On being agents of change: a qualitative study of elective experiences of medical students at the faculty of health sciences; university of cape town; south Africa

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

Expression of hypoxia-inducible factor-1α predicts benefit from hypoxia modification in invasive bladder cancer.

BACKGROUND: The addition of carbogen and nicotinamide (CON) to radiotherapy (RT) improves overall survival in invasive bladder cancer. We explored whether expression of the hypoxia marker hypoxia-inducible factor-1α (HIF-1α) alone or in combination with other markers predicted benefit from CON. METHODS: A retrospective study was carried out using material from patients with high-grade invasive bladder carcinoma enrolled in the BCON phase III trial of RT alone or with CON (RT+CON). HIF-1α expression was studied in 137 tumours using tissue microarrays and immunohistochemistry. Data were available from other studies for carbonic anhydrase IX and glucose transporter 1 protein and gene expression and tumour necrosis. RESULTS: Patients with high HIF-1α expression had improved 5-year local relapse-free survival with RT+CON (47%) compared with RT alone (21%; hazard ratio (HR) 0.48, 95% CI 0.26-0.8, P=0.02), no benefit was seen with low HIF-1α expression (HR 0.81, 95% CI 0.43-1.50, P=0.5). Combinations of markers including necrosis also predicted benefit but did not improve on prediction using necrosis alone. CONCLUSIONS: HIF-1α may be used to predict benefit from CON in patients with bladder cancer but does not improve on use of necrosis.

Enhanced stability of microRNA expression facilitates classification of FFPE tumour samples exhibiting near total mRNA degradation.

BACKGROUND: As degradation of formalin-fixed paraffin-embedded (FFPE) samples limits the ability to profile mRNA expression, we explored factors predicting the success of mRNA expression profiling of FFPE material and investigated an approach to overcome the limitation. METHODS: Bladder (n=140, stored 3-8 years) and cervix (n=160, stored 8-23 years) carcinoma FFPE samples were hybridised to Affymetrix Exon 1.0ST arrays. Percentage detection above background (%DABG) measured technical success. Biological signal was assessed by distinguishing cervix squamous cell carcinoma (SCC) and adenocarcinoma (AC) using a gene signature. As miR-205 had been identified as a marker of SCC, precursor mir-205 was measured by Exon array and mature miR-205 by qRT-PCR. Genome-wide microRNA (miRNA) expression (Affymetrix miRNA v2.0 arrays) was compared in eight newer FFPE samples with biological signal and eight older samples without. RESULTS: RNA quality controls (QCs) (e.g., RNA integrity (RIN) number) failed to predict profiling success, but sample age correlated with %DABG in bladder (R=-0.30, P<0.01) and cervix (R=-0.69, P<0.01). Biological signal was lost in older samples and neither a signature nor precursor mir-205 separated samples by histology. miR-205 qRT-PCR discriminated SCC from AC, validated by miRNA profiling (26-fold higher in SCC; P=1.10 × 10(-5)). Genome-wide miRNA (R=0.95) and small nucleolar RNA (R=0.97) expression correlated well in the eight newer vs older FFPE samples and better than mRNA expression (R=0.72). CONCLUSION: Sample age is the best predictor of successful mRNA profiling of FFPE material, and miRNA profiling overcomes the limitation of age and copes well with older samples.

Exon-array profiling unlocks clinically and biologically relevant gene signatures from formalin-fixed paraffin-embedded tumour samples.

BACKGROUND: Degradation and chemical modification of RNA in formalin-fixed paraffin-embedded (FFPE) samples hamper their use in expression profiling studies. This study aimed to show that useful information can be obtained by Exon-array profiling archival FFPE tumour samples. METHODS: Nineteen cervical squamous cell carcinoma (SCC) and 9 adenocarcinoma (AC) FFPE samples (10-16-year-old) were profiled using Affymetrix Exon arrays. The gene signature derived was tested on a fresh-frozen non-small cell lung cancer (NSCLC) series. Exploration of biological networks involved gene set enrichment analysis (GSEA). Differential gene expression was confirmed using Quantigene, a multiplex bead-based alternative to qRT-PCR. RESULTS: In all, 1062 genes were higher in SCC vs AC, and 155 genes higher in AC. The 1217-gene signature correctly separated 58 NSCLC into SCC and AC. A gene network centered on hepatic nuclear factor and GATA6 was identified in AC, suggesting a role in glandular cell differentiation of the cervix. Quantigene analysis of the top 26 differentially expressed genes correctly partitioned cervix samples as SCC or AC. CONCLUSION: FFPE samples can be profiled using Exon arrays to derive gene expression signatures that are sufficiently robust to be applied to independent data sets, identify novel biology and design assays for independent platform validation.

Interventions for squamous cell carcinoma of the conjunctiva in HIV-infected individuals.

BACKGROUND: Squamous cell carcinoma of the conjunctiva is a rare, slow-growing tumour of the eye, normally affecting elderly men around 70 years of age. In Africa, however, the disease is different. The incidence is rising rapidly, affecting young persons (around 35 years off age), and usually affecting women. It is more aggressive, with a mean history of three months at presentation. This pattern is related to the co-existence of the HIV/AIDS pandemic, high HPV exposure, and solar radiation in the region. Various interventions exist, but despite therapy, there is a high recurrence rate (up to 43%) and poor cosmetic results in late disease. This review was conducted to evaluate the interventions for treatment of conjunctival squamous cell carcinoma in HIV-infected individuals. OBJECTIVES: To evaluate the effect of interventions for treating squamous cell carcinoma of the conjunctiva in HIV-infected individuals on local control, recurrence, death, time to recurrence, and adverse events. SEARCH STRATEGY: Using a sensitive search strategy, we attempted to identify all relevant trials, regardless of language or publication status, from the following electronic databases; Medline/PubMed, CENTRAL, AIDSearch, EMBASE, LILACS, African Healthline, Cochrane HIV/AIDS Specialised Register, and the Cochrane Cancer Network Specialised Register. We searched the clinical trial register of the US National Institutes of Health, searched the international conference proceedings of AIDS and AIDS-related cancers, and contacted individual researchers, research organisations, and pharmaceutical companies that manufacture the drugs used as interventions. Searches were done between September 2005 and June 2006. SELECTION CRITERIA: Randomised controlled trials (RCTs) involving HIV-infected individuals with ocular surface squamous neoplasia. DATA COLLECTION AND ANALYSIS: We independently screened the results of the search to select potentially relevant studies and to retrieve the full articles. We independently applied the inclusion criteria to the potentially relevant studies. No studies were identified that fulfilled the selection criteria. MAIN RESULTS: No RCTs of interventions currently used against conjunctival squamous cell carcinoma in HIV-infected individuals were identified. IMPLICATIONS FOR PRACTICE: Current clinical practice in treatment of squamous cell carcinoma of the conjunctiva rests on a weak evidence base of case series and case reports. IMPLICATIONS FOR RESEARCH: Randomised controlled trials for treatment of this disease are needed in settings where it occurs most frequently. Preventive interventions also need to be identified. HIV/AIDS research has not focused on treatment of this tumour.

Micronutrient supplementation in children and adults with HIV infection.

BACKGROUND: The scale and impact of the HIV/AIDS pandemic has made the search for simple, affordable, safe, and effective public health interventions all the more urgent. Micronutrient supplements hold the promise of meeting these criteria, but their widespread use needs to be based on sound scientific evidence of effectiveness and safety. OBJECTIVES: To assess whether micronutrient supplements are effective in reducing morbidity and mortality in adults and children with HIV infection. SEARCH STRATEGY: The Cochrane Library (CENTRAL), EMBASE, MEDLINE, AIDSearch, CINAHL, and conference proceedings were searched, and pharmaceutical manufacturers and researchers in the field were contacted to locate any ongoing or unpublished trials. SELECTION CRITERIA: Randomised controlled trials comparing the effects of micronutrient supplements (vitamins, trace elements, and combinations of these) with placebo or no treatment on mortality and morbidity in HIV-infected individuals. DATA COLLECTION AND ANALYSIS: Two reviewers independently appraised trial quality and extracted data. Study authors were contacted for additional data where necessary. A meta-analysis was not deemed appropriate due to significant heterogeneity between trials. MAIN RESULTS: Fifteen trials were included. Six trials comparing vitamin A/beta-carotene with placebo in adults failed to show any effects on mortality, morbidity, CD4 and CD8 counts, or on viral load. Four trials of other micronutrients in adults did not affect overall mortality, although there was a reduction in mortality in a low CD4 subgroup. In a large Tanzanian trial in pregnant and lactating women, daily multivitamin supplementation was associated with a number of benefits to both mothers and children: a reduction in maternal mortality from AIDS-related causes; a reduced risk of progression to stage four disease; fewer adverse pregnancy outcomes; less diarrhoeal morbidity; and a reduction in early-child mortality among immunologically- and nutritionally-compromised women. Vitamin A alone reduced all-cause mortality and improved growth in a small sub-group of HIV-infected children in one hospital-based trial, and reduced diarrhoea-associated morbidity in a small HIV-infected sub-group of infants in another trial. AUTHORS' CONCLUSIONS: There is no conclusive evidence at present to show that micronutrient supplementation effectively reduces morbidity and mortality among HIV-infected adults. It is reasonable to support the current WHO recommendations to promote and support adequate dietary intake of micronutrients at RDA levels wherever possible. There is evidence of benefit of vitamin A supplementation in children. The long-term clinical benefits, adverse effects, and optimal formulation of micronutrient supplements require further investigation.

Evaluation of a nutrition supplementation programme in the Northern Cape Province of South Africa.

AIM: This study aimed at assessing the effectiveness regarding implementation and impact of a take-home nutrition supplementation programme, the Protein Energy Malnutrition (PEM) Scheme, that targets malnourished pre-school children and pregnant and lactating women in the Northern Cape Province of South Africa. METHODOLOGY: In assessing implementation of the PEM Scheme, a cross-sectional descriptive study was undertaken over a 6-month period in the six regions of the Northern Cape Province. Interviews were conducted with programme managers and health personnel at clinics who were responsible for implementing the PEM Scheme. In assessing the impact of the PEM Scheme on growth, a retrospective review was done of the clinic records (including anthropometric data) of children enrolled in the PEM Scheme over a 1-year period. RESULTS: About 76% of the budget allocated to the PEM Scheme had been utilised over the 1-year period. The budget for the following financial year was based solely on food supplements purchased in the previous year. Coverage of malnourished pre-school children and eligible pregnant and lactating women for enrolment was estimated to be 50% and 60%, respectively. Eighty-five per cent of health facilities in the province participated in the PEM Scheme. Some of the main problems identified included: lack of training, inappropriate targeting of certain groups, incorrect application especially of discharge criteria for pregnant and lactating women, inadequate assessment for nutrition-related disease, inadequate nutrition counselling and no standardised monitoring. Of the 319 children enrolled over a year, the mean age was 16.2 (standard deviation 16.2) months, 41% had been low-birth-weight and 18% had been diagnosed with tuberculosis. Ten per cent of the children with a weight-for-age Z-score of <-2 moved into the normal Z-score range after being on the PEM Scheme for a mean duration of 8 months. There was an overall improvement in the weight-for-age Z-scores of 25% of the sample, with a significant difference between the mean weight-for-age Z-scores at enrolment and follow-up This was mainly related to significant improvement in the mean weight-for-age Z-scores of children <2 years. CONCLUSIONS: Numerous problems with the PEM Scheme have been identified which could have limited its impact. Recommendations are proposed for improving the effectiveness and impact of the PEM Scheme in the province.

T lymphocytes isolated from patients with advanced colorectal cancer are suitable for gene immunotherapy approaches.

Despite improvements in treatment, the 5-year survival for metastatic colorectal cancer remains poor. Novel approaches such as gene immunotherapy are being investigated to improve treatment. Retroviral gene transfer methods have been shown to transduce primary human T lymphocytes effectively resulting in the expression of therapeutic genes. However, a number of defects have been identified in T lymphocytes isolated from patients bearing tumour, which may have critical implications for the development of gene-targeted T cells as an anticancer therapy. To address this issue, primary T lymphocytes were isolated from patients with advanced colorectal cancer and tested for their ability to be transduced and to express subsequently a chimeric immune receptor consisting of a single-chain antibody fragment antigen-binding moiety specific for carcinoembryonic antigen (CEA) fused to the T cell receptor (TCR) CD3zeta chain. In 10 out of 10 patients, T lymphocytes were transduced, expanded in the absence of selection and tested for functional activity against CEA-expressing tumour cells. In each case, functional-specific cytotoxic activity was observed. Negligible activity was found in control cultures. This study highlights the feasibility of patient-derived T lymphocytes as a source of immune cells for autologous gene immunotherapy approaches.

Routine reporting or sentinel surveys for HIV/AIDS surveillance in resource-poor settings: experience in South Africa, 1991-97.

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.