The effect of AZD9567 vs. prednisolone on glycaemic control in patients with type 2 diabetes mellitus: Results from a phase 2a clinical trial.

AIMS: Corticosteroids are the treatment of choice for many inflammatory diseases but often lead to adverse effects, including hyperglycaemia. This study investigated the mechanisms driving differential effects on glucose control for AZD9567, an oral nonsteroidal selective glucocorticoid receptor modulator vs. prednisolone in 46 patients with type 2 diabetes mellitus. METHODS: In this randomized, double-blind, 2-way cross-over study (NCT04556760), participants received either AZD9567 72 mg and prednisolone 40 mg daily (cohort 1); AZD9567 40 mg and prednisolone 20 mg daily (cohort 2); or placebo and prednisolone 5 mg daily (cohort 3). Treatment duration was 3 days with a 3-week washout between treatment periods. Glycaemic control was assessed after a standardized meal and with continuous glucose monitoring. RESULTS: A significant difference between AZD9567 and prednisolone in favour of AZD9567 was observed for the change from baseline to Day 4 glucose excursions postmeal in cohort 1 (glucose area under the curve from 0 to 4 h -4.54%; 95% confidence interval [CI]: -8.88, -0.01; P = .049), but not in cohort 2 (-5.77%; 95% CI: -20.92, 12.29; P = .435). In cohort 1, significant differences between AZD9567 and prednisolone were also seen for the change from baseline to day 4 in insulin and glucagon secretion postmeal (P < .001 and P = .005, respectively) and change from baseline to Day 4 in GLP-1 response (P = .022). Significant differences between AZD9567 and prednisolone for 24-h glucose control were observed for both cohort 1 (-1.507 mmol/L; 95% CI: -2.0820, -0.9314; P < .001) and cohort 2 (-1.110 mmol/L; 95% CI -1.7257, -0.4941; P < .001). CONCLUSION: AZD9567 significantly reduced treatment-induced hyperglycaemia compared with prednisolone.

The positive impact of conservation action.

Governments recently adopted new global targets to halt and reverse the loss of biodiversity. It is therefore crucial to understand the outcomes of conservation actions. We conducted a global meta-analysis of 186 studies (including 665 trials) that measured biodiversity over time and compared outcomes under conservation action with a suitable counterfactual of no action. We find that in two-thirds of cases, conservation either improved the state of biodiversity or at least slowed declines. Specifically, we find that interventions targeted at species and ecosystems, such as invasive species control, habitat loss reduction and restoration, protected areas, and sustainable management, are highly effective and have large effect sizes. This provides the strongest evidence to date that conservation actions are successful but require transformational scaling up to meet global targets.

Differences in Responses of Immunosuppressed Kidney Transplant Patients to Moderna mRNA-1273 versus Pfizer-BioNTech.

Immunosuppressed kidney transplant (KT) recipients produce a weaker response to COVID-19 vaccination than immunocompetent individuals. We tested antiviral IgG response in 99 KT recipients and 66 healthy volunteers who were vaccinated with mRNA-1273 Moderna or BNT162b2 Pfizer-BioNTech vaccines. A subgroup of participants had their peripheral blood leukocytes (PBLs) evaluated for the frequency of T helper 1 (Th1) cells producing IL-2, IFN-γ and/or TNF-α, and IL-10-producing T-regulatory 1 (Tr) cells. Among KT recipients, 45.8% had anti-SARS-CoV-2 IgG compared to 74.1% of healthy volunteers (p = 0.009); also, anti-viral IgG levels were lower in recipients than in volunteers (p = 0.001). In terms of non-responders (≤2000 U/mL IgG), Moderna's group had 10.8% and Pfizer-BioNTech's group had 34.3% of non-responders at 6 months (p = 0.023); similarly, 15.7% and 31.3% were non-responders in Moderna and Pfizer-BioNTech groups at 12 months, respectively (p = 0.067). There were no non-responders among controls. Healthy volunteers had higher Th1 levels than KT recipients, while Moderna produced a higher Th1 response than Pfizer-BioNTech. In contrast, the Pfizer-BioNTech vaccine induced a higher Tr1 response than the Moderna vaccine (p < 0.05); overall, IgG levels correlated with Th1(fTTNF-α)/Tr1(fTIL-10) ratios. We propose that the higher number of non-responders in the Pfizer-BioNTech group than the Moderna group was caused by a more potent activity of regulatory Tr1 cells in KT recipients vaccinated with the Pfizer-BioNTech vaccine.

Factors associated with the acceptability of Lopinavir/Ritonavir formulations among children living with HIV/AIDS attending care and treatment clinics in Mbeya and Mwanza, Tanzania.

INTRODUCTION: Children living with chronic illnesses are offered formulations based on manufacturer and distributor research. The aim of this study is to better understand the perspectives of children and their caregivers in accepting Lopinavir/ritonavir (LPV/r) formulations. METHODS: 362 participants were recruited from two pediatric HIV/AIDS clinics in Mbeya and Mwanza, Tanzania, from December 2021 to May 2022. A translated questionnaire was piloted and validated at both clinics, followed by the implementation of a cross-sectional study. RESULTS: 169 participants (47.1%) reported general difficulties in swallowing, regardless of formulation, while 34.3% and 38.5% reported vomiting tablets and syrups, respectively. Statistical significance is shown to support that children can swallow medications if they can eat stiffened porridge (Ugali). This correlated with the lower incidence of younger children being able to swallow compared to older children (above six years of age). Children older than six years preferred taking tablets (independent of daily dosage) better than other formulations. Significantly, older children who attend school were associated with high odds of swallowing medicine (AOR = 3.06, 95%CI; 1.32-7.05); however, age was not found to be statistically related to ease of administration for Lopinavir/Ritonavir in this study. CONCLUSIONS: Lopinavir/Ritonavir tablets remain the most accepted formulation among children and adolescents with HIV/AIDS. This study highlights the impact of various factors affecting the acceptability of pediatric formulation, suggesting that children younger than six years, unable to eat Ugali and not attending schools may be most vulnerable regarding their ability to accept Lopinavir/Ritonavir formulations. Further studies are needed to assess the acceptability of other medications in chronically ill children.

Interventions addressing health-related social needs among patients with cancer.

Health-related social needs are prevalent among cancer patients; associated with substantial negative health consequences; and drive pervasive inequities in cancer incidence, severity, treatment choices and decisions, and outcomes. To address the lack of clinical trial evidence to guide health-related social needs interventions among cancer patients, the National Cancer Institute Cancer Care Delivery Research Steering Committee convened experts to participate in a clinical trials planning meeting with the goal of designing studies to screen for and address health-related social needs among cancer patients. In this commentary, we discuss the rationale for, and challenges of, designing and testing health-related social needs interventions in alignment with the National Academy of Sciences, Engineering, and Medicine 5As framework. Evidence for food, housing, utilities, interpersonal safety, and transportation health-related social needs interventions is analyzed. Evidence regarding health-related social needs and delivery of health-related social needs interventions differs in maturity and applicability to cancer context, with transportation problems having the most maturity and interpersonal safety the least. We offer practical recommendations for health-related social needs interventions among cancer patients and the caregivers, families, and friends who support their health-related social needs. Cross-cutting (ie, health-related social needs agnostic) recommendations include leveraging navigation (eg, people, technology) to identify, refer, and deliver health-related social needs interventions; addressing health-related social needs through multilevel interventions; and recognizing that health-related social needs are states, not traits, that fluctuate over time. Health-related social needs-specific interventions are recommended, and pros and cons of addressing more than one health-related social needs concurrently are characterized. Considerations for collaborating with community partners are highlighted. The need for careful planning, strong partners, and funding is stressed. Finally, we outline a future research agenda to address evidence gaps.

Community-Academic Partnership: Intervention to Prepare Community Members for the End-of-Life Journey.

Despite research findings that rural Appalachians prefer to die at home, few people access palliative and hospice care services, and many report limited knowledge about palliative/end-of-life care resources. A community-academic partnership was formed to address this need. Train-the-trainer workshop and materials were co-developed. This study tested the feasibility and cultural acceptability of the training intervention to increase community members' knowledge about palliative/end-of-life care resources for East Tennessee Appalachian people. Community-based participatory research design and culture care theory guided the project, intervention, and research. After engaging in end-of-life training, participants completed a retrospective pretest-posttest survey. Paired samples t tests were used to compare knowledge before and after training. Means and standard deviations were used to report training material usefulness and cultural acceptability. Short-answer qualitative data were analyzed using content analysis. Sixty-six adults completed the survey. Ratings for training materials and cultural/theological acceptability were high. Participant knowledge rankings showed significant improvement after training at the P <.001 level. Qualitative feedback was positive. The training intervention was feasible, culturally acceptable, and effective for increasing East Tennessee Appalachian persons' palliative/end-of-life care knowledge. Community member expertise/collaboration integrated into every stage of the project is the bedrock of cultural acceptability and feasibility.

Inactivation of the paraventricular nucleus attenuates the cardiogenic sympathetic afferent reflex in the spontaneously hypertensive rat.

BACKGROUND: Myocardial ischemia causes the release of bradykinin, which stimulates cardiac afferents, causing sympathetic excitation and chest pain. Glutamatergic activation of the paraventricular hypothalamic nucleus (PVN) in the spontaneously hypertensive rat (SHR) drives elevated basal sympathetic activity. Thus, we tested the hypothesis that inactivation of the PVN attenuates the elevated reflex response to epicardial bradykinin in the SHR and that ionotropic PVN glutamate receptors mediate the elevated reflex. METHODS: We recorded the arterial pressure and renal sympathetic nerve activity (RSNA) response to epicardial bradykinin application in anesthetized SHR and Wistar Kyoto (WKY) rats before and after PVN microinjection of GABA A agonist muscimol or ionotropic glutamate receptor antagonist kynurenic acid. RESULTS: Muscimol significantly decreased the arterial pressure response to bradykinin from 180.4 ±â€Š5.8 to 119.5 ±â€Š6.9 mmHg in the SHR and from 111.8 ±â€Š7.0 to 84.2 ±â€Š8.3 mmHg in the WKY and the RSNA response from 186.2 ±â€Š7.1 to 142.7 ±â€Š7.3% of baseline in the SHR and from 201.0 ±â€Š11.5 to 160.2 ±â€Š9.3% of baseline in the WKY. Kynurenic acid significantly decreased the arterial pressure response in the SHR from 164.5 ±â€Š5.0 to 126.2 ±â€Š7.7 mmHg and the RSNA response from 189.9 ±â€Š13.7to 168.5 ±â€Š12.7% of baseline but had no effect in the WKY. CONCLUSION: These results suggest that tonic PVN activity is critical for the full manifestation of the CSAR in both the WKY and SHR. Glutamatergic PVN activity contributes to the augmented CSAR observed in the SHR.

Characteristics of drug-involved black women under community supervision; implications for retention in HIV clinical trials and healthcare.

This study examined retention and its relationship to mental health, substance use, and social determinants of health in a randomized clinical trial of a behavioral HIV/sexually transmitted infection prevention intervention with drug-involved Black women (N = 348) under community supervision programs in New York City. Using secondary analysis, we used logistic models to test the association between factors related to mental health, substance use, and social determinants of health and follow-up assessment completion (three, six, and 12 months). Participants who were diagnosed with schizophrenia had lower odds of retention. Participants who misused prescription opiates during their lifetime or food insecure in the past 90 days had higher odds of retention throughout the intervention.

Cinchona Alkaloid Polymers Demonstrate Highly Efficient Gene Delivery Dependent on Stereochemistry, Methoxy Substitution, and Length.

Nucleic acid delivery with cationic polymers is a promising alternative to expensive viral-based methods; however, it often suffers from a lower performance. Herein, we present a highly efficient delivery system based on cinchona alkaloid natural products copolymerized with 2-hydroxyethyl acrylate. Cinchona alkaloids are an attractive monomer class for gene delivery applications, given their ability to bind to DNA via both electrostatics and intercalation. To uncover the structure-activity profile of the system, four structurally similar cinchona alkaloids were incorporated into polymers: quinine, quinidine, cinchonine, and cinchonidine. These polymers differed in the chain length, the presence or absence of a pendant methoxy group, and stereochemistry, all of which were found to alter gene delivery performance and the ways in which the polymers overcome biological barriers to transfection. Longer polymers that contained the methoxy-bearing cinchona alkaloids (i.e., quinine and quinidine) were found to have the best performance. These polymers exhibited the tightest DNA binding, largest and most abundant DNA-polymer complexes, and best endosomal escape thanks to their increased buffering capacity and closest nuclear proximity of the payload. Overall, this work highlights the remarkable efficiency of polymer systems that incorporate cinchona alkaloid natural products while demonstrating the profound impact that small structural changes can have on overcoming biological hurdles associated with gene delivery.

Building a better model: abandon kitchen sink regression.

This paper critically examines 'kitchen sink regression', a practice characterised by the manual or automated selection of variables for a multivariable regression model based on p values or model-based information criteria. We highlight the pitfalls of this method, using examples from perinatal/neonatal medicine, and propose more robust alternatives. The concept of directed acyclic graphs (DAGs) is introduced as a tool for describing and analysing causal relationships. We highlight five key issues with 'kitchen sink regression': (1) the disregard for the directionality of variable relationships, (2) the lack of a meaningful causal interpretation of effect estimates from these models, (3) the inflated alpha error rate due to multiple testing, (4) the risk of overfitting and model instability and (5) the disregard for content expertise in model building. We advocate for the use of DAGs to guide variable selection for models that aim to examine associations between a putative risk factor and an outcome and emphasise the need for a more thoughtful and informed use of regression models in medical research.

Novel tactile bottle neck adaptor facilitates eye drop adherence in visually impaired patients.

PURPOSE: To test the use of Ring-IT, a novel 3D tactile bottle neck adaptor in topical eye drop adherence in visually impaired patients. METHODS: Bottle neck ring adaptors with either one, two or three protrusions with cube or sphere endings were designed. In phase 1, low vision was simulated in healthy subjects (n=20) with a 20/200 vision simulator; while in phase 2, visually impaired patients (n=26; 20/70 or worse) were recruited. Subjects were randomised to six combinations of varying protrusions and shapes on medication bottles and asked to identify these traits at different presentations. Responses and time to identify were recorded. RESULTS: Phase 1: 98.3% of subjects correctly identified the number of protrusions. Mean time to identify was 4.5±6.1 s. Identification success for cube and sphere end pieces were 91.7% and 73.3%, with average time for identification of 9.9±7.6 and 10.9±9.0 s. In phase 2, 92.3% of subjects correctly identified the number of protrusions. Mean time to identify was 6.0±3.0 s. Identification success for cube and sphere end pieces were 78.2% and 74.4%; with average time for identification of 7.5±4.8 and 8.5±5.6 s, respectively. CONCLUSIONS: Ring-IT was identified with accuracy and speed by both low vision simulated subjects, and by patients with true limited visual capabilities. These tactile bottle neck ring adaptors can be used as an assistive low vision aid device and may increase eye drop regimen adherence in visually impaired patients.

Centers for Disease Control and Prevention Harvard Program Evaluation Practicum: 10 Years of Partnership in Public Health Program Evaluation.

The Centers for Disease Control and Prevention (CDC)'s Division of Reproductive Health and Harvard T.H. Chan School of Public Health (HSPH) Program Evaluation Practicum (CDC/HSPH Practicum) is a mutually beneficial workforce development partnership formed to provide state, local, and tribal public health organizations with an evaluation plan for a maternal and child health (MCH) program. State, local, and tribal public health organizations submit an MCH program in need of evaluation for inclusion consideration. Student pairs are matched with the selected programs in a 3-week practical field-based experience. This Practicum provides didactic training for both program staff and students followed by field work at the public health organizations. Students provide organizations with comprehensive evaluation plans, complete with logic model, methodology, and indicators. Since the Practicum's inception in 2013, 104 HSPH graduate students have been trained and 30 states and 1 territory have participated and received evaluation plans for their MCH programs. The utility and importance of the CDC/HSPH Practicum is evidenced by program staff and student feedback. Multiple states have implemented the plans designed by the students, with some evaluations leading to program enhancements. The CDC/HSPH Practicum prepares students for the workforce and adds much needed capacity to public health organizations by providing them with evaluation knowledge and skills, and usable evaluation plans to improve MCH-a win-win for all.

Sequencing and characterization of Helcococcus ovis: a comprehensive comparative genomic analysis of virulence.

BACKGROUND: Helcococcus ovis (H. ovis) is an emerging bacterial pathogen that commonly causes opportunistic respiratory, mammary, and uterine infections across mammalian hosts. This study applied long- and short-read whole genome sequencing technologies to identify virulence factors in five H. ovis isolates with low, medium, and high virulence phenotypes. RESULTS: The resulting assemblies contained one circular chromosome ranging from 1,744,566 to 1,850,083 bp in length and had a mean GC content of 27.6%. Phylogenetic and nucleotide identity analyses found low virulence strain KG38 to be part of a clade that forms an outgroup apart from the rest of the H. ovis taxon. Assembling the first complete genomes of the species revealed major genomic rearrangements in KG38. One to six prophage regions were identified in each genome. A novel pathogenicity island was found exclusively in the two high virulence strains (KG37 and KG104), along with two hypothetical transmembrane proteins designated as putative VFs. Finally, three zinc ABC transporters and three Type-II/IV secretion systems were identified as possible virulence determinants in this species. The low virulence strain KG38 has fewer intact paralogs of these operons in its genome compared to the higher virulence isolates, which strongly suggests a role in virulence. This strain is also missing four putative virulence factors (VFs) found in other isolates associated with adherence (collagen adhesin precursor), immune evasion (choline-binding protein A and a PspA-like hypothetical protein) and cell wall synthesis (glycerol-3-phosphate cytidylyltransferase). CONCLUSIONS: In this study, we assembled reference-quality complete genomes for five H. ovis strains to identify putative virulence factors. Phylogenetic analyses of H. ovis isolates revealed the presence of a clade representing a potentially novel species within the genus Helcococcus. A novel pathogenicity island and two hypothetical transmembrane proteins were found exclusively in high-virulence strains. The identification of Zinc ABC transporters and Type-II/IV secretion systems as possible virulence determinants, along with the differences in operon content between the low and high virulence isolates, strongly suggests they also play a role in the bacterium's pathogenicity. Taken together, these findings are a valuable first step toward deciphering the pathogenesis of H. ovis infections.

A remote monitoring-enabled home exercise prescription for patients with interstitial lung disease at risk for exercise-induced desaturation.

RATIONALE: Alternatives to center-based pulmonary rehabilitation are needed to improve patient access to this important therapy. A critical challenge to overcome is how to maximize safety of unsupervised exercise for at-risk patients. We investigated if a novel remote monitoring-enabled mobile health (mHealth) program is safe, feasible, and effective for patients who experience exercise-induced hemoglobin desaturation. METHODS: An interstitial lung disease (ILD) commonly associated with pronounced exercise desaturation was investigated - the rare, female-predominant ILD lymphangioleiomyomatosis (LAM). Over a 12-week program, hemoglobin saturation (SpO2) was continuously recorded during all home exercise sessions. Intervention effects were assessed with 6-min walk test (6MWT), maximal cardiopulmonary exercise test (CPET), lower extremity computerized dynamometry, pulmonary function tests, and health-related quality of life (QoL) surveys. Safety was assessed by blood biomarkers of systemic inflammation and cardiac wall stress, and incidence of adverse events. RESULTS: Fifteen LAM patients enrolled and 14 completed the intervention, with high adherence to aerobic (87 ± 15%) and strength (87 ± 12%) training components. An innovative characterization of exercise training SpO2 revealed that while mild-to-moderate desaturation was common during home workouts, participants were able to self-adjust exercise intensity and supplemental oxygen levels to maintain recommended exercise parameters. Significant improvements included 6MWT distance (+36 ± 34 m, p = 0.003), CPET time (p = 0.04), muscular endurance (p = 0.008), QoL (p = 0.009 to 0.03), and fatigue (p = 0.001 to 0.03). Patient acceptability and satisfaction indicators were high, blood biomarkers remained stable (p > 0.05), and no study-related adverse events occurred. CONCLUSION: A remote monitoring-enabled home exercise program is a safe, feasible, and effective approach even for patients who experience exercise desaturation.

Enhancing pDNA Delivery with Hydroquinine Polymers by Modulating Structure and Composition.

Quinine is a promising natural product building block for polymer-based nucleic acid delivery vehicles as its structure enables DNA binding through both intercalation and electrostatic interactions. However, studies exploring the potential of quinine-based polymers for nucleic acid delivery applications (transfection) are limited. In this work, we used a hydroquinine-functionalized monomer, HQ, with 2-hydroxyethyl acrylate to create a family of seven polymers (HQ-X, X = mole percentage of HQ), with mole percentages of HQ ranging from 12 to 100%. We developed a flow cytometer-based assay for studying the polymer-pDNA complexes (polyplex particles) directly and demonstrate that polymer composition and monomer structure influence polyplex characteristics such as the pDNA loading and the extent of adsorption of serum proteins on polyplex particles. Biological delivery experiments revealed that maximum transgene expression, outperforming commercial controls, was achieved with HQ-25 and HQ-35 as these two variants sustained gene expression over 96 h. HQ-44, HQ-60, and HQ-100 were not successful in inducing transgene expression, despite being able to deliver pDNA into the cells, highlighting that the release of pDNA is likely the bottleneck in transfection for polymers with higher HQ content. Using confocal imaging, we quantified the extent of colocalization between pDNA and lysosomes, proving the remarkable endosomal escape capabilities of the HQ-X polymers. Overall, this study demonstrates the advantages of HQ-X polymers as well as provides guiding principles for improving the monomer structure and polymer composition, supporting the development of the next generation of polymer-based nucleic acid delivery vehicles harnessing the power of natural products.

MET Receptor Tyrosine Kinase Inhibition Reduces Interferon-Gamma (IFN-γ)-Stimulated PD-L1 Expression through the STAT3 Pathway in Melanoma Cells.

Melanoma is the leading cause of death from cutaneous malignancy. While targeted therapy and immunotherapy with checkpoint inhibitors have significantly decreased the mortality rate of this disease, advanced melanoma remains a therapeutic challenge. Here, we confirmed that interferon-gamma (IFN-γ)-induced PD-L1 expression in melanoma cell lines. This increased expression was down-regulated by the reduction in phosphorylated STAT3 signaling via MET tyrosine kinase inhibitor treatment. Furthermore, immunoprecipitation and confocal immunofluorescence microscopy analysis reveals MET and PD-L1 protein-protein interaction and colocalization on the cell surface membrane of melanoma cells. Together, these findings demonstrate that the IFN-γ-induced PD-L1 expression in melanoma cells is negatively regulated by MET inhibition through the JAK/STAT3 signaling pathway and establish the colocalization and interaction between an RTK and a checkpoint protein in melanoma cells.

Effectiveness of the nutrition referral system in a multidisciplinary pancreatic cancer clinic.

PURPOSE: Proactive nutrition screening and intervention is associated with improved outcomes for patients with pancreatic adenocarcinoma (PDAC). To better optimize nutrition amongst our PDAC population, we implemented systematic malnutrition screening in the Johns Hopkins pancreas multidisciplinary clinic (PMDC) and assessed the effectiveness of our nutrition referral system. METHODS: This was a single institution prospective study of patients seen in the PMDC, screened for malnutrition using the Malnutrition Screening Tool (MST) (score range=0 to 5, score > 2 indicates risk of malnutrition), and offered referrals to the oncology dietitian. Patients that requested a referral but did not attend a nutrition appointment were contacted by phone to assess barriers to seeing the dietitian. Univariate (UVA) and multivariable (MVA) analyses were carried out to identify predictors of referral status and appointment completion status. RESULTS: A total of 97 patients were included in the study, of which 72 (74.2%) requested a referral and 25 (25.8%) declined. Of the 72 patients who requested a referral, 31 (43.1%) attended an appointment with the oncology dietitian. Data on information session attendance was available for 35 patients, of which 8 (22.9%) attended a pre-clinic information session in which the importance of optimal nutrition was highlighted. On MVA, information session attendance was significantly associated with requesting a referral (OR: 11.1, 95% CI 1.12-1.0E3, p=0.037) and successfully meeting with the oncology dietitian (OR: 5.88, 95% CI 1.00-33.3, p=0.049). CONCLUSION: PMDC teams should institute educational initiatives on the importance of optimal nutrition in order to increase patient engagement with nutrition services.