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.

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.

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.

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.

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.

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.

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.

Patient-Reported Outcomes in People with Type 2 Diabetes Receiving Tirzepatide in the SURPASS Clinical Trial Programme.

INTRODUCTION: Tirzepatide, a novel glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1 receptor agonist, is approved for glycaemic control for people with type 2 diabetes (T2D). The SURPASS-1 to -5 clinical trials assessed the efficacy of once weekly tirzepatide (5, 10 and 15 mg) versus placebo or active comparators (semaglutide 1 mg, insulin degludec and insulin glargine) in T2D. We evaluated patient-reported outcomes (PROs) that measured overall quality of life (QoL), treatment satisfaction and weight-related attributes across the five SURPASS studies. METHODS: PRO instruments utilised at baseline and primary timepoint (40 weeks for SURPASS-1, -2 and -5; 52 weeks for SURPASS-3 and -4) or early termination visit were EQ-5D-5L (SURPASS-1 to -5); Impact of Weight on Self-Perceptions (SURPASS-1 to -5); Ability to Perform Physical Activities of Daily Living (SURPASS-1 to -5); Diabetes Treatment Satisfaction Questionnaire (SURPASS-2 to -5); and Impact of Weight on Quality of Life-Lite Clinical Trials Version (SURPASS-2 only). RESULTS: Across all five studies at week 40/52, tirzepatide improved patients' QoL measured by general health and weight-related PROs over the comparator. Generally, higher doses of tirzepatide resulted in greater increases in PRO scores. CONCLUSION: Overall, tirzepatide produced significant health and weight-related QoL improvements versus comparators in the five SURPASS studies. CLINICAL TRIAL REGISTRATION: SURPASS-1: NCT03954834; SURPASS-2: NCT03987919; SURPASS-3: NCT03882970; SURPASS-4: NCT03730662; SURPASS-5: NCT04039503.

Tirzepatide is the first glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1 receptor agonist approved for the treatment of people with type 2 diabetes. The SURPASS-1 to -5 clinical trials evaluated the efficacy and safety of tirzepatide (5, 10 and 15 mg) compared with placebo or active comparators (including semaglutide 1 mg and basal insulins) in people with type 2 diabetes. We evaluated other outcomes reported by patients that measured overall quality of life, treatment satisfaction and weight-related attributes across the five SURPASS studies.Five validated questionnaires were completed by patients at the beginning and end of the clinical trials, which was after 40 weeks for SURPASS-1, -2 and -5 and after 52 weeks for SURPASS-3 and -4, or when the person left the trial if this was before the official end. These questionnaires were EQ-5D-5L (SURPASS-1 to -5); Impact of Weight on Self-Perceptions (SURPASS-1 to -5); Ability to Perform Physical Activities of Daily Living (SURPASS-1 to -5); Diabetes Treatment Satisfaction Questionnaire (SURPASS-2 to -5); and Impact of Weight on Quality of Life-Lite Clinical Trials Version (SURPASS-2 only).Across all five studies, treatment with tirzepatide resulted in greater improvements in people's quality of life at the end of the study compared with placebo or treatment with the comparators. Generally, higher doses of tirzepatide resulted in greater increases in questionnaire scores than lower doses of tirzepatide.Overall, tirzepatide 5, 10 or 15 mg treatment resulted in significant health- and weight-related quality of life improvements versus comparators in the five SURPASS studies.

Engineering BioBricks for Deoxysugar Biosynthesis and Generation of New Tetracenomycins.

Tetracenomycins and elloramycins are polyketide natural products produced by several actinomycetes that exhibit antibacterial and anticancer activities. They inhibit ribosomal translation by binding in the polypeptide exit channel of the large ribosomal subunit. The tetracenomycins and elloramycins are typified by a shared oxidatively modified linear decaketide core, yet they are distinguished by the extent of O-methylation and the presence of a 2',3',4'-tri-O-methyl-α-l-rhamnose appended at the 8-position of elloramycin. The transfer of the TDP-l-rhamnose donor to the 8-demethyl-tetracenomycin C aglycone acceptor is catalyzed by the promiscuous glycosyltransferase ElmGT. ElmGT exhibits remarkable flexibility toward transfer of many TDP-deoxysugar substrates to 8-demethyltetracenomycin C, including TDP-2,6-dideoxysugars, TDP-2,3,6-trideoxysugars, and methyl-branched deoxysugars in both d- and l-configurations. Previously, we developed an improved host, Streptomyces coelicolor M1146::cos16F4iE, which is a stable integrant harboring the required genes for 8-demethyltetracenomycin C biosynthesis and expression of ElmGT. In this work, we developed BioBricks gene cassettes for the metabolic engineering of deoxysugar biosynthesis in Streptomyces spp. As a proof of concept, we used the BioBricks expression platform to engineer biosynthesis for d-configured TDP-deoxysugars, including known compounds 8-O-d-glucosyl-tetracenomycin C, 8-O-d-olivosyl-tetracenomycin C, 8-O-d-mycarosyl-tetracenomycin C, and 8-O-d-digitoxosyl-tetracenomycin C. In addition, we generated four new tetracenomycins including one modified with a ketosugar, 8-O-4'-keto-d-digitoxosyl-tetracenomycin C, and three modified with 6-deoxysugars, including 8-O-d-fucosyl-tetracenomycin C, 8-O-d-allosyl-tetracenomycin C, and 8-O-d-quinovosyl-tetracenomycin C. Our work demonstrates the feasibility of BioBricks cloning, with the ability to recycle intermediate constructs, for the rapid assembly of diverse carbohydrate pathways and glycodiversification of a variety of natural products.

Effects of cloth face masks on physical and cognitive performance during maximal exercise testing.

Wearing a cloth face mask has been shown to impair exercise performance; it is essential to understand the impact wearing a cloth face mask may have on cognitive performance. Participants completed two maximal cardiopulmonary exercise tests on a cycle ergometer (with and without a cloth face mask) with a concurrent cognitive task. Blood pressure, heart rate, oxygen saturation, perceived exertion, shortness of breath, accuracy, and reaction time were measured at rest, during each exercise stage, and following a 4-minute recovery period. The final sample included 35 adults (age = 26.1 ± 5.8 years; 12 female/23 male). Wearing a cloth face mask was associated with significant decreases in exercise duration (-2:00 ± 3:40 min, P = 0.003), peak measures of maximal oxygen uptake (-818.9 ± 473.3 mL/min, -19.0 ± 48 mL·min-1·kg-1, P < 0.001), respiratory exchange ratio (-0.04 ± 0.08, P = 0.005), minute ventilation (-36.9 ± 18 L/min), oxygen pulse (-3.9 ± 2.3, P < 0.001), heart rate (-7.9 ± 12.6 bpm, P < 0.001), oxygen saturation (-1.5 ± 2.8%, P = 0.004), and blood lactate (-1.7 ± 2.5 mmol/L, P < 0.001). While wearing a cloth face mask significantly impaired exercise performance during maximal exercise testing, cognitive performance was unaffected in this selected group of young, active adults.

The Impact of Substantial Improvements in HbA1c and Weight Loss on the Medication Preferences of People with Type 2 Diabetes.

Purpose: To quantify the preferences of people with type 2 diabetes (T2D) for treatment attributes of a glucose-dependent insulinotropic polypeptide (GIP)/glucagon-like peptide-1 (GLP-1) receptor agonist (RA) versus an injectable GLP-1 RA medication profile. Patients and Methods: Injection-naive people taking oral medications for T2D in the US and UK completed a web survey including a discrete choice experiment to quantify patients' preferences for five treatment attributes: delivery system, frequency of nausea, frequency of hypoglycemia, HbA1c reduction, and weight reduction. Attributes and levels were based on head-to-head clinical trial data of tirzepatide 5mg, 10mg, and 15mg versus semaglutide 1mg. Preference data were analyzed separately by country using multinomial mixed logit (MXL) models. MXL parameters were used to estimate the predicted preference for each tirzepatide dose versus semaglutide 1mg. Direct preferences for each dose of tirzepatide versus semaglutide 1mg were elicited. Results: Participants (N=620) in the US (N=301) and UK (N=319) were 50.8% and 50.5% female with mean ages of 60.7 years and 58.9 years, respectively. The order and magnitude of relative attribute importance (RAI) scores differed between countries. HbA1c reduction (26.3%) had the greatest impact on US participants' preferences, and hypoglycemia (32.8%) did among UK participants. Attribute-level marginal utility results indicated preferences for greater HbA1c improvements, the single-use pre-filled pen, lower hypoglycemia, greater weight reductions, and lower frequency of nausea. Assuming the availability of only tirzepatide or semaglutide 1mg, the predicted preference for tirzepatide (5, 10, and 15mg) in the US is 95.6% (vs 4.4% for semaglutide 1mg) and in the UK was 86.3% (vs 13.7% for semaglutide 1mg). Conclusion: HbA1c reduction, frequency of hypoglycemia, and weight reduction are key drivers of preferences among people with T2D when considering medication options. Overall, people with T2D are likely to prefer the tirzepatide over the semaglutide 1mg medication profiles.

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.

A Large-Scale, Multiplayer Virtual Reality Deployment: A Novel Approach to Distance Education in Human Anatomy.

The arrival of COVID-19 restrictions and the increasing demand of online instruction options posed challenges to education communities worldwide, especially in human anatomy. In response, Colorado State University developed and deployed an 8-week-long large-scale virtual reality (VR) course to supplement online human anatomy instruction. Students (n = 75) received a VR-capable laptop and head-mounted display and participated in weekly synchronous group laboratory sessions with instructors. The software enabled students to remotely collaborate in a common virtual space to work with human anatomy using an artist-rendered cadaver. Qualitative data were collected on student engagement, confidence, and reactions to the new technology. Quantitative data assessed student knowledge acquisition and retention of anatomical spatial relationships. Results indicated that students performed better in the online course (mean = 82.27%) when compared to previous in-person laboratories (mean = 80.08%). The utilization of VR promoted student engagement and increased opportunities for student interaction with teaching assistants, peers, and course content. Notably, students reported benefits that focused on unique aspects of their virtual learning environment, including the ability to infinitely scale the cadaver and walk inside and around anatomical structures. Results suggested that using VR was equivalent to 2D methods in student learning and retention of anatomical relationships. Overall, the virtual classroom maintained the rigor of traditional gross anatomy laboratories without negatively impacting student examination scores and provided a high level of accessibility, without compromising learner engagement. Supplementary Information: The online version contains supplementary material available at 10.1007/s40670-023-01751-w.

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.

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.

A BioBricks Metabolic Engineering Platform for the Biosynthesis of Anthracyclinones in Streptomyces coelicolor.

Actinomycetes produce a variety of clinically indispensable molecules, such as antineoplastic anthracyclines. However, the actinomycetes are hindered in their further development as genetically engineered hosts for the synthesis of new anthracycline analogues due to their slow growth kinetics associated with their mycelial life cycle and the lack of a comprehensive genetic toolbox for combinatorial biosynthesis. In this report, we tackled both issues via the development of the BIOPOLYMER (BIOBricks POLYketide Metabolic EngineeRing) toolbox: a comprehensive synthetic biology toolbox consisting of engineered strains, promoters, vectors, and biosynthetic genes for the synthesis of anthracyclinones. An improved derivative of the production host Streptomyces coelicolor M1152 was created by deleting the matAB gene cluster that specifies extracellular poly-ß-1,6-N-acetylglucosamine (PNAG). This resulted in a loss of mycelial aggregation, with improved biomass accumulation and anthracyclinone production. We then leveraged BIOPOLYMER to engineer four distinct anthracyclinone pathways, identifying optimal combinations of promoters, genes, and vectors to produce aklavinone, 9-epi-aklavinone, auramycinone, and nogalamycinone at titers between 15-20 mg/L. Optimization of nogalamycinone production strains resulted in titers of 103 mg/L. We structurally characterized six anthracyclinone products from fermentations, including new compounds 9,10-seco-7-deoxy-nogalamycinone and 4-O-ß-d-glucosyl-nogalamycinone. Lastly, we tested the antiproliferative activity of the anthracyclinones in a mammalian cancer cell viability assay, in which nogalamycinone, auramycinone, and aklavinone exhibited moderate cytotoxicity against several cancer cell lines. We envision that BIOPOLYMER will serve as a foundational platform technology for the synthesis of designer anthracycline analogues.

Occupation-specific, high-intensity cardiac rehabilitation for return to work of a young police officer after myocardial infarction from traumatic coronary artery dissection.

Following a traumatic coronary artery dissection and subsequent myocardial infarction from a nonpenetrating strike to the chest by an airborne metal pipe, a 33-year-old male police officer completed 12 weeks of high-intensity, symptom-limited cardiac rehabilitation in order to return to active duty. Physiological and perceptual responses to exercise were used to progress the patient through high-intensity activities that challenged the musculoskeletal and cardiorespiratory systems while simulating real work activities. In addition to substantial improvements in functional capacity (8.6 to 10.3 METS) and left ventricular ejection fraction (20% to 45%), the patient was able to fully return to work as an active-duty police officer.

Efficacy of once-weekly tirzepatide versus once-daily insulin degludec on glycaemic control measured by continuous glucose monitoring in adults with type 2 diabetes (SURPASS-3 CGM): a substudy of the randomised, open-label, parallel-group, phase 3 SURPASS-3 trial.

BACKGROUND: Tirzepatide is a novel dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonist under development for the treatment of type 2 diabetes. In this study, we used continuous glucose monitoring (CGM) to compare the 24 h glucose profile for participants given tirzepatide compared with those given insulin degludec. METHODS: This substudy of the open-label, parallel-group, phase 3 SURPASS-3 trial, was done at 45 sites across six countries (Hungary, Poland, Romania, Spain, Ukraine, and the USA). Eligible participants in the main study were adults with type 2 diabetes, a baseline HbA1c of 7·0-10·5% (53-91 mmol/mol), and a BMI of 25 kg/m2 or more, who were insulin-naive, and treated with metformin alone or in combination with a SGLT2 inhibitor for at least 3 months before screening. Participants in the main study were randomly assigned (1:1:1:1) to receive once-weekly subcutaneous injection of tirzepatide 5 mg, 10 mg, or 15 mg, or once-daily subcutaneous injection of titrated insulin degludec (100 U/mL), using an interactive web-response system. Participants were stratified by country, HbA1c concentration, and concomitant oral antihyperglycaemic medication. A subset of these patients with a normal wake-sleep cycle were enrolled into this substudy, and interstitial glucose values were collected by CGM for approximately 7 days at baseline, 24 weeks, and 52 weeks. The primary outcome was to compare pooled participants assigned to 10 mg and 15 mg tirzepatide versus insulin degludec for the proportion of time that CGM values were in the tight target range (71-140 mg/dL) at 52 weeks, assessed in all randomly assigned participants who received at least one dose of study drug and had an evaluable CGM session at either baseline or after baseline. The secondary outcomes were to compare tirzepatide (5 mg, 10 mg, and 15 mg) versus insulin degludec for the proportion and duration of time in tight target range at 24 and 52 weeks. This was a substudy of the trial registered with ClinicalTrials.gov, NCT03882970, and is complete. FINDINGS: From April 1 to Nov 27, 2019, 313 participants were screened for eligibility, 243 of whom were enrolled in CGM substudy (tirzepatide 5 mg, n=64; tirzepatide 10 mg, n=51; tirzepatide 15 mg, n=73; and insulin degludec, n=55). Patients given once-weekly tirzepatide (pooled 10 mg and 15 mg groups) had a greater proportion of time in tight target range compared with patients given insulin degludec (estimated treatment difference 25% [95% CI 16-33]; p<0·0001). Participants assigned to tirzepatide spent significantly more time in tight target range at 52 weeks compared with those assigned to insulin degludec (5 mg 12% [1-22], p=0·031; 10 mg 24% [13-35], p<0·0001; and 15 mg 25% [14-35], p<0·0001). Participants assigned to tirzepatide 10 mg and 15 mg, but not to tirzepatide 5 mg, spent significantly more time in tight target range at 24 weeks compared with insulin degludec (10 mg 19% [8-30], p=0·0008; 15 mg 21% [11-31], p<0·0001). INTERPRETATION: Once-weekly treatment with tirzepatide showed superior glycaemic control measured using CGM compared with insulin degludec in participants with type 2 diabetes on metformin, with or without a SGLT2 inhibitor. These new data provide additional evidence to the effect of tirzepatide and potential for achieving glycaemic targets without increase of hypoglycaemic risk compared with a basal insulin. FUNDING: Eli Lilly and Company.