IntroductionIn recent years, an unprecedented emphasis has been given to the control of neglected tropical diseases, including soil-transmitted helminths (STHs). The mainstay of STH control is ...school-based deworming (SBD), but mathematical modelling has shown that in all but very low transmission settings, SBD is unlikely to interrupt transmission, and that new treatment strategies are required. This study seeks to answer the question: is it possible to interrupt the transmission of STH, and, if so, what is the most cost-effective treatment strategy and delivery system to achieve this goal?Methods and analysisTwo cluster randomised trials are being implemented in contrasting settings in Kenya. The interventions are annual mass anthelmintic treatment delivered to preschool- and school-aged children, as part of a national SBD programme, or to entire communities, delivered by community health workers. Allocation to study group is by cluster, using predefined units used in public health provision—termed community units (CUs). CUs are randomised to one of three groups: receiving either (1) annual SBD; (2) annual community-based deworming (CBD); or (3) biannual CBD. The primary outcome measure is the prevalence of hookworm infection, assessed by four cross-sectional surveys. Secondary outcomes are prevalence of Ascaris lumbricoides and Trichuris trichiura, intensity of species infections and treatment coverage. Costs and cost-effectiveness will be evaluated. Among a random subsample of participants, worm burden and proportion of unfertilised eggs will be assessed longitudinally. A nested process evaluation, using semistructured interviews, focus group discussions and a stakeholder analysis, will investigate the community acceptability, feasibility and scale-up of each delivery system.Ethics and disseminationStudy protocols have been reviewed and approved by the ethics committees of the Kenya Medical Research Institute and National Ethics Review Committee, and London School of Hygiene and Tropical Medicine. The study has a dedicated web site.Trial registration numberNCT02397772.
Soil-transmitted helminth (STH) infections are predominately controlled by providing children with preventive chemotherapy with either albendazole or mebendazole. However, neither has a high efficacy ...against Trichuris trichiura. This low efficacy limits the overall effectiveness of the current STH control programmes against T. trichiura. It has been demonstrated that co-administering ivermectin with albendazole or mebendazole significantly increases the efficacy of current treatments, which may increase the overall effectiveness of control programmes.
Using a STH transmission mathematical model, we evaluated the potential impact of co-administering ivermectin with albendazole or mebendazole to treat T. trichiura within a preventive chemotherapy programme targeting children (2–15year olds). We evaluated the impact in terms of reduction in prevalent infections, mean worm burden, and prevalence of heavy infections.
Although the current treatment strategy reduced T. trichiura worm burden and prevalence of heavy infections, due to their poor efficacy the long term impact of preventive chemotherapy for children was smaller compared to the other STH. Co-administering ivermectin increased the projected impact of the preventive chemotherapy programme in terms of all three of the explored metrics, practically in high transmission settings. Furthermore, ivermectin co-administration greatly increased the feasibility of and timeframe for breaking transmission.
Co-administering ivermectin notably increased the projected impact of preventive chemotherapy in high transmission settings and increased the feasibility for breaking transmission. This has important implications for control programmes, some of which may be shifting focus from morbidity control to interruption of transmission, and some of which may be logistically unable to provide preventive chemotherapy twice a year as recommended. However, the benefit of co-administering ivermectin is limited by the fact that 2–5year olds are often ineligible to receive treatment.
•The impact of chemotherapy against Trichuris is smaller compared to what can be seen for the other soil-transmitted helminths.•Co-administering ivermectin increases the projected impact of preventive chemotherapy.•It also has the potential to interrupt transmission in some settings.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The drivers of precision medicine are clear: for patients (and physicians) – more options, durable clinical benefit, reduced exposure to non-effective drugs and potential to leverage current ...scientific and technological advances; for the pharmaceutical industry – the potential to tackle core challenges in discovering and developing better and more efficacious medicines, to reduce rates of attrition in drug development and to reduce development costs; for healthcare systems and payers – improved efficiency through the provision of effective care and avoiding ineffective treatments. Oncology has been at the vanguard, the improvements gained in patient survival notable. However, the increasing number of molecular subgroups requires an equally increasing number (and new generation) of highly selective agents targeting inevitably lower incidence molecular segments. Innovative trial designs (umbrella/basket studies) are emerging as a patient-centric approach to drug development, and the rise in public-private partnerships, cross-industry, government and non-profit sector collaborations is enabling implementation of complex clinical trial designs. This poses significant challenges for healthcare systems and regulatory approval. Further substantial evolution of policy and processes, particularly regulatory requirements for approval for new therapeutics, are required.
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BFBNIB, NMLJ, NUK, PNG, UL, UM, UPUK
Among patients who had mutations in
BRCA1
or
BRCA2
and were at high risk for disease progression, those who were assigned to a year of olaparib adjuvant therapy had 3-year invasive disease–free ...survival of 86%, as compared with 77% among those who were assigned to placebo. Few patients stopped olaparib owing to side effects.
Over the past decade, considerable progress has been made in the control, elimination, and eradication of neglected tropical diseases (NTDs). Despite these advances, most NTD programs have recently ...experienced important setbacks; for example, NTD interventions were some of the most frequently and severely impacted by service disruptions due to the coronavirus disease 2019 (COVID-19) pandemic. Mathematical modeling can help inform selection of interventions to meet the targets set out in the NTD road map 2021-2030, and such studies should prioritize questions that are relevant for decision-makers, especially those designing, implementing, and evaluating national and subnational programs. In September 2022, the World Health Organization hosted a stakeholder meeting to identify such priority modeling questions across a range of NTDs and to consider how modeling could inform local decision making. Here, we summarize the outputs of the meeting, highlight common themes in the questions being asked, and discuss how quantitative modeling can support programmatic decisions that may accelerate progress towards the 2030 targets.
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TPS1112
Background: TNBC comprises ≈15% of invasive breast cancer cases and alterations in BRCA1/ 2 are associated with ≈5% of all BCs. Ola (a poly ADP-ribose polymerase inhibitor ...PARPi) is approved for treating pts with HER2-negative metastatic BC with a germline BRCA mutation (g BRCAm), demonstrating an improvement in progression-free survival (PFS). Alterations in other non- BRCA1/2 homologous recombination repair (HRR)-related genes (non- BRCA HRRm) may also confer sensitivity to Ola therapy in pts with TNBC. Ola, AZD1775 (a WEE1 checkpoint inhibitor) and AZD6738 (an ataxia telangiectasia and Rad3-related protein inhibitor) target DNA damage repair and cell cycle regulation. Preclinical studies in TNBC models show synergistic antitumor effects of Ola+AZD1775 and Ola+AZD6738, vs Ola monotherapy supporting the clinical evaluation of these combinations. Methods: VIOLETTE is a global, multicenter, open-label, phase II study (NCT03330847) randomising 1:1:1 450 pts with advanced TNBC to 3 treatment arms: 1) Ola 200 mg bid daily + AZD1775 150 mg bid D1-3, D8-10 q21, 2) Ola 300 mg bid daily + AZD6738 160 mg qd D1-7 q28, or 3) Ola 300 mg bid daily q28. All pts will be stratified by prior platinum exposure. Each treatment arm of ≈150 pts will be comprised of 3 biomarker strata of ≈50 pts each (A: BRCAm; B: non- BRCA HRRm; C: non-HRRm). Centralized tumor molecular testing will be deployed to detect mutation(s) in 15 HRR genes. Eligible pts will have received 1-2 prior lines of chemotherapy for metastatic disease, including an anthracycline or taxane. Exclusion criteria include prior PARPi therapy. The primary endpoint is PFS (each combination vs Ola alone) assessed by blinded, independent central review (RECIST v1.1). Secondary endpoints are objective response rate, duration of response, change in tumor size, and overall survival for comparisons between combinations and for each combination vs Ola alone; drug exposure; and safety and tolerability. The first prespecified futility analysis in Stratum C has met the recruitment target and will be assessed by unblinded review April 2019. Clinical trial information: NCT03330847.
To help clarify the controversy over the detection of expression of the cholecystokinin 1 receptor (CCK1R; CCKAR) in human pancreas.
Applied qRT-PCR to detect CCK1R expression using the SYBR ...green/Smart Cycler II and the QZyme oligonucleotide/ABI PRISM 7500 systems to detect CCK1R expressed message in highly purified cDNAs from human pancreas and other tissues. Samples of normal pancreas were obtained at operation (pancreaticoduodenectomy; Whipple's procedure) and used to ascertain the expression of CCK1R in human tissue and investigate donor individual variability in expression levels by semi-quantitative RT-PCR and scanning densitometry.
We present molecular evidence obtained with advanced qRT-PCR technology that clearly establishes CCK1R expression in human pancreas. Amplification variation in individual human samples is documented here. By targeting different stretches of the sequence with several primer pairs, it was observed that SYBR green qRT-PCR failed to amplify efficiently over GGA-and GAA-rich nucleotide triplet regions, leading to false negative results. The QZyme system quantified the expression with the following distribution: stomach > small intestine approximately colon > brain approximately kidney > pancreas. CCK1R expression levels varied from undetectable, to high levels of expression, in individual samples collected from surgical specimens.
CCK1R message can be conclusively detected and quantified in human pancreas cDNA by targeting the appropriate nucleotide sequence regions of this gene.
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