The power of genetic diversity in genome-wide association studies of lipids.

Increased blood lipid levels are heritable risk factors of cardiovascular disease with varied prevalence worldwide owing to different dietary patterns and medication use1. Despite advances in prevention and treatment, in particular through reducing low-density lipoprotein cholesterol levels2, heart disease remains the leading cause of death worldwide3. Genome-wideassociation studies (GWAS) of blood lipid levels have led to important biological and clinical insights, as well as new drug targets, for cardiovascular disease. However, most previous GWAS4-23 have been conducted in European ancestry populations and may have missed genetic variants that contribute to lipid-level variation in other ancestry groups. These include differences in allele frequencies, effect sizes and linkage-disequilibrium patterns24. Here we conduct a multi-ancestry, genome-wide genetic discovery meta-analysis of lipid levels in approximately 1.65 million individuals, including 350,000 of non-European ancestries. We quantify the gain in studying non-European ancestries and provide evidence to support the expansion of recruitment of additional ancestries, even with relatively small sample sizes. We find that increasing diversity rather than studying additional individuals of European ancestry results in substantial improvements in fine-mapping functional variants and portability of polygenic prediction (evaluated in approximately 295,000 individuals from 7 ancestry groupings). Modest gains in the number of discovered loci and ancestry-specific variants were also achieved. As GWAS expand emphasis beyond the identification of genes and fundamental biology towards the use of genetic variants for preventive and precision medicine25, we anticipate that increased diversity of participants will lead to more accurate and equitable26 application of polygenic scores in clinical practice.

Siglec-15/sialic acid axis as a central glyco-immune checkpoint in breast cancer bone metastasis.

Immunotherapy is a promising approach for treating metastatic breast cancer (MBC), offering new possibilities for therapy. While checkpoint inhibitors have shown great progress in the treatment of metastatic breast cancer, their effectiveness in patients with bone metastases has been disappointing. This lack of efficacy seems to be specific to the bone environment, which exhibits immunosuppressive features. In this study, we elucidate the multiple roles of the sialic acid-binding Ig-like lectin (Siglec)-15/sialic acid glyco-immune checkpoint axis in the bone metastatic niche and explore potential therapeutic strategies targeting this glyco-immune checkpoint. Our research reveals that elevated levels of Siglec-15 in the bone metastatic niche can promote tumor-induced osteoclastogenesis as well as suppress antigen-specific T cell responses. Next, we demonstrate that antibody blockade of the Siglec-15/sialic acid glyco-immune checkpoint axis can act as a potential treatment for breast cancer bone metastasis. By targeting this pathway, we not only aim to treat bone metastasis but also inhibit the spread of metastatic cancer cells from bone lesions to other organs.

A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids.

A major challenge of genome-wide association studies (GWASs) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. We highlight two of the prioritized genes, CREBRF and RRBP1, which show convergent evidence across functional datasets supporting their roles in lipid biology.

PIP2 regulating calcium signal modulates actin cytoskeleton-dependent cytoadherence and cytolytic capacity in the protozoan parasite Trichomonas vaginalis.

Trichomonas vaginalis is a prevalent causative agent that causes trichomoniasis leading to uropathogenic inflammation in the host. The crucial role of the actin cytoskeleton in T. vaginalis cytoadherence has been established but the associated signaling has not been fully elucidated. The present study revealed that the T. vaginalis second messenger PIP2 is located in the recurrent flagellum of the less adherent isolate and is more abundant around the cell membrane of the adherent isolates. The T. vaginalis phosphatidylinositol-4-phosphate 5-kinase (TvPI4P5K) with conserved activity phosphorylating PI(4)P to PI(4, 5)P2 was highly expressed in the adherent isolate and partially colocalized with PIP2 on the plasma membrane but with discrete punctate signals in the cytoplasm. Plasma membrane PIP2 degradation by phospholipase C (PLC)-dependent pathway concomitant with increasing intracellular calcium during flagellate-amoeboid morphogenesis. This could be inhibited by Edelfosine or BAPTA simultaneously repressing parasite actin assembly, morphogenesis, and cytoadherence with inhibitory effects similar to the iron-depleted parasite, supporting the significance of PIP2 and iron in T. vaginalis colonization. Intriguingly, iron is required for the optimal expression and cell membrane trafficking of TvPI4P5K for in situ PIP2 production, which was diminished in the iron-depleted parasites. TvPI4P5K-mediated PIP2 signaling may coordinate with iron to modulate T. vaginalis contact-dependent cytolysis to influence host cell viability. These observations provide novel insights into T. vaginalis cytopathogenesis during the host-parasite interaction.

Hesperetin activates CISD2 to attenuate senescence in human keratinocytes from an older person and rejuvenates naturally aged skin in mice.

BACKGROUND: CDGSH iron-sulfur domain-containing protein 2 (CISD2), a pro-longevity gene, mediates healthspan in mammals. CISD2 is down-regulated during aging. Furthermore, a persistently high level of CISD2 promotes longevity and ameliorates an age-related skin phenotype in transgenic mice. Here we translate the genetic evidence into a pharmaceutical application using a potent CISD2 activator, hesperetin, which enhances CISD2 expression in HEK001 human keratinocytes from an older person. We also treated naturally aged mice in order to study the activator's anti-aging efficacy. METHODS: We studied the biological effects of hesperetin on aging skin using, firstly, a cell-based platform, namely a HEK001 human keratinocyte cell line established from an older person. Secondly, we used a mouse model, namely old mice at 21-month old. In the latter case, we investigate the anti-aging efficacy of hesperetin on ultraviolet B (UVB)-induced photoaging and naturally aged skin. Furthermore, to identify the underlying mechanisms and potential biological pathways involved in this process we carried out transcriptomic analysis. Finally, CISD2 knockdown HEK001 keratinocytes and Cisd2 knockout mice were used to study the Cisd2-dependent effects of hesperetin on skin aging. RESULTS: Four findings are pinpointed. Firstly, in human skin, CISD2 is mainly expressed in proliferating keratinocytes from the epidermal basal layer and, furthermore, CISD2 is down-regulated in the sun-exposed epidermis. Secondly, in HEK001 human keratinocytes from an older person, hesperetin enhances mitochondrial function and protects against reactive oxygen species-induced oxidative stress via increased CISD2 expression; this enhancement is CISD2-dependent. Additionally, hesperetin alleviates UVB-induced damage and suppresses matrix metalloproteinase-1 expression, the latter being a major indicator of UVB-induced damage in keratinocytes. Thirdly, transcriptomic analysis revealed that hesperetin modulates a panel of differentially expressed genes that are associated with mitochondrial function, redox homeostasis, keratinocyte function, and inflammation in order to attenuate senescence. Intriguingly, hesperetin activates two known longevity-associated regulators, namely FOXO3a and FOXM1, in order to suppress the senescence-associated secretory phenotype. Finally, in mouse skin, hesperetin enhances CISD2 expression to ameliorate UVB-induced photoaging and this occurs via a mechanism involving CISD2. Most strikingly, late-life treatment with hesperetin started at 21-month old and lasting for 5 months, is able to retard skin aging and rejuvenate naturally aged skin in mice. CONCLUSIONS: Our results reveal that a pharmacological elevation of CISD2 expression at a late-life stage using hesperetin treatment is a feasible approach to effectively mitigating both intrinsic and extrinsic skin aging and that hesperetin could act as a functional food or as a skincare product for fighting skin aging.

Polygenic Score for the Prediction of Postoperative Nausea and Vomiting: A Retrospective Derivation and Validation Cohort Study.

BACKGROUND: Postoperative nausea and vomiting (PONV) is a key driver of unplanned admission and patient satisfaction following surgery. Because traditional risk factors do not completely explain variability in risk, we hypothesize that genetics may contribute to the overall risk for this complication. The objective of this research is to perform a genome-wide association study of PONV, derive a polygenic risk score for PONV, assess associations between the risk score and PONV in a validation cohort, and compare any genetic contributions to known clinical risks for PONV. METHODS: Surgeries with integrated genetic and perioperative data performed under general anesthesia at Michigan Medicine and Vanderbilt University Medical Center were studied. PONV was defined as nausea or emesis occurring and documented in the PACU. In the Discovery Phase, genome-wide association studies were performed on each genetic cohort and the results were meta-analyzed. Next, in the Polygenic Phase, we assessed whether a polygenic score, derived from genome-wide association study in a derivation cohort from Vanderbilt University Medical Center, improved prediction within a validation cohort from Michigan Medicine, as quantified by discrimination (C-statistic) and net reclassification index. RESULTS: Of 64,523 total patients, 5,703 developed PONV (8.8%). We identified 46 genetic variants exceeding P<1x10-5 threshold, occurring with minor allele frequency > 1%, and demonstrating concordant effects in both cohorts. Standardized polygenic score was associated with PONV in a basic model, controlling for age and sex, (aOR 1.027 per standard deviation increase in overall genetic risk, 95% CI 1.001-1.053, P=0.044), a model based on known clinical risks (aOR 1.029, 95% CI 1.003-1.055, P=0.030), and a full clinical regression, controlling for 21 demographic, surgical, and anesthetic factors, (aOR 1.029, 95% CI 1.002-1.056, P=0.033). The addition of polygenic score improved overall discrimination in models based on known clinical risk factors (c-statistic: 0.616 compared to 0.613, P=0.028) and improved net reclassification of 4.6% of cases. CONCLUSION: Standardized polygenic risk was associated with PONV in all three of our models, but the genetic influence was smaller than exerted by clinical risk factors. Specifically, a patient with a polygenic risk score > 1 standard deviation above the mean, has 2-3% greater odds of developing PONV when compared to the baseline population, which is at least an order of magnitude smaller than the increase associated with having prior PONV/motion sickness (55%), having a history of migraines (17%), or being female (83%), and is not clinically significant. Furthermore, the use of a polygenic risk score does not meaningfully improve discrimination compared to clinical risk factors and is not clinically useful.

Ceftazidime-avibactam versus other antimicrobial agents for treatment of Multidrug-resistant Pseudomonas aeruginosa: a systematic review and meta-analysis.

OBJECTIVES: Multidrug-resistant Pseudomonas aeruginosa (MDR-PA) is a life-threatening infection with limited treatment options. This is the first meta-analysis of recently published data to compare the clinical outcomes of ceftazidime-avibactam (CAZ-AVI) with other antimicrobial agents in treating MDR-PA infections. DESIGN: Systematic review and meta-analysis. DATA SOURCES: PubMed, Embase and the Cochrane Library have been systematically reviewed, for publications in the English language, from database inception to July 2023. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Studies comparing CAZ-AVI outcomes with other antimicrobial agents were included. In-hospital mortality & 30-day mortality were assessed as the main outcomes. DATA EXTRACTION AND SYNTHESIS: Literature screening, data extraction, and the quality evaluation of studies were conducted by two researchers independently, with disagreements resolved by another researcher. The Newcastle-Ottawa Scale was used to assess the bias risk for the included studies. Review Manager V.5.4 was employed for the meta-analysis. RESULTS: The meta-analysis included four retrospective studies, enrolling 1934 patients. The CAZ-AVI group demonstrated significantly lower in-hospital mortality (risk ratio (RR) = 0.60, 95% CI:0.37-0.97, I2 = 74%, p = 0.04) in three studies with 1444 patients and lower 30-day mortality, in 438 patients from three studies (RR = 0.54, 95% CI:0.28-1.05, I2 = 67%, p = 0.07). No significant difference in clinical success, microbiological success, length of hospital, and ICU stay was observed. CONCLUSIONS: This meta-analysis demonstrated that CAZ-AVI treatment significantly lowered in-hospital mortality compared with other antimicrobial agents in MDR-PA infections. However, the analysis only included a few observational studies and high-quality, randomized controlled trials are needed to investigate further the scope of CAZ-AVI in MDR-PA  infections.

Therapeutic efficacy of 180-W GreenLight laser photoselective vaporization of the prostate for storage symptoms concomitant with benign prostatic obstruction and a search for outcome predictors.

PURPOSE: Benign prostatic obstruction (BPO) is the most common cause of lower urinary tract symptoms among men. GreenLight photoselective vaporization of the prostate (GL-PVP) using a 180-W Xcelerated performance system (XPS) laser is a well-established method for treating BPO-induced voiding symptoms. However, its therapeutic effects on storage symptoms remain unclear. This study aimed to analyze the storage outcomes in patients who underwent 180-W XPS GL-PVP for BPO and to identify outcome predictors. MATERIALS AND METHODS: Patients who underwent 180-W XPS GL-PVP for BPO between May 2018 and May 2021 were retrospectively reviewed. Data on clinical characteristics, prostate volume, preoperative and postoperative International Prostate Symptom Scores (IPSS), and preoperative urodynamic parameters were collected. A favorable storage outcome was defined as ≥50% reduction in the IPSS storage subscore. RESULTS: Ninety-nine male patients were included, with a mean age of 69.4 ± 9.6 years and a baseline prostatic volume of 75.9 ± 33.1 mL. The IPSS total, storage, and voiding subscores significantly decreased after GL-PVP (all p < 0.001). Seventy-two patients achieved favorable storage outcome at 6 months. Multivariate analysis revealed that detrusor underactivity was predictive of unfavorable storage outcomes (p = 0.022), while IPSS voiding-to-storage subscore ratio >1.25 and the presence of detrusor overactivity were predictive of favorable storage outcomes (p = 0.008 and 0.033, respectively). CONCLUSION: 180-W XPS GL-PVP provided excellent outcomes in both voiding and storage lower urinary tract symptoms concomitant with BPO. Preoperative IPSS and multichannel urodynamic parameters including detrusor overactivity and underactivity are valuable predictors of postoperative storage outcomes.

Urinary concerns among older adults: a qualitative analysis in the context of healthy aging.

BACKGROUND: Urinary concerns increase with age impacting health and quality of life. The aims of this study were to describe: (1) urinary concerns as an age-related change (ARC); (2) the challenges of urinary concerns; (3) adaptation strategies used to manage urinary concerns; and (4) the value of engaging with aging (EWA) as a framework to promote self-management of urinary concerns. METHODS: Data was used from semi-structured interviews with 29 older adults (mean age 77 years). An iterative coding process was used. A codebook was developed based on a-priori themes derived from the EWA framework, our previous publication, and a line-by-line coding of one of the transcripts. As the analysis progressed, additional codes emerged, enriching the codebook. RESULTS: Six themes emerged: (1) the participants' experiences; (2) responses to urinary concerns, (3) adaptation and management strategies; (4) knowledge and understanding of urinary concerns; (5) available capacities and resources; and (6) the impact of the COVID-19 pandemic on urinary concerns. Participants tended to address their urinary concerns by adjusting routines, medication schedules, or diet patterns. They tried to secure restroom locations or use tools or reminders to resolve their urinary concerns. COVID-19 led to increased inconvenience for older adults to engage in outdoor activities due to the closure of public restrooms. CONCLUSIONS: Our in-depth qualitative analysis found that participants developed personalized adjustments to address their needs and abilities to their urinary concerns. These findings offer insights into the individual aging experience, which will further enhance our understanding and advancement of person-centered care.

Family involvement in mental healthcare practice: Perspectives of mental health nurses, patients, and caregivers.

INTRODUCTION: Family engagement in care has been advocated to promote recovery for patients with mental health conditions. Attitudes of mental health nurses toward the importance of families influence the way they partner with families in mental healthcare. However, little is known about how mental health nurses engage with families and quality of family-centered care (FCC) perceived by patients and caregivers. The study aimed to examine the mediating effect of family nursing practice on the association between mental health nurses' attitudes toward integrating families into care and quality of FCC perceived by patients with schizophrenia and caregivers. DESIGN: A cross-sectional study was conducted. METHODS: A convenience sample of 143 dyads of patients with schizophrenia and their caregivers and 109 mental health nurses were recruited from inpatient wards at two psychiatric hospitals in Taiwan. Demographic and clinical questionnaires, Families' Importance in Nursing Care-Nurses' Attitudes scale, Family Nursing Practice Scale, and Measure of Process of Care for Adults were used to collect data. Data were analyzed using descriptive statistics, independent-sample t-tests, one-way analysis of variance, Pearson correlation coefficients, paired-sample t-tests, and intraclass correlation coefficient (ICC). Mediation analyses were performed using Hayes' PROCESS macro in SPSS (Model 4) with bootstrapping. RESULTS: Mental health nurses exhibited supportive attitudes toward integrating families into care (Mean = 98.96) and greater perceptions of family nursing practice (Mean = 2.44). The concordances between patients and caregivers on perceived quality of family-centered care were significant (ICC = 0.63-0.77). Attitudes of mental health nurses toward integrating families into care had both the total and direct effects on all domains of quality of FCC perceived by patients and caregivers, respectively. The indirect effects of mental health nurses' attitudes toward integrating families into care on aspects of quality of FCC through family nursing practice were significant for patients (95% bias-corrected bootstrap CI of 0.015-0.053) and caregivers (95% bias-corrected bootstrap CI of 0.004-0.041). The magnitude of the indirect effects was medium to large for patients (ES = 0.209-0.257) and caregivers (ES = 0.148-0.221). CONCLUSION: Family nursing practice partially mediated the association between mental health nurses' attitudes toward integrating families into care and aspects of quality of FCC from perspectives of patients and caregivers. CLINICAL RELEVANCE: Interventions tailoring mental health nurses' practice skills and reciprocity with families have the potential to enhance supportive attitudes of mental health nurses toward working with families and further improve perceived quality of FCC in patient-caregiver dyads in mental healthcare practice.

Application of blood-based biomarkers of Alzheimer's disease in clinical practice: Recommendations from Taiwan Dementia Society.

Blood-based biomarkers (BBM) are potentially powerful tools that assist in the biological diagnosis of Alzheimer's disease (AD) in vivo with minimal invasiveness, relatively low cost, and good accessibility. This review summarizes current evidence for using BBMs in AD, focusing on amyloid, tau, and biomarkers for neurodegeneration. Blood-based phosphorylated tau and the Aß42/Aß40 ratio showed consistent concordance with brain pathology measured by CSF or PET in the research setting. In addition, glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) are neurodegenerative biomarkers that show the potential to assist in the differential diagnosis of AD. Other pathology-specific biomarkers, such as α-synuclein and TAR DNA-binding protein 43 (TDP-43), can potentially detect AD concurrent pathology. Based on current evidence, the working group from the Taiwan Dementia Society (TDS) achieved consensus recommendations on the appropriate use of BBMs for AD in clinical practice. BBMs may assist clinical diagnosis and prognosis in AD subjects with cognitive symptoms; however, the results should be interpreted by dementia specialists and combining biochemical, neuropsychological, and neuroimaging information. Further studies are needed to evaluate BBMs' real-world performance and potential impact on clinical decision-making.

Recent progress and strategic perspectives of inorganic solid electrolytes: fundamentals, modifications, and applications in sodium metal batteries.

Solid-state electrolytes (SEs) have attracted overwhelming attention as a promising alternative to traditional organic liquid electrolytes (OLEs) for high-energy-density sodium-metal batteries (SMBs), owing to their intrinsic incombustibility, wider electrochemical stability window (ESW), and better thermal stability. Among various kinds of SEs, inorganic solid-state electrolytes (ISEs) stand out because of their high ionic conductivity, excellent oxidative stability, and good mechanical strength, rendering potential utilization in safe and dendrite-free SMBs at room temperature. However, the development of Na-ion ISEs still remains challenging, that a perfect solution has yet to be achieved. Herein, we provide a comprehensive and in-depth inspection of the state-of-the-art ISEs, aiming at revealing the underlying Na+ conduction mechanisms at different length scales, and interpreting their compatibility with the Na metal anode from multiple aspects. A thorough material screening will include nearly all ISEs developed to date, i.e., oxides, chalcogenides, halides, antiperovskites, and borohydrides, followed by an overview of the modification strategies for enhancing their ionic conductivity and interfacial compatibility with Na metal, including synthesis, doping and interfacial engineering. By discussing the remaining challenges in ISE research, we propose rational and strategic perspectives that can serve as guidelines for future development of desirable ISEs and practical implementation of high-performance SMBs.

A Dual Organic Solvent Zn-Ion Electrolyte Enables Highly Stable Zn Metal Batteries.

Aqueous zinc (Zn) batteries have been regarded as an alternative to lithium-ion batteries due to their high abundance, low cost, and higher intrinsic safety. However, the low Zn plating/stripping reversibility, Zn dendrite growth, and continuous water consumption have hindered the practical application of aqueous Zn anodes. Herein, a hydrous organic Zn-ion electrolyte based on a dual organic solvent, namely hydrated Zn(BF4)2 zinc salt dissolved in dimethyl carbonate (DMC) and vinyl carbonate (EC) solvents [denoted as Zn(BF4)2/DMC/EC], can address these problems, which not only inhibits the side reactions but also promotes uniform Zn plating/stripping through the formation of a stable solid state interface layer and Zn2+-EC/2DMC pairs. This electrolyte enables the Zn electrode to stably undergo >700 cycles at a rate of 1 mA cm-2 with a Coulombic efficiency of 99.71%. Moreover, the full cell paired with V2O5 also demonstrates excellent cycling stability without capacity decay at 1 A g-1 after 1600 cycles.

Regulation of Cecal Microbiota and Improvement of Blood Lipids Using Walnut Non-Dairy Creamer in High-Fat Mice: Replacing Traditional Non-Dairy Creamer.

Non-dairy creamer is a class of microencapsulated powdered fats and oils that are widely used in the food industry. However, the oils used in it are hydrogenated vegetable oils, which contain large amounts of saturated fatty acids and are extremely harmful to the human body. This study investigated the effects of replacing hydrogenated vegetable oil with walnut oil to prepare walnut non-dairy creamer on lipid levels and intestinal microorganisms in mice. The results show that low-dose walnut non-dairy creamer significantly decreased the contents of TC and TG in serum and increased the content of HDL-C (p < 0.01). The contents of MDA, ALT, and AST were significantly decreased, while the content of SOD was increased (p < 0.01). The abundance of Firmicutes in the walnut non-dairy creamer group decreased, and the abundance of Bacteroidetes/Firmicutes (B/F) increased, which significantly increased the richness of Lactobacillus and Oscillospira (p < 0.01). Allobaculum richness was significantly decreased (p < 0.01). In conclusion, a low dose of walnut non-dairy creamer can effectively promote the metabolism of blood lipids in vivo, alleviate oxidative stress injury and lipid accumulation damage to mouse hepatocytes, and ameliorate the adverse effects of a high-fat diet on the intestinal microbiota of mice. This study provides a theoretical basis for the replacement of traditional non-dairy creamer and the research and development of walnut deep processing.

Protein target highlights in CASP15: Analysis of models by structure providers.

We present an in-depth analysis of selected CASP15 targets, focusing on their biological and functional significance. The authors of the structures identify and discuss key protein features and evaluate how effectively these aspects were captured in the submitted predictions. While the overall ability to predict three-dimensional protein structures continues to impress, reproducing uncommon features not previously observed in experimental structures is still a challenge. Furthermore, instances with conformational flexibility and large multimeric complexes highlight the need for novel scoring strategies to better emphasize biologically relevant structural regions. Looking ahead, closer integration of computational and experimental techniques will play a key role in determining the next challenges to be unraveled in the field of structural molecular biology.

Diagnostic metabolomic profiling of Parkinson's disease biospecimens.

BACKGROUND: Reliable and sensitive biomarkers are needed for enhancing and predicting Parkinson's disease (PD) diagnosis. OBJECTIVE: To investigate comprehensive metabolomic profiling of biochemicals in CSF and serum for determining diagnostic biomarkers of PD. METHODS: Fifty subjects, symptomatic with PD for ≥5 years, were matched to 50 healthy controls (HCs). We used ultrahigh-performance liquid chromatography linked to tandem mass spectrometry (UHPLC-MS/MS) for measuring relative concentrations of ≤1.5 kDalton biochemicals. A reference library created from authentic standards facilitated chemical identifications. Analytes underwent univariate analysis for PD association, with false discovery rate-adjusted p-value (≤0.05) determinations. Multivariate analysis (for identifying a panel of biochemicals discriminating PD from HCs) used several biostatistical methods, including logistic LASSO regression. RESULTS: Comparing PD and HCs, strong differentiation was achieved from CSF but not serum specimens. With univariate analysis, 21 CSF compounds exhibited significant differential concentrations. Logistic LASSO regression led to selection of 23 biochemicals (11 shared with those determined by the univariate analysis). The selected compounds, as a group, distinguished PD from HCs, with Area-Under-the-Receiver-Operating-Characteristic (ROC) curve of 0.897. With optimal cutoff, logistic LASSO achieved 100% sensitivity and 96% specificity (and positive and negative predictive values of 96% and 100%). Ten-fold cross-validation gave 84% sensitivity and 82% specificity (and 82% positive and 84% negative predictive values). From the logistic LASSO-chosen regression model, 2 polyamine metabolites (N-acetylcadaverine and N-acetylputrescine) were chosen and had the highest fold-changes in comparing PD to HCs. Another chosen biochemical, acisoga (N-(3-acetamidopropyl)pyrrolidine-2-one), also is a polyamine metabolism derivative. CONCLUSIONS: UHPLC-MS/MS assays provided a metabolomic signature highly predictive of PD. These findings provide further evidence for involvement of polyamine pathways in the neurodegeneration of PD.

Carbonyls and Aerosol Mass Generation from Vaping Nicotine Salt Solutions Using Fourth- and Third-Generation E-Cigarette Devices: Effects of Coil Resistance, Coil Age, and Coil Metal Material.

Aerosol formation and production yields from 11 carbonyls (carbonyl concentration per aerosol mass unit) were investigated (1) from a fourth-generation (4th gen) e-cigarette device at different coil resistances and coil age (0-5000 puffs) using unflavored e-liquid with 2% benzoic acid nicotine salt, (2) between a sub-ohm third-generation (3rd gen) tank mod at 0.12 Ω and a 4th gen pod at 1.2 Ω using e-liquid with nicotine salt, together with nicotine yield, and (3) from 3rd gen coils of different metals (stainless steel, kanthal, nichrome) using e-liquid with freebase nicotine. Coil resistance had an inverse relationship with coil temperature, and coil temperature was directly proportional to aerosol mass formation. Trends in carbonyl yields depended on carbonyl formation mechanisms. Carbonyls produced primarily from thermal degradation chemistry (e.g., formaldehyde, acetaldehyde, acrolein, propionaldehyde) increased per aerosol mass with higher coil resistances, despite lower coil temperature. Carbonyls produced primarily from chemistry initiated by reactive oxygen species (ROS) (e.g., hydroxyacetone, dihydroxyacetone, methylglyoxal, glycolaldehyde, lactaldehyde) showed the opposite trend. Coil age did not alter coil temperature nor aerosol mass formation but had a significant effect on carbonyl formation. Thermal carbonyls were formed optimally at 500 puffs in our study and then declined to a baseline, whereas ROS-derived carbonyls showed a slow rise to a maximum trend with coil aging. The 3rd gen versus 4th gen device comparison mirrored the trends in coil resistance. Nicotine yields per aerosol mass were consistent between 3rd and 4th gen devices. Coil material did not significantly alter aerosol formation nor carbonyl yield when adjusted for wattage. This work shows that sub-ohm coils may not necessarily produce higher carbonyl yields even when they produce more aerosol mass. Furthermore, carbonyl formation is dynamic and not generalizable during the coil's lifetime. Finally, studies that compare data across different e-cigarette devices, coil age, and coil anatomy should account for the aerosol chemistry trends that depend on these parameters.

Fear of falling as a mediator in the association between social frailty and health-related quality of life in community-dwelling older adults.

BACKGROUND: Social frailty is associated with Fear of Falling (FoF) and health-related quality of life (HrQoL). However, how social frailty simultaneously influences FoF and HrQoL remains unclear. The study aims to understand the links between social frailty, FoF, and HrQoL in older adults and the mediating role of FoF in the relations between social frailty and HrQoL. METHODS: In this cross-sectional survey, 1,933 community-dwelling older adults from Changhua County, Taiwan, were interviewed using a self-administrated questionnaire. In total, 1,251 participants with complete data were included for analysis. Data were analyzed using the SPSS PROCESS macro. A simple mediation was employed using social frailty as the independent variable, FoF as the mediator variable, and HrQoL as the outcome variable. RESULTS: Social frailty was associated with HrQoL and indirectly with HrQoL through FoF, and FoF was directly associated with HrQoL. Of the 5-item social frailty index, "going out less frequently" was correlated with HrQoL and indirectly with HrQoL through FoF. Individuals who felt unhelpful toward family or friends had the worst physical HrQoL and did not talk to someone daily had the most negative influence on mental HrQoL. CONCLUSIONS: Social frailty can directly and indirectly, through FoF decrease HrQoL. It also emphasizes the importance of social connectivity in reducing the risk of falls. This study points to the need for social connectivity and fall prevention programs as essential components of strategies to enhance the health and well-being of community-dwelling older adults.

Guided Growth Improves Coxa Valga and Hip Subluxation in Children With Hereditary Multiple Exostoses.

BACKGROUND: In children with severe hereditary multiple exostoses (HME), coxa valga, and hip subluxation are common deformities. The literatures related to surgical management and prevention of hip joint subluxation in HME are scarce. In this study, we aimed to investigate the efficacy of guided growth procedure to correct coxa valga and hip subluxation in HME patients. METHODS: We retrospectively retrieved 12 patients who received guided growth procedures for coxa valga and hip subluxation in HME patients with proximal femur exostoses with a minimum follow-up time of 2 years between 2012 and 2019. Radiographic parameters include head-shaft angle, Hilgenreiner-epiphyseal angle, acetabular index, Reimer migration percentage, center-edged angle, articulo-trochanteric distance, and femoral neck length for comparison between preoperative and latest follow-up results. It was conducted statistically by paired t test and Wilcoxon signed rank test. RESULTS: In this study, the mean difference between preoperative and latest follow-up was significant in head-shaft angle (12±5 degrees; CI, 10-14; P<0.001), Hilgenreiner-epiphyseal angle (12±5 degrees; CI, 10-15; P<0.001), and MP (7%±8%; CI, 3-11; P=0.001). There was a low revision rate (4 of 21, 19%) and no complication in our study. Compared with previous studies on guided growth in children with cerebral palsy and developmental dysplasia of the hip, our study showed good comparable outcomes. CONCLUSION: The results indicated that guided growth improves the hip radiographic parameters of children with HME and may prevent coxa valga and hip subluxations. It is a safe procedure and provides predictable results. LEVEL OF EVIDENCE: Level IV; therapeutic, case series.