Anti-angiogenesis in cancer therapeutics: the magic bullet

Background: Angiogenesis is the formation of new vascular networks from preexisting ones through the migration and proliferation of differentiated endothelial cells. Available evidence suggests that while antiangiogenic therapy could inhibit tumour growth, the response to these agents is not sustained. The aim of this paper was to review the evidence for anti-angiogenic therapy in cancer therapeutics and the mechanisms and management of tumour resistance to antiangiogenic agents. We also explored the latest advances and challenges in this field. Main body of the abstract: MEDLINE and EMBASE databases were searched for publications on antiangiogenic therapy in cancer therapeutics from 1990 to 2020. Vascular endothelial growth factor (VEGF) is the master effector of the angiogenic response in cancers. Anti-angiogenic agents targeting the VEGF and HIF-α pathways include monoclonal antibodies to VEGF (e.g. bevacizumab), small-molecule tyrosine kinase inhibitors (TKIs) e.g. sorafenib, decoy receptor or VEGF trap e.g. aflibercept and VEGFR2 inhibitors (e.g. ramucirumab). These classes of drugs are vascular targeting which in many ways are advantageous over tumour cell targeting drugs. Their use leads to a reduction in the tumour blood supply and growth of the tumour blood vessels. Tumour resistance and cardiovascular toxicity are important challenges which limit the efficacy and long-term use of anti-angiogenic agents in cancer therapeutics. Tumour resistance can be overcome by dual anti-angiogenic therapy or combination with conventional chemotherapy and immunotherapy. Emerging nanoparticle-based therapy which can silence the expression of HIF-α gene expression by antisense oligonucleotides or miRNAs has been developed. Effective delivery platforms are required for such therapy. Short conclusion: Clinical surveillance is important for the early detection of tumour resistance and treatment failure using reliable biomarkers. It is hoped that the recent interest in mesenchymal cell-based and exosome-based nanoparticle delivery platforms will improve the cellular delivery of newer anti-angiogenics in cancer therapeutics

Effect of Baseline Renal Function on Tenofovir-Containing Antiretroviral Therapy Outcomes in Zambia

In this large cohort of human immunodeficiency virus-infected patients receiving first-line antiretroviral therapy in Zambia, individuals who started a tenofovir-containing regimen despite baseline renal dysfunction showed comparable mortality and renal function improvement to those not receiving tenofovi

Urban groundwater quality in Africa : benefits and challenges

Most urban centres in Africa rely on groundwater, in Southern Africa it is estimated that at least 36% of the population relies on groundwater, this number is much larger for many other settlements in Africa. Urban water supplies are reliant on local groundwater sources to supply 25% of water use, from both private and public/municipal sources. Groundwater is important even in areas where groundwater abstraction is limited by low productivity groundwater stores such as those found in hard-rock settings (e.g. granites). Urban centres are a focus for a wide range of human activities past and present that can alter groundwater quality with potential impacts on subsequent groundwater uses. Once contaminated, groundwater can be challenging to clean up. Despite these challenges, groundwater is often of better quality compared to surface water alternatives in urban settings. Groundwater is generally well protected from surface contamination: as water percolates through the soil and deeper rock some contaminants (e.g. bacteria) may be removed. In contrast to surface water pollution, groundwater quality changes are often gradual, allowing scope for the problem to be assessed and interventions and adaptations to be planned and undertaken if recognised early. Even when groundwater is contaminated (e.g. by bacteria or organic contaminants) these are often detected at low concentrations. Compared to surface waters treatment, costs are often lower and simpler treatment solutions are possible due to the reduced pollution loads and fluctuations in groundwaters. Access to groundwater is widely dispersed compared to alternative sources (lakes, rivers and piped supplies). This offers a clear potential to expand groundwater use in many towns and cities to enhance water security (e.g. via public water supply, piped systems with standpipes, self-supply such as private wells and in some cases tankered or sachet groundwater)

An Empirical Approach to Defining Loss to Follow-up Among Patients Enrolled in Antiretroviral Treatment Programs

In many programs providing antiretroviral therapy (ART), clinicians report substantial patient attrition; however, there are no consensus criteria for defining patient loss to follow-up (LTFU). Data on a multisite human immunodeficiency virus (HIV) treatment cohort in Lusaka, Zambia, were used to determine an empirical “days-late” definition of LTFU among patients on ART. Cohort members were classified as either “in care” or LTFU as of December 31, 2007, according to a range of days-late intervals. The authors then looked forward in the database to determine which patients actually returned to care at any point over the following year. The interval that best minimized LTFU misclassification was described as “best-performing.” Overall, 33,704 HIV-infected adults on ART were included. Nearly one-third (n = 10,196) were at least 1 day late for an appointment. The best-performing LTFU definition was 56 days after a missed visit, which had a sensitivity of 84.1% (95% confidence interval (CI): 83.2, 85.0), specificity of 97.5% (95% CI: 97.3, 97.7), and misclassification of 5.1% (95% CI: 4.8, 5.3). The 60-day threshold performed similarly well, with only a marginal difference (<0.1%) in misclassification. This analysis suggests that ≥60 days since the last appointment is a reasonable definition of LTFU. Standardization to empirically derived definitions of LTFU will permit more reliable comparisons within and across programs

Adherence to first-line antiretroviral therapy affects non-virologic outcomes among patients on treatment for more than 12 months in Lusaka, Zambia

Background High-level adherence to antiretroviral therapy (ART) is associated with favourable patient outcomes. In resource-constrained settings, however, there are few validated measures. We examined the correlation between clinical outcomes and the medication possession ratio (MPR), a pharmacy-based measure of adherence

Adherence Support Workers: A Way to Address Human Resource Constraints in Antiretroviral Treatment Programs in the Public Health Setting in Zambia

BACKGROUND: In order to address staff shortages and improve adherence counseling for people on antiretroviral therapy (ART), the Zambia Prevention, Care and Treatment Partnership (ZPCT) developed an innovative strategy of training community volunteers to provide adherence support at the health facility and community levels. The objective of this study was to assess the effectiveness of these 'adherence support workers' (ASWs) in adherence counseling, treatment retention and addressing inadequate human resources at health facilities.METHODOLOGY/PRINCIPAL FINDINGS: The study used quantitative and qualitative research techniques at five selected ART sites in four provinces in Zambia. Five hundred patients on ART were interviewed using a structured questionnaire to compare the quality of adherence counseling before and after the ASW scheme was introduced at the selected sites and between ASWs and HCWs after the introduction of ASWs. In addition, 3,903 and 4,972 electronic records of all new patients accessing antiretroviral therapy for the time period of 12 months before and 12 months after the introduction of ASWs respectively, were analyzed to assess loss to follow-up rates. Two focus group discussions with ASWs and health care workers (HCWs) were conducted in each clinic. Key informant interviews in the ART clinics were also conducted. There was a marked shift of workload from HCWs to ASWs without any compromise in the quality of counseling. Quality of adherence counseling by ASWs was comparable to HCWs after their introduction. The findings suggest that the deployment of ASWs helped reduce waiting times for adherence counseling. Loss to follow-up rates of new clients declined from 15% to 0% after the deployment of ASWs.CONCLUSION: Adherence counseling tasks can be shifted to lay cadres like ASWs without compromising the quality of counseling. Follow-up of clients by ASWs within the community is necessary to improve retention of clients on ART

Estimating Loss to Follow-Up in HIV-Infected Patients on Antiretroviral Therapy: The Effect of the Competing Risk of Death in Zambia and Switzerland

BACKGROUND: Loss to follow-up (LTFU) is common in antiretroviral therapy (ART) programmes. Mortality is a competing risk (CR) for LTFU; however, it is often overlooked in cohort analyses. We examined how the CR of death affected LTFU estimates in Zambia and Switzerland. METHODS AND FINDINGS: HIV-infected patients aged ≥18 years who started ART 2004-2008 in observational cohorts in Zambia and Switzerland were included. We compared standard Kaplan-Meier curves with CR cumulative incidence. We calculated hazard ratios for LTFU across CD4 cell count strata using cause-specific Cox models, or Fine and Gray subdistribution models, adjusting for age, gender, body mass index and clinical stage. 89,339 patients from Zambia and 1,860 patients from Switzerland were included. 12,237 patients (13.7%) in Zambia and 129 patients (6.9%) in Switzerland were LTFU and 8,498 (9.5%) and 29 patients (1.6%), respectively, died. In Zambia, the probability of LTFU was overestimated in Kaplan-Meier curves: estimates at 3.5 years were 29.3% for patients starting ART with CD4 cells <100 cells/µl and 15.4% among patients starting with ≥350 cells/µL. The estimates from CR cumulative incidence were 22.9% and 13.6%, respectively. Little difference was found between naïve and CR analyses in Switzerland since only few patients died. The results from Cox and Fine and Gray models were similar: in Zambia the risk of loss to follow-up and death increased with decreasing CD4 counts at the start of ART, whereas in Switzerland there was a trend in the opposite direction, with patients with higher CD4 cell counts more likely to be lost to follow-up. CONCLUSIONS: In ART programmes in low-income settings the competing risk of death can substantially bias standard analyses of LTFU. The CD4 cell count and other prognostic factors may be differentially associated with LTFU in low-income and high-income settings

An evolving agricultural extension model for lasting impact: How willing are Tanzanian farmers to pay for extension services?

Community-based extension services (CES) are vital for improving farmers’ livelihoods, but most of them face a challenge of sustainability after phasing out of the externally funded initiatives that they are part of. This study estimated farmer’s willingness to pay (WTP) for four types of agricultural extension services (AES) in the cereals’ value chains provided as a part of two United States Agency for International Development (USAID)-funded Feed the Future initiatives in Tanzania. Data were collected from 595 smallholder cereal farmers using a primary survey in four districts of the Southern Highlands. We implemented a double-bounded dichotomous choice contingent valuation method. Average WTP figures ranged from 20,000 to 24,000 TZS (8–10 USD) depending on the type of AES. Several socioeconomic and agriculture-related variables influenced smallholders’ WTP for the extension services. This research explored the feasibility of a farmer-led model as a pathway to delink extension services from public and donor funding to achieve sustainable rural development. Farmers place a monetary value on extension services indicating that policymakers and practitioners should make further efforts to enhance a community’s ability to achieve self-reliance through investments in CES

Effectiveness OF Mulching Under Miraba in Controlling Soil Erosion, Fertility Restoration and Crop Yield in the Usambara Mountains, Tanzania

Soil erosion is a major threat to food security in rural areas of Africa. Field experiments were conducted from 2011 to 2014 in Majulai and Migambo villages with contrasting climatic conditions in Usambara Mountains, Tanzania. The aim was to investigate the effectiveness of mulching in reducing soil erosion and restoring soil fertility for productivity of maize (Zea mays) and beans (Phaseolus vulgaris) under miraba, a unique indigenous soil conservation measure in the area. Soil loss was significantly higher (p<0·05) under miraba sole than under miraba with mulching, for example, 35 versus 20 and 13 versus 8Mg ha1 y1 for Majulai and Migambo villages, respectively, in 2012. Soil fertility status was significantly higher (p<0·05) under miraba with Tughutu mulching than under miraba sole, for example, 0·35 versus 0·25% total N, 37 versus 22 mg kg1 P and 0·6 versus 0·2 cmol(+) kg1K for the Majulai village; and 0·46 versus 0·38 total N, 17·2 versus 10·2 mg kg1 P and 0·50 versus 0·2 cmol(+) kg1K for the Migambo village. Maize and bean yields (Mg ha1) were significantly higher (p<0·05) under miraba with Tughutu mulching than under miraba sole, 2·0 versus 1·3 for maize and 0·9 versus 0·8 for beans in Majulai; and 3·8 versus 2·6 for maize and 1·0 versus 0·8 for beans in the Migambo village in 2012. This implies that Tughutu mulching is more effective in improving crop yield than Tithonia, although both could potentially protect the arable land from degradation caused by water erosion under miraba.status: publishe

The Influence of Selected Soil Conservation Practices on Soil Properties and Crop Yieldsin the Usambara Mountains, Tanzania

The Usambara Mountains in Tanzania are severely affected by soil erosion which has led to deterioration of soil properties and reduced crop productivity. Indigenous soil erosion control measures such as miraba which are widely practised in the area have yielded little success. Field plot experiments were laid down in Majulai and Migambo villages from 2011 – 2014 on typical soils of the area (Acrisols). The aim was to single out soil properties developed under the studied soil conservation practices and their impact on crop productivity with reference to maize (Zea mays) and beans (Phaseolus vulgaris). Results showed that total N, OC, available P, Ca2+, Mg2+, K+ and Ph were powerful (P = .05) attributes that discriminated conservation measures. Magnitudes of the discriminating attributes followed the trend: miraba with Tughutu (Vernonia myriantha) mulching >miraba with Tithonia (Tithonia diversifolia) mulching > miraba sole > cropl and with no ‘Soil and Water Conservation’ (SWC) measures (control). Contents ofmicro-nutrients did not differ significantly with SWC measures except for Zn which was significantly (P = .05) lowin the control. Bulk density and available moisture content (AMC) were also strong discriminators of conservation measures. Maize and bean grain yields differed significantly (P = .05)with the trend: miraba with Tughutu > miraba with Tithonia > miraba sole > control in both villages. Crop yields under miraba were a function of AMC and pH (R2= 0.71); AMC, available P, Ca2+ and K+ (R2= 0.89) under miraba with Tithonia mulching; AMC, available P, Ca2+ and K+ (R2= 0.90) under miraba with Tughutu mulching. These findings imply that miraba with Tughutu mulching had greater potential in improving soil properties and crop yields than miraba with Tithonia mulching and miraba sole.status: publishe