Allogeneic donor CCR5 Δ32 homozygous haemopoietic cell transplantation (HCT) provides the only evidence to date of long-term control of HIV infection. However, availability of conventional CCR5 Δ32 ...homozygous donors is insufficient to develop this as a therapeutic strategy further.
We present a 37-year-old patient with HIV-1 infection and aggressive lymphoma who had disease progression after five lines of radiochemotherapy including an autologous HCT, and in the absence of matched sibling donors, received an allogeneic HCT with four of six HLA-matched CCR5 Δ32 homozygous cord blood cells (StemCyte, Covina, CA), supported with purified CD34+ cells from a haploidentical sibling. Blood or tissue samples were obtained before and weekly after HCT to monitor transplant and HIV infection, including chimerism analysis, CCR5 genotyping and viral tropism, viral isolation and sequence, viral reservoir analysis, immune activation and proliferation, and ex-vivo cell infectivity assays. Combined antiretroviral therapy continued during the procedure.
The patient's HIV was CCR5-tropic by genotypic and phenotypic analyses. Baseline latent reservoir tests showed HIV DNA copies in bulk and resting CD4 T cells and in gut-associated lymphoid tissue, CD4 T-cell-associated HIV RNA, replication competent viral size of 2·1 copies per 10(7) CD4 T cells, and single copy assay of 303 copies per mL. After HCT, plasma HIV DNA load was undetectable by ultrasensitive analyses. Upon cord blood full chimerism, the patient's CCR5 Δ32 homozygous CD4 T cells responded to proliferation and activation stimuli and became resistant to infection by the patient's viral isolate and by laboratory-adapted HIV-1 strains. Death related to lymphoma progression regretfully prevented long-term monitoring of the patient's viral reservoir.
CCR5 Δ32 homozygous cord blood reconstitution can successfully eliminate HIV-1 and render the allogeneic graft recipient's T lymphocytes resistant to HIV infection. Thus, they build on the evidence available to strongly support the use of cord blood as a strategic platform for a broader application of non-functional CCR5 transplantation to other infected individuals.
Spanish Secretariat of Research, the American Foundation for AIDS Research (amfAR).
Physical fitness is an important marker of current and future health status, yet the association between physical fitness and indicators of mental health in youth has not been systematically reviewed ...and meta-analyzed.
The aim of this work was to systematically review and meta-analyze the association between physical fitness components (i.e. cardiorespiratory fitness, muscular fitness, speed-agility, flexibility and fitness composite) and mental health indicators (i.e. psychological well-being and psychological ill-being) in preschoolers, children and adolescents.
Systematic review and meta-analysis.
Systematic searches were conducted in PubMed, Web of Science and Scopus from database inception to May 2020.
Studies (cross-sectional, longitudinal and intervention designs) were included if they measured at least one physical fitness component and one mental health indicator in healthy youth (2-18 years).
A total of 58 unique studies (52 cross-sectional, 4 longitudinal and 4 intervention studies) met all eligibility criteria and were included. There was a significant positive overall association between physical fitness and mental health in children and adolescents (pooled r = 0.206, p < 0.001). We found suggestive evidence of moderation by age group, fitness components and socioeconomic status (all p < 0.08). No relevant studies focusing on preschoolers were identified. Evidence based on longitudinal and intervention studies was limited.
We observed a small to medium sized positive association between physical fitness and overall mental health in youth. However, as the majority of studies were cross-sectional, additional longitudinal and intervention studies are needed to provide evidence of causation.
PROSPERO registration number CRD42017080005.
Abnormally high spiking activity can damage neurons. Signaling systems to protect neurons from the consequences of abnormal discharge activity have been postulated. We generated conditional mutant ...mice that lack expression of the cannabinoid receptor type 1 in principal forebrain neurons but not in adjacent inhibitory intemeurons. In mutant mice, the excitotoxin kainic acid (KA) induced excessive seizures in vivo. The threshold to KA-induced neuronal excitation in vitro was severely reduced in hippocampal pyramidal neurons of mutants. KA administration rapidly raised hippocampal levels of anandamide and induced protective mechanisms in wild-type principal hippocampal neurons. These protective mechanisms could not be triggered in mutant mice. The endogenous cannabinoid system thus provides on-demand protection against acute excitotoxicity in central nervous system neurons.
The relationship between pneumococcal conjugate vaccine-induced antibody responses and protection against community-acquired pneumonia (CAP) and acute otitis media (AOM) is unclear. This study ...assessed the impact of the ten-valent pneumococcal nontypable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) on these end points. The primary objective was to demonstrate vaccine efficacy (VE) in a per-protocol analysis against likely bacterial CAP (B-CAP: radiologically confirmed CAP with alveolar consolidation/pleural effusion on chest X-ray, or non-alveolar infiltrates and C-reactive protein ≥ 40 µg/ml); other protocol-specified outcomes were also assessed.
This phase III double-blind randomized controlled study was conducted between 28 June 2007 and 28 July 2011 in Argentine, Panamanian, and Colombian populations with good access to health care. Approximately 24,000 infants received PHiD-CV or hepatitis control vaccine (hepatitis B for primary vaccination, hepatitis A at booster) at 2, 4, 6, and 15-18 mo of age. Interim analysis of the primary end point was planned when 535 first B-CAP episodes, occurring ≥2 wk after dose 3, were identified in the per-protocol cohort. After a mean follow-up of 23 mo (PHiD-CV, n = 10,295; control, n = 10,201), per-protocol VE was 22.0% (95% CI: 7.7, 34.2; one-sided p = 0.002) against B-CAP (conclusive for primary objective) and 25.7% (95% CI: 8.4%, 39.6%) against World Health Organization-defined consolidated CAP. Intent-to-treat VE was 18.2% (95% CI: 5.5%, 29.1%) against B-CAP and 23.4% (95% CI: 8.8%, 35.7%) against consolidated CAP. End-of-study per-protocol analyses were performed after a mean follow-up of 28-30 mo for CAP and invasive pneumococcal disease (IPD) (PHiD-CV, n = 10,211; control, n = 10,140) and AOM (n = 3,010 and 2,979, respectively). Per-protocol VE was 16.1% (95% CI: -1.1%, 30.4%; one-sided p = 0.032) against clinically confirmed AOM, 67.1% (95% CI: 17.0%, 86.9%) against vaccine serotype clinically confirmed AOM, 100% (95% CI: 74.3%, 100%) against vaccine serotype IPD, and 65.0% (95% CI: 11.1%, 86.2%) against any IPD. Results were consistent between intent-to-treat and per-protocol analyses. Serious adverse events were reported for 21.5% (95% CI: 20.7%, 22.2%) and 22.6% (95% CI: 21.9%, 23.4%) of PHiD-CV and control recipients, respectively. There were 19 deaths (n = 11,798; 0.16%) in the PHiD-CV group and 26 deaths (n = 11,799; 0.22%) in the control group. A significant study limitation was the lower than expected number of captured AOM cases.
Efficacy was demonstrated against a broad range of pneumococcal diseases commonly encountered in young children in clinical practice.
www.ClinicalTrials.gov NCT00466947.
Human Papillomavirus (HPV) prophylactic vaccination has proven effective in preventing new infections, but it does not treat existing HPV infections or associated diseases. Hence, there is still an ...important reservoir of HPV in adults, as vaccination programs are mainly focused on young women. The primary objective of this non-randomized, open-label trial is to evaluate if a 3-dose regimen of Gardasil-9 in HPV16/18-positive women could reduce the infective capacity of their body fluids. We aim to assess if vaccine-induced antibodies could neutralize virions present in the mucosa, thus preventing the release of infective particles and HPV transmission to sexual partners. As our main endpoint, the E1^E4-HaCaT model will be used to assess the infectivity rate of cervical, anal and oral samples, obtained from women before and after vaccination. HPV DNA positivity, virion production, seroconversion, and the presence of antibodies in the exudates, will be evaluated to attribute infectivity reduction to vaccination. Our study will recruit two different cohorts (RIFT-HPV1 and RIFT-HPV2) of non-vaccinated adult women. RIFT-HPV1 will include subjects with an HPV16/18 positive cervical test and no apparent cervical lesions or cervical lesions eligible for conservative treatment. RIFT-HPV2 will include subjects with an HPV16/18 positive anal test and no apparent anal lesions or anal lesions eligible for conservative treatment, as well as women with an HPV16/18 positive cervical test and HPV-associated vulvar lesions. Subjects complying with inclusion criteria for both cohorts will be recruited to the main cohort, RIFT-HPV1. Three doses of Gardasil-9 will be administered intramuscularly at visit 1 (0 months), visit 2 (2 months) and visit 3 (6 months). Even though prophylactic HPV vaccines would not eliminate a pre-existing infection, our results will determine if HPV vaccination could be considered as a new complementary strategy to prevent HPV-associated diseases by reducing viral spread. Trial registration: https://clinicaltrials.gov/ct2/show/NCT05334706.
Acute kidney injury (AKI) and chronic kidney disease (CKD) are associated with decreased renal function and increased mortality risk, while the therapeutic armamentarium is unsatisfactory. The ...availability of adequate animal models may speed up the discovery of biomarkers for disease staging and therapy individualization as well as design and testing of novel therapeutic strategies. Some longstanding animal models have failed to result in therapeutic advances in the clinical setting, such as kidney ischemia–reperfusion injury and diabetic nephropathy models. In this regard, most models for diabetic nephropathy are unsatisfactory in that they do not evolve to renal failure. Satisfactory models for additional nephropathies are needed. These include anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, IgA nephropathy, anti-phospholipase-A2-receptor (PLA2R) membranous nephropathy and Fabry nephropathy. However, recent novel models hold promise for clinical translation. Thus, the AKI to CKD translation has been modeled, in some cases with toxins of interest for human CKD such as aristolochic acid. Genetically modified mice provide models for Alport syndrome evolving to renal failure that have resulted in clinical recommendations, polycystic kidney disease models that have provided clues for the development of tolvaptan, that was recently approved for the human disease in Japan; and animal models also contributed to target C5 with eculizumab in hemolytic uremic syndrome. Some ongoing trials explore novel concepts derived from models, such TWEAK targeting as tissue protection for lupus nephritis. We now review animal models reproducing diverse, genetic and acquired, causes of AKI and CKD evolving to kidney failure and discuss the contribution to clinical translation and prospects for the future.
Evidence suggests that participation in physical activity may support young people's current and future mental health. Although previous reviews have examined the relationship between physical ...activity and a range of mental health outcomes in children and adolescents, due to the large increase in published studies there is a need for an update and quantitative synthesis of effects.
The objectives of this study were to determine the effect of physical activity interventions on mental health outcomes by conducting a systematic review and meta-analysis, and to systematically synthesize the observational evidence (both longitudinal and cross-sectional studies) regarding the associations between physical activity and sedentary behavior and mental health in preschoolers (2-5 years of age), children (6-11 years of age) and adolescents (12-18 years of age).
A systematic search of the PubMed and Web of Science electronic databases was performed from January 2013 to April 2018, by two independent researchers. Meta-analyses were performed to examine the effect of physical activity on mental health outcomes in randomized controlled trials (RCTs) and non-RCTs (i.e. quasi-experimental studies). A narrative synthesis of observational studies was conducted. Studies were included if they included physical activity or sedentary behavior data and at least one psychological ill-being (i.e. depression, anxiety, stress or negative affect) or psychological well-being (i.e. self-esteem, self-concept, self-efficacy, self-image, positive affect, optimism, happiness and satisfaction with life) outcome in preschoolers, children or adolescents.
A total of 114 original articles met all the eligibility criteria and were included in the review (4 RCTs, 14 non-RCTs, 28 prospective longitudinal studies and 68 cross-sectional studies). Of the 18 intervention studies, 12 (3 RCTs and 9 non-RCTs) were included in the meta-analysis. There was a small but significant overall effect of physical activity on mental health in children and adolescents aged 6-18 years (effect size 0.173, 95% confidence interval 0.106-0.239, p < 0.001, percentage of total variability attributed to between-study heterogeneity I
= 11.3%). When the analyses were performed separately for children and adolescents, the results were significant for adolescents but not for children. Longitudinal and cross-sectional studies demonstrated significant associations between physical activity and lower levels of psychological ill-being (i.e. depression, stress, negative affect, and total psychological distress) and greater psychological well-being (i.e. self-image, satisfaction with life and happiness, and psychological well-being). Furthermore, significant associations were found between greater amounts of sedentary behavior and both increased psychological ill-being (i.e. depression) and lower psychological well-being (i.e. satisfaction with life and happiness) in children and adolescents. Evidence on preschoolers was nearly non-existent.
Findings from the meta-analysis suggest that physical activity interventions can improve adolescents' mental health, but additional studies are needed to confirm the effects of physical activity on children's mental health. Findings from observational studies suggest that promoting physical activity and decreasing sedentary behavior might protect mental health in children and adolescents. PROSPERO Registration Number: CRD42017060373.
Context:
MicroRNAs (miRNAs) are valuable circulating biomarkers and therapeutic targets for metabolic diseases.
Objective:
The objective of the study was to define the pattern of circulating miRNAs ...in pregestational and gestational obesity and to explore their associations with maternal metabolic parameters and with markers for pre- and postnatal growth.
Design, Settings, and Main Outcome Measure:
TaqMan low-density arrays were used to profile plasma miRNAs in six women with pregestational obesity (PregestOB), six with gestational obesity (GestOB), and six with normal pregnancies (control) during the second trimester of gestation. The most relevant miRNAs were validated in 70 pregnant women (20 PregestOB, 25 GestOB, and 25 control). Maternal metabolic parameters including glucose, glycated hemoglobin, homeostasis model assessment index of insulin resistance, C-peptide, and lipids were assessed. Placentas were weighed at delivery and newborns also during 6 months of life.
Results:
We identified 13 circulating miRNAs differentially expressed in maternal obesity, including decreased levels of miR-29c, miR-99b, miR-103, miR-221, and miR-340 and increased levels of miR-30a-5p, miR-130a, and miR-150 in GestOB; and decreased levels of miR-122, miR-324–3p, miR-375, and miR-652 and increased levels of miR-625 in both PregestOB and GestOB (P < .05 to P < .0001 vs control). Decreased levels of several of these miRNAs associated with a more adverse maternal metabolic status (more pregnancy weight gain, glucose, glycated hemoglobin, homeostasis model assessment index of insulin resistance, C-peptide, and triacylglycerol and less high density lipoprotein cholesterol), with more placental weight, weight at birth, and weight at 6 months of life (all P < .05 to P < .001).
Conclusions:
This study provides the first identification of altered circulating miRNAs in maternal obesity and suggests a possible role of such miRNAS as markers for pre- and postnatal growth.
In nonurban areas with limited access to thrombectomy-capable centers, optimal prehospital transport strategies in patients with suspected large-vessel occlusion stroke are unknown.
To determine ...whether, in nonurban areas, direct transport to a thrombectomy-capable center is beneficial compared with transport to the closest local stroke center.
Multicenter, population-based, cluster-randomized trial including 1401 patients with suspected acute large-vessel occlusion stroke attended by emergency medical services in areas where the closest local stroke center was not capable of performing thrombectomy in Catalonia, Spain, between March 2017 and June 2020. The date of final follow-up was September 2020.
Transportation to a thrombectomy-capable center (n = 688) or the closest local stroke center (n = 713).
The primary outcome was disability at 90 days based on the modified Rankin Scale (mRS; scores range from 0 no symptoms to 6 death) in the target population of patients with ischemic stroke. There were 11 secondary outcomes, including rate of intravenous tissue plasminogen activator administration and thrombectomy in the target population and 90-day mortality in the safety population of all randomized patients.
Enrollment was halted for futility following a second interim analysis. The 1401 enrolled patients were included in the safety analysis, of whom 1369 (98%) consented to participate and were included in the as-randomized analysis (56% men; median age, 75 IQR, 65-83 years; median National Institutes of Health Stroke Scale score, 17 IQR, 11-21); 949 (69%) comprised the target ischemic stroke population included in the primary analysis. For the primary outcome in the target population, median mRS score was 3 (IQR, 2-5) vs 3 (IQR, 2-5) (adjusted common odds ratio OR, 1.03; 95% CI, 0.82-1.29). Of 11 reported secondary outcomes, 8 showed no significant difference. Compared with patients first transported to local stroke centers, patients directly transported to thrombectomy-capable centers had significantly lower odds of receiving intravenous tissue plasminogen activator (in the target population, 229/482 47.5% vs 282/467 60.4%; OR, 0.59; 95% CI, 0.45-0.76) and significantly higher odds of receiving thrombectomy (in the target population, 235/482 48.8% vs 184/467 39.4%; OR, 1.46; 95% CI, 1.13-1.89). Mortality at 90 days in the safety population was not significantly different between groups (188/688 27.3% vs 194/713 27.2%; adjusted hazard ratio, 0.97; 95% CI, 0.79-1.18).
In nonurban areas in Catalonia, Spain, there was no significant difference in 90-day neurological outcomes between transportation to a local stroke center vs a thrombectomy-capable referral center in patients with suspected large-vessel occlusion stroke. These findings require replication in other settings.
ClinicalTrials.gov Identifier: NCT02795962.
Human placenta exhibits a specific microRNA (miRNA) expression pattern. Some of these miRNAs are dysregulated in pregnancy disorders such as preeclampsia and intrauterine growth restriction and are ...potential biomarkers for these pathologies.
To study the placental miRNA profile in pregnant women with pregestational overweight/obesity (preOB) or gestational obesity (gestOB) and explore the associations between placental miRNAs dysregulated in maternal obesity and prenatal and postnatal growth.
TaqMan Low Density Arrays and real-time polymerase chain reaction were used to profile the placental miRNAs in 70 pregnant women (20 preOB, 25 gestOB, and 25 control). Placentas and newborns were weighed at delivery, and infants were weighed at 1, 4, and 12 months of age.
Eight miRNAs were decreased in placentas from preOB or gestOB (miR-100, miR-1269, miR-1285, miR-181, miR-185, miR-214, miR-296, and miR-487) (all P < 0.05). Among them, miR-100, miR-1285, miR-296, and miR-487 were associated with maternal metabolic parameters (all P < 0.05) and were predictors of lower birth weight (all P < 0.05; R2 > 30%) and increased postnatal weight gain (all P < 0.05; R2 > 20%). In silico analysis showed that these miRNAs were related to cell proliferation and insulin signaling pathways. miR-296 was also present in plasma samples and associated with placental expression and prenatal and postnatal growth parameters (all P < 0.05).
We identified a specific placental miRNA profile in maternal obesity. Placental miRNAs dysregulated in maternal obesity may be involved in mediation of growth-promoting effects of maternal obesity on offspring and could be used as early markers of prenatal and postnatal growth.
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