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Aim: To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple doses of orforglipron (LY3502970), an oral, non‐peptide glucagon‐like peptide‐1 receptor agonist (GLP‐1RA) in healthy participants. Materials and Methods: This was a double‐blind, placebo‐controlled, Phase 1 study. Overtly healthy adults aged 18 to 65 years with body mass index of 20 to 40 kg/m2 and glycated haemoglobin concentration of 47.5 mmol/mol (<6.5%) were eligible. In Part A, participants received single‐dose orforglipron, with four cohorts receiving escalating doses (0.3‐6 mg). In Part B, participants received 4 weeks of daily repeated oral orforglipron with doses escalating weekly to four different final target doses (2‐24 mg). Results: Ninety‐two participants enrolled and received at least one study drug dose (32 in Part A [mean age 43.4 years] and 60 in Part B [mean age 42.5 years]). The most common adverse events were gastrointestinal tract‐related. Pharmacokinetics were approximately dose proportional, and the mean t1/2 was 24.6 to 35.3 hours after a single dose (0.3‐6 mg). On Day 28, the mean t1/2 was 48.1 to 67.5 hours across the dose range (2‐24 mg). Substantial reductions in body weight of up to 5.4 kg were observed after 4 weeks in orforglipron‐treated participants, compared to a reduction of 2.4 kg with placebo (P < 0.05). Orforglipron decreased fasting glucose levels across Days 1 to 28, and gastric emptying was delayed on Day 28. Conclusions: Orforglipron's long half‐life (25‐68 hours) allows once‐daily oral dosing, without water and food restrictions. Orforglipron had a pharmacodynamic and safety profile similar to that of injectable GLP‐1RAs, which supports continued clinical development. [ABSTRACT FROM AUTHOR]

Aim: To report the results of a Phase 1b trial evaluating the safety, pharmacokinetics and pharmacodynamics of orforglipron (LY3502970), an oral, non‐peptide glucagon‐like peptide‐1 receptor agonist (GLP‐1RA), in patients with type 2 diabetes (T2D). Materials and Methods: This was a double‐blind, placebo‐controlled Phase 1 study evaluating five different dosing regimens. The first group established that weekly dose escalation of the daily doses of orforglipron was generally well tolerated. This enabled a parallel‐arm design for the four groups following. Participants were randomized 3:1 to daily doses of orforglipron or placebo for 12 weeks. Eligible participants with T2D were aged 18 to 70 years and had glycated haemoglobin (HbA1c) levels ≥53.0 mmol/mol (7.0%) and ≤91.3 mmol/mol (10.5%). Results: A total of 51 participants received orforglipron and 17 received placebo. In the placebo and orforglipron groups, respectively, baseline HbA1c was 8.1% and 8.0%, and baseline body weight was 90.3 and 88.4 kg. The most common adverse events were gastrointestinal‐related, and occurred early in treatment, similar to findings with other GLP‐1RAs. At Week 12, mean t1/2 ranged from 29 to 49 hours. Mean HbA1c change ranged from −1.5% to −1.8% across orforglipron doses, versus −0.4% with placebo, and body weight change was −0.24 to −5.8 kg across orforglipron doses, versus 0.5 kg with placebo. Conclusions: Orforglipron treatment resulted in meaningful reductions in HbA1c and body weight, with an adverse event profile consistent with that of other GLP‐1RAs. Orforglipron may provide a safe and effective once‐daily oral treatment alternative to injectable GLP‐1RAs or peptide oral formulations without water and food restrictions. [ABSTRACT FROM AUTHOR]

Aim: To assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of basal insulin Fc (BIF; LY3209590), a fusion protein combining a novel single‐chain insulin variant together with human IgG2 Fc domain, following single and multiple once‐weekly BIF administration. Materials and Methods: The single ascending dose, 15‐day study assessed four BIF doses (5‐35 mg) in healthy participants and people with type 2 diabetes (T2D). In the 6‐week multiple ascending dose study, people with T2D, previously treated with basal insulin, received insulin glargine daily or a one‐time loading dose of BIF followed by 5 weeks of once‐weekly dosing (1‐10 mg). Safety, tolerability and PK and glucose PD were examined. Results: Mean ages of people with T2D (N = 57) and healthy participants (N = 16) in the single‐dose study were 58.4 and 35.8 years, respectively; mean body mass index values were 29.5 and 26.1 kg/m2. BIF had a PK half‐life of approximately 17 days, which led to a sustained, dose‐dependent decrease in fasting blood glucose for 5 days or longer. No severe hypoglycaemia was observed. The 6‐week ascending dose study included 33 people with T2D aged 40‐69 years. BIF showed a low peak‐to‐trough ratio of 1.14 after the last dose at week 6 (steady state). Over 6 weeks, BIF seven‐point glucose profiles remained constant and were similar to insulin glargine. Rates and duration of BIF hypoglycaemic events were similar to insulin glargine. Conclusions: BIF was well tolerated and the PK/PD profile enabled once‐weekly dosing with minimal variation in exposure in a treatment interval of 1 week. The findings suggest BIF is suitable for further development as a weekly basal insulin in people with diabetes. [ABSTRACT FROM AUTHOR]

Charles Benson's 1992 (posthumous) essay presents a vision of a "new vocationalism" that integrates academic and occupational curricula, combines classroom instruction with work-based learning, and connects secondary with postsecondary education. It explains the rationale, summarizes existing evidence, analyzes obstacles, and discusses the prospects for these changes. (25 references) (MLH)

Research's lack of influence in education may have the following causes: (1) education may be considered an art that is not analyzable; (2) funding is very limited; (3) adequate, qualified researchers are not available; (4) limited capital investment restricts the impact of technology; and (5) classroom teachers do not share ownership of research and development. (SK)

Pathogen amplification and dissemination into the environment through manure spreading on agriculture land is facilitated by the epidemic spread of 'Salmonella enterica' serovar Newport in dairy cattle. A study was conducted to uncover the survival characteristics of 'Salmonella enterica' serovar Newport in manure and manure-amended soils where the pathogen may be amplified.

Therapeutics for patients hospitalized with coronavirus disease 2019 (COVID‐19) are urgently needed during the pandemic. Bamlanivimab is a potent neutralizing monoclonal antibody that blocks severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2) attachment and entry into human cells, which could potentially lead to therapeutic benefit. J2W‐MC‐PYAA was a randomized, double‐blind, sponsor unblinded, placebo‐controlled, single ascending dose first‐in‐human trial (NCT04411628) in hospitalized patients with COVID‐19. A total of 24 patients received either placebo or a single dose of bamlanivimab (700 mg, 2,800 mg, or 7,000 mg). The primary objective was assessment of safety and tolerability, including adverse events and serious adverse events, with secondary objectives of pharmacokinetic (PK) and pharmacodynamic analyses. Treatment‐emergent adverse event (TEAE) rates were identical in the placebo and pooled bamlanivimab groups (66.7%). There were no apparent dose‐related increases in the number or severity of TEAEs. There were no serious adverse events or deaths during the study, and no discontinuations due to adverse events. PKs of bamlanivimab is linear and exposure increased proportionally with dose following single i.v. administration. The half‐life was ~ 17 days. These results demonstrate the favorable safety profile of bamlanivimab, and provided the initial critical evaluation of safety, tolerability, and PKs in support of the development of bamlanivimab in several ongoing clinical trials. [ABSTRACT FROM AUTHOR]

There are reported cases of relational aggression among learners at public pre-schools in Kenya, however, very scanty research has been done in this regard. The study examined parent attachment relationships and aggressive tendencies among learners during early years in Kenya. Ex-post facto research design was adopted. The sample size consisted of 348 pre-school learners and 277 parents obtained by using the simple random sampling technique. The Parent-child Attachment and Aggressive Tendencies Questionnaires were used to collect data from parents. Construct validity was ensured by the researchers in psychology and early childhood education. Cronbach's alpha was used to establish the reliability of the questionnaires and the subscales had alpha of between 0.7 to 0.9. The results indicated a strong negative correlation (n=68; r = -.827; p < 0.05) between secure attachment and aggressive tendencies; weak (n=80; r =.248; p=.026), positive correlation between parent-child ambivalent attachment and aggressive tendencies; a fairly strong positive correlation (n=40; r =.684; p < 0.05) between parent-child disorganized attachment and aggressive tendencies and a weak positive correlation [n=48; r =.043; p =.772 between avoidant attachment and aggressive tendencies. The study recommends that teacher counselors should ensure early screening for those with vulnerable attachments. [ABSTRACT FROM AUTHOR]

Defining an appropriate and efficient assessment of drug‐induced corrected QT interval (QTc) prolongation (a surrogate marker of torsades de pointes arrhythmia) remains a concern of drug developers and regulators worldwide. In use for over 15 years, the nonclinical International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) S7B and clinical ICH E14 guidances describe three core assays (S7B: in vitro hERG current & in vivo QTc studies; E14: thorough QT study) that are used to assess the potential of drugs to cause delayed ventricular repolarization. Incorporating these assays during nonclinical or human testing of novel compounds has led to a low prevalence of QTc‐prolonging drugs in clinical trials and no new drugs having been removed from the marketplace due to unexpected QTc prolongation. Despite this success, nonclinical evaluations of delayed repolarization still minimally influence ICH E14‐based strategies for assessing clinical QTc prolongation and defining proarrhythmic risk. In particular, the value of ICH S7B‐based "double‐negative" nonclinical findings (low risk for hERG block and in vivo QTc prolongation at relevant clinical exposures) is underappreciated. These nonclinical data have additional value in assessing the risk of clinical QTc prolongation when clinical evaluations are limited by heart rate changes, low drug exposures, or high‐dose safety considerations. The time has come to meaningfully merge nonclinical and clinical data to enable a more comprehensive, but flexible, clinical risk assessment strategy for QTc monitoring discussed in updated ICH E14 Questions and Answers. Implementing a fully integrated nonclinical/clinical risk assessment for compounds with double‐negative nonclinical findings in the context of a low prevalence of clinical QTc prolongation would relieve the burden of unnecessary clinical QTc studies and streamline drug development. [ABSTRACT FROM AUTHOR]