Longitudinal Assessment of Coronavirus Disease 2019 Vaccine Acceptance and Uptake Among Frontline Medical Workers in Los Angeles, California.

BACKGROUND: Sentiments of vaccine hesitancy and distrust in public health institutions have complicated the government-led coronavirus disease 2019 (COVID-19) vaccine control strategy in the United States. As the first to receive the vaccine, COVID-19 vaccine attitudes among frontline workers are consequential for COVID-19 control and public opinion of the vaccine. METHODS: In this study, we used a repeated cross-sectional survey administered at 3 time points between 24 September 2020 and 6 February 2021 to a cohort of employees of the University of California, Los Angeles Health and the Los Angeles County Fire Department. The primary outcome of interest was COVID-19 vaccination intent and vaccine uptake. RESULTS: Confidence in COVID-19 vaccines and vaccine uptake rose significantly over time. At survey 1, confidence in vaccine protection was 46.4% among healthcare workers (HCWs) and 34.6% among first responders (FRs); by survey 3, this had risen to 90.0% and 75.7%, respectively. At survey 1, about one-third of participants intended to receive a vaccine as soon as possible. By survey 3, 96.0% of HCWs and 87.5% of FRs had received a COVID-19 vaccine. CONCLUSIONS: Attitudes toward vaccine uptake increased over the study period, likely a result of increased public confidence in COVID-19 vaccines, targeted communications, a COVID-19 winter surge in Los Angeles County, and ease of access from employer-sponsored vaccine distribution.

A Novel Approach for Fully Automated, Personalized Health Coaching for Adults with Prediabetes: Pilot Clinical Trial.

BACKGROUND: Prediabetes is a high-risk state for the future development of type 2 diabetes, which may be prevented through physical activity (PA), adherence to a healthy diet, and weight loss. Mobile health (mHealth) technology is a practical and cost-effective method of delivering diabetes prevention programs in a real-world setting. Sweetch (Sweetch Health, Ltd) is a fully automated, personalized mHealth platform designed to promote adherence to PA and weight reduction in people with prediabetes. OBJECTIVE: The objective of this pilot study was to calibrate the Sweetch app and determine the feasibility, acceptability, safety, and effectiveness of the Sweetch app in combination with a digital body weight scale (DBWS) in adults with prediabetes. METHODS: This was a 3-month prospective, single-arm, observational study of adults with a diagnosis of prediabetes and body mass index (BMI) between 24 kg/m2 and 40 kg/m2. Feasibility was assessed by study retention. Acceptability of the mobile platform and DBWS were evaluated using validated questionnaires. Effectiveness measures included change in PA, weight, BMI, glycated hemoglobin (HbA1c), and fasting blood glucose from baseline to 3-month visit. The significance of changes in outcome measures was evaluated using paired t test or Wilcoxon matched pairs test. RESULTS: The study retention rate was 47 out of 55 (86%) participants. There was a high degree of acceptability of the Sweetch app, with a median (interquartile range [IQR]) score of 78% (73%-80%) out of 100% on the validated System Usability Scale. Satisfaction regarding the DBWS was also high, with median (IQR) score of 93% (83%-100%). PA increased by 2.8 metabolic equivalent of task (MET)-hours per week (SD 6.8; P=.02), with mean weight loss of 1.6 kg (SD 2.5; P<.001) from baseline. The median change in A1c was -0.1% (IQR -0.2% to 0.1%; P=.04), with no significant change in fasting blood glucose (-1 mg/dL; P=.59). There were no adverse events reported. CONCLUSIONS: The Sweetch mobile intervention program is a safe and effective method of increasing PA and reducing weight and HbA1c in adults with prediabetes. If sustained over a longer period, this intervention would be expected to reduce diabetes risk in this population. TRIAL REGISTRATION: ClincialTrials.gov NCT02896010; https://clinicaltrials.gov/ct2/show/NCT02896010 (Archived by WebCite at http://www.webcitation.org/6xJYxrgse).

Effectiveness of artificial intelligence vs. human coaching in diabetes prevention: a study protocol for a randomized controlled trial.

BACKGROUND: Prediabetes is a highly prevalent condition that heralds an increased risk of progression to type 2 diabetes, along with associated microvascular and macrovascular complications. The Diabetes Prevention Program (DPP) is an established effective intervention for diabetes prevention. However, participation in this 12-month lifestyle change program has historically been low. Digital DPPs have emerged as a scalable alternative, accessible asynchronously and recognized by the Centers for Disease Control and Prevention (CDC). Yet, most digital programs still incorporate human coaching, potentially limiting scalability. Furthermore, existing effectiveness results of digital DPPs are primarily derived from per protocol, longitudinal non-randomized studies, or comparisons to control groups that do not represent the standard of care DPP. The potential of an AI-powered DPP as an alternative to the DPP is yet to be investigated. We propose a randomized controlled trial (RCT) to directly compare these two approaches. METHODS: This open-label, multicenter, non-inferiority RCT will compare the effectiveness of a fully automated AI-powered digital DPP (ai-DPP) with a standard of care human coach-based DPP (h-DPP). A total of 368 participants with elevated body mass index (BMI) and prediabetes will be randomized equally to the ai-DPP (smartphone app and Bluetooth-enabled body weight scale) or h-DPP (referral to a CDC recognized DPP). The primary endpoint, assessed at 12 months, is the achievement of the CDC's benchmark for type 2 diabetes risk reduction, defined as any of the following: at least 5% weight loss, at least 4% weight loss and at least 150 min per week on average of physical activity, or at least a 0.2-point reduction in hemoglobin A1C. Physical activity will be objectively measured using serial actigraphy at baseline and at 1-month intervals throughout the trial. Secondary endpoints, evaluated at 6 and 12 months, will include changes in A1C, weight, physical activity measures, program engagement, and cost-effectiveness. Participants include adults aged 18-75 years with laboratory confirmed prediabetes, a BMI of ≥ 25 kg/m2 (≥ 23 kg/m2 for Asians), English proficiency, and smartphone users. This U.S. study is conducted at Johns Hopkins Medicine in Baltimore, MD, and Reading Hospital (Tower Health) in Reading, PA. DISCUSSION: Prediabetes is a significant public health issue, necessitating scalable interventions for the millions affected. Our pragmatic clinical trial is unique in directly comparing a fully automated AI-powered approach without direct human coach interaction. If proven effective, it could be a scalable, cost-effective strategy. This trial will offer vital insights into both AI and human coach-based behavioral change strategies in real-world clinical settings. TRIAL REGISTRATION: ClinicalTrials.gov NCT05056376. Registered on September 24, 2021, https://clinicaltrials.gov/study/NCT05056376.

Abundant, distinct, and seasonally dynamic bee community in the canopy-aerosphere interface above a temperate forest.

Our understanding of how bees (Apoidea) use temperate forests is largely limited to sampling the understory and forest floor. Studies over the last decade have demonstrated that bee communities are vertically stratified within forests, yet the ecology of bee assemblages immediately above the canopy, the canopy-aerosphere interface, remains unexplored. We sampled and compared bee communities above the canopy of a temperate forest to the understory (1 m), midstory (10 m), and canopy (20 m) on the campus of the University of Massachusetts, in Amherst, Massachusetts, United States from April to August, 2021. Overall, we found that assemblages above the canopy had more bees than in the understory, were distinct in composition from all other strata, and included the greatest proportion of unique species. Bee abundance and species richness were highest in the understory throughout the spring (April and May) and decreased as the season progressed, while bee abundance and species richness at higher strata increased into the summer months. We also found that bees with preferences to nest in moist and rotting wood were largely restricted to canopy and midstory strata. We conclude that bee assemblages occupying the space above the forest canopy are abundant and diverse, and their unique composition suggests that this canopy-aerosphere interface plays an additional role in the bee community of temperate forests. Alternatively, our findings question how forest bee communities should be defined while highlighting the need for research on fundamental processes governing species stratification in and above the canopy.

The design, synthesis, and biological evaluation of PIM kinase inhibitors.

A series of substituted benzofuropyrimidinones with pan-PIM activities and excellent selectivity against a panel of diverse kinases is described. Initial exploration identified aryl benzofuropyrimidinones that were potent, but had cell permeability limitation. Using X-ray crystal structures of the bound PIM-1 complexes with 3, 5m, and 6d, we were able to guide the SAR and identify the alkyl benzofuropyrimidinone (6l) with good PIM potencies, permeability, and oral exposure.

Discovery of XL413, a potent and selective CDC7 inhibitor.

CDC7 is a serine/threonine kinase that has been shown to be required for the initiation and maintenance of DNA replication. Up-regulation of CDC7 is detected in multiple tumor cell lines, with inhibition of CDC7 resulting in cell cycle arrest. In this paper, we disclose the discovery of a potent and selective CDC7 inhibitor, XL413 (14), which was advanced into Phase 1 clinical trials. Starting from advanced lead 3, described in a preceding communication, we optimized the CDC7 potency and selectivity to demonstrate in vitro CDC7 dependent cell cycle arrest and in vivo tumor growth inhibition in a Colo-205 xenograft model.

SAR and in vivo evaluation of 4-aryl-2-aminoalkylpyrimidines as potent and selective Janus kinase 2 (JAK2) inhibitors.

We report the discovery of a series of 4-aryl-2-aminoalkylpyrimidine derivatives as potent and selective JAK2 inhibitors. High throughput screening of our in-house compound library led to the identification of hit 1, from which optimization resulted in the discovery of highly potent and selective JAK2 inhibitors. Advanced lead 10d demonstrated a significant dose-dependent pharmacodynamic and antitumor effect in a mouse xenograft model. Based upon the desirable profile of 10d (XL019) it was advanced into clinical trials.

Toward a structure-based model of salvinorin A recognition of the kappa-opioid receptor.

The structural basis to salvinorin A recognition of the kappa-opioid receptor is evaluated using a combination of site-directed mutagenesis and molecular-modeling techniques. The results show that salvinorin A recognizes a collection of residues in transmembrane II and VII, including Q115, Y119, Y313, I316, and Y320. The mutation of one hydrophobic residue in particular, I316, was found to completely abolish salvinorin A binding. As expected, none of the residues in transmembrane III or VI commonly associated with opiate recognition (such as D138 or E297) appear to be required for ligand binding. On the basis of the results presented here and elsewhere, a binding site model is proposed that aligns salvinorin A vertically within a pocket spanning transmembrane II and VII, with the 2' substituent directed toward the extracellular domains. The model explains the role that hydrophobic contacts play in binding this lipophilic ligand and gives insight into the structural basis to the mu-opioid receptor selectivity of 2'-benzoyl salvinorin (herkinorin).

Synthesis and evaluation of xanomeline analogs--probing the wash-resistant phenomenon at the M1 muscarinic acetylcholine receptor.

A series of xanomeline analogs were synthesized and evaluated for binding at the M(1) muscarinic acetylcholine receptor (M(1) receptor). Specifically, compounds that substitute the O-hexyl chain of xanomeline with polar, ionizable, or conformationally restricted moieties were assessed for their ability to bind to the M(1) receptor in a wash-resistant manner (persistent binding). From our screen, several novel ligands that persistently bind to the M(1) receptor with greater affinity than xanomeline were discovered. Results indicate that persistent binding may arise not only from hydrophobic interactions but also from ionic interactions with a secondary M(1) receptor binding site. Herein, a qualitative model that accounts for both binding scenarios is proposed and applied to understand the structural basis to wash-resistant binding and long-acting effects of xanomeline-based compounds.

A unique binding epitope for salvinorin A, a non-nitrogenous kappa opioid receptor agonist.

Salvinorin A is a potent kappa opioid receptor (KOP) agonist with unique structural and pharmacological properties. This non-nitrogenous ligand lacks nearly all the structural features commonly associated with opioid ligand binding and selectivity. This study explores the structural basis to salvinorin A binding and selectivity using a combination of chimeric and single-point mutant opioid receptors. The experiments were designed based on previous models of salvinorin A that locate the ligand within a pocket formed by transmembrane (TM) II, VI, and VII. More traditional sites of opioid recognition were also explored, including the highly conserved aspartate in TM III (D138) and the KOP selectivity site E297, to determine the role, if any, that these residues play in binding and selectivity. The results indicate that salvinorin A recognizes a cluster of residues in TM II and VII, including Q115, Y119, Y312, Y313, and Y320. Based on the position of these residues within the receptor, and prior study on salvinorin A, a model is proposed that aligns the ligand vertically, between TM II and VII. In this orientation, the ligand spans residues that are spaced one to two turns down the face of the helices within the receptor cavity. The ligand is also in close proximity to EL-2 which, based on chimeric data, is proposed to play an indirect role in salvinorin A binding and selectivity.

Factors affecting branch failures in open-grown trees during a snowstorm in Massachusetts, USA.

In October 2011, a snowstorm in the northeastern USA caused many branch failures of many tree species commonly planted in urbanized settings. Immediately following the storm, we assessed 1,764 trees for possible snow-induced damage and factors affecting it on the campus of the University of Massachusetts in Amherst, MA, USA. Nearly all failures were of branches, most of which were not defective. We used logistic regression to assess whether the probability of branch failure differed among species, diameter at breast height (DBH) and the presence of a defect or leaves increased for different species. We also measured branch morphology of (i) branches that did and did not fail for one angiosperm species and (ii) all branches on a sub-sample (stratified by DBH) of three individuals of seven other angiosperm species. Probability of branch failure differed among species. It also increased with greater DBH in eight of ten species studied, decreased when defects were present in four of ten species, and increased in one species when leaves were present. The relationship between branch failure and DBH appeared to be due to the correlation between DBH and branch morphology, which was mostly similar among species. As DBH increased, so did the mean diameter and length of primary branches, and the cumulative diameter of secondary branches. In contrast, branch slenderness decreased with increasing DBH. Combined, these factors presumably expedited the accumulation of snow on branches due to greater surface area and less flexibility. This explained why most failed branches were not defective. Since the frequency of intense storms is predicted to increase with global climate change, urban foresters should consider the timing of leaf senescence when selecting deciduous trees, to reduce the likelihood of failure of open-grown, deciduous trees in urbanized areas.

Compliance with the ANSI Z133.1 - 2006 safety standard among arborists in New England.

INTRODUCTION: Arboriculture is hazardous work. A consensus safety standard exists, but little is known about compliance with it. This study aimed to determine whether accreditation and certification are associated with safety practices and to identify specific safety practices adhered to most and least. METHOD: Sixty-three tree care companies in southern New England were directly observed on job sites. Adherence to the American National Standards for Arboricultural Operations (ANSI Z133.1 - 2006) was compared across companies that were accredited, non-accredited with certified arborists on staff, and non-accredited without certified arborists on staff. RESULTS: Companies with accreditation or certified arborists demonstrated greater safety compliance than those without. However, low compliance was found across all company types for personal protective equipment (PPE) use, chain saw safety, and chipper safety. CONCLUSIONS: Greater attention to PPE, chain saw, and chipper practices is warranted across the industry. Safety in non-accredited companies without certified arborists especially needs improvement. PRACTICAL APPLICATION: Only partial compliance was found among accredited companies and companies with certified arborists. Intervention strategies are needed for all company types for the use of PPE and safer use of chain saws and chippers.

Optical control of metabotropic glutamate receptors.

G protein-coupled receptors (GPCRs), the largest family of membrane signaling proteins, respond to neurotransmitters, hormones and small environmental molecules. The neuronal function of many GPCRs has been difficult to resolve because of an inability to gate them with subtype specificity, spatial precision, speed and reversibility. To address this, we developed an approach for opto-chemical engineering of native GPCRs. We applied this to the metabotropic glutamate receptors (mGluRs) to generate light-agonized and light-antagonized mGluRs (LimGluRs). The light-agonized LimGluR2, on which we focused, was fast, bistable and supported multiple rounds of on/off switching. Light gated two of the primary neuronal functions of mGluR2: suppression of excitability and inhibition of neurotransmitter release. We found that the light-antagonized tool LimGluR2-block was able to manipulate negative feedback of synaptically released glutamate on transmitter release. We generalized the optical control to two additional family members: mGluR3 and mGluR6. This system worked in rodent brain slices and in zebrafish in vivo, where we found that mGluR2 modulated the threshold for escape behavior. These light-gated mGluRs pave the way for determining the roles of mGluRs in synaptic plasticity, memory and disease.

Molecular recognition of opioid receptor ligands.

The cloning of the opioid receptors and subsequent use of recombinant DNA technology have led to many new insights into ligand binding. Instead of focusing on the structural features that lead to increased affinity and selectivity, researchers are now able to focus on why these features are important. Site-directed mutagenesis and chimeric data have often been at the forefront in answering these questions. Herein, we survey pharmacophores of several opioid ligands in an effort to understand the structural requirements for ligand binding and selectivity. Models are presented and compared to illustrate key sites of recognition for both opiate and nonopiate ligands. The results indicate that different ligand classes may recognize different sites within the receptor, suggesting that multiple epitopes may exist for ligand binding and selectivity.