The dynamic duo: A narrative review on the synergy between stereotactic body radiotherapy and immunotherapy in lung cancer treatment (Review).

Immunotherapy, particularly immune checkpoint inhibitors (ICIs), is undoubtedly one of the major breakthroughs in lung cancer research. Patient survival and prognosis have all been improved as a result, although numerous patients do not respond to immunotherapy due to various immune escape mechanisms of the tumor cells. Recent preclinical and clinical evidence has shown that stereotactic body radiotherapy (SBRT), also known as stereotactic ablative radiotherapy, has a prominent immune priming effect that could elicit antitumor immunity against specific tumor antigens and destroy distant tumor cells, thereby achieving the elusive abscopal effect, with the resulting immuno­active tumor environment also being more conducive to ICIs. Some landmark trials have already demonstrated the survival benefit of the dynamic duo of SBRT plus immunotherapy in metastatic non­small­cell lung cancer, while others such as PEMBRO­RT further suggest that the addition of SBRT to immunotherapy could expand the current indication to those who have historically responded poorly to ICIs. In the present review, the biological mechanisms that drive the synergistic effect of SBRT and immunotherapy were first briefly outlined; then, the current understanding from clinical trials was summarized and new insight into the evolving role of immunotherapy and SBRT synergy in lung cancer treatment was provided. Finally, novel avenues for discovery were highlighted. The innovation of the present review lies in the inclusion of non­ICI immunotherapy in the discussion, which provides a more comprehensive view on the current development and future trend of SBRT + immunotherapy synergy.

Poor subjective sleep quality and trait impulsivity in patients with bipolar disorder.

BACKGROUND: Sleep disturbance and impulsivity are key components of mood vulnerability in bipolar disorder (BD), but few studies have assessed the association between these two symptoms among patients with BD. METHODS: Forty-seven euthymic patients with bipolar I disorder (BDI) or bipolar II disorder (BDII) and 58 age- and sex-matched healthy controls were enrolled in this cross-sectional study. Trait impulsivity was measured using the Barratt Impulsiveness Scale Version 11 (BIS-11), which yielded 3 second-order factors: attention, motor, and non-planning. Subjective sleep quality was assessed using the self-reported Pittsburgh Sleep Quality Index (PSQI). General linear models (GLMs) were used to assess the associations between subjective poor sleep and trait impulsivity with multiple testing corrections. RESULTS: Patients with BD scored higher in BIS-11 and PSQI than healthy controls. PSQI total scores positively correlated with BIS-11 total scores, while sleep disturbance and daytime dysfunction were associated with attentional impulsiveness after controlling for covariates. Participants with higher PSQI total scores (>10) had higher scores in BIS-11 total, attention, and non-planning than those with low PSQI scores (≤5). CONCLUSION: These findings support the hypothesis that poor sleep quality might lead to impulsivity and add to the growing evidence that improving sleep quality may be a therapeutic target for patients with BD.

Prediction and mediation analysis for treatment responses to combined cognitive and physical training for older adults.

Diminished cognitive and physical functions negatively affect the daily functions of individuals. Although combined cognitive and physical training prevents instrumental activities of daily living (IADL) disability in older adults, no predictive model or mediation analysis of IADL after combined training exists. This study aims to employ prediction and mediation analysis to identify the predictors of IADL performance and to elucidate the mediators of the association between baseline global cognition and subsequent IADL performance following combined cognitive and physical training. This study involved 177 participants aged 60 years and older who underwent combined training. Cognitive function was measured with the Montreal Cognitive Assessment (MoCA), Digit Symbol Substitution Test (DSST), Color Trails Test, Word List, and a dual task; physical function with the Timed Up and Go (TUG) test; daily function with the Lawton IADL Scale. We conducted regression analyses to identify the predictors of IADL performance, and mediation analysis to examine whether DSST and TUG mediate the relationship between MoCA and IADL. The pre-intervention DSST and TUG were significant independent predictors of post-intervention IADL. The association between the pre-intervention MoCA and post-intervention IADL was mediated by pre-intervention DSST and TUG. This study highlighted the importance of measuring and improving processing speed and functional mobility before and during interventions to enhance IADL outcomes.Trial registration: NCT03619577, 23/07/2018; NCT04689776, 29/12/2020.

Association between cortical thickness or surface area and divergent thinking in patients with bipolar disorder.

OBJECTIVE: Divergent thinking is a critical creative cognitive process. Its neural mechanisms have been well-studied through structural and functional imaging in healthy individuals but are less explored in patients with bipolar disorder (BD). Because of the traditional link between creativity and BD, this study investigated the structural correlates of divergent thinking in patients with BD through surface-based morphometry. METHODS: Fifty-nine patients diagnosed with BD I or BD II (35.3 ± 8.5 years) and 56 age- and sex-matched controls (33.9 ± 7.4 years) were recruited. The participants underwent structural magnetic resonance imaging and an evaluation of divergent thinking by using the Chinese version of the Abbreviated Torrance Test for Adults (ATTA). FreeSurfer 7.0 was used to generate thickness and surface area maps for each participant. Brainwise regression of the association between cortical thickness or surface area and ATTA performance was conducted using general linear models. RESULTS: Divergent thinking performance did not differ significantly between the patients with BD and the healthy controls. In these patients, total ATTA score was negatively correlated with cortical thickness in the right middle frontal gyrus, right occipital, and left precuneus but positively correlated with the surface area of the right superior frontal gyrus. By contrast, total ATTA scores and cortical thickness or surface area were not significantly correlated among the controls. CONCLUSION: The findings indicate that divergent thinking involves cerebral structures for executive control, mental imagery, and visual processing in patients with BD, and the right prefrontal cortex might be the most crucial of these structures.

Lipid Profiles Impact on the Oncologic Outcome of Upper Tract Urothelial Carcinoma.

Background: The prognosis of upper tract urothelial carcinoma (UTUC) varies, with T3/T4 UTUC having less than 50% 5-year survival post-radical nephroureterectomy (RNU). Lipid profiles including cholesterol (CHOL), low-density lipoprotein (LDL), and triglycerides (TGs), and high-density lipoprotein (HDL) have shown correlations with oncologic outcomes in various cancers. We aimed to investigate the prognostic significance of the lipid profiles in UTUC patients who had received RNU. Methods: In this retrospective study, a total of 217 UTUC patients who underwent RNU were analyzed. Prognostic factors for overall survival (OS), cancer-specific survival (CSS), and progression-free survival (PFS) were assessed using Cox proportional hazards regression model and competing risk analysis. Results: The median follow-up duration was 2.36 years. Fifty-one (23.50%) of the patients experienced tumor progression, 16 (7.37%) died from UTUC, and 41 (18.89%) died from all causes during the follow-up period. Multivariate analysis revealed that elevated CHOL, low HDL, and elevated TG were linked to worse OS (P = 0.0188, 0.0002, and 0.0001, respectively). Higher CHOL, LDL, and TG, as well as lower HDL significantly affected PFS (P < 0.001 for all), and elevated CHOL and TG were associated with poorer CSS (P = 0.0033 and 0.0179). A competing risk model indicated that elevated LDL increased the risk of cancer progression (P = 0.407), with CHOL increasing the risk of UTUC-specific mortality (P = 0.0162). Limitations include retrospective design, limited, single-time sampling and relatively small sample size. Conclusions: Lipid profiles were identified as prognostic indicators for UTUC patients post-RNU. It highlights the potential importance of lipid management in improving tumor-related outcomes.

Combining a wireless radar sleep monitoring device with deep machine learning techniques to assess obstructive sleep apnea severity.

STUDY OBJECTIVES: The gold standard for diagnosing obstructive sleep apnea (OSA) is polysomnography (PSG). However, PSG is a time-consuming method with clinical limitations. This study aimed to create a wireless radar framework to screen the likelihood of 2 levels of OSA severity (ie, moderate-to-severe and severe OSA) in accordance with clinical practice standards. METHODS: We conducted a prospective, simultaneous study using a wireless radar system and PSG in a Northern Taiwan sleep center, involving 196 patients. The wireless radar sleep monitor, incorporating hybrid models such as deep neural decision trees, estimated the respiratory disturbance index relative to the total sleep time established by PSG (RDIPSG_TST), by analyzing continuous-wave signals indicative of breathing patterns. Analyses were performed to examine the correlation and agreement between the RDIPSG_TST and apnea-hypopnea index, results obtained through PSG. Cut-off thresholds for RDIPSG_TST were determined using Youden's index, and multiclass classification was performed, after which the results were compared. RESULTS: A strong correlation (ρ = 0.91) and agreement (average difference of 0.59 events/h) between apnea-hypopnea index and RDIPSG_TST were identified. In terms of the agreement between the 2 devices, the average difference between PSG-based apnea-hypopnea index and radar-based RDIPSG_TST was 0.59 events/h, and 187 out of 196 cases (95.41%) fell within the 95% confidence interval of differences. A moderate-to-severe OSA model achieved an accuracy of 90.3% (cut-off threshold for RDIPSG_TST: 19.2 events/h). A severe OSA model achieved an accuracy of 92.4% (cut-off threshold for RDIPSG_TST: 28.86 events/h). The mean accuracy of multiclass classification performance using these cut-off thresholds was 83.7%. CONCLUSIONS: The wireless-radar-based sleep monitoring device, with cut-off thresholds, can provide rapid OSA screening with acceptable accuracy and also alleviate the burden on PSG capacity. However, to independently apply this framework, the function of determining the radar-based total sleep time requires further optimizations and verification in future work. CITATION: Lin S-Y, Tsai C-Y, Majumdar A, et al. Combining a wireless radar sleep monitoring device with deep machine learning techniques to assess obstructive sleep apnea severity. J Clin Sleep Med. 2024;20(8):1267-1277.

Early double-balloon enteroscopy was not related to better clinical outcomes in patients with suspected overt small bowel bleeding.

BACKGROUND: Device-assisted enteroscopy has been used for over 20 years for the management of patients with suspected small bowel bleeding. Unlike esophagogastroduodenoscopy and colonoscopy, the appropriate timing of enteroscopy is still unknown. In recent guidelines, early enteroscopy is suggested to maximize diagnostic yield and therapeutic yield in patients with suspected small bowel bleeding. However, few studies have identified its influence on clinical outcomes, including mortality or rebleeding rate. We conducted this study to evaluate the influence of the timing of double-balloon enteroscopy on clinical outcomes in patients with suspected small bowel bleeding. METHODS: Patients with overt small bowel bleeding who underwent double-balloon enteroscopy from January 2013 to February 2021 were retrospectively reviewed. Patients were categorized into an early enteroscopy group (≤14 days) and a nonearly enteroscopy group (>14 days). Clinical outcomes, including short-term mortality and rebleeding rate, long-term mortality and rebleeding rate, diagnostic yield, and therapeutic yield, were analyzed. RESULTS: A total of 100 patients (mean age, 66.2 years; 53% male) were included, and 44 patients were stratified into the early enteroscopy group. The diagnostic yield, therapeutic yield, mortality, and rebleeding rate were similar between two groups. In multivariate conditional logistic regression analysis, there were no significant differences between two groups regarding the 30-day rebleeding rate (adjusted odds ratio [aOR], 1.43; 95% CI, 0.47-4.33), 90-day rebleeding rate (aOR, 1.18; 95% CI, 0.47-2.94), 30-day mortality rate (aOR, 1.29; 95% CI, 0.21-8.13), 90-day mortality rate (aOR, 1.94; 95% CI, 0.48-7.87), and 90-day bleeding-related mortality (aOR, 2.18; 95% CI, 0.24-19.52). The Kaplan-Meier survival curve analysis showed that the timing of DBE was not associated with the long-term rebleeding rate or mortality rate ( p = 0.57 and 0.83, respectively). CONCLUSION: The timing of enteroscopy did not influence the clinical outcomes, including the short-term mortality rate, short-term rebleeding rate, long-term mortality rate, and rebleeding rate, in patients with suspected overt small bowel bleeding.

Genomic data revealed inbreeding despite a geographically connected stable effective population size since the Holocene in the protected Formosan Long-Arm Scarab beetle, Cheirotonus formosanus.

Biodiversity conservation is a top priority in the face of global environmental change, and the practical restoration of biodiversity has emerged as a key objective. Nevertheless, the question of how to effectively contribute to biodiversity restoration and identify suitable systems for such efforts continues to present major challenges. By using genome-wide SNP data, our study revealed that populations from different mountain ranges of the Formosan Long-Arm Scarab beetle, a flagship species that receives strict protection, exhibited a single genetic cluster with no subdivision. Additionally, our result implied an association between the demographic history and historical fluctuations in climate and environmental conditions. Furthermore, we showed that, despite a stable and moderately sized effective population over recent history, all the individuals we studied exhibited signs of genetic inbreeding. We argued that the current practice of protecting the species as one evolutionarily significant unit remains the best conservation plan and that recent habitat change may have led to the pattern of significant inbreeding. We closed by emphasizing the importance of conservation genetic studies in guiding policy decisions and highlighting the potential of genomic data for identifying ideal empirical systems for genetic rescue, or assisted gene flow studies.

A Comparison between Chicago Classification Versions 3.0 and 4.0 and Their Impact on Manometric Diagnoses in Esophageal High-Resolution Manometry Cases.

High-resolution manometry (HRM) facilitates the detailed evaluation of esophageal motility. In December 2020, Chicago classification (CC) version 4.0 introduced modifications to improve consistency and accuracy. We conducted this study to compare the differences in the interpretations of HRM examinations between CC 3.0 and 4.0. Consecutive HRM records at a Taiwan tertiary medical center, including wet swallows and MRS performed in both supine and sitting positions from October 2019 to May 2021, were retrospectively reviewed and analyzed using both CC versions 3.0 and 4.0. A total of 105 patients were enrolled, and 102 patients completed the exam, while three could not tolerate HRM sitting up. Refractory gastroesophageal reflux disease (GERD) symptoms (n = 65, 63.7%) and dysphagia (n = 37, 36.3%) were the main indications. A total of 18 patients (17.6%) were reclassified to new diagnoses using CC 4.0. Of the 11 patients initially diagnosed with absent contractility, 3 (27.3%) were reclassified as having Type 1 achalasia. Of the 18 patients initially diagnosed with IEM, 6 (33.3%) were reclassified as normal. The incidence of diagnosis changes was similar in both the dysphagia and refractory GERD symptoms groups (21.6% versus 15.3%, p = 0.43). The use of CC 4.0 led to changes in the diagnoses of esophageal motility disease, irrespective of examination indications. Early adoption improves the accuracy of diagnoses and affects patient management.

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.

Proprioceptive and olfactory deficits in individuals with Parkinson disease and mild cognitive impairment.

BACKGROUND: Individuals with neurodegenerative diseases such as Parkinson disease (PD) and Alzheimer's (AD) disease often present with perceptual impairments at an early clinical stage. Therefore, early identification and quantification of these impairments could facilitate diagnosis and early intervention. OBJECTIVES: This study aimed to compare proprioceptive and olfactory sensitivities in individuals diagnosed with PD and mild cognitive impairment (MCI). METHODS: Proprioception in the forearm and olfactory function were measured in neurotypical older adults, individuals with PD, and individuals with MCI. Position and passive motion senses were assessed using a passive motion apparatus. The traditional Chinese version of the University of Pennsylvania smell identification test (UPSIT-TC) and the smell threshold test (STT) were used to identify and discriminate smell, respectively. RESULTS: Position sense threshold between the groups differed significantly (p < 0.001), with the PD (p < 0.001) and MCI (p = 0.004) groups showing significantly higher than the control group. The control group had significantly higher mean UPSIT-TC scores than the PD (p < 0.001) and MCI (p = 0.006) groups. The control group had a significantly lower mean STT threshold than the PD and MCI groups (p < 0.001 and p = 0.008, respectively). UPSIT-TC scores significantly correlated with disease progression in PD (r = - 0.50, p = 0.008) and MCI (r = 0.44, p = 0.04). CONCLUSIONS: Proprioceptive and olfactory sensitivities were reduced in individuals with PD and MCI, and these deficits were related to disease severity. These findings support previous findings indicating that perceptual loss may be a potential biomarker for diagnosing and monitoring disease progression in individuals with neurodegenerative diseases.

Efficacy of Vestibular Rehabilitation in Vestibular Neuritis: A Systematic Review and Meta-analysis.

OBJECTIVE: This study aimed to evaluate the efficacy of vestibular rehabilitation in vestibular neuritis. DESIGN: A randomized controlled trial was collected from MEDLINE, Embase, Cochrane Library, PEDro, LILACS, and Google Scholar before May 2023. RESULTS: This study included 12 randomized controlled trials involving 536 patients with vestibular neuritis. Vestibular rehabilitation was comparable with steroids in dizziness handicap inventory score at the first, sixth, and 12th months (pooled mean differences: -4.00, -0.21, and -0.31, respectively); caloric lateralization at the third, sixth, and 12th months (pooled mean difference: 1.10, 4.76, and -0.31, respectively); and abnormal numbers of vestibular-evoked myogenic potentials at the first, sixth, and 12th months. Patients receiving a combination of rehabilitation and steroid exhibited significant improvement in dizziness handicap inventory score at the first, third, and 12th months (mean difference: -14.86, pooled mean difference: -4.63, mean difference: -9.50, respectively); caloric lateralization at the first and third months (pooled mean difference: -10.28, pooled mean difference: -8.12, respectively); and numbers of vestibular-evoked myogenic potentials at the first and third months (risk ratios: 0.66 and 0.60, respectively) than did those receiving steroids alone. CONCLUSIONS: Vestibular rehabilitation is recommended for patients with vestibular neuritis. A combination of vestibular rehabilitation and steroids is more effective than steroids alone in the treatment of patients with vestibular neuritis.

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.

Association between air pollutant exposure, body water distribution and sleep disorder indices in individuals with low-arousal-threshold obstructive sleep apnoea.

BACKGROUND: Air pollution may alter body water distribution, it may also be linked to low-arousal-threshold obstructive sleep apnoea (low-ArTH OSA). Here, we explored the mediation effects of air pollution on body water distribution and low-ArTH OSA manifestations. METHODS: In this retrospective study, we obtained sleep centre data from healthy participants and patients with low-ArTH OSA (N=1924) in northern Taiwan. Air pollutant exposure at different time intervals (1, 3, 6 and 12 months) was estimated using the nearest station estimation method, and government air-quality data were also obtained. Regression models were used to assess the associations of estimated exposure, sleep disorder indices and body water distribution with the risk of low-ArTH OSA. Mediation analysis was performed to explore the relationships between air pollution, body water distribution and sleep disorder indices. RESULTS: First, exposure to particulate matter (PM) with a diameter of ≤10 µm (PM10) for 1 and 3 months and exposure to PM with a diameter of ≤2.5 µm (PM2.5) for 3 months were significantly associated with the Apnoea-Hypopnoea Index (AHI), Oxygen Desaturation Index (ODI), Arousal Index (ArI) and intracellular-to-extracellular water ratio (I-E water ratio). Significant associations were observed between the risk of low-ArTH OSA and 1- month exposure to PM10 (OR 1.42, 95% CI 1.09 to 1.84), PM2.5 (OR 1.33, 95% CI 1.02 to 1.74) and ozone (OR 1.27, 95% CI 1.01 to 1.6). I-E water ratio alternation caused by 1-month exposure to PM10 and 3-month exposure to PM2.5 and PM10 had partial mediation effects on AHI and ODI. CONCLUSION: Air pollution can directly increase sleep disorder indices (AHI, ODI and ArI) and alter body water distribution, thus mediating the risk of low-ArTH OSA.

Digital phenotyping: An equal opportunity approach to reducing disparities in Alzheimer's disease and related dementia research.

A rapidly aging world population is fueling a concomitant increase in Alzheimer's disease (AD) and related dementias (ADRD). Scientific inquiry, however, has largely focused on White populations in Australia, the European Union, and North America. As such, there is an incomplete understanding of AD in other populations. In this perspective, we describe research efforts and challenges of cohort studies from three regions of the world: Central America, East Africa, and East Asia. These cohorts are engaging with the Davos Alzheimer's Collaborative (DAC), a global partnership that brings together cohorts from around the world to advance understanding of AD. Each cohort is poised to leverage the widespread use of mobile devices to integrate digital phenotyping into current methodologies and mitigate the lack of representativeness in AD research of racial and ethnic minorities across the globe. In addition to methods that these three cohorts are already using, DAC has developed a digital phenotyping protocol that can collect ADRD-related data remotely via smartphone and/or in clinic via a tablet to generate a common data elements digital dataset that can be harmonized with additional clinical and molecular data being collected at each cohort site and when combined across cohorts and made accessible can provide a global data resource that is more racially/ethnically represented of the world population.

Ultra-Broadband High-Entropy Oxide Absorber Layer for Enhanced Photodetector Performance.

A novel light-absorbing material of high-entropy oxide (HEO) has been synthesized using the hydrothermal method. The HEO has six metals, namely, Fe, Ni, Mn, Cr, Mg, and Cu. The obtained HEO light absorber is demonstrated to show unprecedented broadband absorption, ranging from 310 to 1400 nm. The photodetector having a structure of Ag/HEO/n-Si has been evaluated for its performance. Under the illumination of various light wavelengths, the photodetector exhibits a remarkably wide range of photoresponse from 365 to 1050 nm, giving wide-spectrum photocurrent densities in the order of 1 mA/cm2, a responsibility as high as 3.5 A/W (850 nm), and an external quantum efficiency (EQE) of more than 700% (850 nm), outperforming all of the reported oxide-based photodetectors. The superior device performance is attributed to the excellent light absorbance and EQE of the oxygen vacancy-containing HEO. Moreover, a number of tests, including the abrasion test, temperature endurance, acidic resistance, on-off switching cycling, and 3 dB bandwidth measurement, show the excellent reliability of the obtained HEO-based photodetector.

Inflammasome-mediated glucose limitation induces antibiotic tolerance in Staphylococcus aureus.

Staphylococcus aureus is a leading human pathogen that frequently causes relapsing infections. The failure of antibiotics to eradicate infection contributes to infection relapse. Host-pathogen interactions have a substantial impact on antibiotic susceptibility and the formation of antibiotic tolerant cells. In this study, we interrogate how a major S. aureus virulence factor, α-toxin, interacts with macrophages to alter the microenvironment of the pathogen, thereby influencing its susceptibility to antibiotics. We find α-toxin-mediated activation of the NLRP3 inflammasome induces antibiotic tolerance. Induction of tolerance is driven by increased glycolysis in the host cells, resulting in glucose limitation and ATP depletion in S. aureus. Additionally, inhibition of NLRP3 activation improves antibiotic efficacy in vitro and in vivo, suggesting that this strategy has potential as a host-directed therapeutic to improve outcomes. Our findings identify interactions between S. aureus and the host that result in metabolic crosstalk that can determine the outcome of antimicrobial therapy.

Machine learning approaches for predicting sleep arousal response based on heart rate variability, oxygen saturation, and body profiles.

Objective: Obstructive sleep apnea is a global health concern, and several tools have been developed to screen its severity. However, most tools focus on respiratory events instead of sleep arousal, which can also affect sleep efficiency. This study employed easy-to-measure parameters-namely heart rate variability, oxygen saturation, and body profiles-to predict arousal occurrence. Methods: Body profiles and polysomnography recordings were collected from 659 patients. Continuous heart rate variability and oximetry measurements were performed and then labeled based on the presence of sleep arousal. The dataset, comprising five body profiles, mean heart rate, six heart rate variability, and five oximetry variables, was then split into 80% training/validation and 20% testing datasets. Eight machine learning approaches were employed. The model with the highest accuracy, area under the receiver operating characteristic curve, and area under the precision recall curve values in the training/validation dataset was applied to the testing dataset and to determine feature importance. Results: InceptionTime, which exhibited superior performance in predicting sleep arousal in the training dataset, was used to classify the testing dataset and explore feature importance. In the testing dataset, InceptionTime achieved an accuracy of 76.21%, an area under the receiver operating characteristic curve of 84.33%, and an area under the precision recall curve of 86.28%. The standard deviations of time intervals between successive normal heartbeats and the square roots of the means of the squares of successive differences between normal heartbeats were predominant predictors of arousal occurrence. Conclusions: The established models can be considered for screening sleep arousal occurrence or integrated in wearable devices for home-based sleep examination.

The effect of sequential combination of mirror therapy and robot-assisted therapy on motor function, daily function, and self-efficacy after stroke.

Robot-assisted therapy and mirror therapy are both effective in promoting upper limb function after stroke and combining these two interventions might yield greater therapeutic effects. We aimed to examine whether using mirror therapy as a priming strategy would augment therapeutic effects of robot-assisted therapy. Thirty-seven chronic stroke survivors (24 male/13 female; age = 49.8 ± 13.7 years) were randomized to receive mirror therapy or sham mirror therapy prior to robot-assisted therapy. All participants received 18 intervention sessions (60 min/session, 3 sessions/week). Outcome measures were evaluated at baseline and after the 18-session intervention. Motor function was assessed using Fugl-Meyer Assessment and Wolf Motor Function Test. Daily function was assessed using Nottingham Extended Activities of Daily Living Scale. Self-efficacy was assessed using Stroke Self-Efficacy Questionnaires and Daily Living Self-Efficacy Scale. Data was analyzed using mixed model analysis of variance. Both groups demonstrated statistically significant improvements in measures of motor function and daily function, but no significant between-group differences were found. Participants who received mirror therapy prior to robot-assisted therapy showed greater improvements in measures of self-efficacy, compared with those who received sham mirror therapy. Our findings suggest that sequentially combined mirror therapy with robot-assisted therapy could be advantageous for enhancing self-efficacy post-stroke.Trial registration: ClinicalTrials.gov Identifier: NCT03917511. Registered on 17/04/2019, https://clinicaltrials.gov/ct2/show/ NCT03917511.

Clinical trials of new drugs for Alzheimer disease: a 2020-2023 update.

Alzheimer's disease (AD) is the leading cause of dementia, presenting a significant unmet medical need worldwide. The pathogenesis of AD involves various pathophysiological events, including the accumulation of amyloid and tau, neuro-inflammation, and neuronal injury. Clinical trials focusing on new drugs for AD were documented in 2020, but subsequent developments have emerged since then. Notably, the US-FDA has approved Aducanumab and Lecanemab, both antibodies targeting amyloid, marking the end of a nearly two-decade period without new AD drugs. In this comprehensive report, we review all trials listed in clinicaltrials.gov, elucidating their underlying mechanisms and study designs. Ongoing clinical trials are investigating numerous promising new drugs for AD. The main trends in these trials involve pathophysiology-based, disease-modifying therapies and the recruitment of participants in earlier stages of the disease. These trends underscore the significance of conducting fundamental research on pathophysiology, prevention, and intervention prior to the occurrence of brain damage caused by AD.