Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) belong to an important therapeutic class for treatment of type 2 diabetes. Six GLP-1 RAs, each utilizing a unique drug delivery strategy, are now approved by the Food and Drug Administration (FDA) and additional, novel GLP-1 RAs are still under development, making for a crowded marketplace and fierce competition among the manufacturers of these products. As rapid elimination is a major challenge for clinical application of GLP-1 RAs, various half-life extension strategies have been successfully employed including sequential modification, attachment of fatty-acid to peptide, fusion with human serum albumin, fusion with the fragment crystallizable (Fc) region of a monoclonal antibody, sustained drug delivery systems, and PEGylation. In this review, we discuss the scientific rationale of the various half-life extension strategies used for GLP-1 RA development. By analyzing and comparing different approved GLP-1 RAs and those in development, we focus on assessing how half-life extending strategies impact the pharmacokinetics, pharmacodynamics, safety, patient usability and ultimately, the commercial success of GLP-1 RA products. We also anticipate future GLP-1 RA development trends. Since similar drug delivery strategies are also applied for developing other therapeutic peptides, we expect this case study of GLP-1 RAs will provide generalizable concepts for the rational design of therapeutic peptides products with extended duration of action.

Objective: High-dose methotrexate (HDMTX) is a mainstay therapeutic agent for the treatment of diverse hematological malignancies, and it plays a significant role in interindividual variability regarding the pharmacokinetics and toxicity. The genetic association of HDMTX has been widely investigated, but the conflicting results have complicated the clinical utility. Therefore, this systematic review aims to determine the role of gene variants within the HDMTX pathway and to fill the gap between knowledge and clinical practice.Methods: Databases including EMBASE, PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), and the Clinical Trials.gov were searched from inception to November 2020. We included twelve single-nucleotide polymorphisms (SNPs) within the HDMTX pathway, involving RFC1, SLCO1B1, ABCB1, FPGS, GGH, MTHFR, DHFR, TYMS, and ATIC. Meta-analysis was conducted by using Cochrane Collaboration Review Manager software 5.3. The odds ratios (ORs) or hazard ratios (HRs) with 95% confidence interval (95% CI) were analyzed to evaluate the associations between SNPs and clinical outcomes. This study was performed according to the PRISMA guideline.Results: In total, 34 studies with 4102 subjects were identified for the association analysis. Nine SNPs involving MTHFR, RFC1, ABCB1, SLCO1B1, TYMS, FPGS, and ATIC genes were investigated, while none of studies reported the polymorphisms of GGH and DHFR yet. Two SNPs were statistically associated with the increased risk of HDMTX toxicity: MTHFR 677C>T and hepatotoxicity (dominant, OR=1.52, 95% CI=1.03-2.23; recessive, OR=1.68, 95% CI=1.10–2.55; allelic, OR=1.41, 95% CI=1.01–1.97), mucositis (dominant, OR=2.11, 95% CI=1.31–3.41; allelic, OR=1.91, 95% CI=1.28–2.85), and renal toxicity (recessive, OR=3.54, 95% CI=1.81–6.90; allelic, OR=1.89, 95% CI=1.18–3.02); ABCB1 3435C>T and hepatotoxicity (dominant, OR=3.80, 95% CI=1.68-8.61), whereas a tendency toward the decreased risk of HDMTX toxicity was present in three SNPs: TYMS 2R>3R and mucositis (dominant, OR=0.66, 95% CI=0.47–0.94); RFC1 80A>G and hepatotoxicity (recessive, OR=0.35, 95% CI=0.16–0.76); and MTHFR 1298A>C and renal toxicity (allelic, OR=0.41, 95% CI=0.18–0.97). Since the data of prognosis outcomes was substantially lacking, current studies were underpowered to investigate the genetic association.Conclusions: We conclude that genotyping of MTHFR and/or ABCB1 polymorphisms prior to treatment, MTHFR 677C>T particularly, is likely to be potentially useful with the aim of tailoring HDMTX therapy and thus reducing toxicity in patients with hematological malignancies.

There have been changes in the political systems of several African countries which were under colonial rule. Consequently, more than 32 African countries launched "land to the tiller" reforms between 1990s and 2000s alone. Land reform programs gave rise to the new breed of farmers, the smallholder farmers. This new breed of farmers is faced with market challenges yet they are key to Africa's development. This desk study reviews theories of entrepreneurship that could explain how smallholder farmers in Africa engage in markets. Classical theories, neoclassical theories, and neo Austrian theories, and the Schumpeterian approach to entrepreneurship are reviewed. The paper revealed the weaknesses of these theories and concluded that they do not sufficiently explain how smallholder farmers in Africa engage in markets. The theories' limited insight to the African context gave rise to the concept of collective entrepreneurship which is centered on entrepreneurial behavior and skills of farmer organizations or farmer groups. The review has also found out that although collective entrepreneurship is considered as an appropriate tool for rural development, there are potential problems which can undermine its effectiveness. The paper recommended the concept of collective entrepreneurship to be developed into a theory using evidence from Africa.

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The study investigated how collective entrepreneurship by smallholder beef farmers in Chipinge district in Zimbabwe unlocks market opportunities. The sample size consisted of 62beef smallholder farmers, 31members from farmer groups and 31individuals. Thirty-one members were purposively sampled from a census of five beef farmer groups in lower Chipinge while the other half were randomly selected from the same area. All the 62 smallholder farmers were interviewed using a household questionnaire. GET2 Test was used to assess farmers' entrepreneurial behavior. Results showed a higher (p = 0.01)overall entrepreneurial behavior in smallholder farmers in groups than in individual farmers. However, the majority of smallholder farmers (74 percent) operating in groups exhibited medium level of overall entrepreneurial behavior; while most of the farmers operating outside groups (77 percent) demonstrated low level of overall entrepreneurial behavior. Collective action coupled with components of entrepreneurial behavior such as creative tendency and calculated risk helped beef farmers from groups to access formal beef markets in urban areas where transparent grading and pricing systems were guaranteed. By eliminating exploitative middlemen from the supply chain, farmer groups received almost double the prices offered to individual farmers, and paid lower transaction costs as unit costs decrease with increasing volumes. Smallholder farmers who operated outside groups, operated as individuals and could not penetrate formal markets; as a consequence, they ended up selling to local informal markets within their local periphery. It is concluded that collective entrepreneurship helps reduce transaction costs, increase farmers' bargaining power and improve formal market access.