N-octane diffusivity enhancement via carbon dioxide in silica slit-shaped nanopores – a molecular dynamics simulation

Equilibrium molecular dynamics simulations were conducted to study the competitive adsorption and diffusion of mixtures containing n-octane and carbon dioxide confined in slit-shaped silica pores of width 1.9 nm. Atomic density profiles substantiate strong interactions between CO2 molecules and the protonated pore walls. Non-monotonic change in n-octane self-diffusion coefficients as a function of CO2 loading was observed. CO2 preferential adsorption to the pore surface is likely to attenuate the surface adsorption of n-octane, lower the activation energy for n-octane diffusivity, and consequently enhance n-octane mobility at low CO2 loading. This observation was confirmed by conducting test simulations for pure n-octane confined in narrower pores. At high CO2 loading, n-octane diffusivity is hindered by molecular crowding. Thus, n-octane diffusivity displays a maximum. In contrast, within the concentration range considered here, the self-diffusion coefficient predicted for CO2 exhibits a monotonic increase with loading, which is attributed to a combination of effects including the saturation of the adsorption capacity of the silica surface. Test simulations suggest that the results are strongly dependent on the pore morphology, and in particular on the presence of edges that can preferentially adsorb CO2 molecules and therefore affect the distribution of these molecules equally on the pore surface, which appears to be required to provide the effective enhancement of n-octane diffusivity

Evaluation of changes in sexual response and factors influencing sexuality during pregnancy among Nigerian women in Jos, Nigeria

Background: Pregnancy is characterized by physical, hormonal and psychological changes that could influence women’s sexuality. The study aimed at ascertaining changes in the women’s sexual domains as well as factors affecting their sexual responses.Methods: A total of 177 healthy heterosexual pregnant Nigerian women at term and in stable marital relationships were included in the study. Authors’ designed structured questionnaire featuring socio-demographic and obstetric characteristics as well as assessment of their sexual desire, arousal, orgasm, sexual satisfaction and pain compared to the pre-pregnancy period was used to collect the information. Data was analyzed using SPSS version 16 for windows.Results: Mean age of the women was 30.9 ± 4.7 years. Majority of them reported decline in sexual desire, arousal, frequency of orgasm and sexual satisfaction compared to the pre-pregnancy period. Reduce sexual desire was marked in the first trimester but sexual desire peaked in second trimester. Women aged ≥31 years were four times more likely to experience increase frequency of orgasm (OR 4.0, 95% CI 1.9 – 8.7, P = 0.02) while those with tertiary education (OR 2.2, 95% CI 1.1 – 4.2, P = 0.02) and unplanned pregnancy (OR 2.4, 95% CI 1.8 – 5.0, P = 0.04) were more likely to experience decreased sexual satisfaction compared to the pre-pregnancy period.Conclusions: Pregnancy is associated with decline in all domains of female sexual response cycle among the women. Older maternal age positively impacts on frequency of attainment of orgasm while tertiary educational level and unplanned pregnancy negatively affect their sexual satisfaction during pregnancy

Subordinate Effect of -21M HLA-B Dimorphism on NK Cell Repertoire Diversity and Function in HIV-1 Infected Individuals of African Origin

Natural Killer (NK) cells play an important role in antiviral defense and their potent effector function identifies them as key candidates for immunotherapeutic interventions in chronic viral infections. Their remarkable functional agility is achieved by virtue of a wide array of germline-encoded inhibitory and activating receptors ensuring a self-tolerant and tunable repertoire. NK cell diversity is generated by a combination of factors including genetic determinants and infections/environmental factors, which together shape the NK cell pool and functional potential. Recently a genetic polymorphism at position -21 of HLA-B, which influences the supply of HLA-E binding peptides and availability of HLA-E for recognition by the inhibitory NK cell receptor NKG2A, was shown to have a marked influence on NK cell functionality in healthy human cytomegalovirus (HCMV) seronegative Caucasian individuals. In this study, -21 methionine (M)-expressing alleles supplying HLA-E binding peptides were largely poor ligands for inhibitory killer immunoglobulin-like receptors (KIRs), and a bias to NKG2A-mediated education of functionally-potent NK cells was observed. Here, we investigated the effect of this polymorphism on the phenotype and functional capacity of peripheral blood NK cells in a cohort of 36 African individuals with human immunodeficiency virus type 1 (HIV-1)/HCMV co-infection. A similarly profound influence of dimorphism at position -21 of HLA-B on NK cells was not evident in these subjects. They predominantly expressed African specific HLA-B and -C alleles that contribute a distinct supply of NKG2A and KIR ligands, and these genetic differences were compounded by the marked effect of HIV-1/HCMV co-infection on NK cell differentiation. Together, these factors resulted in a lack of correlation of the HLA-B -21 polymorphism with surface abundance of HLA-E and loss of the NK cell functional advantage in subjects with -21M HLA-B alleles. Instead, our data suggest that during HIV/HCMV co-infection exposure of NK cells to an environment that displays altered HLA-E ligands drives adaptive NKG2C+ NK cell expansions influencing effector responses. Increased efforts to understand how NK cells are functionally calibrated to self-HLA during chronic viral infections will pave the way to developing targeted therapeutic interventions to overcome the current barriers to enhancing immune-based antiviral control

Improving postpartum care delivery and uptake by implementing context-specific interventions in four countries in Africa: a realist evaluation of the Missed Opportunities in Maternal and Infant Health (MOMI) project.

Postpartum care (PPC) has remained relatively neglected in many interventions designed to improve maternal and neonatal health in sub-Saharan Africa. The Missed Opportunities in Maternal and Infant Health project developed and implemented a context-specific package of health system strengthening and demand generation in four African countries, aiming to improve access and quality of PPC. A realist evaluation was conducted to enable nuanced understanding of the influence of different contextual factors on both the implementation and impacts of the interventions. Mixed methods were used to collect data and test hypothesised context-mechanism-outcome configurations: 16 case studies (including interviews, observations, monitoring data on key healthcare processes and outcomes), monitoring data for all study health facilities and communities, document analysis and participatory evaluation workshops. After evaluation in individual countries, a cross-country analysis was conducted that led to the development of four middle-range theories. Community health workers (CHWs) were key assets in shifting demand for PPC by 'bridging' communities and facilities. Because they were chosen from the community they served, they gained trust from the community and an intrinsic sense of responsibility. Furthermore, if a critical mass of women seek postpartum healthcare as a result of the CHWs bridging function, a 'buzz' for change is created, leading eventually to the acceptability and perceived value of attending for PPC that outweighs the costs of attending the health facility. On the supply side, rigid vertical hierarchies and defined roles for health facility workers (HFWs) impede integration of maternal and infant health services. Additionally, HFWs fear being judged negatively which overrides the self-efficacy that could potentially be gained from PPC training. Instead the main driver of HFWs' motivation to provide comprehensive PPC is dependent on accountability systems for delivering PPC created by other programmes. The realist evaluation offers insights into some of the contextual factors that can be pivotal in enabling the community-level and service-level interventions to be effective

Booster vaccination against SARS-CoV-2 induces potent immune responses in people with HIV

BACKGROUND: People with HIV on antiretroviral therapy with good CD4 T cell counts make effective immune responses following vaccination against SARS-CoV-2. There are few data on longer term responses and the impact of a booster dose. METHODS: Adults with HIV were enrolled into a single arm open label study. Two doses of ChAdOx1 nCoV-19 were followed twelve months later by a third heterologous vaccine dose. Participants had undetectable viraemia on ART and CD4 counts >350 cells/µl. Immune responses to the ancestral strain and variants of concern were measured by anti-spike IgG ELISA, MesoScale Discovery (MSD) anti-spike platform, ACE-2 inhibition, Activation Induced Marker (AIM) assay and T cell proliferation. FINDINGS: 54 participants received two doses of ChAdOx1 nCoV-19. 43 received a third dose (42 with BNT162b2; 1 with mRNA-1273) one year after the first dose. After the third dose, total anti-SARS-CoV-2 spike IgG titres (MSD), ACE-2 inhibition and IgG ELISA results were significantly higher compared to Day 182 titres (P < 0.0001 for all three). SARS-CoV-2 specific CD4+ T cell responses measured by AIM against SARS-CoV-2 S1 and S2 peptide pools were significantly increased after a third vaccine compared to 6 months after a first dose, with significant increases in proliferative CD4 + and CD8+ T cell responses to SARS-CoV-2 S1 and S2 after boosting. Responses to Alpha, Beta, Gamma, and Delta variants were boosted, although to a lesser extent for Omicron. CONCLUSIONS: In PWH receiving a third vaccine dose, there were significant increases in B and T cell immunity, including to known VOCs

Expression of type I interferon-associated genes at antiretroviral therapy interruption predicts HIV virological rebound

Although certain individuals with HIV infection can stop antiretroviral therapy (ART) without viral load rebound, the mechanisms under-pinning 'post-treatment control' remain unclear. Using RNA-Seq we explored CD4 T cell gene expression to identify evidence of a mechanism that might underpin virological rebound and lead to discovery of associated biomarkers. Fourteen female participants who received 12 months of ART starting from primary HIV infection were sampled at the time of stopping therapy. Two analysis methods (Differential Gene Expression with Gene Set Enrichment Analysis, and Weighted Gene Co-expression Network Analysis) were employed to interrogate CD4+ T cell gene expression data and study pathways enriched in post-treatment controllers versus early rebounders. Using independent analysis tools, expression of genes associated with type I interferon responses were associated with a delayed time to viral rebound following treatment interruption (TI). Expression of four genes identified by Cox-Lasso (ISG15, XAF1, TRIM25 and USP18) was converted to a Risk Score, which associated with rebound (p < 0.01). These data link transcriptomic signatures associated with innate immunity with control following stopping ART. The results from this small sample need to be confirmed in larger trials, but could help define strategies for new therapies and identify new biomarkers for remission

Treatment of COVID-19 with remdesivir in the absence of humoral immunity: a case report

The response to the coronavirus disease 2019 (COVID-19) pandemic has been hampered by lack of an effective severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antiviral therapy. Here we report the use of remdesivir in a patient with COVID-19 and the prototypic genetic antibody deficiency X-linked agammaglobulinaemia (XLA). Despite evidence of complement activation and a robust T cell response, the patient developed persistent SARS-CoV-2 pneumonitis, without progressing to multi-organ involvement. This unusual clinical course is consistent with a contribution of antibodies to both viral clearance and progression to severe disease. In the absence of these confounders, we take an experimental medicine approach to examine the in vivo utility of remdesivir. Over two independent courses of treatment, we observe a temporally correlated clinical and virological response, leading to clinical resolution and viral clearance, with no evidence of acquired drug resistance. We therefore provide evidence for the antiviral efficacy of remdesivir in vivo, and its potential benefit in selected patients

Treatment of COVID-19 with remdesivir in the absence of humoral immunity: a case report

The response to the coronavirus disease 2019 (COVID-19) pandemic has been hampered by lack of an effective severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antiviral therapy. Here we report the use of remdesivir in a patient with COVID-19 and the prototypic genetic antibody deficiency X-linked agammaglobulinaemia (XLA). Despite evidence of complement activation and a robust T cell response, the patient developed persistent SARS-CoV-2 pneumonitis, without progressing to multi-organ involvement. This unusual clinical course is consistent with a contribution of antibodies to both viral clearance and progression to severe disease. In the absence of these confounders, we take an experimental medicine approach to examine the in vivo utility of remdesivir. Over two independent courses of treatment, we observe a temporally correlated clinical and virological response, leading to clinical resolution and viral clearance, with no evidence of acquired drug resistance. We therefore provide evidence for the antiviral efficacy of remdesivir in vivo, and its potential benefit in selected patients

The RIO trial: rationale, design, and the role of community involvement in a randomised placebo-controlled trial of antiretroviral therapy plus dual long-acting HIV-specific broadly neutralising antibodies (bNAbs) in participants diagnosed with recent HIV infection-study protocol for a two-stage randomised phase II trial

Background: Antiretroviral therapy (ART) has led to dramatic improvements in survival for people living with HIV, but is unable to cure infection, or induce viral control off therapy. Designing intervention trials with novel agents with the potential to confer a period of HIV remission without ART remains a key scientific and community goal. We detail the rationale, design, and outcomes of a randomised, placebo-controlled trial of two HIV-specific long-acting broadly neutralising antibodies (bNAbs): 3BNC117-LS and 10-1074-LS, which target CD4 binding site and V3 loop respectively, on post-treatment viral control. Methods: RIO is a randomised, placebo-controlled, double-blinded prospective phase II study. Eligible individuals will have started ART within 3 months of primary HIV infection and have viral sequences that appear to be sensitive to both bNAbs. It will randomise 72 eligible participants 1:1 to the following arms via a two-stage design. In Stage 1, arm A participants are given dual long-acting (LS-variants) bNAbs infusions, followed by intensively monitored Analytical Treatment Interruption (ATI) (n = 36); in arm B, participants receive placebo infusions followed by ATI. The primary endpoint will be time to viral rebound within 36 weeks after ATI. Upon viral rebound, the participant and researcher are unblinded. Participants in arm A recommence ART and complete the study. Participants in arm B are invited to restart ART and enroll into Stage 2 where they will receive open-label LS bNAbs, followed by a second ATI 24 weeks after. Secondary and exploratory endpoints include adverse events, time to undetectable viraemia after restarting ART, immunological markers, HIV proviral DNA, serum bNAb concentrations in blood, bNAb resistance at viral rebound, and quality of life measures. Discussion: The two-stage design was determined in collaboration with community involvement. This design allows all participants the option to receive bNAbs. It also tests the hypothesis that bNAbs may drive sustained HIV control beyond the duration of detectable bNAb concentrations. Community representatives were involved at all stages. This included the two-stage design, discussion on the criteria to restart ART, frequency of monitoring visits off ART, and reducing the risk of onward transmission to HIV-negative partners. It also included responding to the challenges of COVID-19. Trial registration: The protocol is registered on Clinical.trials.gov and EudraCT and has approval from UK Ethics and MHRA