Racial and ethnic associations with comprehensive cancer center access and clinical trial enrollment for acute leukemia.

BACKGROUND: Clinical trial participation at Comprehensive Cancer Centers (CCC) is inequitable for minoritized racial and ethnic groups with acute leukemia. CCCs care for a high proportion of adults with acute leukemia. It is unclear if participation inequities are due to CCC access, post-access enrollment, or both. METHODS: We conducted a retrospective cohort study of adults with acute leukemia (2010-2019) residing within Massachusetts, the designated catchment area of the Dana-Farber/Harvard Cancer Center (DF/HCC). Individuals were categorized as non-Hispanic Asian (NHA), Black (NHB), White (NHW), Hispanic White (HW), or Other. Decomposition analyses assessed covariate contributions to disparities in (1) access to DF/HCC care and (2) post-access enrollment. RESULTS: Of 3698 individuals with acute leukemia, 85.9% were NHW, 4.5% HW, 4.3% NHB, 3.7% NHA, and 1.3% Other. Access was lower for HW (age- and sex-adjusted OR = 0.64, 95% CI = 0.45 to 0.90) and reduced post-access enrollment for HW (aOR = 0.54, 95% CI =0.34 to 0.86) and NHB (aOR = 0.60, 95% CI = 0.39 to 0.92) compared to NHW. Payor and socioeconomic status (SES) accounted for 25.2% and 21.2% of the +1.1% absolute difference in HW access. Marital status and SES accounted for 8.0% and 7.0% of the -8.8% absolute disparity in HW enrollment; 76.4% of the disparity was unexplained. SES and marital status accounted for 8.2% and 7.1% of the -9.1% absolute disparity in NHB enrollment; 73.0% of the disparity was unexplained. CONCLUSIONS: A substantial proportion of racial and ethnic inequities in acute leukemia trial enrollment at CCCs are from post-access enrollment, the majority of which was not explained by sociodemographic factors.

The DIAD Approach to Correlative Synchrotron X-ray Imaging and Diffraction Analysis of Human Enamel.

The Dual Imaging and Diffraction (DIAD) beamline at Diamond Light Source (Didcot, U.K.) implements a correlative approach to the dynamic study of materials based on concurrent analysis of identical sample locations using complementary X-ray modalities to reveal structural detail at various length scales. Namely, the underlying beamline principle and its practical implementation allow the collocation of chosen regions within the sample and their interrogation using real-space imaging (radiography and tomography) and reciprocal space scattering (diffraction). The switching between the two principal modes is made smooth and rapid by design, so that the data collected is interlaced to obtain near-simultaneous multimodal characterization. Different specific photon energies are used for each mode, and the interlacing of acquisition steps allows conducting static and dynamic experiments. Building on the demonstrated realization of this state-of-the-art approach requires further refining of the experimental practice, namely, the methods for gauge volume collocation under different modes of beam-sample interaction. To address this challenge, experiments were conducted at DIAD devoted to the study of human dental enamel, a hierarchical structure composed of hydroxyapatite mineral nanocrystals, as a static sample previously affected by dental caries (tooth decay) as well as under dynamic conditions simulating the process of acid demineralization. Collocation and correlation were achieved between WAXS (wide-angle X-ray scattering), 2D (radiographic), and 3D (tomographic) imaging. While X-ray imaging in 2D or 3D modes reveals real-space details of the sample microstructure, X-ray scattering data for each gauge volume provided statistical nanoscale and ultrastructural polycrystal reciprocal-space information such as phase and preferred orientation (texture). Careful registration of the gauge volume positions recorded during the scans allowed direct covisualization of the data from two modalities. Diffraction gauge volumes were identified and visualized within the tomographic data sets, revealing the underlying local information to support the interpretation of the diffraction patterns. The present implementation of the 4D microscopy paradigm allowed following the progression of demineralization and its correlation with time-dependent WAXS pattern evolution in an approach that is transferable to other material systems.

Therapeutic Inertia and Delays in Insulin Intensification in Type 2 Diabetes: A Literature Review.

Background: Therapeutic inertia leading to delays in insulin initiation or intensification is a major contributor to lack of optimal diabetes care. This report reviews the literature summarizing data on therapeutic inertia and delays in insulin intensification in the management of type 2 diabetes. Methods: A literature search was conducted of the Allied & Complementary Medicine, BIOSIS Previews, Embase, EMCare, International Pharmaceutical Abstracts, MEDLINE, and ToxFile databases for clinical studies, observational research, and meta-analyses from 2012 to 2022 using search terms for type 2 diabetes and delay in initiating/intensifying insulin. Twenty-two studies met inclusion criteria. Results: Time until insulin initiation among patients on two to three antihyperglycemic agents was at least 5 years, and mean A1C ranged from 8.7 to 9.8%. Early insulin intensification was linked with reduced A1C by 1.4%, reduction of severe hypoglycemic events from 4 to <1 per 100 person-years, and diminution in risk of heart failure (HF) by 18%, myocardial infarction (MI) by 23%, and stroke by 28%. In contrast, delayed insulin intensification was associated with increased risk of HF (64%), MI (67%), and stroke (51%) and a higher incidence of diabetic retinopathy. In the views of both patients and providers, hypoglycemia was identified as a primary driver of therapeutic inertia; 75.5% of physicians reported that they would treat more aggressively if not for concerns about hypoglycemia. Conclusion: Long delays before insulin initiation and intensification in clinically eligible patients are largely driven by concerns over hypoglycemia. New diabetes technology that provides continuous glucose monitoring may reduce occurrences of hypoglycemia and help overcome therapeutic inertia associated with insulin initiation and intensification.

DYSPNEA AND MECHANICAL VENTILATION: APPLYING PHYSIOLOGY TO GUIDE THERAPY.

While advances in our understanding of mechanical ventilation have improved mortality from acute respiratory distress syndrome, recent studies indicate a rising incidence of post-ventilation mental health sequelae, including post-traumatic stress disorder (PTSD). Concurrent research on the physiology of dyspnea provides insights about the role of multiple sources of sensory information underlying respiratory discomfort along with the contribution of efferent-afferent dissociation to dyspnea, and the subsequent relationship of dyspnea to a range of affective responses, including fear and anxiety. An understanding of the mechanisms of dyspnea may provide holistic approaches to managing acute respiratory failure that can achieve the best physical and emotional outcomes for patients requiring mechanical ventilation.

Vitamin D Deficiency (VDD) and Benefits of Supplementation in Veterans with IBS-D.

Many veterans deployed to Gulf War areas suffer from persistent chronic diarrhea that is disabling and affects their quality of life. The causes for this condition have eluded investigators until recently and recent literature has shed light on the effect of vitamin D on the brain-gut axis. This study focused on determining clinical causes contributing to diarrhea and assessed whether reversing the identified causes, specifically vitamin D deficiency (VDD), could reduce the incidence of diarrhea in Gulf War veterans (GWVs). All patients completed a workup that included serologies (IBD, celiac), routine laboratory tests (CBC, chemistry panels, TSH, T4, CRP), cultures for enteric pathogens (C diff, bacteria, viruses, small intestinal bacterial overgrowth (SIBO)), and upper and lower endoscopies with histology and a trial of cholestyramine to exclude choleretic diarrhea and rifaximin for dysbiosis. A total of 4221 veterans were screened for chronic diarrhea, yielding 105 GWVs, of which 69 GWVs had irritable bowel syndrome with diarrhea (IBS-D). Paired t-tests demonstrated that all GWVs had VDD (t-11.62, df68 and sig(2-tailed) 0.0001) (defined as a vitamin D level less than 30 ng/mL with normal ranges of 30-100 ng/mL) but no positive serologies, inflammatory markers, abnormal endoscopies, cultures, or histology to explain their persistent diarrhea. There was no correlation with age, BMI, or inflammation. Some zip codes had a higher frequency of GWVs with VDD, but the number of deployments had no impact. Treatment with vitamin D supplementation (3000-5000 units), given in the morning, based on weight, reduced the number of bowel movements per day (p < 0.0001) without causing hypercalcemia. We suggest that VDD is important in the etiology of IBS-D in GWVs and that vitamin D supplementation significantly reduces diarrhea.

Genome-wide study of genetic polymorphisms predictive for outcome from first-line oxaliplatin-based chemotherapy in colorectal cancer patients.

We conducted the first large genome-wide association study to identify novel genetic variants that predict better (or poorer) prognosis in colorectal cancer patients receiving standard first-line oxaliplatin-based chemotherapy vs chemotherapy without oxaliplatin. We used data from two phase III trials, NCCTG N0147 and NCCTG N9741 and a population-based patient cohort, DACHS. Multivariable Cox proportional hazards models were employed, including an interaction term between each SNP and type of treatment for overall survival (OS) and progression-free survival. The analysis was performed for studies individually, and the results were combined using fixed-effect meta-analyses separately for resected stage III colon cancer (3098 patients from NCCTG N0147 and 549 patients from DACHS) and mCRC (505 patients from NCCTG N9741 and 437 patients from DACHS). We further performed gene-based analysis as well as in silico bioinformatics analysis for CRC-relevant functional genomic annotation of identified loci. In stage III colon cancer patients, a locus on chr22 (rs11912167) was associated with significantly poorer OS after oxaliplatin-based chemotherapy vs chemotherapy without oxaliplatin (Pinteraction < 5 × 10-8 ). For mCRC patients, three loci on chr1 (rs1234556), chr12 (rs11052270) and chr15 (rs11858406) were found to be associated with differential OS (P < 5 × 10-7 ). The locus on chr1 located in the intronic region of RCSD1 was replicated in an independent cohort of 586 mCRC patients from ALGB/SWOG 80405 (Pinteraction = .04). The GWA gene-based analysis yielded for RCSD1 the most significant association with differential OS in mCRC (P = 6.6 × 10-6 ). With further investigation into its biological mechanisms, this finding could potentially be used to individualize first-line treatment and improve clinical outcomes.

BayesTME: An end-to-end method for multiscale spatial transcriptional profiling of the tissue microenvironment.

Spatial variation in cellular phenotypes underlies heterogeneity in immune recognition and response to therapy in cancer and many other diseases. Spatial transcriptomics holds the potential to quantify such variation, but existing analysis methods are limited by their focus on individual tasks such as spot deconvolution. We present BayesTME, an end-to-end Bayesian method for analyzing spatial transcriptomics data. BayesTME unifies several previously distinct analysis goals under a single, holistic generative model. This unified approach enables BayesTME to deconvolve spots into cell phenotypes without any need for paired single-cell RNA-seq. BayesTME then goes beyond spot deconvolution to uncover spatial expression patterns among coordinated subsets of genes within phenotypes, which we term spatial transcriptional programs. BayesTME achieves state-of-the-art performance across myriad benchmarks. On human and zebrafish melanoma tissues, BayesTME identifies spatial transcriptional programs that capture fundamental biological phenomena such as bilateral symmetry and tumor-associated fibroblast and macrophage reprogramming. BayesTME is open source.

Differential Inhibition of Anaplerotic Pyruvate Carboxylation and Glutaminolysis-Fueled Anabolism Underlies Distinct Toxicity of Selenium Agents in Human Lung Cancer.

Past chemopreventive human trials on dietary selenium supplements produced controversial outcomes. They largely employed selenomethionine (SeM)-based diets. SeM was less toxic than selenite or methylseleninic acid (MSeA) to lung cancer cells. We thus investigated the toxic action of these Se agents in two non-small cell lung cancer (NSCLC) cell lines and ex vivo organotypic cultures (OTC) of NSCLC patient lung tissues. Stable isotope-resolved metabolomics (SIRM) using 13C6-glucose and 13C5,15N2-glutamine tracers with gene knockdowns were employed to examine metabolic dysregulations associated with cell type- and treatment-dependent phenotypic changes. Inhibition of key anaplerotic processes, pyruvate carboxylation (PyC) and glutaminolysis were elicited by exposure to MSeA and selenite but not by SeM. They were accompanied by distinct anabolic dysregulation and reflected cell type-dependent changes in proliferation/death/cell cycle arrest. NSCLC OTC showed similar responses of PyC and/or glutaminolysis to the three agents, which correlated with tissue damages. Altogether, we found differential perturbations in anaplerosis-fueled anabolic pathways to underlie the distinct anti-cancer actions of the three Se agents, which could also explain the failure of SeM-based chemoprevention trials.

Baseline Quality of Life is a Strong and Independent Prognostic Factor for Overall Survival in Metastatic Colorectal Cancer.

BACKGROUND: Previous studies have established that higher baseline quality of life (QOL) scores are associated with improved survival in patients with metastatic colorectal cancer (mCRC). We examined the relationship between overall survival (OS) and baseline QOL. PATIENTS AND METHODS: A total of 1 247 patients with mCRC participating in N9741 (comparing bolus 5-FU/LV, irinotecan [IFL] vs infusional 5-FU/leucovorin [LV]/oxaliplatin [FOLFOX] vs. irinotecan/oxaliplatin [IROX]) provided data at baseline on overall QOL using a single-item linear analogue self-assessment (LASA) 0-100 point scale. The association of OS according to clinically deficient (defined as CD-QOL, score 0-50) vs not clinically deficient (nCD-QOL, score 51-100) baseline QOL scores was tested. A multivariable analysis using Cox proportional hazards modeling was performed to adjust for the effects of multiple baseline factors. An exploratory analysis was performed evaluating OS according to baseline QOL status among patients who did or did not receive second-line therapy. RESULTS: Baseline QOL was a strong predictor of OS for the whole cohort (CD-QOL vs nCD-QOL: 11.2 months vs 18.4 months, P < .0001), and in each arm IFL 12.4 vs 15.1 months, FOLFOX 11.1 months vs 20.6 months, and IROX 8.9 months vs 18.1 months. Baseline QOL was associated with baseline performance status (PS) (P < .0001). After adjusting for PS and treatment arm, baseline QOL was still associated with OS (P = .017). CONCLUSIONS: Baseline QOL is an independent prognostic factor for OS in patients with mCRC. The demonstration that patient-assessed QOL and PS are independent prognostic indicators suggests that these assessments provide important complementary prognostic information.

Plasma 25-Hydroxyvitamin D Levels and Survival in Stage III Colon Cancer: Findings from CALGB/SWOG 80702 (Alliance).

PURPOSE: To assess whether higher plasma 25-hydroxyvitamin D [25(OH)D] is associated with improved outcomes in colon cancer and whether circulating inflammatory cytokines mediate such association. EXPERIMENTAL DESIGN: Plasma samples were collected from 1,437 patients with stage III colon cancer enrolled in a phase III randomized clinical trial (CALGB/SWOG 80702) from 2010 to 2015, who were followed until 2020. Cox regressions were used to examine associations between plasma 25(OH)D and disease-free survival (DFS), overall survival (OS), and time to recurrence (TTR). Mediation analysis was performed for circulating inflammatory biomarkers of C-reactive protein (CRP), IL6, and soluble TNF receptor 2 (sTNF-R2). RESULTS: Vitamin D deficiency [25(OH)D <12 ng/mL] was present in 13% of total patients at baseline and in 32% of Black patients. Compared with deficiency, nondeficient vitamin D status (≥12 ng/mL) was significantly associated with improved DFS, OS, and TTR (all Plog-rank<0.05), with multivariable-adjusted HRs of 0.68 (95% confidence interval, 0.51-0.92) for DFS, 0.57 (0.40-0.80) for OS, and 0.71 (0.52-0.98) for TTR. A U-shaped dose-response pattern was observed for DFS and OS (both Pnonlinearity<0.05). The proportion of the association with survival that was mediated by sTNF-R2 was 10.6% (Pmediation = 0.04) for DFS and 11.8% (Pmediation = 0.05) for OS, whereas CRP and IL6 were not shown to be mediators. Plasma 25(OH)D was not associated with the occurrence of ≥ grade 2 adverse events. CONCLUSIONS: Nondeficient vitamin D is associated with improved outcomes in patients with stage III colon cancer, largely independent of circulation inflammations. A randomized trial is warranted to elucidate whether adjuvant vitamin D supplementation improves patient outcomes.

Single-cell multi-omics in the medicinal plant Catharanthus roseus.

Advances in omics technologies now permit the generation of highly contiguous genome assemblies, detection of transcripts and metabolites at the level of single cells and high-resolution determination of gene regulatory features. Here, using a complementary, multi-omics approach, we interrogated the monoterpene indole alkaloid (MIA) biosynthetic pathway in Catharanthus roseus, a source of leading anticancer drugs. We identified clusters of genes involved in MIA biosynthesis on the eight C. roseus chromosomes and extensive gene duplication of MIA pathway genes. Clustering was not limited to the linear genome, and through chromatin interaction data, MIA pathway genes were present within the same topologically associated domain, permitting the identification of a secologanin transporter. Single-cell RNA-sequencing revealed sequential cell-type-specific partitioning of the leaf MIA biosynthetic pathway that, when coupled with a single-cell metabolomics approach, permitted the identification of a reductase that yields the bis-indole alkaloid anhydrovinblastine. We also revealed cell-type-specific expression in the root MIA pathway.

The association between genetically elevated polyunsaturated fatty acids and risk of cancer.

BACKGROUND: The causal relevance of polyunsaturated fatty acids (PUFAs) for risk of site-specific cancers remains uncertain. METHODS: Using a Mendelian randomization (MR) framework, we assessed the causal relevance of PUFAs for risk of cancer in European and East Asian ancestry individuals. We defined the primary exposure as PUFA desaturase activity, proxied by rs174546 at the FADS locus. Secondary exposures were defined as omega 3 and omega 6 PUFAs that could be proxied by genetic polymorphisms outside the FADS region. Our study used summary genetic data on 10 PUFAs and 67 cancers, corresponding to 562,871 cases and 1,619,465 controls, collected by the Fatty Acids in Cancer Mendelian Randomization Collaboration. We estimated odds ratios (ORs) for cancer per standard deviation increase in genetically proxied PUFA exposures. FINDINGS: Genetically elevated PUFA desaturase activity was associated (P < 0.0007) with higher risk (OR [95% confidence interval]) of colorectal cancer (1.09 [1.07-1.11]), esophageal squamous cell carcinoma (1.16 [1.06-1.26]), lung cancer (1.06 [1.03-1.08]) and basal cell carcinoma (1.05 [1.02-1.07]). There was little evidence for associations with reproductive cancers (OR = 1.00 [95% CI: 0.99-1.01]; Pheterogeneity = 0.25), urinary system cancers (1.03 [0.99-1.06], Pheterogeneity = 0.51), nervous system cancers (0.99 [0.95-1.03], Pheterogeneity = 0.92) or blood cancers (1.01 [0.98-1.04], Pheterogeneity = 0.09). Findings for colorectal cancer and esophageal squamous cell carcinoma remained compatible with causality in sensitivity analyses for violations of assumptions. Secondary MR analyses highlighted higher omega 6 PUFAs (arachidonic acid, gamma-linolenic acid and dihomo-gamma-linolenic acid) as potential mediators. PUFA biosynthesis is known to interact with aspirin, which increases risk of bleeding and inflammatory bowel disease. In a phenome-wide MR study of non-neoplastic diseases, we found that genetic lowering of PUFA desaturase activity, mimicking a hypothetical intervention to reduce cancer risk, was associated (P < 0.0006) with increased risk of inflammatory bowel disease but not bleeding. INTERPRETATION: The PUFA biosynthesis pathway may be an intervention target for prevention of colorectal cancer and esophageal squamous cell carcinoma but with potential for increased risk of inflammatory bowel disease. FUNDING: Cancer Resesrch UK (C52724/A20138, C18281/A19169). UK Medical Research Council (MR/P014054/1). National Institute for Health Research (NIHR202411). UK Medical Research Council (MC_UU_00011/1, MC_UU_00011/3, MC_UU_00011/6, and MC_UU_00011/4). National Cancer Institute (R00 CA215360). National Institutes of Health (U01 CA164973, R01 CA60987, R01 CA72520, U01 CA74806, R01 CA55874, U01 CA164973 and U01 CA164973).

Authorization of midwives to perform basic emergency obstetric and newborn care signal functions in Argentina, Ghana, and India: A multi-country validation study of a key global maternal and newborn health indicator.

BACKGROUND: Midwives' authorization to deliver the seven basic emergency obstetric and newborn care (BEmONC) functions is a core policy indicator in global monitoring frameworks, yet little evidence supports whether such data are captured accurately, or whether authorization demonstrates convergence with midwives' skills and actual provision of services. In this study, we aimed to validate the data reported in global monitoring frameworks (criterion validity) and to determine whether a measure of authorization is a valid indicator for BEmONC availability (construct validity). METHODS: We conducted a validation study in Argentina, Ghana, and India. To assess accuracy of the reported data on midwives' authorization to provide BEmONC services, we reviewed national regulatory documents and compared with reported country-specific data in Countdown to 2030 and the World Health Organization Maternal, Newborn, Child and Adolescent Health Policy Survey. To assess whether authorization demonstrates convergent validity with midwives' skills, training, and performance of BEmONC signal functions, we surveyed 1257 midwives/midwifery professionals and assessed variance. RESULTS: We detected discrepancies between data reported in the global monitoring frameworks and the national regulatory framework in all three countries. We found wide variations between midwives' authorization to perform signal functions and their self-reported skills and actual performance within the past 90 days. The percentage of midwives who reported performing all signal functions for which they were authorized per country-specific regulations was 17% in Argentina, 23% in Ghana, and 31% in India. Additionally, midwives in all three countries reported performing some signal functions that the national regulations did not authorize. CONCLUSION: Our findings suggest limitations in criterion and construct validity for this indicator in Argentina, Ghana, and India. Some signal functions such as assisted vaginal delivery may be obsolete based on current practice patterns. Findings suggest the need to re-examine the emergency interventions that should be included as BEmONC signal functions.

Measuring adequacy of the midwifery workforce using standards of competency and scope of work: Exploring the density and distribution of midwives in three low- and middle-income countries using cross-sectional and geospatial data.

BACKGROUND: A global midwifery shortage hampers the goal of ending preventable maternal/newborn mortality and stillbirths. Whether current measures of midwifery workforce adequacy are valid is unknown. We compare two measures of density and distribution of midwifery professionals to assess their consistency, and explore how incorporating midwifery scope, competency, and the adjusting reference population impacts this critical metric. METHODS AND FINDINGS: We collected a census of midwives employed in eligible facilities in our study settings, (422 in Ghana; 909 in India), assessed the number practicing within the scope of work for midwifery professionals defined in the International Labor Organization International Standard Classification of Occupations, and whether they reported possessing the ICM essential competencies for basic midwifery practice. We altered the numerator, iteratively narrowing it from a simple count to include data on scope of practice and competency and reported changes in value. We altered the denominator by calculating the number of midwives per 10,000 total population, women of reproductive age, pregnancies, and births and explored variation in the indicator. Across four districts in Ghana, density of midwives decreased from 8.59/10,000 total population when counting midwives from facility staffing rosters to 1.30/10,000 total population when including only fully competent midwives by the ICM standard. In India, no midwives met the standard, thus the midwifery density of 1.37/10,000 total population from staffing rosters reduced to 0.00 considering competency. Changing the denominator to births vastly altered subnational measures, ranging from ~1700% change in Tolon to ~8700% in Thiruvallur. CONCLUSION: Our study shows that varying underlying parameters significantly affects the value of the estimate. Factoring in competency greatly impacts the effective coverage of midwifery professionals. Disproportionate differences were noted when need was estimated based on total population versus births. Future research should compare various estimates of midwifery density to health system process and outcome measures.

Overlapping Local and Systemic Defense Induced by an Oomycete Fatty Acid MAMP and Brown Seaweed Extract in Tomato.

Eicosapolyenoic fatty acids are integral components of oomycete pathogens that can act as microbe-associated molecular patterns to induce disease resistance in plants. Defense-inducing eicosapolyenoic fatty acids include arachidonic acid (AA) and eicosapentaenoic acid and are strong elicitors in solanaceous plants, with bioactivity in other plant families. Similarly, extracts of a brown seaweed, Ascophyllum nodosum, used in sustainable agriculture as a biostimulant of plant growth, may also induce disease resistance. A. nodosum, similar to other macroalgae, is rich in eicosapolyenoic fatty acids, which comprise as much as 25% of total fatty acid composition. We investigated the response of roots and leaves from AA or a commercial A. nodosum extract (ANE) on root-treated tomatoes via RNA sequencing, phytohormone profiling, and disease assays. AA and ANE significantly altered transcriptional profiles relative to control plants, inducing numerous defense-related genes with both substantial overlap and differences in gene expression patterns. Root treatment with AA and, to a lesser extent, ANE also altered both salicylic acid and jasmonic acid levels while inducing local and systemic resistance to oomycete and bacterial pathogen challenge. Thus, our study highlights overlap in both local and systemic defense induced by AA and ANE, with potential for inducing broad-spectrum resistance against pathogens. [Formula: see text] Copyright © 2023 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

The value of donkeys to livelihood provision in northern Ghana.

Increased demand for the supply of donkey hides for use in the Traditional Chinese Medicine e'jiao, is leading to a re-appraisal of donkeys' contributions to livelihoods across the world. This research aimed to understand the utilitarian value donkeys provide to poor small holder farmers, especially women, in their efforts to make a living in two rural communities in northern Ghana. Uniquely, children and donkey butchers were interviewed for the first time about their donkeys. A qualitative thematic analysis was undertaken of data disaggregated by sex, age and donkey-ownership. The majority of protocols were repeated during a second visit, ensuring comparative data between one wet, and one dry season. Donkeys are more important in people's lives than had previously been recognised and are highly valued by their owners for their help in reducing drudgery and the multi-functional services they offer. Hiring out donkeys to generate income is a secondary role for people who own donkeys, especially women. However, for financial and cultural reasons the way donkeys are kept results in the loss of a certain percentage of the animals to the donkey meat market, as well as the global hides trade. Increasing demand for donkey meat, coupled with increasing demand for donkeys for farming, is leading to donkey price inflation and theft of donkeys. This is putting pressure on the donkey population of neighbouring Burkina Faso and pricing resource-poor non-donkey owners out of the market. E'jiao has put the spotlight on the value of dead donkeys for the first time, especially to governments and middlemen. This study shows that the value of live donkeys to poor farming households is substantial. It attempts to understand and document this value thoroughly, should the majority of donkeys in West Africa be rounded up and slaughtered for the value of their meat and skin instead.

Protection against Doxorubicin-Induced Cardiotoxicity by Ergothioneine.

Background: Anthracyclines such as doxorubicin remain a primary treatment for hematological malignancies and breast cancers. However, cardiotoxicity induced by anthracyclines, possibly leading to heart failure, severely limits their application. The pathological mechanisms of anthracycline-induced cardiac injury are believed to involve iron-overload-mediated formation of reactive oxygen species (ROS), mitochondrial dysfunction, and inflammation. The dietary thione, ergothioneine (ET), is avidly absorbed and accumulated in tissues, including the heart. Amongst other cytoprotective properties, ET was shown to scavenge ROS, decrease proinflammatory mediators, and chelate metal cations, including Fe2+, preventing them from partaking in redox activities, and may protect against mitochondrial damage and dysfunction. Plasma ET levels are also strongly correlated to a decreased risk of cardiovascular events in humans, suggesting a cardioprotective role. This evidence highlights ET's potential to counteract anthracycline cardiotoxicity. Methods and Findings: We investigated whether ET supplementation can protect against cardiac dysfunction in mice models of doxorubicin-induced cardiotoxicity and revealed that it had significant protective effects. Moreover, ET administration in a mouse breast cancer model did not exacerbate the growth of the tumor or interfere with the chemotherapeutic efficacy of doxorubicin. Conclusion: These results suggest that ET could be a viable co-therapy to alleviate the cardiotoxic effects of anthracyclines in the treatment of cancers.

The polyphenol epigallocatechin gallate lowers circulating catecholamine concentrations and alters lipid metabolism during graded exercise in man: a randomized cross-over study.

PURPOSE: Physical exercise is shown to mitigate catecholamine metabolites; however, it is unknown if exercise-induced increases in sympatho-adrenal activity or catecholamine metabolites are influenced by ingestion of specific catechins found within green tea. This study explored the impact of epigallocatechin gallate (EGCG) ingestion on catecholamine metabolism during graded cycle exercise in humans. METHODS: Eight males (22.4 ± 3.3 years, BMI:25.7 ± 2.4 kg.m2) performed a randomised, placebo-controlled, single-blind, cross-over trial after consumption (1450 mg) of either EGCG or placebo (PLAC) and performed graded cycling to volitional exhaustion. Venous bloods were taken at rest, 2 h post-ingestion and after every 3-min stage. Blood variables were analysed for catecholamines, catecholamine metanephrines and metabolic variables at rest, 2 h post-ingestion (POST-ING), peak rate of lipid oxidation (FATpeak), lactate threshold (LT) and peak rate of oxygen consumption (VO2peak). Data were analysed using SPSS (Version 26). RESULTS: Resting catecholamine and metanephrines were similar between trials. Plasma adrenaline (AD) was lower in ECGC treatment group between trials at FATpeak (P < 0.05), LT (P < 0.001) and VO2peak (P < 0.01). Noradrenaline (NA) was lower under EGCG at POST (P < 0.05), FATpeak (P < 0.05), LT (P < 0.01) and VO2peak (P < 0.05) compared to PLAC. Metanephrines, glucose and lactate increased similarly with exercise intensity in both trials. Lipid oxidation rate was 32% lower in EGCG at FATpeak (EGCG 0.33 ± 0.14 vs. PLAC 0.49 ± 0.11 g.min-1, P < 0.05). Cycle time to exhaustion was similar (NS). CONCLUSION: Acute EGCG supplementation reduced circulating catecholamines but not; metanephrine, glucose or lactates, response to graded exercise. Lower circulating catecholamines may explain a lower lipid oxidation rate.

Plants, pollinators and their interactions under global ecological change: The role of pollen DNA metabarcoding.

Anthropogenic activities are triggering global changes in the environment, causing entire communities of plants, pollinators and their interactions to restructure, and ultimately leading to species declines. To understand the mechanisms behind community shifts and declines, as well as monitoring and managing impacts, a global effort must be made to characterize plant-pollinator communities in detail, across different habitat types, latitudes, elevations, and levels and types of disturbances. Generating data of this scale will only be feasible with rapid, high-throughput methods. Pollen DNA metabarcoding provides advantages in throughput, efficiency and taxonomic resolution over traditional methods, such as microscopic pollen identification and visual observation of plant-pollinator interactions. This makes it ideal for understanding complex ecological networks and their responses to change. Pollen DNA metabarcoding is currently being applied to assess plant-pollinator interactions, survey ecosystem change and model the spatiotemporal distribution of allergenic pollen. Where samples are available from past collections, pollen DNA metabarcoding has been used to compare contemporary and past ecosystems. New avenues of research are possible with the expansion of pollen DNA metabarcoding to intraspecific identification, analysis of DNA in ancient pollen samples, and increased use of museum and herbarium specimens. Ongoing developments in sequencing technologies can accelerate progress towards these goals. Global ecological change is happening rapidly, and we anticipate that high-throughput methods such as pollen DNA metabarcoding are critical for understanding the evolutionary and ecological processes that support biodiversity, and predicting and responding to the impacts of change.

Mind- and Body-Based Interventions Improve Glycemic Control in Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis.

Aims/Hypothesis: Only 51% of patients with type 2 diabetes achieve the hemoglobin A1c (HbA1c) <7% target. Mind and body practices have been increasingly used to improve glycemic control among patients with type 2 diabetes, but studies show inconsistent efficacy. The authors conducted a systematic review and meta-analysis to assess the association between mind and body practices, and mean change in HbA1c and fasting blood glucose (FBG) in patients with type 2 diabetes. Methods: The authors conducted a literature search of Ovid MEDLINE, Embase, and ClinicalTrials.gov seeking through June 10, 2022, published articles on mind and body practices and type 2 diabetes. Two reviewers independently appraised full text of articles. Only intervention studies were included. Reviewers extracted data for meta-analysis. Restricted maximum likelihood random-effects modeling was used to calculate the mean differences and summary effect sizes. The authors assessed heterogeneity using Cochran's Q and I2 statistics. Funnel plots were generated for each outcome to gauge publication bias. Weighted linear models were used to conduct study-level meta-regression analyses of practice frequency. Results: The authors identified 587 articles with 28 meeting the inclusion criteria. A statistically significant and clinically relevant mean reduction in HbA1c of -0.84% (95% confidence interval [CI]: -1.10% to -0.58%; p < 0.0001) was estimated. Reduction was observed in all intervention subgroups: mindfulness-based stress reduction: -0.48% (95% CI: -0.72% to -0.23%; p = 0.03), qigong: -0.66% (95% CI: -1.18% to -0.14%; p = 0.01), and yoga: -1.00% (95% CI: -1.38% to -0.63%; p < 0.0001). Meta-regression revealed that for every additional day of yoga practice per week, the raw mean HbA1c differed by -0.22% (95% CI: -0.44% to -0.003%; p = 0.046) over the study period. FBG significantly improved following mind and body practices, with overall mean difference of -22.81 mg/dL (95% CI: -33.07 to -12.55 mg/dL; p < 0.0001). However, no significant association was found between the frequency of weekly yoga practice and change in FBG over the study period. Conclusions/Interpretation: Mind and body practices are strongly associated with improvement in glycemic control in patients with type 2 diabetes. The overall mean reduction in HbA1c and FBG was clinically significant, suggesting that mind and body practices may be an effective, complementary nonpharmacological intervention for type 2 diabetes. Additional analyses revealed that the mean decrease in HbA1c was greater in studies requiring larger number of yoga practice sessions each week.