Facet overhang: A novel parameter in the pathophysiology of multifidus muscle atrophy.

The relationship between degenerative zygapophysial joint (facet) arthropathy and multifidus muscle atrophy has not been rigorously evaluated. The purpose of this study was to determine if specific morphological features of degenerative facet arthropathy are correlated with multifidus muscle atrophy. We retrospectively reviewed medical records and imaging studies of patients with lumbar spinal stenosis. Facet overhang, bridging osteophyte formation, facet effusion, and facet angles were evaluated by univariable and multivariable regression to identify independent associations with deep and superficial parts of the multifidus total cross-sectional area (tCSA), functional cross-sectional area (fnCSA), and fatty infiltration (FI). Facet overhang was classified as severe in 50 females (53.2%) versus 56 males (36.9%) (p = 0.030). Severity of facet overhang and female sex were independently associated with smaller deep part of the multifidus tCSA and fnCSA as well as higher FI, reflecting greater atrophy of the deep region compared to total muscle mass. In comparison, severe facet overhang (p < 0.001; OR = 3.47, 95% CI = 2.13-5.66) and female sex (p < 0.001; OR = 4.19, 95% CI = 2.58-6.79) were independently associated only with higher superficial part of the multifidus FI, reflecting muscle steatosis without significant lean muscle atrophy. In patients with degenerative lumbar spinal stenosis, facet overhang is an independent risk factor for deep part of the multifidus atrophy. Bridging osteophyte formation, facet effusion, and facet angles were not independently associated with deep part of the multifidus atrophy.

Hallmarks of improved immunological responses in the vaccination of more physically active elderly females.

Physical inactivity is one of the leading contributors to worldwide morbidity and mortality. The elderly are particularly susceptible since the features of physical inactivity overlap with the outcomes of natural aging - including the propensity to develop cardiovascular diseases, cancer, diabetes mellitus, sarcopenia and cognitive impairment. The age-dependent loss of immune function, or immunosenescence, refers to the progressive depletion of primary immune resources and is linked to the development of many of these conditions. Immunosenescence is primarily driven by chronic immune activation and physical activity interventions have demonstrated the potential to reduce the risk of complications in the elderly by modulating inflammation and augmenting the immune system. Since poor vaccination outcome is a hallmark of immunosenescence, the assessment of vaccine efficacy provides a window to study the immunological effects of regular physical activity. Using an accelerator-based study, we demonstrate in a Singaporean Chinese cohort that elderly women (n=56) who walk more after vaccination display greater post-vaccination expansion of monocytes and plasmablasts in peripheral blood. Active elderly female participants also demonstrated lower baseline levels of IP-10 and Eotaxin, and the upregulation of genes associated with monocyte/macrophage phagocytosis. We further describe postive correlations between the monocyte response and the post-vaccination H1N1 HAI titres of participants. Finally, active elderly women reveal a higher induction of antibodies against Flu B in their 18-month second vaccination follow-up. Altogether, our data are consistent with better immunological outcomes in those who are more physically active and highlight the pertinent contribution of monocyte activity.

Functional Redundancy in the Hydroxycinnamate Catabolism Pathways of the Salt Marsh Bacterium Sagittula stellata E-37.

The hydroxycinnamates (HCAs) ferulate and p-coumarate are among the most abundant constituents of lignin, and their degradation by bacteria is an essential step in the remineralization of vascular plant material. Here, we investigate the catabolism of these two HCAs by the marine bacterium Sagittula stellata E-37, a member of the roseobacter lineage with lignolytic potential. Bacterial degradation of HCAs is often initiated by the activity of a hydroxycinnamoyl-coenzyme A (hydroxycinnamoyl-CoA) synthase. Genome analysis of S. stellata revealed the presence of two feruloyl-CoA (fcs) synthase homologs, an unusual occurrence among characterized HCA degraders. In order to elucidate the role of these homologs in HCA catabolism, fcs-1 and fcs-2 were disrupted using insertional mutagenesis, yielding both single and double fcs mutants. Growth on p-coumarate was abolished in the fcs double mutant, whereas maximum cell yield on ferulate was only 2% of that of the wild type. Interestingly, the single mutants demonstrated opposing phenotypes, where the fcs-1 mutant showed impaired growth (extended lag and ∼60% of wild-type rate) on p-coumarate, and the fcs-2 mutant showed impaired growth (extended lag and ∼20% of wild-type rate) on ferulate, pointing to distinct but overlapping roles of the encoded fcs homologs, with fcs-1 primarily dedicated to p-coumarate utilization and fcs-2 playing a dominant role in ferulate utilization. Finally, a tripartite ATP-independent periplasmic (TRAP) family transporter was found to be required for growth on both HCAs. These findings provide evidence for functional redundancy in the degradation of HCAs in S. stellata E-37 and offer important insight into the genetic complexity of aromatic compound degradation in bacteria.IMPORTANCE Hydroxycinnamates (HCAs) are essential components of lignin and are involved in various plant functions, including defense. In nature, microbial degradation of HCAs is influential to global carbon cycling. HCA degradation pathways are also of industrial relevance, as microbial transformation of the HCA, ferulate, can generate vanillin, a valuable flavoring compound. Yet, surprisingly little is known of the genetics underlying bacterial HCA degradation. Here, we make comparisons to previously characterized bacterial HCA degraders and use a genetic approach to characterize genes involved in catabolism and uptake of HCAs in the environmentally relevant marine bacterium Sagittula stellata We provide evidence of overlapping substrate specificity between HCA degradation pathways and uptake proteins. We conclude that S. stellata is uniquely poised to utilize HCAs found in the complex mixtures of plant-derived compounds in nature. This strategy may be common among marine bacteria residing in lignin-rich coastal waters and has potential relevance to biotechnology sectors.

Documentation of Improved Outcomes for Intracranial Aneurysm Management Over a 15-Year Interval.

BACKGROUND AND PURPOSE: Despite rapid advancements in intracranial aneurysm management, there is no evidence as of yet that this has translated into improvement in overall prognosis. METHODS: We compared 2 periods of aneurysm management, 1998 to 2003 (n=1023 aneurysms) and 2007 to 2013 (n=1499 aneurysms), at a single, high-volume neurovascular center. Our outcome of interest was low or moderate disability (Glasgow Outcome Scale score of 4 or 5) at 6 months or more post treatment. RESULTS: There were significant improvements in outcome for surgical, endovascular, and overall treatment of unruptured (adjusted odds ratio [OR], 2.33; P=0.0091; adjusted OR, 4.40; P=0.0271; and adjusted OR, 2.58; P=0.0008, respectively) and ruptured (adjusted OR, 3.18; P=0.0004; adjusted OR, 3.54; P=0.0001; and adjusted OR, 3.11; P<0.0001, respectively) aneurysms from the first to the second time period. In 2007 to 2013, the proportion of cases with low or moderate disability at 6 months post subarachnoid hemorrhage was 75.6% for surgical clipping and 76.6% for endovascular therapy. CONCLUSIONS: We report significantly improved outcomes over time for overall aneurysm management and for multiple patient subgroups, associated with increased usage of endovascular therapy.

Clinical presentation, progression, and treatment outcomes of moyamoya disease in the elderly.

BACKGROUND: Moyamoya disease is a vascular disorder characterized by progressive stenosis of the internal carotid artery. The presentation, progression, treatment options, and post-operative clinical outcomes for elderly (60 and older) Moyamoya patients have never been reported. METHODS: A retrospective analysis of all patients who were diagnosed with Moyamoya disease by the senior authors between 1991 and 2016 was performed. Patients who were 60 years or older at the time of surgery or last follow-up were further evaluated. RESULTS: Seventy patients were diagnosed with probable or definite Moyamoya disease during the study period (1991-2016). Eight patients (11.4 %; six females: two males; median age 63; range, 60-71 years) were found to be 60 years or older at the time of surgery or last follow-up and were included in the study. All patients had a modified Rankin scale (mRS) of either one or two (median 1) pre-operatively. Six patients (75 %) underwent surgical treatment on a total on seven hemispheres. Post-surgery, one patient had an improved mRS score, three had no changes, and two had worsening in their mRS scores. Both patients who did not undergo surgical interventions suffered from intra-parenchymal hemorrhages post-diagnosis. CONCLUSIONS: Moyamoya disease is most commonly seen in young and middle-aged patients. Presentation in the elderly (defined as 60 years and older in this study) is rare, and has never been reported in the literature. In this study, both direct and indirect revascularization procedures demonstrated potential benefit in some of these patients, with stabilization of progressive symptoms.

Middle meningeal artery: Gateway for effective transarterial Onyx embolization of dural arteriovenous fistulas.

Curative transarterial embolization of noncavernous sinus dural arteriovenous fistulas (dAVFs) is challenging. We sought to evaluate the role of the middle meningeal artery (MMA) in endovascular treatment of these lesions. We performed a retrospective cohort study on patients who underwent transarterial Onyx embolization of a noncavernous sinus dAVFs with contribution from the MMA at a major academic institution in the United States from January 2009 to January 2015. Twenty consecutive patients who underwent transarterial Onyx embolization of a noncavernous sinus dAVF were identified. One patient was excluded as there was no MMA contribution to the dAVF. All of the remaining 19 patients (61.3 ± 13.8 years of age) underwent transarterial embolization through the MMA. Six patients (31.6%) presented with intraparenchymal or subarachnoid hemorrhage from the dAVF. The overall angiographic cure rate was 73.7% upon last follow up. In 71.4% of successfully treated patients transarterial embolization of the MMA alone was sufficient to achieve angiographic cure. When robust MMA supply was present, MMA embolization resulted in angiographic cure even after embolization of other arterial feeders had failed in 92.9% of patients. A robust contribution of the MMA to the fistula was the single most important predictor for successful embolization (P = 0.00129). We attribute our findings to the fairly straight, non-tortuous course of the MMA that facilitates microcatheter access, navigation, and Onyx penetration. Noncavernous sinus dAVF can be successfully embolized with transarterial Onyx through the MMA, as long as supply is robust. A transvenous approach is rarely necessary. Clin. Anat. 29:718-728, 2016. © 2016 Wiley Periodicals, Inc.

The microbial metabolite urolithin A reduces Clostridioides difficile toxin expression and toxin-induced epithelial damage.

Clostridioides difficile is a Gram-positive, anaerobic, spore-forming bacterium responsible for antibiotic-associated pseudomembranous colitis. Clostridioides difficile infection (CDI) symptoms can range from diarrhea to life-threatening colon damage. Toxins produced by C. difficile (TcdA and TcdB) cause intestinal epithelial injury and lead to severe gut barrier dysfunction, stem cell damage, and impaired regeneration of the gut epithelium. Current treatment options for intestinal repair are limited. In this study, we demonstrate that treatment with the microbial metabolite urolithin A (UroA) attenuates CDI-induced adverse effects on the colon epithelium in a preclinical model of CDI-induced colitis. Moreover, our analysis suggests that UroA treatment protects against C. difficile-induced inflammation, disruption of gut barrier integrity, and intestinal tight junction proteins in the colon of CDI mice. Importantly, UroA treatment significantly reduced the expression and release of toxins from C. difficile without inducing bacterial cell death. These results indicate the direct regulatory effects of UroA on bacterial gene regulation. Overall, our findings reveal a novel aspect of UroA activity, as it appears to act at both the bacterial and host levels to protect against CDI-induced colitis pathogenesis. This research sheds light on a promising avenue for the development of novel treatments for C. difficile infection.IMPORTANCETherapy for Clostridioides difficile infections includes the use of antibiotics, immunosuppressors, and fecal microbiota transplantation. However, these treatments have several drawbacks, including the loss of colonization resistance, the promotion of autoimmune disorders, and the potential for unknown pathogens in donor samples. To date, the potential benefits of microbial metabolites in CDI-induced colitis have not been fully investigated. Here, we report for the first time that the microbial metabolite urolithin A has the potential to block toxin production from C. difficile and enhance gut barrier function to mitigate CDI-induced colitis.

The microbial metabolite Urolithin A reduces C. difficile toxin expression and repairs toxin-induced epithelial damage.

Clostridioides difficile is a gram-positive, anaerobic, spore-forming bacterium that is responsible for antibiotic-associated pseudomembranous colitis. Clostridioides difficile infection (CDI) symptoms can range from diarrhea to life-threatening colon damage. Toxins produced by C. difficile (TcdA and TcdB) cause intestinal epithelial injury and lead to severe gut barrier dysfunction, stem cell damage, and impaired regeneration of the gut epithelium. Current treatment options for intestinal repair are limited. In this study, we demonstrate that treatment with the microbial metabolite urolithin A (UroA) attenuates CDI-induced adverse effects on the colon epithelium in a preclinical model of CDI-induced colitis. Moreover, our analysis suggests that UroA treatment protects against C. difficile-induced inflammation, disruption of gut barrier integrity, and intestinal tight junction proteins in the colon of CDI mice. Importantly, UroA treatment significantly reduced the expression and release of toxins from C. difficile, without inducing bacterial cell death. These results indicate the direct regulatory effects of UroA on bacterial gene regulation. Overall, our findings reveal a novel aspect of UroA activities, as it appears to act at both the bacterial and host levels to protect against CDI-induced colitis pathogenesis. This research sheds light on a promising avenue for the development of novel treatments for C. difficile infection.

Tackling prediction uncertainty in machine learning for healthcare.

Predictive machine-learning systems often do not convey the degree of confidence in the correctness of their outputs. To prevent unsafe prediction failures from machine-learning models, the users of the systems should be aware of the general accuracy of the model and understand the degree of confidence in each individual prediction. In this Perspective, we convey the need of prediction-uncertainty metrics in healthcare applications, with a focus on radiology. We outline the sources of prediction uncertainty, discuss how to implement prediction-uncertainty metrics in applications that require zero tolerance to errors and in applications that are error-tolerant, and provide a concise framework for understanding prediction uncertainty in healthcare contexts. For machine-learning-enabled automation to substantially impact healthcare, machine-learning models with zero tolerance for false-positive or false-negative errors must be developed intentionally.

Retrospective analysis of factors that affect driving assessment outcomes after stroke.

INTRODUCTION: More than 50% of people do not resume driving post-stroke. Potential disincentives include limited knowledge about assessment, access to services, cost and fear of failure. Factors contributing to a successful return to driving have been the focus of limited research. AIM: To determine the proportion of people with stroke who successfully pass their first on-road occupational therapy driving assessment, and factors associated with a successful assessment outcome. METHODS: A retrospective cohort study design was used. The primary data collection method was a review of 441 consecutive occupational therapy driving assessment reports from one Australian metropolitan centre. Participants had a diagnosis of stroke, a driving licence pre-stroke and completed a driving assessment between 1999 and 2010. RESULTS: Of the 441 records analysed, the mean age of drivers was 65.4 years (SD: 15.4). The majority (53.7%) passed their first assessment (pass/conditional pass); only 8.8% failed. A weak relationship was found between initial driving assessment outcome and time post-stroke (r(s)  = 0.19), but a fair relationship with younger age (r(s)  = 0.31) and higher scores on three off-road assessments (r(s)  = -0.26 to -0.28). The strongest predictors of initial driving assessment outcome were off-road assessment scores, age, gender and time post-stroke (R(2)  = 19.7%, P < 0.01). CONCLUSIONS: Data on stroke severity are required to confirm these preliminary predictors of driving assessment outcome. Stroke severity should be routinely documented by driving assessment services for use in future research.

Rapid, Efficient, and Cost-Effective Gene Editing of Enterococcus faecium with CRISPR-Cas12a.

Considered a serious threat by the Centers for Disease Control and Prevention, multidrug-resistant Enterococcus faecium is an increasing cause of hospital-acquired infection. Here, we provide details on a single-plasmid CRISPR-Cas12a system for generating clean deletions and insertions. Single manipulations were carried out in under 2 weeks, with successful deletions/insertions present in >80% of the clones tested. Using this method, we generated three individual clean deletion mutations in the acpH, treA, and lacL genes and inserted codon-optimized unaG, enabling green fluorescent protein (GFP)-like fluorescence under the control of the trehalase operon. The use of in vivo recombination for plasmid construction kept costs to a minimum. IMPORTANCE Enterococcus faecium is increasingly associated with hard-to-treat antibiotic-resistant infections. The ability to generate clean genomic alterations is the first step in generating a complete mechanistic understanding of how E. faecium acquires pathogenic traits and causes disease. Here, we show that CRISPR-Cas12a can be used to quickly (under 2 weeks) and cheaply delete or insert genes into the E. faecium genome. This substantial improvement over current methods should speed up research on this important opportunistic pathogen.

A scalable artificial intelligence platform that automatically finds copy number variations (CNVs) in journal articles and transforms them into a database: CNV extraction, transformation, and loading AI (CNV-ETLAI).

BACKGROUND: Although copy number variations (CNVs) are infrequent, each anomaly is unique, and multiple CNVs can appear simultaneously. Growing evidence suggests that CNVs contribute to a wide range of diseases. When CNVs are detected, assessment of their clinical significance requires a thorough literature review. This process can be extremely time-consuming and may delay disease diagnosis. Therefore, we have developed CNV Extraction, Transformation, and Loading Artificial Intelligence (CNV-ETLAI), an innovative tool that allows experts to classify and interpret CNVs accurately and efficiently. METHODS: We combined text, table, and image processing algorithms to develop an artificial intelligence platform that automatically extracts, transforms, and organizes CNV information into a database. To validate CNV-ETLAI, we compared its performance to ground truth datasets labeled by a human expert. In addition, we analyzed the CNV data, which was collected using CNV-ETLAI via a crowdsourcing approach. RESULTS: In comparison to a human expert, CNV-ETLAI improved CNV detection accuracy by 4% and performed the analysis 60 times faster. This performance can improve even further with upscaling of the CNV-ETLAI database as usage increases. 5,800 CNVs from 2,313 journal articles were collected. Total CNV frequency for the whole chromosome was highest for chromosome X, whereas CNV frequency per 1 Mb of genomic length was highest for chromosome 22. CONCLUSIONS: We have developed, tested, and shared CNV-ETLAI for research and clinical purposes (https://lmic.mgh.harvard.edu/CNV-ETLAI). Use of CNV-ETLAI is expected to ease and accelerate diagnostic classification and interpretation of CNVs.

Gender differences in multifidus fatty infiltration, sarcopenia and association with preoperative pain and functional disability in patients with lumbar spinal stenosis.

BACKGROUND: In patients with lumbar spinal stenosis, female gender has been associated with higher pain and functional disability. Sarcopenia and multifidus atrophy have also been associated with symptomatic severity. PURPOSE: The purpose of this study was to determine if gender differences in sarcopenia and multifidus atrophy are associated with gender disparities in disease symptomatology. STUDY DESIGN: Prospectively collected medical records and imaging studies were retrospectively reviewed. PATIENT SAMPLE: We retrospectively reviewed medical records and imaging studies for 63 patients with clinically and radiologically defined lumbar spinal stenosis at L3/4 or L4/5 who underwent minimally invasive decompression. OUTCOME MEASURES: Pain and functional disability were measured using the Oswestry Disability Index (ODI) and visual analogue scores for back pain (VASB) and leg pain (VASL). METHODS: Multifidus total cross sectional area (tCSA), multifidus functional cross sectional area (fnCSA), multifidus fatty infiltration (FI), psoas tCSA, and psoas relative cross sectional area (rCSA) were evaluated by univariable and multivariable regression to identify gender linked and gender independent predictors of higher ODI, VASB, and VASL. RESULTS: Female gender was significantly associated with lower multifidus fnCSA (p < .001), higher multifidus FI (p < .001), lower psoas tCSA (p < .001), lower psoas rCSA (p = .002), and higher preoperative ODI (p = .008). Lower psoas rCSA (p = .044) and psoas tCSA in the lowest sex specific quartile (p = .034) were significantly associated with higher preoperative VASB and psoas rCSA less than the sex specific median (p = .050) was significantly associated with higher preoperative VASL after controlling for age and gender. Multifidus FI was significantly associated with preoperative ODI after adjusting for age (p = .048) but not after controlling additionally for gender (p = .651). CONCLUSIONS: Female patients with lumbar spinal stenosis may develop more severe and functionally significant multifidus atrophy, resulting in a more severe clinical course with higher functional disability. Sarcopenia was significantly associated with higher preoperative back pain and leg pain in both male and female patients with lumbar spinal stenosis.

CBCT Evaluation of Buccolingual Orientation of Inferior Alveolar Canal in Mandibular Posterior Region for Implant Planning.

Purpose: Inferior alveolar nerve (IAN) can be subjected to iatrogenic injury during implant surgical procedures. The purpose of this retrospective study was to identify the buccolingual orientation of IAN in posterior mandible as adjunct information for implant planning and to estimate ethnicity-, sex-, and side-related variations in Malaysian population. Material and Methods. A total of 121 CBCT images were viewed with eXamVision software. The buccolingual position of IAN was identified in the posterior region. Buccal bone width (B), canal thickness (C), and lingual bone width (L) were measured at the horizontal canal levels. Kruskal-Wallis H test and Friedman test were used to analyze the buccolingual position. One-way ANOVA was performed to evaluate the variations in B, C, and L values. Results: Overall, most of the IANs were located on the lingual sides of the second molar regions (left: 71.9%; right: 71.1%) and at the centers of the first molar regions (left: 57.9%; right: 47.10%) and exited through the mental foramen before the second premolar regions. There was statistically significant difference in the buccolingual position of the IAN between the sexes in the left second premolar regions (P = 0.03). There was variation in B between the sexes in the left first molar regions (P = 0.01). Statistically significant differences in C and L were also found between different ethnic groups (P = 0.04). Between both sides, there were variations in C in the first molar regions (P < 0.001) and the second molar regions (P = 0.03). Conclusion: From the second molar to the second premolar, the buccal bone width decreased while the lingual bone width increased. There were variations between ethnicities, sexes, and sides among Malaysians.

Sarcopenia Is an Independent Risk Factor for Subsequent Osteoporotic Vertebral Fractures Following Percutaneous Cement Augmentation in Elderly Patients.

Introduction: Subsequent osteoporotic vertebral fractures (SOVF) are a serious complication of osteoporosis that can lead to spinal deformity, chronic pain and disability. Several risk factors have been previously identified for developing SOVF. However, there are conflicting reports regarding the association between sarcopenia and multiple vertebral compression fractures. As such, the goal of this study was to investigate whether sarcopenia is an independent risk factor of SOVF. Methods: This was a retrospective case-control study of elderly patients who underwent percutaneous vertebral augmentation (PVA) due to a new osteoporotic vertebral compression fracture (OVCF). Collected data included: age, sex, BMI, steroid treatment, fracture level and type, presence of kyphosis at the level of the fracture and bone mineral density (BMD). Identification of SVOFs was based on clinical notes and imaging corroborating the presence of a new fracture. Sarcopenia was measured using the normalized psoas muscle total cross-sectional area (nCSA) at the L4 level. Results: Eighty-nine patients that underwent PVA were followed for a minimum of 24 months. Average age was 80.2 ± 7.1 years; 58 were female (65.2%) and 31 male (34.8%). Psoas muscle nCSA was significantly associated with age (p = 0.031) but not with gender (p = 0.129), corticosteroid treatment (p = 0.349), local kyphosis (p = 0.715), or BMD (p = 0.724). Sarcopenia was significantly associated with SOVF (p = 0.039) after controlling for age and gender. Conclusions: Psoas muscle nCSA can be used as a standalone diagnostic tool of sarcopenia in patients undergoing PVA. In patients undergoing PVA for OVCF, sarcopenia is an independent risk factor for SOVF.

Prediction of oxygen requirement in patients with COVID-19 using a pre-trained chest radiograph xAI model: efficient development of auditable risk prediction models via a fine-tuning approach.

Risk prediction requires comprehensive integration of clinical information and concurrent radiological findings. We present an upgraded chest radiograph (CXR) explainable artificial intelligence (xAI) model, which was trained on 241,723 well-annotated CXRs obtained prior to the onset of the COVID-19 pandemic. Mean area under the receiver operating characteristic curve (AUROC) for detection of 20 radiographic features was 0.955 (95% CI 0.938-0.955) on PA view and 0.909 (95% CI 0.890-0.925) on AP view. Coexistent and correlated radiographic findings are displayed in an interpretation table, and calibrated classifier confidence is displayed on an AI scoreboard. Retrieval of similar feature patches and comparable CXRs from a Model-Derived Atlas provides justification for model predictions. To demonstrate the feasibility of a fine-tuning approach for efficient and scalable development of xAI risk prediction models, we applied our CXR xAI model, in combination with clinical information, to predict oxygen requirement in COVID-19 patients. Prediction accuracy for high flow oxygen (HFO) and mechanical ventilation (MV) was 0.953 and 0.934 at 24 h and 0.932 and 0.836 at 72 h from the time of emergency department (ED) admission, respectively. Our CXR xAI model is auditable and captures key pathophysiological manifestations of cardiorespiratory diseases and cardiothoracic comorbidities. This model can be efficiently and broadly applied via a fine-tuning approach to provide fully automated risk and outcome predictions in various clinical scenarios in real-world practice.

Endoplasmic reticulum stress response and bile acid signatures associate with multi-strain seroresponsiveness during elderly influenza vaccination.

The elderly are an important target for influenza vaccination, and the determination of factors that underlie immune responsiveness is clinically valuable. We evaluated the immune and metabolic profiles of 205 elderly Singaporeans administered with Vaxigrip. Despite high seroprotection rates, we observed heterogeneity in the response. We stratified the cohort into complete (CR) or incomplete responders (IR), where IR exhibited signs of accelerated T cell aging. We found a higher upregulation of genes associated with the B-cell endoplasmic-reticulum stress response in CR, where XBP-1 acts as a key upstream regulator. B-cells from IR were incapable of matching the level of XBP-1 upregulation observed in CR after inducing ER stress with tunicamycin in vitro. Metabolic signatures also distinguished CR and IR - as CR presented with a greater diversity of bile acids. Our findings suggest that the ER-stress pathway activation could improve influenza vaccination in the elderly.

Horticultural Therapy Reduces Biomarkers of Immunosenescence and Inflammaging in Community-Dwelling Older Adults: A Feasibility Pilot Randomized Controlled Trial.

BACKGROUND: With the challenges that aging populations pose to health care, interventions that facilitate alleviation of age-related morbidities are imperative. A prominent risk factor for developing age-related morbidities is immunosenescence, characterized by increased chronic low-grade inflammation, resulting in T-cell exhaustion and senescence. Contact with nature and associated physical activities have been shown to boost immunity in older adults and may be promoted in the form of horticultural therapy (HT). We aimed to examine the effects of HT on immunosenescence. METHOD: We conducted a randomized controlled trial with 59 older adults assigned to either the HT intervention or waitlist control group. Older adults in the HT intervention group underwent HT intervention program over 6 months. Venous blood was drawn at baseline and at the third and sixth month from the commencement of this study. For participants who attended all 3 blood collection time points (HT: n = 22; waitlist: n = 24), flow cytometry analysis was performed on whole blood samples to evaluate the kinetics of lymphocyte subsets over the intervention period, revealing the composition of CD4+ and CD8+ subsets expressing exhaustion markers-CD57, CTLA4, and KLRG1. Enzyme-linked immunosorbent assays were employed to measure changes in plasma IL-6 levels. RESULTS: HT is associated with increased numbers of naive CD8+ T cells and fewer CTLA4-expressing terminally differentiated effector CD4+ and CD8+ memory T cells re-expressing CD45RA (TEMRA). Furthermore, IL-6 levels were reduced during HT, and the frequencies of naive and TEMRA CD8+ T cells were found to be associated with IL-6 levels. CONCLUSION: HT is associated with a reduction in the levels of biomarkers that measure the extent of T-cell exhaustion and inflammaging in older adults. The positive effects of HT on T-cell exhaustion were associated with the reduction of IL-6 levels.

Effects of choral singing versus health education on cognitive decline and aging: a randomized controlled trial.

We conducted a randomized controlled trial to examine choral singing's effect on cognitive decline in aging. Older Singaporeans who were at high risk of future dementia were recruited: 47 were assigned to choral singing intervention (CSI) and 46 were assigned to health education program (HEP). Participants attended weekly one-hour choral singing or weekly one-hour health education for two years. Change in cognitive function was measured by a composite cognitive test score (CCTS) derived from raw scores of neuropsychological tests; biomarkers included brain magnetic resonance imaging, oxidative damage and immunosenescence. The average age of the participants were 70 years and 73/93 (78.5%) were female. The change of CCTS from baseline to 24 months was 0.05 among participants in the CSI group and -0.1 among participants in the HEP group. The between-group difference (0.15, p=0.042) became smaller (0.12, p=0.09) after adjusting for baseline CCTS. No between-group differences on biomarkers were observed. Our data support the role of choral singing in improving cognitive health in aging. The beneficial effect is at least comparable than that of health education in preventing cognitive decline in a community of elderly people. Biological mechanisms underlying the observed efficacy should be further studied.