urinary concentrations of BPA and TCS were measured in the first trimester by liquid chromatography-tandem mass spectrometry using isotope dilution. Blood pressure was measured during each trimester. Multinomial regression was performed to estimate the adjusted odds ratio (aOR) and 95% confidence intervals (CI) for the associations between these phenols and GH and preeclampsia. Results BPA and TCS were not associated with GH or preeclampsia. However, in multiparous women, BPA (0.50–1.30 µg/L) was associated with decreased risk of GH (aOR =0.45; 95%CI: 0.21–0.98) while among nulliparous women, TCS was associated with an increased risk of GH (3.60–32.60 µg/L; aOR = 2.58; 95% CI: 1.09–6.13 and > 32.60 µg/L: aOR = 2.74; 95% CI: 1.15–6.51). Conclusion BPA and TCS urinary concentrations were not associated with GH or preeclampsia; however, our results suggest an association between TCS and GH in nulliparous women. Additional studies are required to confirm our results.

SUMMARYWe examined the association between a history of smallpox vaccination and immune activation (IA) in a population of antiretroviral therapy-naïve people living with HIV (PLHIV). A cross-sectional study was conducted in Senegal from July 2015 to March 2017. Smallpox vaccination was ascertained by the presence of smallpox vaccine scar and IA by the plasma level ofβ-2-microglobulin (β2m). The association was analysed using logistic regression and linear regression models. The study population comprised 101 PLHIV born before 1980 with a median age of 47 years (interquartile range (IQR) = 42–55); 57·4% were women. Smallpox vaccine scar was present in 65·3% and the medianβ2m level was 2·59 mg/l (IQR = 2·06–3·86). After adjustment, the presence of smallpox vaccine scar was not associated with aβ2m level ⩾2·59 mg/l (adjusted odds ratio 0·94; 95% confidence interval 0·32–2·77). This result was confirmed by the linear regression model. Our study does not find any association between the presence of smallpox vaccine scar and theβ2m level and does not support any association between a previous smallpox vaccination and HIV disease progression. In this study, IA is not a significant determinant of the reported non-targeted effect of smallpox vaccination in PLHIV.

Background: There is a paucity of data on the dynamics of human papillomavirus (HPV) antibodies in children. We aimed to describe the vertical transmission and clearance of antibodies against HPV6, 11, 16 and 18 in children.Methods: We used data from pregnant women recruited into the HERITAGE cohort study between 2009 and 2012 who were positive for HPV-DNA at baseline. Dried blood spots were collected during the first trimester in pregnant participants, and at birth, 6, 12, and 24 months of age in children. The level of total immunoglobulin G (IgG) against HPV6, 11, 16 and 18 were measured using Luminex immunoassays. Spearman's coefficients were used to correlate HPV antibody levels between newborns and mothers. Panel and Kaplan-Meier graphics described antibody dynamics in the first 24 months of life.Findings: Antibodies from newborns and mothers (n = 58 pairs) were moderately to highly correlated with coefficients of 0·81 (95% confidence intervals (CI):0·70–0·88), 0·68 (95% CI:0·5–0·80), 0·90 (95% CI:0·83–0·94) and 0·85 (95% CI:0·76–0·91) against HPV6, 11, 16 and 18, respectively. In newborns seropositive at birth, anti-HPV antibodies were cleared by 80% and 100% at 12 and 24 months, respectively. Only two children presented detectable HPV antibodies at 24 months. The first child had no detectable antibodies at birth and the second presented increasing levels after two undetected measures.Interpretation: Correlation between mother and newborn IgG antibodies against HPV suggests vertical transfer. Most children cleared anti-HPV antibodies within six to 12 months.Funding: The Canadian Institutes of Health Research (CIHR) Keywords: Human papillomavirus, Serology, Mother-newborn correlation, Vertically acquired immunity, Antibody clearance, Antibody dynamics

Background The potential association between the presence or replacement of dental amalgams and gestational hypertension (GH) is unclear. Objective To assess the association between the presence or replacement of dental amalgams and the risk of GH in a prospective cohort study. Methods We assessed dental amalgam status (presence or replacement), blood mercury concentrations, and measured blood pressure (BP) in 1817 pregnant women recruited in 10 Canadian cities. BP was assessed in each trimester of pregnancy and mercury concentrations in 1st and 3rd trimesters. Logistic regression analysis was performed to estimate the adjusted odds ratios (aOR) and 95% confidence intervals (CI) for the associations between dental amalgam status and GH. Concurrent measures with systolic BP (SBP) and diastolic BP (DBP) were assessing through linear generalized estimating equations. Results Dental amalgam status was weakly statistically correlated with mercury concentrations but there was no evidence of an association with GH in women having 1–4 (aOR = 1.31 (0.92, 1.85)) or ≥ 5 dental amalgams (aOR = 1.32 (0.86, 2.04)), compared to women without amalgam reported at first trimester. Dental amalgam replacement reported in the first or third trimester was similarly not associated with GH (aOR = 0.75 (0.40, 1.42) and 0.73 (0.39, 1.34), respectively) but with SBP (beta = −1.58 (−2.95, −0.02)). Conclusion We found weak correlations between dental amalgams and blood mercury among pregnant women. However, the presence of dental amalgams or their replacement was not associated with GH but with decreased SBP for the replacement. Further studies are required.

Objective: To evaluate the association of antiretroviral therapy (ART) type and duration of exposure with early placental function using biomarkers of aneuploidy screening. Study design: Three hundred thirty-eight pregnant women living with HIV were enrolled in two Canadian centers. Multiple linear regressions were performed adjusting for confounding factors (race, age, gestational age, body mass index, parity, smoking, and fetal sex). Results: Women receiving ART had significantly increased second trimester alpha-fetoprotein (AFP) levels (β = 0.147, 95% CI = [0.067–0.227] for protease inhibitor-based ART and β = 0.176, 95% CI = [0.080–0.272] for ART without protease inhibitor) compared to women who received no treatment. However, there was no significant association between ART type and the levels of free β-human chorionic gonadotrophin (β-hCG), pregnancy-associated plasma protein-A (first trimester), unconjugated estriol, total hCG, and inhibin A (second trimester). No significant association was shown between biomarker levels and duration of ART exposure. Conclusion: Early placental function does not appear to be significantly affected by ART, except for AFP.

Background and Objectives: The aim of the study was to perform the first randomized trial comparing the diagnostic yield, bloodiness, and cellularity of the 25G standard needle (25S) and the 25G ProCore™ needle (25P). Materials and Methods: All patients referred to the tertiary care referral center for EUS guided fine-needle aspiration (EUS-FNA) of suspicious solid pancreatic lesions were eligible. EUS-FNA was performed in each lesion with both 25S and 25P needles (the choice of the first needle was randomized), using a multipass sampling pattern, without stylet or suction. Rapid on-site evaluation was used when possible. Pap-stained slides were read by a single experienced cytopathologist, blinded to the needle type. Results: One hundred and forty-three patients were recruited. Samples were positive for cancer in 122/143 (85.3%) with the 25S needle versus 126/143 (88.1%) with the 25P needle, negative in 17/143 (11.9%) with the 25S needle versus 13/143 (9.1%) with the 25P needle, and suspicious in 4/143 (2.8%) with each needle. There was no difference in any outcome based on the type of the first needle. No carryover effect was detected (P = 0.214; NS). Cumulative logistic regression analyses showed no associations between the type of needle and diagnostic yield for cancer, cellularity, or bloodiness. The difference in the yield for cancer was 2.9% (−4.2; 10.1%); with the confidence interval upper within the predetermined noninferiority margin of 15%. Conclusion: The 25S needle is noninferior to the 25P needle for diagnosing cancer in suspicious pancreatic lesions.

Perinatal route of transmission of human papillomavirus (HPV) has been demonstrated in several small studies. We designed a large prospective cohort study (HERITAGE) to better understand perinatal HPV. The objective of this article is to present the study design and preliminary data. In the first phase of the study, we recruited 167 women in Montreal, Canada, during the first trimester of pregnancy. An additional 850 are currently being recruited in the ongoing phase. Cervicovaginal samples were obtained from mothers in the first trimester and tested for HPV DNA from 36 mucosal genotypes (and repeated in the third trimester for HPV-positive mothers). Placental samples were also taken for HPV DNA testing. Conjunctival, oral, pharyngeal and genital samples were collected for HPV DNA testing in children of HPV-positive mothers at every 3–6 months from birth until 2 years of age. Blood samples were collected in mother and children for HPV serology testing. We found a high prevalence of HPV in pregnant women (45%[95%CI:37–53%]) and in placentas (14%[8–21%]). The proportion of HPV positivity (any site) among children at birth/3-months was 11%[5–22%]. HPV was detected in children in multiple sites including the conjunctiva (5%[10–14%]). The ongoing HERITAGE cohort will help provide a better understanding of perinatal HPV. Keywords: Human papillomavirus (HPV), Perinatal transmission, Pregnancy, Placenta, Children, Persistence

As per the American Society for Colposcopy and Cervical Pathology guidelines, human papillomavirus (HPV) testing is currently used as part of cervical cancer screening and during colposcopy follow-up. The present project evaluated if the application of acetic acid (AA) impacts HPV test results. Methods We conducted a prospective nonrandomized interventional study. Participants referred for colposcopy were eligible if immunocompetent, older than 18 years, and not pregnant. Women in group A (controls) received 2 consecutive HPV tests without application of AA. Women in group B had a first HPV sample collected before the application of AA and a second sample collected 3 minutes after application of AA. Samples were tested for HPV DNA with Hybrid Capture 2 (HC2) according to the manufacturer's instructions. Results From October 17, 2012, to January 10, 2013, approximately 101 women were recruited in 2 colposcopy clinics. In each group, concordance was 98%, with only 1 participant having discordant results (testing negative on the first sample and positive on the second sample). We found no statistically significant difference in relative light units(RLUs) between groups (median of difference, - 0.02 vs -0.05 RLU; p = .93). Conclusions The results of this study suggest that acetic acid at concentrations of 3% to 5% and sequential cervical sampling do not modify the result of HPV testing by Hybrid Capture 2.

To identify the potential complications associated with RBC transfusions.Prospective observational study.PICU in a tertiary children's hospital.All children consecutively admitted to our PICU during a 1-year period.None.Data were abstracted from medical charts prospectively. Outcomes possibly attributable to RBC transfusions were looked for daily. In transfused cases, it was considered that an outcome was associated with a transfusion only if it was observed after the first RBC transfusion. During the 1-year study period, 913 consecutive admissions were documented, 842 of which were included. Among them, 144 (17%) were transfused at least once. When comparing transfused cases with nontransfused cases, the odds ratio for new or progressive multiple organ dysfunction syndrome was 5.14 (95% CI, 3.28-8.06; p0.001). This association remained statistically significant in the multivariable analysis (odds ratio, 3.85; 95% CI, 2.38-6.24; p0.001). Transfused cases were ventilated longer than nontransfused cases (14.1 ± 32.6 vs 4.3 ± 9.6 d, p0.001), even after adjustment in a Cox model. The PICU length of stay was significantly increased for transfused cases (12.4 ± 26.2 vs 4.9 ± 10.2 d, p0.001), even after controlling for potential confounders. The paired analysis for comparison of pretransfusion and posttransfusion values showed that the arterial partial pressure in oxygen was significantly reduced within the 6 hours after the first RBC transfusion (mean difference, 25.6 torr, 95% CI, 5.7-45.4; p = 0.029). The paired analysis also showed an increased proportion of renal replacement therapy.RBC transfusions in critically ill children were associated with prolonged mechanical ventilation and prolonged PICU stay. The risk of new or progressive multiple organ dysfunction syndrome was also increased in some transfused children. Furthermore, our study questions the ability of stored RBCs to improve oxygenation in critically ill children. Practitioners should take into account these data when prescribing an RBC transfusion to PICU patients.