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Background. Climate change and environmental degradation have severe public health impacts. Education about planetary health (PH) and sustainable healthcare (SH), or the interdependence of health and healthcare and planetary ecosystems, is developing globally to enable health professionals to protect public health from these threats, and to build sustainable healthcare systems. Objective. To assess the status of PH and SH in health professions education in South African (SA) faculties of health sciences as a foundation for future work. Methods. Educators at all 24 SA faculties of health sciences were surveyed regarding undergraduate and postgraduate faculty courses with PH- and SH-related learning objectives and outcomes, learning activities and assessments. Pivot tables were constructed to analyse their responses. Results. Forty-one responses were received, representing 9 health professions from 15 of 24 faculties of health sciences in SA (62.5%). More than half (53.7%) were unaware of any courses with PH and SH content at their faculties. Nineteen respondents from 11 faculties reported 44 courses and provided data on 18 non-duplicate courses. Learning activities included advising patients about environmental and health co-benefits of their lifestyle choices (33.3%); written assignments (38.9%); oral presentations (55.6%); and community-based research (38.9%). Nine courses (50%) reported PH- and SH-related assessments, most commonly oral presentations (88.9%); reflective essays (77.8%); multiple-choice or short assessment questions (55.6%); and research outputs (55.6%). Conclusion. Education about PH and SH is starting to develop in SA faculties, although with a limited variety of learning activities and assessments. This study provides a useful baseline for curriculum development and assessment of progress. [ABSTRACT FROM AUTHOR]

Background. Climate change and polluting healthcare systems are significant threats to public health. Education about planetary health and environmentally sustainable healthcare is needed to equip health professionals to meet these challenges. Objectives. To assess the knowledge, perceptions and understanding of climate change and environmental sustainability among undergraduate health sciences students at the Faculty of Health Sciences (FHS), University of Cape Town (UCT). Methods. Two student-led focus groups helped to design a cross-sectional survey of all undergraduate health sciences students. The survey findings were analysed quantitatively and thematically. Results. The 264 respondents included 211 medical and 53 health and rehabilitation students. Two-thirds of respondents (64.4%) claimed awareness but little understanding of climate change, which was understood mainly as changes in weather and climate patterns (40%) as a result of human activities (96.6%). Most (72%) were aware of the concept of environmental sustainability, but with little understanding. Students' main sources of information about climate change were the internet (84.1%) and social media (77.3%). Two-thirds believed that climate change will highly impact their patients' health and quality of life. Most (58.3%) thought that health professionals can help to prevent climate change by educating patients and promoting sustainable lifestyles. Nearly half (47.3%) thought it important to teach climate change and environmental sustainability in the curriculum. Conclusion. Climate change and environmental sustainability have been poorly incorporated into current FHS, UCT curricula. Students acknowledged that these concepts are important and should be taught. The FHS should integrate planetary health and environmental sustainability into its curricula, in line with global efforts. [ABSTRACT FROM AUTHOR]

Background. Student electives during the 5th year of the University of Cape Town (UCT) medical curriculum provide a 4-week work experience in the health system. The reflective reports of past students indicate that the electives may significantly shape their developing identities as health professionals and agents of change. Objective. To better understand how 5th-year medical elective students perceive themselves as agents of change to strengthen the elective programme in the Faculty of Health Sciences, UCT. The hypothesis was that the more choice that students are given over their learning, the greater is their sense of agency. Methods. Thirteen 5th-year student volunteers participated in four focus group discussions soon after completing their electives in district, regional or tertiary health facilities in the South African health system. Thematic analysis of the transcripts was performed independently by two of the authors. Results. Key themes were the importance of providing holistic patient-centred care, becoming a competent health professional, working within the health team and advocating for a better health system. The elective experience helped students to be more confident in their abilities and to better understand how to effect change at a clinical and health system level. Conclusion. This study supported the hypothesis that the more choice students have over their learning, the greater is their sense of agency. The electives are appreciated as opportunities to develop clinical skills and competencies and to better understand the role of future doctors within the health team and health system. The value of the UCT elective programme could be enhanced by greater promotion, funding for rural electives, and post-elective peer-topeer feedback sessions. This study will inform planning for an extended 2016 medical elective programme in the Faculty. [ABSTRACT FROM AUTHOR]

Information from routine and sentinel surveillance was used to monitor the HIV/AIDS epidemic in KwaZulu-Natal, South Africa between 1991 and 1997. Comparisons were made between data obtained from (1) sentinel surveillance for antenatal HIV infection, pulmonary tuberculosis (PTB), and AIDS in a single health district and (2) province-wide sentinel surveillance for antenatal HIV infection, legally required notification of cases of PTB, and voluntary notification of AIDS cases. HIV prevalence among antenatal clinic attenders in the sentinel district rose rapidly and at similar rates to provincial figures: 4.2% vs 4.8% in 1992 to 25.9% vs 26.9% in 1997. PTB incidence increased four-fold in the sentinel district over the study period, whereas provincial PTB figures from passive surveillance fluctuated widely and showed no clear increase (Chi-square for trend 425.5, P<0.00001). AIDS incidence in the sentinel district increased dramatically while provincial data from the voluntary reporting system showed a less consistent and much slower rise (Chi-square for trend 9.07, P=0.003). Incidence of AIDS in 1997 was estimated as 437/10(5) in the sentinel district compared to 32/10(5) in the provincial figures. Routine disease notification and voluntary reporting systems are likely to underestimate the impact of the HIV/AIDS epidemic in resource-poor settings. Sentinel surveillance at representative sites should be developed to validate or replace passive surveillance systems. [ABSTRACT FROM AUTHOR]

Purpose: Tumor hypoxia is an adverse prognostic factor in head and neck squamous cell carcinoma (HNSCC). We assessed whether patients with hypoxic HNSCC benefited from the addition of nimorazole to definitive intensity modulated radiation therapy (IMRT)., Methods and Materials: NIMRAD was a phase 3, multicenter, placebo-controlled, double-anonymized trial of patients with HNSCC unsuitable for concurrent platinum chemotherapy or cetuximab with definitive IMRT (NCT01950689). Patients were randomized 1:1 to receive IMRT (65 Gy in 30 fractions over 6 weeks) plus nimorazole (1.2 g/m 2 daily, before IMRT) or placebo. The primary endpoint was freedom from locoregional progression (FFLRP) in patients with hypoxic tumors, defined as greater than or equal to the median tumor hypoxia score of the first 50 patients analyzed (≥0.079), using a validated 26-gene signature. The planned sample size was 340 patients, allowing for signature generation in 85% and an assumed hazard ratio (HR) of 0.50 for nimorazole effectiveness in the hypoxic group and requiring 66 locoregional failures to have 80% power in a 2-tail log-rank test at the 5% significance level., Results: Three hundred thirty-eight patients were randomized by 19 centers in the United Kingdom from May 2014 to May 2019, with a median follow-up of 3.1 years (95% CI, 2.9-3.4). Hypoxia scores were available for 286 (85%). The median patient age was 73 years (range, 44-88; IQR, 70-76). There were 36 (25.9%) locoregional failures in the hypoxic group, in which nimorazole + IMRT did not improve FFLRP (adjusted HR, 0.72; 95% CI, 0.36-1.44; P = .35) or overall survival (adjusted HR, 0.96; 95% CI, 0.53-1.72; P = .88) compared with placebo + IMRT. Similarly, nimorazole + IMRT did not improve FFLRP or overall survival in the whole population. In total (N = 338), 73% of patients allocated nimorazole adhered to the drug for ≥50% of IMRT fractions. Nimorazole + IMRT caused more acute nausea compared with placebo + IMRT (Common Terminology Criteria for Adverse Events version 4.0 G1+2: 56.6% vs 42.4%, G3: 10.1% vs 5.3%, respectively; P < .05)., Conclusions: Addition of the hypoxia modifier nimorazole to IMRT for locally advanced HNSCC in older and less fit patients did not improve locoregional control or survival., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Muscle invasive bladder cancer (MIBC) is a molecularly diverse disease with varied clinical outcomes. Molecular studies typically employ bulk sequencing analysis, giving a transcriptomic snapshot of a section of the tumour. However, tumour tissues are not homogeneous, but are composed of distinct compartments such as the tumour and stroma. To investigate the molecular profiles of bladder cancer, whilst also maintaining the spatial complexity of the tumours, we employed whole transcriptome Digital Spatial Profiling (DSP). With this method we generated a dataset of transcriptomic profiles of tumour epithelium, stroma, and immune infiltrate. With these data we investigate the spatial relationship of molecular subtype signatures and ligand signalling events. We find that Basal/Squamous and Classical subtypes are mostly restricted to tumour regions, while the stroma-rich subtype signatures are abundant within the stroma itself. Additionally, we identify ligand signalling events occurring between tumour, stroma, and immune infiltrate regions, such as immune infiltrate derived GPNMB, which was highly correlated with VEGFA expression within the tumour. These findings give us new insights into the diversity of MIBC at a molecular level and provide a dataset with detailed spatial information that was not available before in bladder cancer research., (© 2024. The Author(s).)

Background: Soft tissue sarcomas (STS) are rare, heterogeneous tumours and biomarkers are needed to inform management. We previously derived a prognostic tumour microenvironment classifier (24-gene hypoxia signature). Here, we developed/validated an assay for clinical application., Methods: Technical performance of targeted assays (Taqman low-density array, nanoString) was compared in 28 prospectively collected formalin-fixed, paraffin-embedded (FFPE) biopsies. The nanoString assay was biologically validated by comparing to HIF-1α/CAIX immunohistochemistry (IHC) in clinical samples. The Manchester (n = 165) and VORTEX Phase III trial (n = 203) cohorts were used for clinical validation. The primary outcome was overall survival (OS)., Results: Both assays demonstrated excellent reproducibility. The nanoString assay detected upregulation of the 24-gene signature under hypoxia in vitro, and 16/24 hypoxia genes were upregulated in tumours with high CAIX expression in vivo. Patients with hypoxia-high tumours had worse OS in the Manchester (HR 3.05, 95% CI 1.54-5.19, P = 0.0005) and VORTEX (HR 2.13, 95% CI 1.19-3.77, P = 0.009) cohorts. In the combined cohort, it was independently prognostic for OS (HR 2.24, 95% CI 1.42-3.53, P = 0.00096) and associated with worse local recurrence-free survival (HR 2.17, 95% CI 1.01-4.68, P = 0.04)., Conclusions: This study comprehensively validates a microenvironment classifier befitting FFPE STS biopsies. Future uses include: (1) selecting high-risk patients for perioperative chemotherapy; and (2) biomarker-driven trials of hypoxia-targeted therapies., (© 2023. The Author(s).)

Background: The coronavirus disease 2019 (COVID-19) pandemic hit South Africa in March 2020, severely disrupting health services and health education. This fundamentally impacted the training of future health professionals and catalysed a significant response from across the health education sector. In 2020, the South African Association of Health Educationalists requested members to submit reflections on different aspects of their COVID-19 related educational responses.Responding to the pandemic: Seven vignettes focused specifically on clinical training in the context of primary care and family medicine. This short report highlights the key insights that emerged from these vignettes, considering what has been learnt in terms of health professions education and what we need to take forward. These insights include building on what was already in place, the student role, technology in the clinical learning context, taking workshops online, vulnerability and presence and the way going forward., Discussion and Conclusion: The contributions emphasised the value of existing relationships between the health services and training institutions, collaboration and transparent communication between stakeholders when navigating a crisis, responsiveness to the changed platform and dynamic environment and aligning teaching with healthcare needs. It is more important than ever to set explicit goals, have clarity of purpose when designing learning opportunities and to provide support to students. Some of these learning points may be appropriate for similar contexts in Africa. How we inculcate what we have learned into the post-pandemic period will bear testimony to the extent to which this crisis has enabled us to re-imagine health professions education.

Purpose: Many muscle-invasive bladder cancers are hypoxic, which limits the efficacy of radiation therapy. Hypoxia modification using carbogen and nicotinamide has been tested in a phase 3 trial, Bladder Carbogen Nicotinamide. We present mature follow-up data with biomarker predictions of outcomes., Methods and Materials: Bladder Carbogen Nicotinamide is a prospective, phase 3, multicenter, randomized, 2-arm, nonblinded clinical trial. Participants were randomized to receive radical radiation therapy (RT; control arm) alone or with the addition of carbogen (98% O2; 2% CO2) and nicotinamide (CON). Patients with muscle-invasive or high-grade non-muscle invasive bladder cancer were included. Tumor tissue was collected at entry and was analyzed for tumor necrosis, hypoxia (24-gene signature), and basal and luminal tumor molecular subtypes. Overall survival (OS) and disease-free survival and relationships with biomarker status outcomes are analyzed using multivariable Cox regression and log-rank analysis., Results: We analyzed 333 patients with a median follow-up of 10.3 years. The 10-year OS rates were 30% (95% confidence interval [CI], 0.23-0.39) in RT + CON patients and 24% (95% CI, 0.18-0.33) in the RT-alone patients (hazard ratio [HR], 0.80; 95% CI, 0.61-1.04; P = .08). The greatest benefit from CON was seen in patients with tumor necrosis (n = 79; 5-year OS, 53% vs. 33% in patients without tumor necrosis; HR, 0.59; 95% CI, 0.36-0.99; P = .04). Cases with a high hypoxia gene score (n = 75) had a 5-year OS rate of 51%, compared to 34% for a low score (HR, 0.64; 95% CI, 0.38-1.08; P = .09); those with the basal molecular subtype (n = 70) had a 5-year OS rate of 58%, compared to 38% for those with the luminal subtype (HR, 0.58; 95% CI, 0.32-1.06; P = .08)., Conclusions: Although the improvement in long-term OS in the whole population is not statistically significant, patients selected by necrosis and high hypoxia gene score benefitted from hypoxia modification., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: The intersection of health and climate change is often absent or under-represented in sub-national government strategies. This analysis of the literature, using a new methodological framework, highlights priority focus areas for a sub-national government response to health and climate change, using the Western Cape (WC) province of South Africa as a case study., Methods: A methodological framework was created to conduct a review of priority focus areas relevant for sub-national governments. The framework encompassed the establishment of a Project Steering Group consisting of relevant, sub-national stakeholders (e.g. provincial officials, public and environmental health specialists and academics); an analysis of local climatic projections as well as an analysis of global, national and sub-national health risk factors and impacts., Results: Globally, the discussion of health and climate change adaptation strategies in sub-national, or provincial government is often limited. For the case study presented, multiple health risk factors were identified. WC climatic projections include a warmer and potentially drier future with an increased frequency and intensity of extreme weather events. WC government priority focus areas requiring further research on health risk factors include: population migration and environmental refugees, land use change, violence and human conflict and vulnerable groups. WC government priority focus areas for further research on health impacts include: mental ill-health, non-communicable diseases, injuries, poisonings (e.g. pesticides), food and nutrition insecurity-related diseases, water- and food-borne diseases and reproductive health. These areas are currently under-addressed, or not addressed at all, in the current provincial climate change strategy., Conclusions: Sub-national government adaptation strategies often display limited discussion on the health and climate change intersect. The methodological framework presented in this case study can be globally utilized by other sub-national governments for decision-making and development of climate change and health adaptation strategies. Additionally, due to the broad range of sectoral issues identified, a primary recommendation from this study is that sub-national governments internationally should consider a "health and climate change in all policies" approach when developing adaptation and mitigation strategies to address climate change., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose To cross-validate T1-weighted oxygen-enhanced (OE) MRI measurements of tumor hypoxia with intrinsic susceptibility MRI measurements and to demonstrate the feasibility of translation of the technique for patients. Materials and Methods Preclinical studies in nine 786-0-R renal cell carcinoma (RCC) xenografts and prospective clinical studies in eight patients with RCC were performed. Longitudinal relaxation rate changes (∆R1) after 100% oxygen inhalation were quantified, reflecting the paramagnetic effect on tissue protons because of the presence of molecular oxygen. Native transverse relaxation rate (R2*) and oxygen-induced R2* change (∆R2*) were measured, reflecting presence of deoxygenated hemoglobin molecules. Median and voxel-wise values of ∆R1 were compared with values of R2* and ∆R2*. Tumor regions with dynamic contrast agent-enhanced MRI perfusion, refractory to signal change at OE MRI (referred to as perfused Oxy-R), were distinguished from perfused oxygen-enhancing (perfused Oxy-E) and nonperfused regions. R2* and ∆R2* values in each tumor subregion were compared by using one-way analysis of variance. Results Tumor-wise and voxel-wise ∆R1 and ∆R2* comparisons did not show correlative relationships. In xenografts, parcellation analysis revealed that perfused Oxy-R regions had faster native R2* (102.4 sec -1 vs 81.7 sec -1 ) and greater negative ∆R2* (-22.9 sec -1 vs -5.4 sec -1 ), compared with perfused Oxy-E and nonperfused subregions (all P < .001), respectively. Similar findings were present in human tumors (P < .001). Further, perfused Oxy-R helped identify tumor hypoxia, measured at pathologic analysis, in both xenografts (P = .002) and human tumors (P = .003). Conclusion Intrinsic susceptibility biomarkers provide cross validation of the OE MRI biomarker perfused Oxy-R. Consistent relationship to pathologic analyses was found in xenografts and human tumors, demonstrating biomarker translation. Published under a CC BY 4.0 license. Online supplemental material is available for this article.

Background: Despite high metastasis rates, adjuvant/neoadjuvant systemic therapy for localised soft tissue sarcoma (STS) is not used routinely. Progress requires tailoring therapy to features of tumour biology, which need exploration in well-documented cohorts. Hypoxia has been linked to metastasis in STS and is targetable. This study evaluated hypoxia prognostic markers in the phase III adjuvant radiotherapy VorteX trial., Methods: Formalin-fixed paraffin-embedded tumour biopsies, fresh tumour/normal tissue and blood were collected before radiotherapy. Immunohistochemistry for HIF-1α, CAIX and GLUT1 was performed on tissue microarrays and assessed by two scorers (one pathologist). Prognostic analysis of disease-free survival (DFS) used Kaplan-Meier and Cox regression., Results: Biobank and outcome data were available for 203 out of 216 randomised patients. High CAIX expression was associated with worse DFS (hazard ratio 2.28, 95% confidence interval: 1.44-3.59, P<0.001). Hypoxia-inducible factor-1α and GLUT1 were not prognostic. Carbonic anhydrase IX remained prognostic in multivariable analysis., Conclusions: The VorteX-Biobank contains tissue with linked outcome data and is an important resource for research. This study confirms hypoxia is linked to poor prognosis in STS and suggests that CAIX may be the best known marker. However, overlap between single marker positivity was poor and future work will develop an STS hypoxia gene signature to account for tumour heterogeneity.

Anaplastic (ATC) and certain follicular thyroid-carcinomas (FTCs) are radioresistant. The Phosphatidylinositide 3-kinase (PI3K) pathway is commonly hyperactivated in thyroid-carcinomas. PI3K can modify the PI3K-related kinases (PIKKs) in response to radiation: How PIKKs interact with PI3K and contribute to radioresistance in thyroid-carcinomas is unknown. Further uncertainties exist in how these interactions function under the radioresistant hypoxic microenvironment. Under normoxia/anoxia, ATC (8505c) and FTC (FTC-133) cells were irradiated, with PI3K-inhibition (via GDC-0941 and PTEN-reconstitution into PTEN-null FTC-133s) and effects on PIKK-activation, DNA-damage, clonogenic-survival and cell cycle, assessed. FTC-xenografts were treated with 5 × 2 Gy, ± 50 mg/kg GDC-0941 (twice-daily; orally) for 14 days and PIKK-activation and tumour-growth assessed. PIKK-expression was additionally assessed in 12 human papillary thyroid-carcinomas, 13 FTCs and 12 ATCs. GDC-0941 inhibited radiation-induced activation of Ataxia-telangiectasia mutated (ATM), ATM-and Rad3-related (ATR) and DNA-dependent protein kinase catalytic subunit (DNA-PKcs). Inhibition of ATM and DNA-PKcs was PI3K-dependent, since activation was reduced in PTEN-reconstituted FTC-133s. Inhibition of PIKK-activation was greater under anoxia: Consequently, whilst DNA-damage was increased and prolonged under both normoxia and anoxia, PI3K-inhibition only reduced clonogenic-survival under anoxia. GDC-0941 abrogated radiation-induced cell cycle arrest, an effect most likely linked to the marked inhibition of ATR-activation. Importantly, GDC-0941 inhibited radiation-induced PIKK-activation in FTC-xenografts leading to a significant increase in time taken for tumours to triple in size: 26.5 ± 5 days (radiation-alone) versus 31.5 ± 5 days (dual-treatment). PIKKs were highly expressed across human thyroid-carcinoma classifications, with ATM scoring consistently lower. Interestingly, some loss of ATM and DNA-PKcs was observed. These data provide new insight into the mechanisms of hypoxia-associated radioresistance in thyroid-carcinoma.

Unlabelled: A systematic review and meta-analysis were performed to determine the effect of therapeutic hypothermia using low-technology methods, in settings with facilities for intensive care, in term or near-term infants with hypoxic-ischaemic encephalopathy on mortality, neurological morbidity at discharge and neurological morbidity at 6-24 months., Conclusion: Meta-analysis of three randomised controlled studies showed that low-technology therapeutic hypothermia in an intensive care setting significantly reduced the mortality and the neurological morbidity in survivors at discharge., (©2014 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Background: Estrogen is thought to aid maintenance of insulin sensitivity potentially through modulation of a counter-regulatory mechanism that interferes with the contribution of adaptive and innate immune systems to visceral fat deposition. We evaluated the impact of estrogen on long-term high fat diet (HFD) intake in B- and T-cell deficient and immunocompetent animals comparatively., Methods: A total of 16 BALB and 16 SCID mice, 8 of each sex and strain, were randomized to receive low fat diet, 4.1% fat or HFD, 35% fat, such that there was a group of both each sex and each strain receiving each diet. Biweekly levels of adiponectin, leptin and insulin levels were assessed and a glucose tolerance test (GTT) was performed after 13 weeks., Results: Unlike their male counterparts, HFD-fed SCID females neither gained weight, nor became insulin resistant. Meanwhile, in the HFD-fed BALB groups both males and females gained weight similarly, but remarkable sexual dimorphism was nonetheless observed. The females had notable higher adiponectin levels as compared to males (10-60 μg/mL vs. 6-10 μg/mL respectively) causing the adiponectin-to-leptin (A/L) ratio to reach 80 one week after HFD initiation. The A/L dropped to 10, still higher than males, by week 13, but dropped to 2 by the end of the study in agreement with inverse insulin trends. None of the HFD-fed female groups developed insulin resistance (IR) by week 13, while all male counterparts had. Similar results were observed in the HFD-fed SCID groups whereby the females did not develop IR and had a higher A/L; however, adiponectin levels were comparable between groups (5-11 μg/mL)., Conclusions: The present study provides lacking evidence indicating that estrogen may be sufficient to prevent weight gain and development of glucose intolerance in high-fat fed B- and T-cell deficient mice., (Copyright © 2014 Elsevier Ltd. All rights reserved.)