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ERJ Open Research May 2024COPD is a major healthcare problem and cause of mortality worldwide. COPD patients at increased mortality risk are those who are more symptomatic, have lower lung... (Review)
Review
COPD is a major healthcare problem and cause of mortality worldwide. COPD patients at increased mortality risk are those who are more symptomatic, have lower lung function and lower diffusing capacity of the lung for carbon monoxide, decreased exercise capacity, belong to the emphysematous phenotype and those who have concomitant bronchiectasis. Mortality risk seems to be greater in patients who experience COPD exacerbations and in those who suffer from concomitant cardiovascular and/or metabolic diseases. To predict the risk of death in COPD patients, several composite scores have been created using different parameters. In previous years, large studies (also called mega-trials) have evaluated the efficacy of different therapies on COPD mortality, but until recently only nonpharmaceutical interventions have proven to be effective. However, recent studies on fixed combinations of triple therapy (long-acting β-agonists, long-acting muscarinic antagonists and inhaled corticosteroids) have provided encouraging results, showing for the first time a reduction in mortality compared to dual therapies. The aim of the present review is to summarise available data regarding mortality risk in COPD patients and to describe pharmacological therapies that have shown effectiveness in reducing mortality.
PubMed: 38887682
DOI: 10.1183/23120541.00850-2023 -
International Journal of Molecular... May 2024Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common metabolic disease of the liver, characterized by hepatic steatosis in more than 5% of...
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common metabolic disease of the liver, characterized by hepatic steatosis in more than 5% of hepatocytes. However, despite the recent approval of the first drug, resmetirom, for the management of metabolic dysfunction-associated steatohepatitis, decades of target exploration and hundreds of clinical trials have failed, highlighting the urgent need to find new druggable targets for the discovery of innovative drug candidates against MASLD. Here, we found that glutathione S-transferase alpha 1 (GSTA1) expression was negatively associated with lipid droplet accumulation and . Overexpression of GSTA1 significantly attenuated oleic acid-induced steatosis in hepatocytes or high-fat diet-induced steatosis in the mouse liver. The hepatoprotective and anti-inflammatory drug bicyclol also attenuated steatosis by upregulating GSTA1 expression. A detailed mechanism showed that GSTA1 directly interacts with fatty acid binding protein 1 (FABP1) and facilitates the degradation of FABP1, thereby inhibiting intracellular triglyceride synthesis by impeding the uptake and transportation of free fatty acids. Conclusion: GSTA1 may be a good target for the discovery of innovative drug candidates as GSTA1 stabilizers or enhancers against MASLD.
Topics: Glutathione Transferase; Animals; Humans; Mice; Fatty Acid-Binding Proteins; Fatty Liver; Up-Regulation; Liver; Diet, High-Fat; Male; Mice, Inbred C57BL; Hepatocytes; Lipid Metabolism; Oleic Acid; Hep G2 Cells; Triglycerides; Isoenzymes
PubMed: 38791126
DOI: 10.3390/ijms25105086 -
Plant Disease May 2024spp. is a widely cultivated ornamental plant in gardens or parks in Taiwan. In September 2021, withering leaves and grayish-brown lesions were observed on the lower...
spp. is a widely cultivated ornamental plant in gardens or parks in Taiwan. In September 2021, withering leaves and grayish-brown lesions were observed on the lower stem of plumed cockscombs ( var. ) in Taichung City, with an incidence of about 22% in 136 plants after continuous precipitation, impacting the aesthetic value of the landscape. Symptomatic plants were collected, surface disinfected with 70% EtOH for ~20 sec., blotted dried, and excised diseased tissues (~ 3×3 mm) were placed on 2% water agar. Four representative isolates were obtained after purification and the colonies were white with aerial and non-septated hyphae on V8 agar for 7 days. Sporangia were ovoid, ellipsoid or obpyriform, papillate, (26.3-55.9) 38.0 × 29.0 (20.1-40.6) µm (n = 200) (Ahonsi et al. 2007). Chlamydospores were spherical, terminal or intercalary, 26.0 (15.1-40.4) µm (n = 200). All isolates belong to A2 mating type with amphigynous antheridia and plerotic oospores, 21.0 (17.7-25.7) µm (n = 200), resembling the descriptions of (Erwin & Ribeiro 1996). For molecular identification, sequences of the ITS, β-tubulin (β-tub), and EF-1α regions of all isolates were amplified using ITS1/ITS4, TUBUF2/TUBUR1, and ELONGF1/ELONGR1 primers, respectively (White et al. 1990; Kroon et al. 2004). BLAST analyses of isolates cap1-2 (ITS: OQ581785; β-tub: OQ590022; EF-1α: OQ590026), cap1-3 (ITS: OQ581786; β-tub: OQ590023; EF-1α: OQ590027), cap2-1 (ITS: OQ581787; β-tub: OQ590024; EF-1α: OQ590028), and cap2-2 (ITS: OQ581788; β-tub: OQ590025; EF-1α: OQ590029) showed 100% of ITS identity, 99.5 to 99.9% of β-tub identity, and 99.4 to 99.6% of EF-1α identity with (ITS: MG865551; β-tub: MH493987; EF-1α: MH359043). Phylogenetic trees were constructed using concatenated ITS, β-tub, and EF-1α sequences based on maximum likelihood with a GTR+G model in MEGA X and Bayesian inference method in Geneious Prime 2022.2. All isolates were clustered in with similar topology, thereby were identified as . To confirm pathogenicity, 7 to 10-day-old seedlings and 6-week-old plumed cockscomb plants were inoculated in separate trials and each experiment was conducted twice. For each seedling, the lower stem was inoculated with 50 μl of zoospore suspension (10 zoospores/ml), 3 plants per isolate, and then incubated at 30±2℃ with 12 h light. For adult plants, each was inoculated with mycelial plugs from one V8 plate of 10-day-old , 5 plants per isolate, and incubated at 25±2℃ in a greenhouse. Control plants were inoculated with sterile water and V8 agar plugs, respectively. Stem and root rot were observed on seedlings 4 days after inoculation while wilting and lower stem browning were observed on adult plants 2 months after inoculation. All control plants remained healthy at the end of repeated trials and identical pathogens were re-isolated only from symptomatic plants, thus fulfilling Koch's rules. has been reported causing root rot and stem necrosis not only on cockscomb (. Hort. ex Burvenich) in Argentina (Frezzi 1950), but also infecting several ornamental plants recently in Taiwan (Ann et al. 2018). To our knowledge, this is the first report of stem blight caused by on plumed cockscombs in Taiwan. This finding suggests limited options for landscaping and the host preference of the isolates obtained in this study should warrant further studies.
PubMed: 38783581
DOI: 10.1094/PDIS-04-23-0667-PDN -
American Heart Journal May 2024As a mega-biobank linked to a national healthcare system, the Million Veteran Program (MVP) can directly improve the health care of participants. To determine the...
BACKGROUND
As a mega-biobank linked to a national healthcare system, the Million Veteran Program (MVP) can directly improve the health care of participants. To determine the feasibility and outcomes of returning medically actionable genetic results to MVP participants, the program launched the MVP Return Of Actionable Results (MVP-ROAR) Study, with familial hypercholesterolemia (FH) as an exemplar actionable condition.
METHODS
The MVP-ROAR Study consists of a completed single-arm pilot phase and an ongoing randomized clinical trial (RCT), in which MVP participants are recontacted and invited to receive clinical confirmatory gene sequencing testing and a telegenetic counseling intervention. The primary outcome of the RCT is 6-month change in low-density lipoprotein cholesterol (LDL-C) between participants receiving results at baseline and those receiving results after 6 months.
RESULTS
The pilot developed processes to identify and recontact participants nationally with probable pathogenic variants in low-density lipoprotein receptor (LDLR) on the MVP genotype array, invite them to clinical confirmatory gene sequencing, and deliver a telegenetic counseling intervention. Among participants in the pilot phase, 8 (100%) had active statin prescriptions after 6 months. Results were shared with 16 first-degree family members. Six-month ΔLDL-C (low-density lipoprotein cholesterol) after the genetic counseling intervention was -37 mg/dL (95% CI: -12 to -61; p=0.03). The ongoing RCT will determine between-arm differences in this primary outcome.
CONCLUSION
While underscoring the importance of clinical confirmation of research results, the pilot phase of the MVP-ROAR Study marks a turning point in MVP and demonstrates the feasibility of returning genetic results to participants and their providers. The ongoing RCT will contribute to understanding how such a program might improve patient health care and outcomes.
PubMed: 38762090
DOI: 10.1016/j.ahj.2024.04.021 -
Cerebral Cortex (New York, N.Y. : 1991) May 2024Anhedonia is a transdiagnostic symptom and associated with a spectrum of reward deficits among which the motivational dysfunction is poorly understood. Previous studies...
Anhedonia is a transdiagnostic symptom and associated with a spectrum of reward deficits among which the motivational dysfunction is poorly understood. Previous studies have established the abnormal cost-benefit trade-off as a contributor to motivational deficits in anhedonia and its relevant psychiatric diseases. However, it remains elusive how the anhedonic neural dynamics underlying reward processing are modulated by effort expenditure. Using an effort-based monetary incentive delay task, the current event-related potential study examined the neural dynamics underlying the effort-reward interplay in anhedonia using a nonclinical sample who scored high or low on an anhedonia questionnaire. We found that effort prospectively decreased reward effect on the contingent variation negativity and the target-P3 but retrospectively enhanced outcome effect on the feedback-P3 following effort expenditure. Compared to the low-anhedonia group, the high-anhedonia group displayed a diminished effort effect on the target-P3 during effort expenditure and an increased effort-enhancement effect for neutral trials during the feedback-P3 period following effort expenditure. Our findings suggest that anhedonia is associated with an inefficient control and motivation allocation along the efforted-based reward dynamics from effort preparation to effort production.
Topics: Anhedonia; Humans; Reward; Male; Female; Young Adult; Motivation; Electroencephalography; Adult; Evoked Potentials; Brain; Adolescent
PubMed: 38741268
DOI: 10.1093/cercor/bhae193 -
Clinical Chemistry May 2024Vitamin D, acknowledged since the 1930s for its role in preventing rickets, gained additional prominence in relation to fragility fracture prevention in the late 1980s....
BACKGROUND
Vitamin D, acknowledged since the 1930s for its role in preventing rickets, gained additional prominence in relation to fragility fracture prevention in the late 1980s. From the early 2000s, connections between vitamin D deficiency and extra-skeletal pathologies emerged, alongside increased awareness of widespread deficits. This prompted crucial debates on optimal serum concentrations, expected to conclude when the outcomes of high-dose supplementation randomized controlled trials were available. Skepticism arose with inconclusive results from these trials.
CONTENT
This review begins with an exploration of vitamin D metabolism, followed by a detailed description of the measurement of vitamin D metabolites and the crucial role of standardization. Subsequent sections focus on the association of vitamin D with bone health and explore the extra-skeletal effects. The review concludes with a comprehensive discussion on the definition of vitamin D status and its implications for supplementation.
SUMMARY
Despite standardization efforts, assay variations and challenges still exist, especially in specific patient groups. Vitamin D supplementation has a significant impact on bone metabolism and optimal vitamin D status improves the efficacy of antiresorptive drugs such as bisphosphonates. The extra-skeletal effects of vitamin D remain debated, but may include potential benefits in conditions such as respiratory infections and cancer mortality, particularly in deficient individuals. The definition of vitamin D sufficiency is nuanced, especially when variations in population groups and analytical methods are taken into account. Despite ongoing debates and recent mega-trials tempering enthusiasm, vitamin D remains a complex and essential element in human health. Further research is needed to clarify its role in various health outcomes and guide supplementation strategies.
PubMed: 38712647
DOI: 10.1093/clinchem/hvae056 -
Clinical Nutrition (Edinburgh, Scotland) May 2024Clinical trials supplementing the long-chain polyunsaturated fatty acids (LCPUFAs) docosahexaenoic acid (DHA) and arachidonic acid (AA) to preterm infants have shown... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND & AIM
Clinical trials supplementing the long-chain polyunsaturated fatty acids (LCPUFAs) docosahexaenoic acid (DHA) and arachidonic acid (AA) to preterm infants have shown positive effects on inflammation-related morbidities, but the molecular mechanisms underlying these effects are not fully elucidated. This study aimed to determine associations between DHA, AA, and inflammation-related proteins during the neonatal period in extremely preterm infants.
METHODS
A retrospective exploratory study of infants (n = 183) born below 28 weeks gestation from the Mega Donna Mega trial, a randomized multicenter trial designed to study the effect of DHA and AA on retinopathy of prematurity. Serial serum samples were collected after birth until postnatal day 100 (median 7 samples per infant) and analyzed for phospholipid fatty acids and proteins using targeted proteomics covering 538 proteins. Associations over time between LCPUFAs and proteins were explored using mixed effect modeling with splines, including an interaction term for time, and adjusted for gestational age, sex, and center.
RESULTS
On postnatal day one, 55 proteins correlated with DHA levels and 10 proteins with AA levels. Five proteins were related to both fatty acids, all with a positive correlation. Over the first 100 days after birth, we identified 57 proteins to be associated with DHA and/or AA. Of these proteins, 41 (72%) related to inflammation. Thirty-eight proteins were associated with both fatty acids and the overall direction of association did not differ between DHA and AA, indicating that both LCPUFAs similarly contribute to up- and down-regulation of the preterm neonate inflammatory proteome. Primary examples of this were the inflammation-modulating cytokines IL-6 and CCL7, both being negatively related to levels of DHA and AA in the postnatal period.
CONCLUSIONS
This study supports postnatal non-antagonistic and potentially synergistic effects of DHA and AA on the inflammation proteome in preterm infants, indicating that supplementation with both fatty acids may contribute to limiting the disease burden in this vulnerable population.
CLINICAL REGISTRATION NUMBER
ClinicalTrials.gov (NCT03201588).
Topics: Humans; Docosahexaenoic Acids; Arachidonic Acid; Infant, Extremely Premature; Infant, Newborn; Female; Retrospective Studies; Male; Inflammation; Proteome
PubMed: 38603973
DOI: 10.1016/j.clnu.2024.03.031 -
JCI Insight Apr 2024BACKGROUNDAs Omicron is prompted to replicate in the upper airway, neutralizing antibodies (NAbs) delivered through inhalation might inhibit early-stage infection in the...
BACKGROUNDAs Omicron is prompted to replicate in the upper airway, neutralizing antibodies (NAbs) delivered through inhalation might inhibit early-stage infection in the respiratory tract. Thus, elucidating the prophylactic efficacy of NAbs via nasal spray addresses an important clinical need.METHODSThe applicable potential of a nasal spray cocktail containing 2 NAbs was characterized by testing its neutralizing potency, synergetic neutralizing mechanism, emergency protective and therapeutic efficacy in a hamster model, and pharmacokinetics/pharmacodynamic (PK/PD) in human nasal cavity.RESULTSThe 2 NAbs displayed broad neutralizing efficacy against Omicron, and they could structurally compensate each other in blocking the Spike-ACE2 interaction. When administrated through the intranasal mucosal route, this cocktail demonstrated profound efficacy in the emergency prevention in hamsters challenged with authentic Omicron BA.1. The investigator-initiated trial in healthy volunteers confirmed the safety and the PK/PD of the NAb cocktail delivered via nasal spray. Nasal samples from the participants receiving 4 administrations over a course of 16 hours demonstrated potent neutralization against Omicron BA.5 in an ex vivo pseudovirus neutralization assay.CONCLUSIONThese results demonstrate that the NAb cocktail nasal spray provides a good basis for clinical prophylactic efficacy against Omicron infections.TRIAL REGISTRATIONwww.chictr.org.cn, ChiCTR2200066525.FUNDINGThe National Science and Technology Major Project (2017ZX10202203), the National Key Research and Development Program of China (2018YFA0507100), Guangzhou National Laboratory (SRPG22-015), Lingang Laboratory (LG202101-01-07), Science and Technology Commission of Shanghai Municipality (YDZX20213100001556), and the Emergency Project from the Science & Technology Commission of Chongqing (cstc2021jscx-fyzxX0001).
Topics: Animals; Cricetinae; Humans; Nasal Sprays; China; Antibodies, Neutralizing; Trachea; Healthy Volunteers
PubMed: 38587080
DOI: 10.1172/jci.insight.171034 -
World Journal of Urology Mar 2024Diagnostic ureteroscopy (dURS) is optional in the assessment of patients with upper tract urothelial carcinoma (UTUC) and provides the possibility of obtaining histology.
PURPOSE
Diagnostic ureteroscopy (dURS) is optional in the assessment of patients with upper tract urothelial carcinoma (UTUC) and provides the possibility of obtaining histology.
METHODS
To evaluate endoscopic biopsy techniques and outcomes, we assessed data from patients from the CROES-UTUC registry. The registry includes multicenter prospective collected data on diagnosis and management of patients suspected having UTUC.
RESULTS
We assessed 2380 patients from 101 centers. dURS with biopsy was performed in 31.6% of patients. The quality of samples was sufficient for diagnosis in 83.5% of cases. There was no significant association between biopsy techniques and quality (p = 0.458). High-grade biopsy accurately predicted high-grade disease in 95.7% and high-risk stage disease in 86%. In ureteroscopic low-grade tumours, the prediction of subsequent low-grade disease was 66.9% and low-risk stage Ta-disease 35.8%. Ureteroscopic staging correctly predicted non-invasive Ta-disease and ≥ T1 disease in 48.9% and 47.9% of patients, respectively. Cytology outcomes did not provide additional value in predicting tumour grade.
CONCLUSION
Biopsy results adequately predict high-grade and high-risk disease, but approximately one-third of patients are under-staged. Two-thirds of patients with low-grade URS-biopsy have high-risk stage disease, highlighting the need for improved diagnostics to better assess patient risk and guide treatment decisions.
CLINICAL TRIAL REGISTRATION
The study was registered at ClinicalTrials.gov (ClinicalTrials.gov NCT02281188; https://clinicaltrials.gov/ct2/show/NCT02281188 ).
Topics: Humans; Urinary Bladder Neoplasms; Carcinoma, Transitional Cell; Ureteral Neoplasms; Prospective Studies; Ureteroscopy; Biopsy; Kidney Neoplasms
PubMed: 38507109
DOI: 10.1007/s00345-024-04866-w -
Heliyon Mar 2024This study aimed to evaluate high-yielding, stable sorghum genotypes and determine the ideal (representative and discriminating) testing environments for genotypes in...
This study aimed to evaluate high-yielding, stable sorghum genotypes and determine the ideal (representative and discriminating) testing environments for genotypes in the humid lowlands of Ethiopia. A total of forty-two sorghum genotypes were used for a field trial conducted in six different environments using a randomized complete block design. Yield stability, Additive main effect, multiplicative interaction (AMMI), and genotype and genotype by environment interaction (GGE) were computed. The AMMI analysis explained 62.85% of the G×E variance. The AMMI1 biplot revealed that (G4; Mok079 and (G16; Ba066) genotypes had higher grain yields. AMMI2 biplot suggested that genotypes (G18; Y0470),(G23;100620), (G29; PML981475), and (G11; ETSC300373-4) show higher sensitivity to environmental changes because of their strong genotype-by-environment interactions. The GGE captured 79.46% of the GGE variance, and the GGE biplot identified genotypes (G4; Mok079), (G10; Sl081) and (G16; Ba066) were the most stable genotypes whereas(G39; ETSC120051-3) was the least stable genotypes. The GGE biplot identified Assosa (AS20) as a suitable environment, whereas PW20 and JM20 were the most discriminating and non-representative environments. The GGE biplot was found to identify three main mega-environments for sorghum growing in the humid lowlands of Ethiopia., both the AMMI and GGE biplots revealed (G4; Mok079) had the highest level of adaptability to all tested environments and was approved by the National Variety Release Committee for release in 2022.
PubMed: 38434414
DOI: 10.1016/j.heliyon.2024.e26528