31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study

Introduction: The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures. Methods: In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025. Findings: Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2–6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MRI were more frequent in patients than in controls (157 [61%] of 259 vs 14 [27%] of 52; p&lt;0·0001) and independently associated with COVID-19 status (odds ratio [OR] 2·9 [95% CI 1·5–5·8]; padjusted=0·0023) after adjusting for relevant confounders. Compared with controls, patients were more likely to have MRI evidence of lung abnormalities (p=0·0001; parenchymal abnormalities), brain abnormalities (p&lt;0·0001; more white matter hyperintensities and regional brain volume reduction), and kidney abnormalities (p=0·014; lower medullary T1 and loss of corticomedullary differentiation), whereas cardiac and liver MRI abnormalities were similar between patients and controls. Patients with multiorgan abnormalities were older (difference in mean age 7 years [95% CI 4–10]; mean age of 59·8 years [SD 11·7] with multiorgan abnormalities vs mean age of 52·8 years [11·9] without multiorgan abnormalities; p&lt;0·0001), more likely to have three or more comorbidities (OR 2·47 [1·32–4·82]; padjusted=0·0059), and more likely to have a more severe acute infection (acute CRP &gt;5mg/L, OR 3·55 [1·23–11·88]; padjusted=0·025) than those without multiorgan abnormalities. Presence of lung MRI abnormalities was associated with a two-fold higher risk of chest tightness, and multiorgan MRI abnormalities were associated with severe and very severe persistent physical and mental health impairment (PHOSP-COVID symptom clusters) after hospitalisation. Interpretation: After hospitalisation for COVID-19, people are at risk of multiorgan abnormalities in the medium term. Our findings emphasise the need for proactive multidisciplinary care pathways, with the potential for imaging to guide surveillance frequency and therapeutic stratification

Environmental concern, race and socio-economic status in post-apartheid South Africa, 1996-2006

Thesis (MA)--Stellenbosch University, 2013.ENGLISH ABSTRACT: This thesis examines longitudinally the nature of environmental concern in post-apartheid South Africa. During the years of colonialism and apartheid, environmental policy making and implementation was characterised by environmental racism that focused on ecocentric notions of nature conservation and protection, to the exclusion of black, coloured and Asian South Africans. The post-apartheid government has attempted to rectify the exclusion of black people from environmental rights, by enshrining in the Bill of Rights the right to an environment that is not harmful to South Africans' health or well-being. In light of the Bill of Rights unique political and practical implementation in South Africa, and on the basis of a comprehensive review of the empirical and theoretical literature on environmental concern, two hypotheses were formulated for testing in this thesis. The first, which is informed by an environmentalism of the poor or “empty-belly environmentalism” theory, proposes that South Africans have become more environmentally concerned since the end of apartheid. The second hypothesis is informed by the post-materialist thesis, and examines whether controlling for socio-economic status eliminates difference in environmental concern amongst the various race groups. The research design applied in this thesis is a longitudinal analysis of secondary data, in particular World Values Survey data. The results of this analysis led to a rejection of the first hypotheses, and a partial rejection of the second hypothesis. Additionally, the results reveal that since 1996 environmental concern has become less influenced by race and class. The thesis also contributes methodologically to future research on environmental concern, by raising concerns about the operationalisation and conceptualisation of environmental concern in the World Values Survey.AFRIKAANSE OPSOMMING: Hierdie tesis ondersoek die aard van omgewingsbesorgdheid in post-apartheid Suid-Afrika. Gedurende die jare van kolonialisme en apartheid was beleidmaking en -implementering gekenmerk deur omgewingsrassisme wat op ekosentriese opvattings van natuurbewaring en -beskerming gefokus het. Dit het tot die uitsluiting van swart, bruin en Asiatiese Suid-Afrikaners gelei. Die post-apartheid regering het gepoog om hierdie groot ongelykhede reg te stel, deur die reg tot 'n omgewing wat nie skadelik vir hul gesondheid of welsyn is nie, vas te lê in die Handves van Menseregte. In die lig van hierdie omgewingsbeleidspunte se unieke politieke en praktiese implementering in Suid-Afrika, en op grond van 'n omvattende oorsig van die empiriese en teoretiese literatuur oor omgewingsbesordheid, is twee hipoteses in hierdie tesis getoets. Die eerste hipotese, waaraan 'n omgewingsbewustheid van die armes of "leë maag omgewingsbewustheid"-teorie gestalte verleen het, voer aan dat Suid-Afrikaners sedert die einde van apartheid meer omgewingsbesorgd geword het. Die tweede hipotese, wat voortvloei uit die post-materialistiese tesis, ondersoek of die verskil tussen die rasgroepe in terme van omgewingsbesorgheid verdwyn as hulle sosio-ekonomiese status konstant gehou word. Die navorsingsontwerp van hierdie tesis is 'n longitudinale ontleding van sekondêre data. Die resultate van hierdie analise onthul dat omgewingsbesorgdheid sedert 1996 minder volgens ras en klas gestruktureer word; buitendien is die eerste hipotese verwerp en die tweede hipotese gedeeltelik verwerp. Hierdie resultate het kommer oor die operasionalisering en konseptualisering van omgewingsbesorgdheid in die “World Values Survey” gewek

Factors associated with HIV in younger and older adult men in South Africa: findings from a cross-sectional survey.

Objective This study investigated the behavioural, psychosocial and biological factors associated with HIV in a younger group of men (15 to 24 years) compared with an older group of men (25 to 35 years). Design A household-based, cross-sectional study was conducted. Setting Men were randomly selected using a two-stage random sampling method in KwaZulu-Natal, South Africa, between June 2014 and June 2015. Participants Overall, we interviewed 1472 younger men and 1138 older men. Only participants who could speak English or Zulu, were able to provide informed consent and who were expected to be living in the study area for the next 12 months were enrolled into the study. Primary and secondary outcomes HIV status was the primary outcome for the study. Men’s HIV status was derived from blood samples collected in the study which were tested for HIV antibodies. Results HIV prevalence was higher among older men (35.4%, 95% CI: 31.7 to 39.1) than younger men (7.6%, 95% CI: 6.2 to 9.4, p<0.01). Older men, who completed secondary school had a lower likelihood of being HIV positive (adjusted OR (AOR): 0.41, 95% CI: 0.27 to 0.63, p<0.001) and those with greater food insecurity had a higher likelihood of being HIV positive (AOR: 1.57, 95% CI: 1.05 to 2.34, p=0.04). Younger men with a higher number of lifetime sexual partners had a higher likelihood of being HIV positive (AOR: 1.04, 95% CI: 0.99 to 1.09, p=0.09). Conclusion Given that the HIV prevalence is higher in the older men, community based interventions need to target older men for medical circumcision and support HIV positive men to improve their material conditions early. For younger men intervening to reduce HIV risk behaviours at a young age before these behaviours become entrenched should be central to HIV prevention programmes

Genomic reconstruction of the SARS-CoV-2 epidemic in England

AbstractThe evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus leads to new variants that warrant timely epidemiological characterization. Here we use the dense genomic surveillance data generated by the COVID-19 Genomics UK Consortium to reconstruct the dynamics of 71 different lineages in each of 315 English local authorities between September 2020 and June 2021. This analysis reveals a series of subepidemics that peaked in early autumn 2020, followed by a jump in transmissibility of the B.1.1.7/Alpha lineage. The Alpha variant grew when other lineages declined during the second national lockdown and regionally tiered restrictions between November and December 2020. A third more stringent national lockdown suppressed the Alpha variant and eliminated nearly all other lineages in early 2021. Yet a series of variants (most of which contained the spike E484K mutation) defied these trends and persisted at moderately increasing proportions. However, by accounting for sustained introductions, we found that the transmissibility of these variants is unlikely to have exceeded the transmissibility of the Alpha variant. Finally, B.1.617.2/Delta was repeatedly introduced in England and grew rapidly in early summer 2021, constituting approximately 98% of sampled SARS-CoV-2 genomes on 26 June 2021.</jats:p