Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes.

BACKGROUND: Tirzepatide is a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 (GLP-1) receptor agonist that is under development for the treatment of type 2 diabetes. The efficacy and safety of once-weekly tirzepatide as compared with semaglutide, a selective GLP-1 receptor agonist, are unknown. METHODS: In an open-label, 40-week, phase 3 trial, we randomly assigned 1879 patients, in a 1:1:1:1 ratio, to receive tirzepatide at a dose of 5 mg, 10 mg, or 15 mg or semaglutide at a dose of 1 mg. At baseline, the mean glycated hemoglobin level was 8.28%, the mean age 56.6 years, and the mean weight 93.7 kg. The primary end point was the change in the glycated hemoglobin level from baseline to 40 weeks. RESULTS: The estimated mean change from baseline in the glycated hemoglobin level was -2.01 percentage points, -2.24 percentage points, and -2.30 percentage points with 5 mg, 10 mg, and 15 mg of tirzepatide, respectively, and -1.86 percentage points with semaglutide; the estimated differences between the 5-mg, 10-mg, and 15-mg tirzepatide groups and the semaglutide group were -0.15 percentage points (95% confidence interval [CI], -0.28 to -0.03; P = 0.02), -0.39 percentage points (95% CI, -0.51 to -0.26; P<0.001), and -0.45 percentage points (95% CI, -0.57 to -0.32; P<0.001), respectively. Tirzepatide at all doses was noninferior and superior to semaglutide. Reductions in body weight were greater with tirzepatide than with semaglutide (least-squares mean estimated treatment difference, -1.9 kg, -3.6 kg, and -5.5 kg, respectively; P<0.001 for all comparisons). The most common adverse events were gastrointestinal and were primarily mild to moderate in severity in the tirzepatide and semaglutide groups (nausea, 17 to 22% and 18%; diarrhea, 13 to 16% and 12%; and vomiting, 6 to 10% and 8%, respectively). Of the patients who received tirzepatide, hypoglycemia (blood glucose level, <54 mg per deciliter) was reported in 0.6% (5-mg group), 0.2% (10-mg group), and 1.7% (15-mg group); hypoglycemia was reported in 0.4% of those who received semaglutide. Serious adverse events were reported in 5 to 7% of the patients who received tirzepatide and in 3% of those who received semaglutide. CONCLUSIONS: In patients with type 2 diabetes, tirzepatide was noninferior and superior to semaglutide with respect to the mean change in the glycated hemoglobin level from baseline to 40 weeks. (Funded by Eli Lilly; SURPASS-2 ClinicalTrials.gov number, NCT03987919.).

Reduction of prevalence of patients meeting the criteria for metabolic syndrome with tirzepatide: a post hoc analysis from the SURPASS Clinical Trial Program.

BACKGROUND: Metabolic syndrome is characterized as the co-occurrence of interrelated cardiovascular risk factors, including insulin resistance, hyperinsulinemia, abdominal obesity, dyslipidemia and hypertension. Once weekly tirzepatide is approved in the US and EU for the treatment of type 2 diabetes (T2D) and obesity. In the SURPASS clinical trial program for T2D, tirzepatide demonstrated greater improvements in glycemic control, body weight reduction and other cardiometabolic risk factors versus placebo, subcutaneous semaglutide 1 mg, insulin degludec, and insulin glargine. This post hoc analysis assessed the effect of tirzepatide use on the prevalence of patients meeting the criteria for metabolic syndrome across SURPASS 1-5. METHODS: Metabolic syndrome was defined as having ≥ 3 of 5 criteria according to the US National Cholesterol Education Program: Adult Treatment Panel III. Analyses were based on on-treatment data at the primary endpoint from patients adherent to treatment (taking ≥ 75% study drug). A logistic regression model with metabolic syndrome status as the response variable, metabolic syndrome status at the baseline visit as an adjustment, and randomized treatment as fixed explanatory effect was used. The effect of tirzepatide use on the prevalence of patients meeting the criteria for metabolic syndrome by categorical weight loss, background medication and gender were assessed. RESULTS: In SURPASS, the prevalence of patients meeting the criteria for metabolic syndrome at baseline was 67-88% across treatment groups with reductions at the primary endpoint to 38-64% with tirzepatide versus 64-82% with comparators. Reductions in the prevalence of patients meeting the criteria for metabolic syndrome was significantly greater with all tirzepatide doses versus placebo, semaglutide 1 mg, insulin glargine, and insulin degludec (p < 0.001). Individual components of metabolic syndrome were also reduced to a greater extent with tirzepatide vs comparators. Greater reductions in body weight were associated with greater reductions in the prevalence of patients meeting the criteria for metabolic syndrome and its individual components. Background SGLT2i or sulfonylurea use or gender did not impact the change in prevalence of patients meeting the criteria for metabolic syndrome. CONCLUSIONS: In this post hoc analysis, tirzepatide at all doses studied was associated with a greater reduction in the prevalence of patients meeting the criteria for metabolic syndrome compared to placebo, semaglutide 1 mg, insulin degludec, and insulin glargine. Although more evidence is needed, these data would support greater potential improvement in cardiovascular risk factor profile with tirzepatide treatment in people across the continuum of T2D.

Systolic blood pressure reduction with tirzepatide in patients with type 2 diabetes: insights from SURPASS clinical program.

BACKGROUND: Tirzepatide, a once-weekly glucose-dependent insulinotropic polypeptide/ glucagon-like peptide-1 receptor agonist, is approved in the United States, Europe and Japan for the treatment of type 2 diabetes. Across the SURPASS-1 to -5 clinical studies, tirzepatide 5, 10 and 15 mg demonstrated significant improvements in glycated haemoglobin A1c (HbA1c) (- 1.9 to - 2.6%), body weight (- 6.6 to - 13.9%) and systolic blood pressure (SBP) (- 2.8 to - 12.6 mmHg) at the end of study treatment. METHODS: Post-hoc mediation analyses were conducted to evaluate weight-loss dependent and weight-loss independent effects of tirzepatide on SBP reductions across the 5 SURPASS studies. The safety population (all randomized patients who took at least 1 dose of study drug) of each study was analyzed. Additional analyses were conducted at individual study level or pooled across 5 SURPASS trials. RESULTS: The difference in mean SBP change from baseline at 40 weeks (total effect) between the tirzepatide and comparator groups was - 1.3 to - 5.1 mmHg (tirzepatide 5 mg), - 1.7 to - 6.5 mmHg (tirzepatide 10 mg) and - 3.1 to - 11.5 mmHg (tirzepatide 15 mg). These SBP reductions were primarily mediated through weight loss, with different degrees of contributions from weight-loss independent effects across the different trials. In the SURPASS-4 study, which enrolled patients with established cardiovascular disease, weight-loss independent effects explained 33% to 57% of difference in SBP change between tirzepatide and insulin glargine groups. In a pooled analysis of the SURPASS-1 to -5 studies, there was a significant (p < 0.001) but weak correlation (r = 0.18 to 0.22) between change in body weight and SBP. Reductions in SBP with tirzepatide were not dependent on concomitant antihypertensive medications at baseline as similar reductions were observed whether participants were receiving them or not (interaction p = 0.77). The largest SBP reductions were observed in the highest baseline category (> 140 mmHg), while those in the first quartile of baseline SBP category (< 122 mmHg) observed no further decrease in SBP. CONCLUSIONS: Tirzepatide-induced SBP reduction was primarily mediated through weight loss, with different degrees of contributions from weight-loss independent effects across the different trials. SBP reduction was not dependent on antihypertensive medication use but dependent on baseline SBP value, alleviating theoretical concerns of hypotension.

Upcycling the anthracyclines: New mechanisms of action, toxicology, and pharmacology.

The anthracyclines are a family of natural products isolated from soil bacteria with over 2000 chemical representatives. Since their discovery seventy years ago by Waksman and co-workers, anthracyclines have become one of the best-characterized anticancer chemotherapies in clinical use. The anthracyclines exhibit broad-spectrum antineoplastic activity for the treatment of a variety of solid and liquid tumors, however, their clinical use is limited by their dose-limiting cardiotoxicity. In this review article, we discuss the toxicity of the anthracyclines on several organ systems, including new insights into doxorubicin-induced cardiotoxicity. In addition, we discuss new medicinal chemistry developments in the biosynthesis of new anthracycline analogs and the synthesis of new anthracycline analogs with diminished cardiotoxicity. Lastly, we review new studies that describe the repurposing of the anthracyclines, or "upcycling" of the anthracyclines, as anti-infective agents, or drugs for niche indications. Altogether, the anthracyclines remain a mainstay in the clinic with a potential new "lease on life" due to deeper insight into the mechanism underlying their cardiotoxicity and new developments into potential new clinical indications for their use. Keywords: Anthracycline, chemotherapy, toxicology, medicinal chemistry, biosynthesis.

Once-weekly tirzepatide versus once-daily insulin degludec as add-on to metformin with or without SGLT2 inhibitors in patients with type 2 diabetes (SURPASS-3): a randomised, open-label, parallel-group, phase 3 trial.

BACKGROUND: Tirzepatide is a novel dual glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonist under development for the treatment of type 2 diabetes. We aimed to assess the efficacy and safety of tirzepatide versus titrated insulin degludec in people with type 2 diabetes inadequately controlled by metformin with or without SGLT2 inhibitors. METHODS: In this open-label, parallel-group, multicentre (122 sites), multinational (13 countries), phase 3 study, eligible participants (aged ≥18 years) had a baseline glycated haemoglobin (HbA1c) of 7·0-10·5%, body-mass index of at least 25 kg/m2, stable weight, and were insulin-naive and treated with metformin alone or in combination with an SGLT2 inhibitor for at least 3 months before screening. Participants were randomly assigned (1:1:1:1), using an interactive web-response system, to once-weekly subcutaneous injection of tirzepatide (5, 10, or 15 mg) or once-daily subcutaneous injection of titrated insulin degludec, and were stratified by country, HbA1c, and concomitant use of oral antihyperglycaemic medications. Tirzepatide was initially given at 2·5 mg and the dose was escalated by 2·5 mg every 4 weeks until the assigned dose was reached. Insulin degludec was initially given at 10 U per day and was titrated once weekly to a fasting self-monitored blood glucose of less than 5·0 mmol/L (<90 mg/dL), following a treat-to-target algorithm, for 52 weeks. The primary efficacy endpoint was non-inferiority of tirzepatide 10 mg or 15 mg, or both, versus insulin degludec in mean change from baseline in HbA1c at week 52. Key secondary efficacy endpoints were non-inferiority of tirzepatide 5 mg versus insulin degludec in mean change from baseline in HbA1c at week 52, superiority of all doses of tirzepatide versus insulin degludec in mean change from baseline in HbA1c and bodyweight, and the proportion of participants achieving HbA1c of less than 7·0% (<53 mmol/mol) at week 52. We used a boundary of 0·3% to establish non-inferiority in HbA1c difference between treatments. Efficacy and safety analyses were assessed in the modified intention-to-treat population (all participants who received at least one dose of study drug). This trial is registered with ClinicalTrials.gov, number NCT03882970, and is complete. FINDINGS: Between April 1 and Nov 15, 2019, we assessed 1947 participants for eligibility, 1444 of whom were randomly assigned to treatment. The modified intention-to-treat population was 1437 participants from the tirzepatide 5 mg (n=358), tirzepatide 10 mg (n=360), tirzepatide 15 mg (n=359), and insulin degludec (n=360) groups. From a mean baseline HbA1c of 8·17% (SD 0·91), the reductions in HbA1c at week 52 were 1·93% (SE 0·05) for tirzepatide 5 mg, 2·20% (0·05) for tirzepatide 10 mg, and 2·37% (0·05) for tirzepatide 15 mg, and 1·34% (0·05) for insulin degludec. The non-inferiority margin of 0·3% was met. The estimated treatment difference (ETD) versus insulin degludec ranged from -0·59% to -1·04% for tirzepatide (p<0·0001 for all tirzepatide doses). The proportion of participants achieving a HbA1c of less than 7·0% (<53 mmol/mol) at week 52 was greater (p<0·0001) in all three tirzepatide groups (82%-93%) versus insulin degludec (61%). At week 52, from a baseline of 94·3 kg (SD 20·1), all three tirzepatide doses decreased bodyweight (-7·5 kg to -12·9 kg), whereas insulin degludec increased bodyweight by 2·3 kg. The ETD versus insulin degludec ranged from -9·8 kg to -15·2 kg for tirzepatide (p<0·0001 for all tirzepatide doses). The most common adverse events in tirzepatide-treated participants were mild to moderate gastrointestinal events that decreased over time. A higher incidence of nausea (12-24%), diarrhoea (15-17%), decreased appetite (6-12%), and vomiting (6-10%) was reported in participants treated with tirzepatide than in those treated with insulin degludec (2%, 4%, 1%, and 1%, respectively). Hypoglycaemia (<54 mg/dL or severe) was reported in five (1%), four (1%), and eight (2%) participants on tirzepatide 5, 10, and 15 mg, respectively, versus 26 (7%) on insulin degludec. Treatment discontinuation due to an adverse event was more common in the tirzepatide groups than in the insulin degludec group. Five participants died during the study; none of the deaths were considered by the investigators to be related to the study treatment. INTERPRETATION: In patients with type 2 diabetes, tirzepatide (5, 10, and 15 mg) was superior to titrated insulin degludec, with greater reductions in HbA1c and bodyweight at week 52 and a lower risk of hypoglycaemia. Tirzepatide showed a similar safety profile to that of GLP-1 receptor agonists. FUNDING: Eli Lilly and Company.

Effects of wearing a cloth face mask on performance, physiological and perceptual responses during a graded treadmill running exercise test.

OBJECTIVES: To (1) determine if wearing a cloth face mask significantly affected exercise performance and associated physiological responses, and (2) describe perceptual measures of effort and participants' experiences while wearing a face mask during a maximal treadmill test. METHODS: Randomised controlled trial of healthy adults aged 18-29 years. Participants completed two (with and without a cloth face mask) maximal cardiopulmonary exercise tests (CPETs) on a treadmill following the Bruce protocol. Blood pressure, heart rate, oxygen saturation, exertion and shortness of breath were measured. Descriptive data and physical activity history were collected pretrial; perceptions of wearing face masks and experiential data were gathered immediately following the masked trial. RESULTS: The final sample included 31 adults (age=23.2±3.1 years; 14 women/17 men). Data indicated that wearing a cloth face mask led to a significant reduction in exercise time (-01:39±01:19 min/sec, p<0.001), maximal oxygen consumption (VO2max) (-818±552 mL/min, p<0.001), minute ventilation (-45.2±20.3 L/min), maximal heart rate (-8.4±17.0 beats per minute, p<0.01) and increased dyspnoea (1.7±2.9, p<0.001). Our data also suggest that differences in SpO2 and rating of perceived exertion existed between the different stages of the CPET as participant's exercise intensity increased. No significant differences were found between conditions after the 7-minute recovery period. CONCLUSION: Cloth face masks led to a 14% reduction in exercise time and 29% decrease in VO2max, attributed to perceived discomfort associated with mask-wearing. Compared with no mask, participants reported feeling increasingly short of breath and claustrophobic at higher exercise intensities while wearing a cloth face mask. Coaches, trainers and athletes should consider modifying the frequency, intensity, time and type of exercise when wearing a cloth face mask.

Pathway Engineering of Anthracyclines: Blazing Trails in Natural Product Glycodiversification.

The anthracyclines are structurally diverse anticancer natural products that bind to DNA and poison the topoisomerase II-DNA complex in cancer cells. Rational modifications in the deoxysugar functionality are especially advantageous for synthesizing drugs with improved potency. Combinatorial biosynthesis of glycosyltransferases and deoxysugar synthesis enzymes is indispensable for the generation of glycodiversified anthracyclines. This Synopsis considers recent advances in glycosyltransferase structural biology and site-directed mutagenesis, pathway engineering, and deoxysugar combinatorial biosynthesis with a focus on the generation of "new-to-nature" anthracycline analogues.

The development of a manual-based digital memory notebook intervention with case study illustrations.

There is currently a need to identify feasible and effective interventions to help older individuals suffering from memory loss maintain functional independence and quality of life. To improve upon paper and pencil memory notebook interventions, the Digital Memory Notebook (DMN) application (app) was developed iteratively with persons with cognitive impairment. In this paper we detail a manual-based intervention for training use of the DMN app. A series of three case studies are described to illustrate the clinical process of the DMN intervention, the key components of the intervention and participants' perceptions of the intervention. The Reliable Change Index was applied to pre/post intervention scores that examined everyday memory lapses, daily functioning, coping self-efficacy, satisfaction with life, and quality of life with standardized measures. Following the intervention, two of three participants self-reported a clinically significant reduction in everyday memory lapses and improved everyday functioning. One participant reported clinically significant change in quality of life. All participants demonstrated clinically significant changes in their ability to cope with problems and build self-efficacy. Furthermore, all participants scored in the normative range post-intervention on the measure of satisfaction with life. Clinical observations and participant feedback were used for refinement of the DMN intervention (ClinicalTrials.gov NCT03453554).

Risk Factors for Transfusions Following Total Joint Arthroplasty in Patients With Rheumatoid Arthritis.

BACKGROUND/OBJECTIVE: Despite effective therapies, rheumatoid arthritis (RA) can result in joint destruction requiring total joint arthroplasty to maintain patient function. An estimated 16% to 70% of those undergoing total joint arthroplasty of the hip or knee will receive a blood transfusion. Few studies have described risk factors for blood transfusion following total joint arthroplasty in patients with RA. The aim of this study was to identify demographic and clinical risk factors associated with receiving a blood transfusion following total joint arthroplasty among patients with RA. METHODS: A retrospective study (n = 3270) was conducted using deidentified patient health claims information from a commercially insured, US data set (2007-2009). Data analysis included descriptive statistics and multivariate logistic regression. RESULTS: Females were more likely to receive a blood transfusion (odds ratio [OR], 1.48; 95% confidence interval [CI], 1.16-1.87; p = 0.001). When compared with those in the South, patients residing the Midwest were less likely to receive a blood transfusion following total joint arthroplasty (OR, 0.56; 95% CI, 0.44-0.71). Relative to those receiving total knee arthroplasty, patients who underwent total hip arthroplasty were more likely to receive a blood transfusion (OR, 1.39; 95% CI, 1.14-1.70), and patients who underwent a total shoulder arthroplasty were less likely to receive a blood transfusion (OR, 0.14; 95% CI, 0.05-0.38; p < 0.001). Patients with a history of anemia were more likely to receive a blood transfusion compared with those who did not have this diagnosis (OR, 3.30; 95% CI, 2.62-4.14; p < 0.001). CONCLUSIONS: Risk factors for the receipt of blood transfusions among RA patients who have undergone total joint arthroplasty were identified.

Treatment patterns in patients with type 2 diabetes mellitus treated with glucagon-like peptide-1 receptor agonists: Higher adherence and persistence with dulaglutide compared with once-weekly exenatide and liraglutide.

AIMS: To compare adherence (proportion of days covered [PDC]), persistence, and treatment patterns among patients with type 2 diabetes mellitus (T2DM) newly initiating glucagon-like peptide-1 receptor agonists (GLP-1RAs). More specifically, the main objectives were to compare dulaglutide vs exenatide once weekly and dulaglutide vs liraglutide. METHODS: Patients with T2DM newly initiating dulaglutide, albiglutide, exenatide once weekly, exenatide twice daily and liraglutide between November 2014 and April 2015 were hierarchically selected from Truven Health's MarketScan Research Databases. Propensity score matching was used to account for selection bias. Adherence to and persistence with the index GLP-1RA, and switching and augmentation patterns were assessed during the 6-month post-index period. RESULTS: Mean adherence for the matched cohorts was significantly higher for dulaglutide than for exenatide once weekly (0.72 vs 0.61; P < .0001) and liraglutide (0.71 vs 0.67; P < .0001). The percentage of patients achieving PDC ≥ 0.80 was significantly higher for dulaglutide compared with exenatide once weekly (54.2% vs 37.9%; P < .0001) and liraglutide (53.5% vs 44.3%; P < .0001). The mean (standard deviation) days on treatment for all matched patients was significantly higher for patients in the dulaglutide cohort compared with those in the exenatide once-weekly (148.4 [55.4] vs 123.6 [61.6]; P < .0001) and liraglutide cohorts (146.0 [56.9] vs 137.4 [60.1]; P < .0001). A significantly lower proportion of patients on dulaglutide discontinued treatment compared with those on exenatide once weekly (26.2% vs 48.4%; P < .0001) and those on liraglutide (28.0% vs 35.6%; P < .0001). CONCLUSIONS: Dulaglutide initiators had significantly higher adherence, were more persistent, and had lower discontinuation rates compared with initiators of exenatide once weekly or liraglutide during the 6-month follow-up period.

Determining Current Insulin Pen Use Practices and Errors in the Inpatient Setting.

BACKGROUND: The use of insulin pens in the inpatient setting has continued to be a controversial decision. Insulin pens provide several advantages, but given significant reports of medication errors, several organizations have issued alerts to caution users about safety concerns. A survey was conducted to assess the prevalence of insulin pen use and current utilization trends in the inpatient setting. METHODS: The 31-question guided-logic survey was developed based on review of primary literature regarding insulin pen utilization and evaluated by a panel of medication safety experts from a variety of health care settings. The survey was sent electronically to subscribers of medication safety organizations. RESULTS: The survey was completed by 474 respondents. Approximately three fourths of respondents indicated insulin pens were on formulary at their institution (n = 332; 74%). Of those who have had insulin pens on formulary, 15% (n = 49) are no longer using them. The most common reasons for not utilizing pens were cost and safety concerns. Pens were reported to be stored in the pharmacy prior to administration (n = 230; 78%) and in a patient's bin (n = 202; 69%) afterward. More than half of respondents use two patient identifiers on the pen and label with a bar code. Approximately 30% reported that an insulin pen has been used on more than one patient at least once in their institution, while 6% were not sure. CONCLUSION: Insulin pens are widely being used in the inpatient setting. Various mitigation strategies are employed to reduce the risk of harm associated with insulin pen use. Health care professionals believe insulin pens are clinically useful and can be used safely in the inpatient setting. Many organizations and expert panels disseminate best practices in an effort to help ensure their safety. Further studies are needed to assess and validate the risk mitigation strategies identified through this research.

A Clinic-Based Measure of Everyday Planning Ability: The Overnight Trip Task.

OBJECTIVE: Traditional measures of cognitive abilities most used by neuropsychologists are generally low in ecological validity and only capture a small proportion of the variance of a person's true functional capacity. This study evaluates the association between clinic-based performance and parallel real-world completion of an everyday planning test, the Overnight Trip Task (OTT). METHOD: A cross-sectional cohort of 65 community-dwelling older adults completed a battery of cognitive assessments and two formats of the OTT: the paper-and-pencil clinic OTT, which was completed remotely through video conferencing (Zoom), and the parallel real-world OTT (RW-OTT), which was completed at home between sessions. Both formats required participants to plan for what they would pack and prepare for a hypothetical overnight trip based on a provided story that included rules and embedded contingencies. RESULTS: The clinic OTT demonstrated a small-to-moderate relationship with the RW-OTT (r = 0.35) and no relationship with measures of learning, long delay recall, an executive function composite, and a measure of everyday planning. Hierarchical regressions indicated that the clinic OTT demonstrated incremental validity above an executive function composite measure and global cognition when predicting self-reported everyday functioning and RW-OTT performance. CONCLUSIONS: The clinic OTT showed only modest association with the RW-OTT and discriminate but not convergent validity was demonstrated. The clinic OTT showed incremental validity when predicting self-reported everyday functioning and RW-OTT performance above more traditional measures. Before the clinic OTT could be considered a reliable and valid clinic-based measure for predicting real-world behavior, additional research would be needed.

Metagenome-assembled genome sequences of two cyanobacterial cultures from Homa Bay County, Kenya.

Metagenome-assembled genomes were generated for two xenic cyanobacterial strains collected from aquatic sources in Kenya and sequenced by NovaSeq S4. Here, we report the classification and genome statistics of Microcystis panniformis WG22 and Limnospira fusiformis LS22.

Naturalistic assessment of everyday multitasking in Parkinson's disease with and without mild cognitive impairment.

Objective: Multitasking is an essential part of everyday functioning often not formally assessed by traditional neuropsychological tests. Although individuals with Parkinson's disease (PD) experience both motor and cognitive difficulties, previous research has demonstrated more pronounced functional difficulties with the presence of mild cognitive impairment (PD-MCI). The current study compared individuals with PD-MCI, PD with normal cognition (PD-NC), and healthy controls on a naturalistic task of multitasking, the Day Out Task (DOT). Method: Participants were 38 healthy older adults (HOA), 23 individuals with PD-NC, and 15 individuals with PD-MCI. Participants completed a battery of neuropsychological tasks and the DOT. Informants also completed a self-reported questionnaire of participants' everyday executive functioning. Results: Compared to PD-NC and HOA, participants with PD-MCI were less accurate and efficient and took longer to complete the DOT. After controlling for motor performance, only DOT accuracy remained worse, with poorer accuracy resulted from more subtasks being left incomplete or being completed inaccurately by the PD-MCI group. DOT sequencing was a significant predictor of informant reported everyday dysexecutive symptoms. Conclusions: The findings highlight that individuals with PD-MCI are likely to experience difficulties completing complex everyday tasks due to both motor and cognitive impairments. Clinicians may therefore recommend strategies to support efficiency and accuracy in complex tasks of everyday functioning in treatment considerations.

Tirzepatide Immunogenicity on Pharmacokinetics, Efficacy, and Safety: Analysis of Data From Phase 3 Studies.

CONTEXT: Antidrug antibodies (ADA) can potentially affect drug pharmacokinetics, safety, and efficacy. OBJECTIVE: This work aimed to evaluate treatment-emergent (TE) ADA in tirzepatide (TZP)-treated participants across 7 phase 3 trials and their potential effect on pharmacokinetics, efficacy, and safety. METHODS: ADA were assessed at baseline and throughout the study until end point, defined as week 40 (SURPASS-1, -2, and -5) or week 52 (SURPASS-3, -4, Japan-Mono, and Japan-Combo). Samples for ADA characterization were collected at SURPASS trial sites. Participants included ADA-evaluable TZP-treated patients with type 2 diabetes (N = 5025). Interventions included TZP 5, 10, or 15 mg. ADA were detected and characterized for their ability to cross-react with native glucose-dependent insulinotropic polypeptide (nGIP) and glucagon-like peptide-1 (nGLP-1), neutralize tirzepatide activity on GIP and GLP-1 receptors, and neutralize nGIP and nGLP-1. RESULTS: TE ADA developed in 51.1% of tirzepatide-treated patients. Proportions were similar across dose groups. Maximum ADA titers ranged from 1:20 to 1: 81 920 among TE ADA+ patients. Neutralizing antibodies (NAb) against TZP activity on GIP and GLP-1 receptors were observed in 1.9% and 2.1% of patients, respectively. Less than 1.0% of patients had cross-reactive NAb against nGIP or nGLP-1. TE ADA status, ADA titer, and NAb status had no effect on the pharmacokinetics or efficacy of TZP. More TE ADA+ patients experienced hypersensitivity reactions or injection site reactions than TE ADA- patients. The majority of hypersensitivity and injection site reactions were nonserious and nonsevere, and most events occurred and/or resolved irrespective of TE ADA status or titer. CONCLUSION: Immunogenicity did not affect TZP pharmacokinetics or efficacy. The majority of hypersensitivity or injection site reactions experienced by TE ADA+ patients were mild to moderate in severity.

Tirzepatide Improved Markers of Islet Cell Function and Insulin Sensitivity in People With T2D (SURPASS-2).

CONTEXT: In previous SURPASS studies tirzepatide reduced hemoglobin glycated A1c (HbA1c) and body weight and improved markers of insulin sensitivity and ß-cell function to a greater extent than comparators. OBJECTIVE: Explore changes in biomarkers of ß-cell function and insulin sensitivity and in efficacy profiles in baseline biomarker quartile analyses with tirzepatide compared to semaglutide. DESIGN: Post hoc analysis of SURPASS-2 phase 3 trial (participants randomly assigned to receive weekly subcutaneous tirzepatide or semaglutide for 40 weeks). SETTING: Post hoc analysis of 128 sites in 8 countries. PARTICIPANTS: A total of 1879 participants with type 2 diabetes. INTERVENTIONS: Once-weekly tirzepatide (5, 10, 15 mg) or semaglutide 1 mg. MAIN OUTCOMES MEASURES: Change in homeostatic model assessment indices for pancreatic ß-cell function (HOMA2-B) and for insulin resistance (HOMA2-IR), fasting glucagon, fasting C-peptide, and fasting insulin. RESULTS: At week 40, a greater increase in HOMA2-B was seen with tirzepatide (5, 10, 15 mg) doses (96.9-120.4%) than with semaglutide 1 mg (84.0%) (P < .05). There was a greater reduction in HOMA2-IR with all doses of tirzepatide (15.5%-24.0%) than with semaglutide 1 mg (5.1%) (P < .05). Tirzepatide 10 and 15 mg resulted in a significant reduction in both fasting C-peptide (5.2%-6.0%) and fasting glucagon (53.0%-55.3%) compared with an increase of C-peptide (3.3%) and a reduction of glucagon (47.7%) with semaglutide 1 mg (P < .05). HbA1c and body weight reductions were greater with all tirzepatide doses than semaglutide within each HOMA2-B and HOMA2-IR baseline quartile. CONCLUSION: In this post hoc analysis, improvements in HbA1c and weight loss were consistent and significantly higher with tirzepatide, regardless of baseline ß-cell function and insulin resistance, compared with semaglutide.

The recent disappearance of a persistent Planktothrix bloom: Characterization of a regime shift in the phytoplankton of Sandusky Bay (USA).

Sandusky Bay is the drowned mouth of the Sandusky River in the southwestern portion of Lake Erie. The bay is a popular recreation location and a regional source for drinking water. Like the western basin of Lake Erie, Sandusky Bay is known for being host to summer cyanobacterial harmful algal blooms (cHABs) year after year, fueled by runoff from the predominantly agricultural watershed and internal loading of legacy nutrients (primarily phosphorus). Since at least 2003, Sandusky Bay has harbored a microcystin-producing bloom of Planktothrix agardhii, a species of filamentous cyanobacteria that thrives in low light conditions. Long-term sampling (2003-2018) of Sandusky Bay revealed regular Planktothrix-dominated blooms during the summer months, but in recent years (2019-2022), 16S rRNA gene community profiling revealed that Planktothrix has largely disappeared. From 2017-2022, microcystin decreased well below the World Health Organization (WHO) guidelines. Spring TN:TP ratios increased in years following dam removal, yet there were no statistically significant shifts in other physicochemical variables, such as water temperature and water clarity. With the exception of the high bloom of Planktothrix in 2018, there was no statistical difference in chlorophyll during all other years. Concurrent with the disappearance of Planktothrix, Cyanobium spp. have become the dominant cyanobacterial group. The appearance of other potential toxigenic genera (i.e., Aphanizomenon, Dolichospermum, Cylindrospermopsis) may motivate monitoring of new toxins of concern in Sandusky Bay. Here, we document the regime shift in the cyanobacterial community and propose evidence supporting the hypothesis that the decline in the Planktothrix bloom was linked to the removal of an upstream dam on the Sandusky River.

Bacterial community and cyanotoxin gene distribution of the Winam Gulf, Lake Victoria, Kenya.

The Winam Gulf (Kenya) is frequently impaired by cyanobacterial harmful algal blooms (cHABs) due to inadequate wastewater treatment and excess agricultural nutrient input. While phytoplankton in Lake Victoria have been characterized using morphological criteria, our aim is to identify potential toxin-producing cyanobacteria using molecular approaches. The Gulf was sampled over two successive summer seasons, and 16S and 18S ribosomal RNA gene sequencing was performed. Additionally, key genes involved in production of cyanotoxins were examined by quantitative PCR. Bacterial communities were spatially variable, forming distinct clusters in line with regions of the Gulf. Taxa associated with diazotrophy were dominant near Homa Bay. On the eastern side, samples exhibited elevated cyrA abundances, indicating genetic capability of cylindrospermopsin synthesis. Indeed, near the Nyando River mouth in 2022, cyrA exceeded 10 million copies L-1 where there were more than 6000 Cylindrospermopsis spp. cells mL-1. In contrast, the southwestern region had elevated mcyE gene (microcystin synthesis) detections near Homa Bay where Microcystis and Dolichospermum spp. were observed. These findings show that within a relatively small embayment, composition and toxin synthesis potential of cHABs can vary dramatically. This underscores the need for multifaceted management approaches and frequent cyanotoxin monitoring to reduce human health impacts.

Reduction in cardiopulmonary and cognitive performance after COVID-19 in a competitive athlete.

A 23-year-old male competitive athlete performed a maximal cardiopulmonary exercise test on a cycle ergometer with a concurrent cognitive test on an iPad 6 days before and 19 weeks after a nonhospitalized COVID-19 illness. Results indicated reductions in time to exhaustion (-3.25 min), peak oxygen consumption (-1.68 mL/kg/min), and accuracy (-8%) during peak exertion despite his return to prior levels of activity. Reductions in functional or cognitive performance in competitive athletes may elicit noticeable differences in athletic performance; therefore, fitness specialists should consider the assessment of both cognitive function as well as aerobic capacity in athletes following COVID-19, regardless of severity, to facilitate safe and effective return to activity.