Malaria in pregnancy: experience with intermittent preventive treatment in a University Teaching Hospital in southern Nigeria

No Abstrac

'I was in control of it from the start: A qualitative study of mens experiences of positive adjustment following a heart attack

A qualitative design was used to explore the experience of positive adjustment following a heart attack. Ten men attending a cardiac rehabilitation programme completed in-depth semi-structured interviews. An overarching theme: ‘I was in control of it from the start’ emerged with six subthemes, relating to intrapersonal and interpersonal factors and processes. The subthemes reflected the importance of identifying controllable versus non-controllable factors and employing adaptive coping strategies

HIV Care Cascade Among Adolescents in a "Test and Treat" Community-Based Intervention: HPTN 071 (PopART) for Youth Study.

PURPOSE: The PopART for Youth (P-ART-Y) study was nested within the HPTN 071 (PopART) trial, a three-arm community randomized trial in 21 communities in Zambia and South Africa. The P-ART-Y study evaluated the acceptability and uptake of a combination HIV prevention package among young people. We report on the HIV care cascade for adolescents aged 10-19 years from 14 communities receiving the full HIV prevention package in Zambia and South Africa. METHODS: Adolescents were offered participation in the PopART intervention, which included universal home-based HIV testing, linkage to care, antiretroviral therapy (ART) adherence, and other services. Data were collected from September 2016 to December 2017, covering the third round (R3) of the intervention. RESULTS: We enumerated (listed) 128,241 adolescents (Zambia: 95,295 and South Africa: 32,946). Of the adolescents offered HIV testing, 81.9% accepted in Zambia and 70.3% in South Africa. Knowledge of HIV status was higher among older adolescents and increased from 31.4% before R3 to 88.3% at the end of R3 in Zambia and from 28.3% to 79.5% in South Africa. Overall, there were 1,710 (1.9%) adolescents identified as living with HIV by the end of R3 (515 new diagnoses and 1,195 self-reported). Of the new diagnoses, 335 (65.0%) were girls aged 15-19 years. The median time to initiate ART was 5 months. ART coverage before and after R3 increased from 61.3% to 78.7% in Zambia and from 65.6% to 87.8% in South Africa, with boys having higher uptake than girls in both countries. CONCLUSIONS: The PopART intervention substantially increased coverage toward the first and second UNAIDS 90-90-90 targets in adolescents

Predictors of timely linkage-to-ART within universal test and treat in the HPTN 071 (PopART) trial in Zambia and South Africa: findings from a nested case-control study.

INTRODUCTION: HPTN 071 (PopART) is a three-arm community randomized trial in Zambia and South Africa evaluating the impact of a combination HIV prevention package, including universal test and treat (UTT), on HIV incidence. This nested study examined factors associated with timely linkage-to-care and ART initiation (TLA) (i.e. within six-months of referral) in the context of UTT within the intervention communities of the HPTN 071 (PopART) trial. METHODS: Of the 7572 individuals identified as persons living with HIV (PLWH) (and not on antiretroviral treatment (ART)) during the first year of the PopART intervention provided by Community HIV-care Providers (CHiPs) through door-to-door household visits, individuals who achieved TLA (controls) and those who did not (cases), stratified by gender and community, were randomly selected to be re-contacted for interview. Standardized questionnaires were administered to explore factors potentially associated with TLA, including demographic and behavioural characteristics, and participants' opinions on HIV and related services. Odds ratios comparing cases and controls were estimated using a multi-variable logistic regression. RESULTS: Data from 705 participants (333 cases/372 controls) were analysed. There were negligible differences between cases and controls by demographic characteristics including age, marital or socio-economic position. Prior familiarity with the CHiPs encouraged TLA (aOR of being a case: 0.58, 95% CI: 0.39 to 0.86, p = 0.006). Participants who found clinics overcrowded (aOR: 1.51, 95% CI: 1.08 to 2.12, p = 0.006) or opening hours inconvenient (aOR: 1.63, 95% CI: 1.06 to 2.51, p = 0.02) were less likely to achieve TLA, as were those expressing stronger feelings of shame about having HIV (ptrend  = 0.007). Expressing "not feeling ready" (aOR: 2.75, 95% CI: 1.89 to 4.01, p < 0.001) and preferring to wait until they felt sick (aOR: 2.00, 95% CI: 1.27 to 3.14, p = 0.02) were similarly indicative of being a case. Worrying about being seen in the clinic or about how staff treated patients was not associated with TLA. While the association was not strong, we found that the greater the number of self-reported lifetime sexual partners the more likely participants were to achieve TLA (ptrend  = 0.06). There was some evidence that participants with HIV-positive partners on ART were less likely to be cases (aOR: 0.75, 95% CI: 0.53 to 1.06, p = 0.07). DISCUSSION: The lack of socio-demographic differences between cases and controls is encouraging for a "universal" intervention that seeks to ensure high coverage across whole communities. Making clinics more "patient-friendly" could enhance treatment uptake further. The finding that those with higher risk behaviour are more actively engaging with UTT holds promise for treatment-as-prevention

Modeling and Rescue of RP2 Retinitis Pigmentosa Using iPSC-Derived Retinal Organoids

RP2 mutations cause a severe form of X-linked retinitis pigmentosa (XLRP). The mechanism of RP2-associated retinal degeneration in humans is unclear, and animal models of RP2 XLRP do not recapitulate this severe phenotype. Here, we developed gene-edited isogenic RP2 knockout (RP2 KO) induced pluripotent stem cells (iPSCs) and RP2 patient-derived iPSC to produce 3D retinal organoids as a human retinal disease model. Strikingly, the RP2 KO and RP2 patient-derived organoids showed a peak in rod photoreceptor cell death at day 150 (D150) with subsequent thinning of the organoid outer nuclear layer (ONL) by D180 of culture. Adeno-associated virus-mediated gene augmentation with human RP2 rescued the degeneration phenotype of the RP2 KO organoids, to prevent ONL thinning and restore rhodopsin expression. Notably, these data show that 3D retinal organoids can be used to model photoreceptor degeneration and test potential therapies to prevent photoreceptor cell death

A CI-Independent Form of Replicative Inhibition: Turn Off of Early Replication of Bacteriophage Lambda

Several earlier studies have described an unusual exclusion phenotype exhibited by cells with plasmids carrying a portion of the replication region of phage lambda. Cells exhibiting this inhibition phenotype (IP) prevent the plating of homo-immune and hybrid hetero-immune lambdoid phages. We have attempted to define aspects of IP, and show that it is directed to repλ phages. IP was observed in cells with plasmids containing a λ DNA fragment including oop, encoding a short OOP micro RNA, and part of the lambda origin of replication, oriλ, defined by iteron sequences ITN1-4 and an adjacent high AT-rich sequence. Transcription of the intact oop sequence from its promoter, pO is required for IP, as are iterons ITN3–4, but not the high AT-rich portion of oriλ. The results suggest that IP silencing is directed to theta mode replication initiation from an infecting repλ genome, or an induced repλ prophage. Phage mutations suppressing IP, i.e., Sip, map within, or adjacent to cro or in O, or both. Our results for plasmid based IP suggest the hypothesis that there is a natural mechanism for silencing early theta-mode replication initiation, i.e. the buildup of λ genomes with oop+ oriλ+ sequence

Understanding the Treatment Algorithm of Patients with Metastatic Pancreatic Neuroendocrine Neoplasms: A Single-Institution Retrospective Analysis Comparing Outcomes of Chemotherapy, Molecular Targeted Therapy, and Peptide Receptor Radionuclide Therapy in 255 Patients

Background The number of therapeutic options for patients with pancreatic neuroendocrine neoplasms (PNEN) has increased, but the optimal therapeutic algorithm has not been defined due to lack of randomised trials comparing different modalities. Methods We performed a retrospective study in patients with metastatic PNEN treated with ≥1 line of systemic therapy. The relationship between baseline characteristics, treatment type and time to treatment failure (TTF), time to progression (TTP) and overall survival (OS) was analysed using the Kaplan-Meier method. Univariate and multivariate analyses were performed using the Cox proportional hazards model. Results Two hundred and fifty-five patients with metastatic PNEN had 491 evaluable lines of therapy. Independent predictors of TTF included treatment type, Ki-67, tumour grade and chromogranin A. To reduce selection bias, a subgroup of 114 patients with grade 2 (G2) metastatic pancreatic neuroendocrine tumours (PNET) was analysed separately. These patients had received 234 lines of treatment (105 chemotherapy, 82 molecular targeted therapy, and 47 peptide receptor radionuclide therapy [PRRT]). In the G2 cohort, TTF and TTP were superior for PRRT compared with both chemotherapy and molecular targeted therapy. OS in the G2 cohort was also superior for those that had received PRRT compared with those that had not (median 84 vs 56 months; HR 0.55, 95%CI 0.31-0.98, p=0.04). Conclusions This study suggests that PRRT is associated with superior clinical outcomes relative to other systemic therapies for G2 metastatic PNET. Prospective studies are required to confirm these observations

The grinch who stole wisdom

Dr. Seuss is wise. How the Grinch Stole Christmas (Seuss, 1957) could serve as a parable for our time. It can also be seen as a roadmap for the development of contemplative wisdom. The abiding popularity of How the Grinch Stole Christmas additionally suggests that contemplative wisdom is more readily available to ordinary people, even children, than is normally thought. This matters because from the point of view of contemplatives in any of the world's philosophies or religions, people are confused about wisdom. The content of the nascent field of wisdom studies, they might say, is largely not wisdom at all but rather what it's like to live in a particular kind of prison cell, a well appointed cell perhaps, but not a place that makes possible either personal satisfaction or deep problem solving. I believe that what the contemplative traditions have to say is important; they offer a different orientation to what personal wisdom is, how to develop it, and how to use it in the world than is presently contained in either our popular culture or our sciences. In order to illustrate this I will examine, in some detail, one contemplative path within Buddhism. Buddhism is particularly useful in this respect because its practices are nontheistic and thus avoid many of the cultural landmines associated with the contemplative aspects of Western religions

OX40 and 4-1BB delineate distinct immune profiles in sarcoma.

Systemic relapse after radiotherapy and surgery is the major cause of disease-related mortality in sarcoma patients. Combining radiotherapy and immunotherapy is under investigation as a means to improve response rates. However, the immune contexture of sarcoma is understudied. Here, we use a retrospective cohort of sarcoma patients, treated with neoadjuvant radiotherapy, and TCGA data. We explore therapeutic targets of relevance to sarcoma, using genomics and multispectral immunohistochemistry to provide insights into the tumor immune microenvironment across sarcoma subtypes. Differential gene expression between radioresponsive myxoid liposarcoma (MLPS) and more radioresistant undifferentiated pleomorphic sarcoma (UPS) indicated UPS contained higher transcript levels of a number of immunotherapy targets (CD73/NT5E, CD39/ENTPD1, CD25/IL2RA, and 4-1BB/TNFRSF9). We focused on 4-1BB/TNFRSF9 and other costimulatory molecules. In TCGA data, 4-1BB correlated to an inflamed and exhausted phenotype. OX40/TNFRSF4 and 4-1BB/TNFRSF9 were highly expressed in sarcoma subtypes versus other cancers. Despite OX40 and 4-1BB being described as Treg markers, we identified that they delineate distinct tumor immune profiles. This was true for sarcoma and other cancers. While only a limited number of samples could be analyzed, spatial analysis of OX40 expression identified two diverse phenotypes of OX40+ Tregs, one associated with and one independent of tertiary lymphoid structures (TLSs). Patient stratification is of intense interest for immunotherapies. We provide data supporting the viewpoint that a cohort of sarcoma patients, appropriately selected, are promising candidates for immunotherapies. Spatial profiling of OX40+ Tregs, in relation to TLSs, could be an additional metric to improve future patient stratification

HPTN 071 (PopART): A Cluster-Randomized Trial of the Population Impact of an HIV Combination Prevention Intervention Including Universal Testing and Treatment: Mathematical Model

BACKGROUND: The HPTN 052 trial confirmed that antiretroviral therapy (ART) can nearly eliminate HIV transmission from successfully treated HIV-infected individuals within couples. Here, we present the mathematical modeling used to inform the design and monitoring of a new trial aiming to test whether widespread provision of ART is feasible and can substantially reduce population-level HIV incidence. METHODS AND FINDINGS: The HPTN 071 (PopART) trial is a three-arm cluster-randomized trial of 21 large population clusters in Zambia and South Africa, starting in 2013. A combination prevention package including home-based voluntary testing and counseling, and ART for HIV positive individuals, will be delivered in arms A and B, with ART offered universally in arm A and according to national guidelines in arm B. Arm C will be the control arm. The primary endpoint is the cumulative three-year HIV incidence. We developed a mathematical model of heterosexual HIV transmission, informed by recent data on HIV-1 natural history. We focused on realistically modeling the intervention package. Parameters were calibrated to data previously collected in these communities and national surveillance data. We predict that, if targets are reached, HIV incidence over three years will drop by >60% in arm A and >25% in arm B, relative to arm C. The considerable uncertainty in the predicted reduction in incidence justifies the need for a trial. The main drivers of this uncertainty are possible community-level behavioral changes associated with the intervention, uptake of testing and treatment, as well as ART retention and adherence. CONCLUSIONS: The HPTN 071 (PopART) trial intervention could reduce HIV population-level incidence by >60% over three years. This intervention could serve as a paradigm for national or supra-national implementation. Our analysis highlights the role mathematical modeling can play in trial development and monitoring, and more widely in evaluating the impact of treatment as prevention