Effect modification by statin use status on the association between fine particulate matter (PM2.5) and cardiovascular mortality.

BACKGROUND: Numerous studies have linked fine particulate matter (PM2.5) to increased cardiovascular mortality. Less is known how the PM2.5-cardiovascular mortality association varies by use of cardiovascular medications. This study sought to quantify effect modification by statin use status on the associations between long-term exposure to PM2.5 and mortality from any cardiovascular cause, coronary heart disease (CHD), and stroke. METHODS: In this nested case-control study, we followed 1.2 million community-dwelling adults aged ≥66 years who lived in Ontario, Canada from 2000 through 2018. Cases were patients who died from the three causes. Each case was individually matched to up to 30 randomly selected controls using incidence density sampling. Conditional logistic regression models were used to estimate odds ratios (ORs) for the associations between PM2.5 and mortality. We evaluated the presence of effect modification considering both multiplicative (ratio of ORs) and additive scales (the relative excess risk due to interaction, RERI). RESULTS: Exposure to PM2.5 increased the risks for cardiovascular, CHD, and stroke mortality. For all three causes of death, compared with statin users, stronger PM2.5-mortality associations were observed among non-users [e.g. for cardiovascular mortality corresponding to each interquartile range increase in PM2.5, OR = 1.042 (95% CI, 1.032-1.053) vs OR = 1.009 (95% CI, 0.996-1.022) in users, ratio of ORs = 1.033 (95% CI, 1.019-1.047), RERI = 0.039 (95% CI, 0.025-0.050)]. Among users, partially adherent users exhibited a higher risk of PM2.5-associated mortality than fully adherent users. CONCLUSIONS: The associations of chronic exposure to PM2.5 with cardiovascular and CHD mortality were stronger among statin non-users compared to users.

Dietary patterns and intrinsic capacity in older adults: a 6-year prospective cohort study.

OBJECTIVES: Only a few studies have investigated dietary patterns and intrinsic capacity (IC). This study examined the prospective associations between dietary patterns, IC, and IC sub-domains over 6 years in community-dwelling Korean older adults. DESIGN: A prospective cohort study. SETTING AND PARTICIPANTS: Data were obtained from participants aged 70-84 years in the Korean Frailty and Aging Cohort Study (2016-2022). The study population included 665 enrollees at baseline who completed IC and dietary data. METHODS: Dietary data were obtained from baseline surveys of the nutritional sub-cohort using two nonconsecutive 24-hour dietary recalls, and dietary patterns were derived using cluster analysis. IC was constructed by measuring cognitive, locomotor, vitality, sensory, and psychological domains. A generalized estimating equation was used to analyze the longitudinal associations between dietary patterns, IC, and IC sub-domain scores. RESULTS: In total, 665 enrollees were included in the analysis. After adjusting for confounders, in older men, the dietary pattern of cluster 1 (variety of healthy foods and alcohols) compared to that of cluster 2 (rice and kimchi) was positively associated with changes in the IC score (ß = 0.41, 95% confidence interval [CI] = 0.04-0.78). In older women, the dietary pattern of cluster 1 (variety of healthy foods) was positively associated with changes in the IC score (ß = 0.30, 95% CI = 0.02-0.58), IC score group (ß = 0.11, 95% CI = 0.02-0.20), and psychological domain (ß = 0.25, 95% CI = 0.11-0.38) compared to that of cluster 3 (rice, vegetables, and kimchi). CONCLUSIONS: Dietary patterns (variety of healthy foods) were positively associated with changes in IC scores and their sub-domains in older adults.

Modified Thoracoabdominal Nerves Block Through Perichondral Approach: A Systematic Review and Meta-analysis.

PURPOSE: This systematic review and meta-analysis aimed to investigate the postoperative analgesic efficacy and safety of the modified thoracoabdominal nerve block through the perichondral approach (M-TAPA) in abdominal surgeries. DESIGN: Systematic review and meta-analysis. METHODS: We searched electronic databases to identify relevant studies comparing M-TAPA with conventional analgesic techniques. The primary outcome was the requirement for rescue analgesia at 12 and 24 hours postsurgery. Secondary outcomes included the 11-point numerical rating scale pain scores at 0, 1, 2, 4, 6, 8, 12, and 24 hours following surgery, global quality of recovery scores, and postoperative adverse events. FINDINGS: Five randomized controlled trials involving 308 patients were analyzed. M-TAPA showed no significant difference in the requirement for rescue analgesia at 12 hours (relative risk [RR]: 0.87; 95% confidence interval [CI]: 0.62, 1.22; P = .424; I2 = 40.7%; Ph = .185) and 24 hours (RR: 0.67; 95% CI: 0.22, 1.99; P = .252; I2 = 90.3%; Ph < .001) postsurgery compared to non-M-TAPA. No significant differences in numerical rating scale pain scores or global quality of recovery scores were found between the two groups (all P < .05). However, M-TAPA was associated with a lower occurrence of nausea (RR: 0.37; 95% CI: 0.22, 0.68; P < .001; I2 = 0%; Ph = .834), vomiting (RR: 0.32; 95% CI: 0.17, 0.62; P < .001; I2 = 0%; Ph = .884), and itching (RR: 0.38; 95% CI: 0.21, 0.70; P = .002; I2 = 0%; Ph = .826). CONCLUSIONS: There was no significant difference in analgesic efficacy and safety between M-TAPA and non-M-TAPA techniques.

The Life Functioning Scale: a Measurement Tool Developed to Assess the Physical Functioning Abilities of Community-Dwelling Adults Aged 50 Years or Older.

Background: This study aimed to develop an instrument for assessing physical functioning among adults aged 50 years or older living in the community. Methods: Based on a review of various national health surveys and cohort studies, a 144-item bank was constructed for assessing physical functioning. Focus group interviews were conducted among adults aged 50 years or older to investigate their level of understanding of 60 selected items, followed by a pretest of the items on a nationally representative sample (n = 508). The final 25-item questionnaire was tested on an independent sample (n = 259) for validity and reliability based on classical test and item response theories. Predictive validity at the 6-month follow-up was tested in a separate sample (n = 263). Results: The newly developed Life Functioning (LF) scale assessed the dimensions of functional limitations, disabilities, and social activities. The scale satisfied a one-dimensionality assumption with good item fit and demonstrated criterion validity, construct validity, high internal consistency (Cronbach's alpha = 0.93), and test-retest reliability (intra-class correlation coefficient = 0.84; 95% CI, 0.76-0.89). The LF scale comprised 25 items with a total score ranging from 0 to 100. Higher scores indicated higher levels of functioning. The LF score was significantly associated with the physical functioning score at 6 months. Conclusion: The LF scale was developed to assess the physical functioning of people in their late midlife or older. Future studies should test the instrument on a national sample and evaluate its application in diverse population subgroups.

Attention-deficit/hyperactivity disorder and subsequent diagnoses of major psychiatric disorders: a nationwide population-based study.

We evaluated the risk of being diagnosed with various psychiatric disorders after an attention-deficit/hyperactivity disorder (ADHD) diagnosis using data from South Korea's National Health Insurance Service from 2002 to 2019, which covers approximately 97% of the country's population. ADHD and control groups were selected after propensity score matching was performed for individuals diagnosed with ADHD and their age- and sex-matched counterparts from the general population. Comorbid psychiatric disorders included depressive disorder, bipolar disorder, tic disorder, and schizophrenia. The incidence of newly diagnosed psychiatric disorders was compared between the groups. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated and adjusted for ADHD medication prescription. After matching, 353,898 individuals were assigned to each of the two groups. Compared to the control group, the ADHD group showed a significantly higher risk of being subsequently diagnosed with depressive disorder, bipolar disorder, schizophrenia, and tic disorder. The onset age of depressive disorder, bipolar disorder, and schizophrenia in the ADHD group was 16-17 years, approximately 5 years earlier than that in the control group. The risk for depression was the highest in individuals with high income levels, and that for schizophrenia was the highest among rural patients. The median length of the follow-up time until the diagnosis of each comorbid psychiatric disorder was 7.53, 8.43, 8.53, and 8.34 years for depressive disorder, bipolar disorder, schizophrenia, and tic disorder, respectively. Individuals with ADHD had an overall higher risk of being diagnosed with subsequent psychiatric disorders than did the controls. Hence, they should be carefully screened for other psychiatric symptoms from an early age and followed up for an extended duration, along with appropriate interventions for ADHD symptoms, including psychosocial treatments and educational approaches.

Germline BARD1 variants predispose to mesothelioma by impairing DNA repair and calcium signaling.

We report that ~1.8% of all mesothelioma patients and 4.9% of those younger than 55, carry rare germline variants of the BRCA1 associated RING domain 1 (BARD1) gene that were predicted to be damaging by computational analyses. We conducted functional assays, essential for accurate interpretation of missense variants, in primary fibroblasts that we established in tissue culture from a patient carrying the heterozygous BARD1V523A mutation. We found that these cells had genomic instability, reduced DNA repair, and impaired apoptosis. Investigating the underlying signaling pathways, we found that BARD1 forms a trimeric protein complex with p53 and SERCA2 that regulates calcium signaling and apoptosis. We validated these findings in BARD1-silenced primary human mesothelial cells exposed to asbestos. Our study elucidated mechanisms of BARD1 activity and revealed that heterozygous germline BARD1 mutations favor the development of mesothelioma and increase the susceptibility to asbestos carcinogenesis. These mesotheliomas are significantly less aggressive compared to mesotheliomas in asbestos workers.

Trends in degenerative lumbar spinal surgery during the early COVID-19 pandemic in Republic of Korea: A national study utilizing the national health insurance database.

During the first year of the COVID-19 pandemic, the Republic of Korea (ROK) experienced three epidemic waves in February, August, and November 2020. These waves, combined with the overarching pandemic, significantly influenced trends in spinal surgery. This study aimed to investigate the trends in degenerative lumbar spinal surgery in ROK during the early COVID-19 pandemic, especially in relation to specific epidemic waves. Using the National Health Information Database in ROK, we identified all patients who underwent surgery for degenerative lumbar spinal diseases between January 1, 2019 and December 31, 2020. A joinpoint regression was used to assess temporal trends in spinal surgeries over the first year of the COVID-19 pandemic. The number of surgeries decreased following the first and second epidemic waves (p<0.01 and p = 0.34, respectively), but these were offset by compensatory increases later on (p<0.01 and p = 0.05, respectively). However, the third epidemic wave did not lead to a decrease in surgical volume, and the total number of surgeries remained comparable to the period before the pandemic. When compared to the pre-COVID-19 period, average LOH was reduced by 1 day during the COVID-19 period (p<0.01), while mean hospital costs increased significantly from 3,511 to 4,061 USD (p<0.01). Additionally, the transfer rate and the 30-day readmission rate significantly decreased (both p<0.01), while the reoperation rate remained stable (p = 0.36). Despite the impact of epidemic waves on monthly surgery numbers, a subsequent compensatory increase was observed, indicating that surgical care has adapted to the challenges of the pandemic. This adaptability, along with the stable total number of operations, highlights the potential for healthcare systems to continue elective spine surgery during public health crises with strategic resource allocation and patient triage. Policies should ensure that surgeries for degenerative spinal diseases, particularly those not requiring urgent care but crucial for patient quality of life, are not unnecessarily halted.

Access Barriers, Trusted Channels, and Misconceptions About the COVID-19 Vaccine Among Rural Immigrant Farmworkers.

Background: Although COVID-19 has disproportionately impacted immigrant agricultural workers, vaccination efforts have been challenging. Barriers to immunization include language, visa status, and access to medical care. Additionally, vaccine hesitancy, mistrust, and misinformation contributed to low uptake. Methods: A community needs assessment was conducted with immigrant agricultural workers (n = 9) and community stakeholders (n = 15) in rural areas of Maryland and Delaware. In-depth interviews were recorded, transcribed verbatim, and analyzed using template analysis. Results: The participants named trusted and untrusted sources, sources of misinformation, and barriers to accessing information and physical locations to receive the vaccine as reasons for not getting the vaccine. Trusted sources included known community leaders and television programs. Some barriers mentioned were fear of deportation, lack of paid time off, language barriers, and difficulty navigating the U.S. healthcare system. Discussion: There is a need for culturally-tailored programs that address misinformation and barriers and use community-based programming.

Modulation of diabetic wound healing using carbon monoxide gas-entrapping materials.

Diabetic wound healing is uniquely challenging to manage due to chronic inflammation and heightened microbial growth from elevated interstitial glucose. Carbon monoxide (CO), widely acknowledged as a toxic gas, is also known to provide unique therapeutic immune modulating effects. To facilitate delivery of CO, we have designed hyaluronic acid-based CO-gas-entrapping materials (CO-GEMs) for topical and prolonged gas delivery to the wound bed. We demonstrate that CO-GEMs promote the healing response in murine diabetic wound models (full-thickness wounds and pressure ulcers) compared to N2-GEMs and untreated controls.

Mediating role of health literacy in relationship between frailty and health-related quality of life in community-dwelling older adults.

PURPOSE: The aim of this study was to investigate the mediating effects of health literacy on the relationship between frailty and health-related quality of life (HRQOL) among community-dwelling older adults. METHODS: This study used the Korean Frailty and Aging Cohort Database (KFACD) for secondary data analysis. We selected data from 1,631 people without missing main variable values for analysis. Frailty was determined based on the modified Fried's phenotype [MFP], and HRQOL was measured using the Korean version of the 5-level EuroQol questionnaire (EQ-5D-5L). Health literacy was assessed using the questions on the Behavioral Risk Factor Surveillance System (BRFSS) used by the U.S. Center for Disease Control and Prevention. To examine the mediating role of health literacy in the relationship between frailty and HRQOL, Baron & Kenny's three-step mediating effect verification method was utilized. RESULTS: The participants had a mean frailty score of 1.37±1.02, health literacy score of 8.56±2.59, and HRQOL score of 0.84±0.10. Frailty was negatively correlated with health literacy (r = -0.27, p < .001) and HRQOL (r = -0.32, p < .001), while health literacy was positively correlated with HRQOL (r = 0.34, p < .001). We observed that health literacy played a partial mediating role in the relationship between frailty and HRQOL. CONCLUSION: To increase older adults' HRQOL, measures that directly prevent and manage frailty as well as interventions that target the enhancement of health literacy are needed.

Effect of aerobic exercise and particulate matter exposure duration on the diversity of gut microbiota.

Inhalation of ambient particulate matter (PM) can disrupt the gut microbiome, while exercise independently influences the gut microbiome by promoting beneficial bacteria. In this study, we analyzed changes in gut microbial diversity and composition in response to combined interventions of PM exposure and aerobic exercise, extending up to 12 weeks. This investigation was conducted using mice, categorized into five groups: control group (Con), exercise group (EXE), exercise group followed by 3-day exposure to PM (EXE + 3-day PM), particulate matter exposure (PM), and PM exposure with concurrent treadmill exercise (PME). Notably, the PM group exhibited markedly lower alpha diversity and richness compared to the Con group and our analysis of beta diversity revealed significant variations among the intervention groups. Members of the Lachnospiraceae family showed significant enhancement in the exercise intervention groups (EXE and PME) compared to the Con and PM groups. The biomarker Lactobacillus, Coriobacteraceae, and Anaerofustis were enriched in the EXE group, while Desulfovibrionaceae, Mucispirillum schaedleri, Lactococcus and Anaeroplasma were highly enriched in the PM group. Differential abundance analysis revealed that Paraprevotella, Bacteroides, and Blautia were less abundant in the 12-week PM exposure group than in the 3-day PM exposure group. Moreover, both the 3-day and 12-week PM exposure groups exhibited a reduced relative abundance of Bacteroides uniformis, SMB53, and Staphylococcus compared to non-PM exposure groups. These findings will help delineate the possible roles and associations of altered microbiota resulting from the studied interventions, paving the way for future mechanistic research.

Asymmetric voltage amplification using a capacitive load energy management circuit in a triboelectric nanogenerator.

We investigated the polarity dependence of a capacitive energy management circuit in a triboelectric nanogenerator (TENG) power system. In a half-wave rectifying circuit, the Simulation Program with Integrated Circuit Emphasis and analytical models show that the charge dump to the load varied depending on the polarity of the rectifying circuit even with the same charge output from TENG. Depending on the polarity of the rectifying circuit, a fast saturation of the direct current (DC) output voltage or a high DC output voltage was obtained. Experiments with a half-wave rectifier and Bennet doubler confirmed our simulation and theoretical results. The charge dump from the minimum capacitance of the separated TENG to the load capacitance and the charge dump from the maximum capacitance of the contacted TENG to the load resulted in asymmetric charging behavior. We concluded that it is necessary to analyze the TENG and the capacitive energy management circuit as a single system rather than considering them as independent units in the rectifying circuit of the TENG. This work can provide insights for the design of triboelectric energy harvesting systems.

Clinical benefits of surgical ablation during isolated aortic valve replacement: a nationwide study.

OBJECTIVES: To compare the early- and long-term clinical outcomes of concomitant surgical ablation (SA) for atrial fibrillation (AF) during isolated aortic valve replacement (AVR) using data from the Korean National Health Insurance Service Database. METHODS: Of 23,332 adult patients who underwent AVR between 2003 and 2019, those with underlying AF with or without concomitant SA were extracted, and propensity score matching analysis was performed. RESULTS: Overall, 1,741 patients with underlying AF with (n = 445, group A) or without (n = 1,296, group N) concomitant SA during isolated AVR were enrolled, from whom 435 pairs were matched in a 1:1 ratio using propensity score matching analysis. The operative mortality and early postoperative morbidities, including bleeding reoperation, stroke, permanent pacemaker implantation and acute kidney injury were comparable between the groups. The overall survival showed no differences between the groups. However, the cumulative incidence of new-onset late ischaemic stroke was significantly lower in group A than group N in propensity score-matched patients [2.3 vs 3.5 per 100 patient-years, adjusted hazard ratio (95% confidence interval) 0.64 (0.43-0.96), Group A versus Group N, respectively]. The cumulative incidence of other morbidities such as reoperation, permanent pacemaker implantation and progression to chronic renal failure showed no difference between groups. CONCLUSIONS: The incidence of late ischaemic stroke was significantly lower when concomitant SA was performed during isolated AVR in patients with underlying AF. Therefore, concomitant SA should be actively considered in patients with underlying AF undergoing isolated AVR to prevent the occurrence of late ischaemic stroke.

The Association Between Prenatal Food Insecurity and Breastfeeding Initiation and Exclusive Breastfeeding Duration: A Longitudinal Study Using Oregon PRAMS and PRAMS-2, 2008-2015.

Background: In the United States, 11.1% of households experience food insecurity; however, pregnant women are disproportionately affected. Maternal food insecurity may affect infant feeding practices, for example, through being a source of chronic stress that may alter the decision to initiate and continue breastfeeding. Thus, we sought to determine whether prenatal food insecurity was associated with breastfeeding (versus not) and exclusive breastfeeding duration among Oregon women. Method: The Oregon Pregnancy Risk Assessment Monitoring System (PRAMS) data of live births from 2008 to 2015 and the Oregon PRAMS-2 follow-up survey were used (n = 3,624) in this study. Associations with breastfeeding initiation and duration were modeled with multivariable logistic regression and accelerated failure time (AFT), respectively. Models were adjusted for maternal sociodemographic and pre-pregnancy health characteristics. Results: Nearly 10% of women experienced prenatal food insecurity. For breastfeeding initiation, unadjusted models suggested non-significant decreased odds (odds ratio (OR) 0.88 [confidence intervals (CI): 0.39, 1.99]), whereas adjusted models revealed a non-significant increased odds (OR 1.41 [CI: 0.58, 3.47]). Unadjusted AFT models suggested that food-insecure mothers had a non-significant decrease in exclusive breastfeeding duration (OR 0.76 [CI: 0.50, 1.17]), but adjustment for covariates attenuated results (OR 0.89 [CI: 0.57, 1.39]). Conclusions: Findings suggest minimal differences in breastfeeding practices when exploring food security status in the prenatal period, though the persistence of food insecurity may affect exclusive breastfeeding duration. Lower breastfeeding initiation may be due to other explanatory factors correlated with food insecurity and breastfeeding, such as education and marital status.

Distinct spatiotemporal patterns of cortical thinning in Alzheimer's disease-type cognitive impairment and subcortical vascular cognitive impairment.

Previous studies on Alzheimer's disease-type cognitive impairment (ADCI) and subcortical vascular cognitive impairment (SVCI) has rarely explored spatiotemporal heterogeneity. This study aims to identify distinct spatiotemporal cortical atrophy patterns in ADCI and SVCI. 1,338 participants (713 ADCI, 208 SVCI, and 417 cognitively unimpaired elders) underwent brain magnetic resonance imaging (MRI), amyloid positron emission tomography, and neuropsychological tests. Using MRI, this study measures cortical thickness in five brain regions (medial temporal, inferior temporal, posterior medial parietal, lateral parietal, and frontal areas) and utilizes the Subtype and Stage Inference (SuStaIn) model to predict the most probable subtype and stage for each participant. SuStaIn identifies two distinct cortical thinning patterns in ADCI (medial temporal: 65.8%, diffuse: 34.2%) and SVCI (frontotemporal: 47.1%, parietal: 52.9%) patients. The medial temporal subtype of ADCI shows a faster decline in attention, visuospatial, visual memory, and frontal/executive domains than the diffuse subtype (p-value < 0.01). However, there are no significant differences in longitudinal cognitive outcomes between the two subtypes of SVCI. Our study provides valuable insights into the distinct spatiotemporal patterns of cortical thinning in patients with ADCI and SVCI, suggesting the potential for individualized therapeutic and preventive strategies to improve clinical outcomes.

TGF-ß blockade drives a transitional effector phenotype in T cells reversing SIV latency and decreasing SIV reservoirs in vivo.

HIV-1 persistence during ART is due to the establishment of long-lived viral reservoirs in resting immune cells. Using an NHP model of barcoded SIVmac239 intravenous infection and therapeutic dosing of anti-TGFBR1 inhibitor galunisertib (LY2157299), we confirm the latency reversal properties of in vivo TGF-ß blockade, decrease viral reservoirs and stimulate immune responses. Treatment of eight female, SIV-infected macaques on ART with four 2-weeks cycles of galunisertib leads to viral reactivation as indicated by plasma viral load and immunoPET/CT with a 64Cu-DOTA-F(ab')2-p7D3-probe. Post-galunisertib, lymph nodes, gut and PBMC exhibit lower cell-associated (CA-)SIV DNA and lower intact pro-virus (PBMC). Galunisertib does not lead to systemic increase in inflammatory cytokines. High-dimensional cytometry, bulk, and single-cell (sc)RNAseq reveal a galunisertib-driven shift toward an effector phenotype in T and NK cells characterized by a progressive downregulation in TCF1. In summary, we demonstrate that galunisertib, a clinical stage TGF-ß inhibitor, reverses SIV latency and decreases SIV reservoirs by driving T cells toward an effector phenotype, enhancing immune responses in vivo in absence of toxicity.

Temporal variations in the gut microbial diversity in response to high-fat diet and exercise.

High-fat diet-induced obesity is a pandemic caused by an inactive lifestyle and increased consumption of Western diets and is a major risk factor for diabetes and cardiovascular diseases. In contrast, exercise can positively influence gut microbial diversity and is linked to a decreased inflammatory state. To understand the gut microbial variations associated with exercise and high-fat diet over time, we conducted a longitudinal study to examine the effect of covariates on gut microbial diversity and composition. Young mice were divided into four groups: Chow-diet (CHD), high-fat diet (HFD), high-fat diet + exercise (HFX), and exercise only (EXE) and underwent experimental intervention for 12 weeks. Fecal samples at week 0 and 12 were collected for DNA extraction, followed by 16S library preparation and sequencing. Data were analyzed using QIIME 2, R and MicrobiomeAnalyst. The Bacteroidetes-to-Firmicutes ratio decreased fivefold in the HFD and HFX groups compared to that in the CHD and EXE groups and increased in the EXE group over time. Alpha diversity was significantly increased in the EXE group longitudinally (p < 0.02), whereas diversity (Shannon, Faith's PD, and Fisher) and richness (ACE) was significantly reduced in the HFD (p < 0.005) and HFX (p < 0.03) groups over time. Beta diversity, based on the Jaccard, Bray-Curtis, and unweighted UniFrac distance metrics, was significant among the groups. Prevotella, Paraprevotella, Candidatus arthromitus, Lactobacillus salivarius, L. reuteri, Roseburia, Bacteroides uniformis, Sutterella, and Corynebacterium were differentially abundant in the chow-diet groups (CHD and EXE). Exercise significantly reduced the proportion of taxa characteristic of a high-fat diet, including Butyricimonas, Ruminococcus gnavus, and Mucispirillum schaedleri. Diet, age, and exercise significantly contributed to explaining the bacterial community structure and diversity in the gut microbiota. Modulating the gut microbiota and maintaining its stability can lead to targeted microbiome therapies to manage chronic and recurrent diseases and infections.

Identification of novel Nrf2-activating neuroprotective agents: Elucidation of structural congeners of (-)-galiellalactone and congener-based novel Nrf2 activators.

Herein, (-)-galiellalactone 1 congeners responsible for the nuclear factor erythroid 2-related factor 2 (Nrf2)-activating neuroprotective effects were elucidated. Additionally, novel congener-based Nrf2 activators were identified using a drug repositioning strategy. (-)-Galiellalactone, which comprises a tricyclic lactone skeleton, significantly activates antioxidant response element (ARE)-mediated transcription in neuroblastoma SH-SY5Y cells. Interestingly, two cyclohexene-truncated [3.3] bicyclic lactone analogs, which possess an exocyclic α-methylene-γ-butyrolactone moiety, exhibited higher Nrf2/ARE transcriptional activities than the parent (-)-galiellalactone. We confirmed that the cyclohexene moiety embedding the [3.3] bicyclic lactone congener does not play the essential role of (-)-galiellalactone for Nrf2/ARE activation. Nrf2/ARE activation by novel analogs resulted in the upregulation of downstream antioxidative and phase II detoxifying enzymes, heme oxygenase-1, and NAD(P)H quinone oxidoreductase 1, which are closely related to the cytoprotective effects on neurodegenerative diseases. (-)-Galiellalactone and its [3.3] bicyclic variants 3l and 3p increased the expression of antioxidant genes and exhibited neuroprotective effects against 6-hydroxydopamine-mediated neurotoxicity in the neuroblastoma SH-SY5Y cell line.

Association Between Baseline Gait Parameters and Future Fall Risk in Patients With De Novo Parkinson's Disease: Forward Versus Backward Gait.

BACKGROUND AND PURPOSE: Falls are not uncommon even in patients with early stages of Parkinson's disease (PD). The aims of this study were to determine the relationships between gait parameters and falls and identify crucial gait parameters for predicting future falls in patients with de novo PD. METHODS: We prospectively recruited patients with de novo PD, and evaluated their baseline demographics, global cognitive function on the Montreal Cognitive Assessment test, and parkinsonian motor symptoms including their subtypes. Both forward gait (FG) and backward gait (BG) were measured using the GAITRite system. The history of falls in consecutive patients with de novo PD was examined along with 1 year of follow-up data. RESULTS: Among the 76 patients with de novo PD finally included in the study, 16 (21.1%) were classified as fallers. Fallers had slower gait and shorter stride for FG and BG parameters than did non-fallers, while stride-time variability was greater in fallers but only for BG. Multivariable logistic regression analysis revealed that slow gait was an independent risk factor in BG. CONCLUSIONS: Among the patients with de novo PD, gait speed and stride length were more impaired for both FG and BG in fallers than in non-fallers. It was particularly notable that slow BG was significantly associated with future fall risk, indicating that BG speed is a potential biomarker for predicting future falls in patients with early-stage PD.

Impact of formulation on solid oxygen-entrapping materials to overcome tumor hypoxia.

Tumor hypoxia, resulting from rapid tumor growth and aberrant vascular proliferation, exacerbates tumor aggressiveness and resistance to treatments like radiation and chemotherapy. To increase tumor oxygenation, we developed solid oxygen gas-entrapping materials (O2-GeMs), which were modeled after clinical brachytherapy implants, for direct tumor implantation. The objective of this study was to investigate the impact different formulations of solid O2-GeMs have on the entrapment and delivery of oxygen. Using a Parr reactor, we fabricated solid O2-GeMs using carbohydrate-based formulations used in the confectionary industry. In evaluating solid O2-GeMs manufactured from different sugars, the sucrose-containing formulation exhibited the highest oxygen concentration at 1 mg/g, as well as the fastest dissolution rate. The addition of a surface coating to the solid O2-GeMs, especially polycaprolactone, effectively prolonged the dissolution of the solid O2-GeMs. In vivo evaluation confirmed robust insertion and positioning of O2-GeMs in a malignant peripheral nerve sheath tumor, highlighting potential clinical applications.