A dietary commensal microbe enhances antitumor immunity by activating tumor macrophages to sequester iron.

Innate immune cells generate a multifaceted antitumor immune response, including the conservation of essential nutrients such as iron. These cells can be modulated by commensal bacteria; however, identifying and understanding how this occurs is a challenge. Here we show that the food commensal Lactiplantibacillus plantarum IMB19 augments antitumor immunity in syngeneic and xenograft mouse tumor models. Its capsular heteropolysaccharide is the major effector molecule, functioning as a ligand for TLR2. In a two-pronged manner, it skews tumor-associated macrophages to a classically active phenotype, leading to generation of a sustained CD8+ T cell response, and triggers macrophage 'nutritional immunity' to deploy the high-affinity iron transporter lipocalin-2 for capturing and sequestering iron in the tumor microenvironment. This process induces a cycle of tumor cell death, epitope expansion and subsequent tumor clearance. Together these data indicate that food commensals might be identified and developed into 'oncobiotics' for a multi-layered approach to cancer therapy.

Girdling behavior of the longhorn beetle modulates the host plant to enhance larval performance.

BACKGROUND: Preingestive behavioral modulations of herbivorous insects on the host plant are abundant over insect taxa. Those behaviors are suspected to have functions such as deactivation of host plant defenses, nutrient accumulation, or modulating plant-mediated herbivore interactions. To understand the functional consequence of behavioral modulation of insect herbivore, we studied the girdling behavior of Phytoecia rufiventris Gautier (Lamiinae; Cerambycidae) on its host plant Erigeron annuus L. (Asteraceae) that is performed before endophytic oviposition in the stem. RESULTS: The girdling behavior significantly increased the larval performance in both field monitoring and lab experiment. The upper part of the girdled stem exhibited lack of jasmonic acid induction upon larval attack, lowered protease inhibitor activity, and accumulated sugars and amino acids in compared to non-girdled stem. The girdling behavior had no effect on the larval performance of a non-girdling longhorn beetle Agapanthia amurensis, which also feeds on the stem of E. annuus during larval phase. However, the girdling behavior decreased the preference of A. amurensis females for oviposition, which enabled P. rufiventris larvae to avoid competition with A. amurensis larvae. CONCLUSIONS: In conclusion, the girdling behavior modulates plant physiology and morphology to provide a modulated food source for larva and hide it from the competitor. Our study implies that the insect behavior modulations can have multiple functions, providing insights into adaptation of insect behavior in context of plant-herbivore interaction.

An Antibody-CRISPR/Cas Conjugate Platform for Target-Specific Delivery and Gene Editing in Cancer.

The CRISPR/Cas system has been introduced as an innovative tool for therapy, however achieving specific delivery to the target has been a major challenge. Here, an antibody-CRISPR/Cas conjugate platform that enables specific delivery and target gene editing in HER2-positive cancer is introduced. The CRISPR/Cas system by replacing specific residues of Cas9 with an unnatural amino acid is engineered, that can be complexed with a nanocarrier and bioorthogonally functionalized with a monoclonal antibody targeting HER2. The resultant antibody-conjugated CRISPR/Cas nanocomplexes can be specifically delivered and induce gene editing in HER2-positive cancer cells in vitro. It is demonstrated that the in vivo delivery of the antibody-CRISPR/Cas nanocomplexes can effectively disrupt the plk1 gene in HER2-positive ovarian cancer, resulting in substantial suppression of tumor growth. The current study presents a useful therapeutic platform for antibody-mediated delivery of CRISPR/Cas for the treatment of various cancers and genetic diseases.

Association Between Orthostatic Hypertension and Frailty Among Older Patients With Hypertension.

BACKGROUND: Frailty frequently coexists with hypertension in older patients. We aimed to evaluate the association between frailty and positional change in blood pressure, especially orthostatic hypertension. METHODS: Participants were recruited from 12 University hospitals in South Korea. Using a digital device, trained research nurses measured blood pressure in the supine and standing positions. Physical frailty was evaluated using the Korean version of the FRAIL questionnaire, gait speed, and handgrip strength. Orthostatic hypertension was defined as a ≥20-mm Hg increase in systolic blood pressure within 3 minutes of standing and upright systolic blood pressure of ≥140 mm Hg. RESULTS: We analyzed the data of 2065 participants who had been enrolled until December 31, 2022. The mean age was 73.2±5.6 years, and 52.0% were female. The mean blood pressure was 137.1±14.9/75.1±9.7 mm Hg. Among the participants, 1886 (91.3%) showed normal response after standing, but 94 (4.6%) had orthostatic hypertension, and 85 (4.1%) had orthostatic hypotension. Orthostatic hypertension was associated with female sex, obesity, cognitive function, physical frailty, and lower quality of life. In the multivariable analysis, body mass index and frailty status were independently associated with orthostatic hypertension. CONCLUSIONS: Orthostatic hypertension is associated with physical frailty, cognitive impairment, and low quality of life in older patients with hypertension. Therefore, evaluation of orthostatic blood pressure changes to confirm orthostatic hypertension or hypotension in frail older adults will serve as an important diagnostic procedure in vulnerable patients. Further studies are required to identify the underlying mechanisms of this association.

Characteristics According to Frailty Status Among Older Korean Patients With Hypertension.

BACKGROUND: As the prevalence of hypertension increases with age and the proportion of the older population is also on the rise, research on the characteristics of older hypertensive patients and the importance of frailty is necessary. This study aimed to identify clinical characteristics of older hypertension in Korea and to investigate these characteristics based on frailty status. METHODS: The HOW to Optimize eLDerly systolic BP (HOWOLD-BP) is a prospective, multicenter, open-label, randomized clinical trial that aims to compare intensive (target systolic blood pressure [SBP] ≤ 130 mmHg) with standard (target SBP ≤ 140 mmHg) treatment to reduce cardiovascular events in older hypertensive Korean patients aged ≥ 65 years. Data were analyzed through a screening assessment of 2,085 patients recruited from 11 university hospitals. Demographic, functional (physical and cognitive), medical history, laboratory data, quality of life, and medication history of antihypertensive drugs were assessed. RESULTS: The mean age was 73.2 years (standard deviation ± 5.60), and 48.0% (n = 1,001) were male. Prevalent conditions included dyslipidemia (66.5%), obesity (body mass index ≥ 25 kg/m², 53.6%), and diabetes (28.9%). Dizziness and orthostatic hypotension were self-reported by 1.6% (n = 33) and 1.2% (n = 24), respectively. The majority of patients were on two antihypertensive drugs (48.4%), while 27.5% (n = 574) and 20.8% (n = 433) were on 1 and 3 antihypertensive medications, respectively. Frail to pre-frail patients were older and also tended to have dependent instrumental activities of daily living, slower gait speed, weaker grip strength, lower quality of life, and lower cognitive function. The frail to pre-frail group reported more dizziness (2.6% vs. 1.2%, P < 0.001) and had concerning clinical factors, including lower glomerular filtration rate, more comorbidities such as diabetes, stroke, and a history of admission. Frail to pre-frail older hypertensive patients used slightly more antihypertensive medications than robust older hypertensive patients (1.95 vs. 2.06, P = 0.003). Pre-frail to frail patients often chose beta-blockers as a third medication over diuretics. CONCLUSION: This study described the general clinical characteristics of older hypertensive patients in Korea. Frail hypertensive patients face challenges in achieving positive clinical outcomes because of multifactorial causes: they are older, have more morbidities, decreased function, lower quality of life and cognitive function, and take more antihypertensive medications. Therefore, it is essential to comprehensively evaluate and monitor disease-related or drug-related adverse events more frequently during regular check-ups, which is necessary for pre-frail to frail older patients with hypertension. TRIAL REGISTRATION: Clinical Research Information Service Identifier: KCT0003787.

Efficacy and safety of combination therapy with telmisartan, rosuvastatin, and ezetimibe in patients with dyslipidemia and hypertension: A randomized, double-blind, multicenter, therapeutic confirmatory, phase III clinical trial.

This study aimed to compare and evaluate the efficacy of the blood pressure (BP) control and cholesterol-lowering effects and safety of combination therapy with telmisartan, rosuvastatin, and ezetimibe versus rosuvastatin and ezetimibe double therapy or telmisartan single therapy in dyslipidemia patients with hypertension. After a wash-out/therapeutic lifestyle change period of ≥4 weeks, a total of 100 eligible patients were randomized and received one of three treatments for 8 weeks: (1) telmisartan 80 mg/rosuvastatin 20 mg/ezetimibe 10 mg (TRE), (2) rosuvastatin 20 mg/ezetimibe 10 mg (RE), or (3) telmisartan 80 mg (T). The primary endpoint was the efficacy evaluation of TRE by comparing changes in mean sitting systolic blood pressure (msSBP) and mean percentage change in low-density lipoprotein-C (LDL-C) from baseline after 8 weeks of treatment. The least square (LS) mean (SE) changes in msSBP at 8 weeks compared with baseline were -23.02 (3.04) versus -7.18 (3.09) mmHg in the TRE and RE groups, respectively (p < .0001), and -25.80 (2.74) versus -14.92 (2.65) mmHg in the TRE and T groups, respectively (p = .0005). The percentage changes in the mean (SD) LDL-C at 8 weeks compared with baseline were -54.97% (3.49%) versus -0.17% (3.23%) in the TRE and T groups, respectively (p < .0001). No serious adverse events occurred, and no statistically significant differences in the incidence of overall AEs and adverse drug reactions occurred among the three groups. TRE therapy significantly decreased msSBP and LDL-C compared to RE or T therapy with comparable safety and tolerability profiles.

Estimation of Validity of A-Mode Ultrasound for Measurements of Muscle Thickness and Muscle Quality.

This study aimed to determine whether amplitude modulation (A-mode) ultrasound (US) provides accurate and reliable measurements comparable to those obtained using brightness modulation (B-mode) US under diverse conditions. Thirty healthy participants (15 women and 15 men) underwent measurements of subcutaneous fat thickness (SFT), muscle thickness (MT), and muscle quality (MQ) in the trapezius and biceps brachii muscles using both US modes before and after exercises designed to stimulate the respective muscles. Among the three key indices, the results demonstrated the high validity of the A-mode, with minimal mean differences (MDs) between the two devices less than 0.91 mm and intra-class correlation coefficients (ICCs) exceeding 0.95 for all measures. In addition, the correlation coefficients between the error scores and average scores for the trapezius and biceps brachii suggested no evidence of systematic error. The trapezius MT and MQ significantly increased, and the biceps brachii MT significantly increased after the exercises (p < 0.05). Notably, both the A- and B-modes exhibited the same trend in these post-exercise changes in the muscle. This study suggests that low-cost and low-resolution A-mode US provides measurements of SFT, MT, and MQ similar to the more expensive, high-resolution B-mode imaging. A-mode US is an affordable and portable alternative for muscle assessment.

Effectiveness of a Nurse-Led Mobile-Based Health Coaching Program for Patients With Prostate Cancer at High Risk of Metabolic Syndrome: Randomized Waitlist Controlled Trial.

BACKGROUND: Androgen deprivation therapy (ADT), a standard treatment for prostate cancer (PC), causes many physical side effects. In particular, it causes metabolic changes such as fasting glucose abnormalities or accumulation of body fat, and its continuation can lead to metabolic syndrome (MetS), which is closely related to diabetes and cardiovascular disease. Therefore, it is important to maintain and practice a healthy lifestyle in patients with PC. OBJECTIVE: This study aims to evaluate the effectiveness of a nurse-led mobile-based program that aims to promote a healthy lifestyle in patients with PC undergoing ADT with MetS risk factors. METHODS: This was a single-blind, randomized, waitlist control interventional study. A total of 48 patients were randomly assigned to the experimental and waitlist control groups at the urology cancer clinic of a tertiary general hospital in South Korea. The inclusion criteria were patients who had undergone ADT for >6 months, had at least 1 of the 5 MetS components in the abnormal range, and could access a mobile-based education program. The experimental group attended a 4-week mobile-based program on exercise and diet that included counseling and encouragement to maintain a healthy lifestyle, whereas the control group was placed on a waitlist and received usual care during the follow-up period, followed by the intervention. The primary outcome was a change in the lifestyle score. The secondary outcomes were changes in 5 MetS components, body composition, and health-related quality of life. The outcomes were measured at 6 weeks and 12 weeks after the initiation of the intervention. Each participant was assigned to each group in a sequential order of enrollment in a 4×4 permuted block design randomization table generated in the SAS (SAS Institute) statistical program. A linear mixed model was used for statistical analysis. RESULTS: A total of 24 participants were randomly assigned to each group; however, 2 participants in the experimental group dropped out for personal reasons before starting the intervention. Finally, 46 participants were included in the intention-to-treat analysis. The experimental group showed more positive changes in the healthy lifestyle score (ß=29.23; P≤.001), level of each MetS component (fasting blood sugar: ß=-12.0; P=.05 and abdominal circumference: ß=-2.49; P=.049), body composition (body weight: ß=-1.52; P<.001 and BMI: ß=-0.55; P<.001), and the urinary irritative and obstructive domain of health-related quality of life (ß=14.63; P<.001) over time than the waitlist control group. CONCLUSIONS: Lifestyle changes through nurse-led education can improve level of each MetS components, body composition, and ADT side effects. Nurses can induce positive changes in patients' lifestyles and improve the self-management of patients starting ADT through this program. TRIAL REGISTRATION: Clinical Research Information Service KCT0006560; http://tinyurl.com/yhvj4vwh.

Metabolic syndrome awareness in the general Korean population: results from a nationwide survey.

BACKGROUND/AIMS: Metabolic syndrome (MetS) raises the risk of cardiovascular disease and type 2 diabetes. An awareness of MetS is vital for early detection and proactive management, which can mitigate the risks associated with MetS. Therefore, our study aimed to investigate the level of awareness of MetS among the Korean population. METHODS: We conducted a nationwide survey between January and February 2023 among a representative sample of the Korean population using an online survey. Information regarding the awareness of MetS and its risk, the importance of lifestyle modification, and health behavior were collected. The question about the awareness of MetS was "How much do you think you know about MetS?" and there were five answers: 1) I know very well, 2) I know well, 3) I know a little, 4) I do not know, and 5) I have no idea. The high-awareness group was defined as those who answered that they knew very well or well. RESULTS: Among 1,000 participants (mean age, 45.7 ± 13.2 yr), 29% were unaware of MetS, and only 20.8% had high awareness. The high-awareness group was significantly more knowledgeable about lifestyle modifications and demonstrated better health behaviors. After adjustment for possible confounding factors, younger age, low household income, and absence of comorbidity were independently associated with a lack of awareness regarding MetS. CONCLUSION: The high-awareness group showed greater knowledge of the importance of lifestyle modifications and better health behaviors regarding MetS. The findings highlight the need for improved public education and awareness programs regarding MetS.

A Mobile App for Comprehensive Symptom Management in People With Parkinson's Disease: A Pilot Usability Study.

There is an increasing need for highly accessible health management platforms for comprehensive symptoms of Parkinson disease. Mobile apps encompassing nonmotor symptoms have been rarely developed since these symptoms are often subjective and difficult to reflect what individuals actually experience. The study developed an app for comprehensive symptom management and evaluated its usability and feasibility. A single-group repeated measurement experimental design was used. Twenty-two participants used the app for 6 weeks. Monitoring of nonmotor symptoms, games to address motor symptoms, and medication management were incorporated in the app. Quantitative outcomes were self-assessed through an online questionnaire, and one-on-one telephone interviews were conducted to understand the user's point of view. The successful experience of self-monitoring had improved participants' self-efficacy ( Z = -3.634, P < .001) and medication adherence ( Z = -3.371, P = .001). Facilitators included a simple-to-use interface, entertaining content, and medication helps. Barriers included simple forgetfulness and digital literacy, including unfamiliarity with mobile phone manipulation itself. The study suggested insight into the app use related to acceptability of mobile technology. The preliminary effects on self-efficacy and medication adherence will guide future nursing interventions using mobile health. Our approach will contribute to improving the continuum of care for Parkinson disease by promoting self-monitoring of symptoms.

Screening patients requiring secondary lumbar surgery for degenerative lumbar spine diseases: a nationwide sample cohort study.

This study aims to identify healthcare costs indicators predicting secondary surgery for degenerative lumbar spine disease (DLSD), which significantly impacts healthcare budgets. Analyzing data from the National Health Insurance Service-National Sample Cohort (NHIS-NSC) database of Republic of Korea (ROK), the study included 3881 patients who had surgery for lumbar disc herniation (LDH), lumbar spinal stenosis without spondylolisthesis (LSS without SPL), lumbar spinal stenosis with spondylolisthesis (LSS with SPL), and spondylolysis (SP) from 2006 to 2008. Patients were categorized into two groups: those undergoing secondary surgery (S-group) and those not (NS-group). Surgical and interim costs were compared, with S-group having higher secondary surgery costs ($1829.59 vs $1618.40 in NS-group, P = 0.002) and higher interim costs ($30.03; 1.86% of initial surgery costs vs $16.09; 0.99% of initial surgery costs in NS-group, P < 0.0001). The same trend was observed in LDH, LSS without SPL, and LSS with SPL (P < 0.0001). Monitoring interim costs trends post-initial surgery can effectively identify patients requiring secondary surgery.

Impact of caregiver relationship on self-care in patients with Parkinson's disease: A cross-sectional study using Riegel's theory of self-care of chronic illness.

AIMS: To explore how the characteristics of patients and caregivers affect self-care in patients with Parkinson's disease (PD). DESIGN: A multicentre cross-sectional study. METHOD: We followed the STROBE checklist. Parkinson's disease patients aged 50 years and older and their caregivers were recruited from two tertiary hospitals and the Korean Parkinson's Disease Association website. Patient characteristics, including social support, relationship quality with caregivers, self-care efficacy and self-care, were analysed. Caregiver characteristics were also evaluated, including caregiving duration, social support, relationship quality with patients, contribution to patients' self-care efficacy and contribution to patients' self-care. RESULTS: The characteristics of patients and caregivers (103 pairs) were hierarchically regressed into patient self-care domains (maintenance, monitoring and management). Most patients and caregivers gave a self-care efficacy and self-care management rating of moderate. In three regression models, patient self-care efficacy was positively related to three domains of patient self-care. Self-care maintenance decreased as patients' disease duration increased. Self-care monitoring was positively related to the education level of patients and caregiving duration. Self-care management showed an inverse relationship with caregiving duration and a positive relationship with caregiver contribution. CONCLUSION: Self-care efficacy was important in promoting PD patients' self-care maintenance, monitoring and management. The contributions of caregivers were also critical in increasing PD patients' self-care management. IMPLICATIONS FOR THE PROFESSION AND PATIENT CARE: To increase patients' self-care efficacy and self-care, educational interventions containing information about the disease, symptom management, and problem-solving should be implemented. Since caregivers are deeply involved in patients' self-care, educational interventions for caregivers should also be provided. IMPACT: This study closed the literature gap by examining the self-care efficacy and self-care of Korean PD patients. Findings demonstrated the importance of caregiver roles on patients' self-care and health. PATIENT OR PUBLIC CONTRIBUTION: Two tertiary hospitals and the Korean Parkinson's Disease Association assisted during the recruitment process.

Changes in alcohol consumption habits and risk of atrial fibrillation: a nationwide population-based study.

AIMS: Heavy alcohol consumption is an established risk factor for atrial fibrillation (AF). However, the association between habitual changes in heavy habitual drinkers and incident AF remains unclear. The aim of this study was to evaluate whether absolute abstinence or reduced drinking decreases incident AF in heavy habitual drinkers. METHODS AND RESULTS: Atrial fibrillation-free participants with heavy alcohol consumption registered in the Korean National Health Insurance Service database between 2005 and 2008 were enrolled. Habitual changes in alcohol consumption between 2009 and 2012 were classified as sustained heavy drinking, reduced drinking, and absolute abstinence. The primary outcome measure was new-onset AF during the follow-up. To minimize the effect of confounding variables on outcome events, inverse probability of treatment weighting (IPTW) analysis was performed. Overall, 19 425 participants were evaluated. The absolute abstinence group showed a 63% lower incidence of AF (IPTW hazard ratio: 0.379, 95% confidence interval: 0.169-0.853) than did the sustained heavy drinking group. Subgroup analysis identified that abstinence significantly reduced incident AF in participants with normal body mass index and without hypertension, diabetes, dyslipidaemia, heart failure, stroke, chronic kidney disease, or coronary artery disease (all P-value <0.05). There was no statistical difference in incident AF in participants with reduced drinking compared with sustained heavy alcohol group. CONCLUSION: Absolute abstinence could reduce the incidence of AF in heavy alcohol drinkers. Comprehensive clinical measures and public health policies are warranted to motivate alcohol abstinence in heavy drinkers.

In this study of 19 425 participants, we investigated whether alcohol consumption reduction was associated with lower risk of incident atrial fibrillation (AF) in individuals with chronic heavy alcohol consumption. The absolute abstinence significantly reduced incident AF, but reducing alcohol consumption was not associated with a lower incident AF. The benefit of absolute abstinence for incidence of AF was significantly identified in participants with normal body mass index and without hypertension, diabetes, dyslipidaemia, heart failure, stroke, chronic kidney disease, or coronary artery disease.

No Interference of H9 Extract on Trastuzumab Pharmacokinetics in Their Combinations.

Trastuzumab is used to treat breast cancer patients overexpressing human epidermal growth factor receptor 2, but resistance and toxicity limit its uses, leading to attention to trastuzumab combinations. Recently, the synergistic effect of trastuzumab and H9 extract (H9) combination against breast cancer has been reported. Because drug exposure determines its efficacy and toxicity, the question of whether H9 changes trastuzumab exposure in the body has been raised. Therefore, this study aimed to characterize trastuzumab pharmacokinetics and elucidate the effect of H9 on trastuzumab pharmacokinetics at a combination dose that shows synergism in mice. As a result, trastuzumab showed linear pharmacokinetics after its intravenous administration from 1 to 10 mg/kg. In the combination of trastuzumab and H9, single and 2-week treatments of oral H9 (500 mg/kg) did not influence trastuzumab pharmacokinetics. In the multiple-combination treatments of trastuzumab and H9 showing their synergistic effect (3 weeks of trastuzumab with 2 weeks of H9), the pharmacokinetic profile of trastuzumab was comparable to that of 3 weeks of trastuzumab alone. In tissue distribution, the tissue to plasma ratios of trastuzumab below 1.0 indicated its limited distributions within the tissues, and these patterns were unaffected by H9. These results suggest that the systemic and local exposures of trastuzumab are unchanged by single and multiple-combination treatments of H9.

Risk-benefit trade-offs and precision utilities in phase I-II clinical trials.

BACKGROUND: Identifying optimal doses in early-phase clinical trials is critically important. Therapies administered at doses that are either unsafe or biologically ineffective are unlikely to be successful in subsequent clinical trials or to obtain regulatory approval. Identifying appropriate doses for new agents is a complex process that involves balancing the risks and benefits of outcomes such as biological efficacy, toxicity, and patient quality of life. PURPOSE: While conventional phase I trials rely solely on toxicity to determine doses, phase I-II trials explicitly account for both efficacy and toxicity, which enables them to identify doses that provide the most favorable risk-benefit trade-offs. It is also important to account for patient covariates, since one-size-fits-all treatment decisions are likely to be suboptimal within subgroups determined by prognostic variables or biomarkers. Notably, the selection of estimands can influence our conclusions based on the prognostic subgroup studied. For example, assuming monotonicity of the probability of response, higher treatment doses may yield more pronounced efficacy in favorable prognosis compared to poor prognosis subgroups when the estimand is mean or median survival. Conversely, when the estimand is the 3-month survival probability, higher treatment doses produce more pronounced efficacy in poor prognosis compared to favorable prognosis subgroups. METHODS AND CONCLUSIONS: Herein, we first describe why it is essential to consider clinical practice when designing a clinical trial and outline a stepwise process for doing this. We then review a precision phase I-II design based on utilities tailored to prognostic subgroups that characterize efficacy-toxicity risk-benefit trade-offs. The design chooses each patient's dose to optimize their expected utility and allows patients in different prognostic subgroups to have different optimal doses. We illustrate the design with a dose-finding trial of a new therapeutic agent for metastatic clear cell renal cell carcinoma.

Simple and Multiplexed Detection of Nucleic Acid Targets Based on Fluorescent Ring Patterns and Deep Learning Analysis.

Simple diagnostic tests for nucleic acid targets can provide great advantages for applications such as rapid pathogen detection. Here, we developed a membrane assay for multiplexed detection of nucleic acid targets based on the visualization of two-dimensional fluorescent ring patterns. A droplet of the assay solution is applied to a cellulose nitrate membrane, and upon radial chromatographic flow and evaporation of the solvent, fluorescent patterns appear under UV irradiation. The target nucleic acid is isothermally amplified and is immediately hybridized with fluorescent oligonucleotide probes in a one-pot reaction. We established the fluorescent ring assay integrated with isothermal amplification (iFluor-RFA = isothermal fluorescent ring-based radial flow assay), and feasibility was tested using nucleic acid targets of the receptor binding domain (RBD) and RNA-dependent RNA polymerase (RdRp) genes of SARS-CoV-2. We demonstrate that the iFluor-RFA method is capable of specific and sensitive detection in the subpicomole range, as well as multiplexed detection even in complex solutions. Furthermore, we applied deep learning analysis of the fluorescence images, showing that patterns could be classified as positive or negative and that quantitative amounts of the target could be predicted. The current technique, which is a membrane pattern-based nucleic acid assay combined with deep learning analysis, provides a novel approach in diagnostic platform development that can be versatilely applied for the rapid detection of infectious pathogens.

Implications of the Use of Artificial Intelligence Predictive Models in Health Care Settings : A Simulation Study.

BACKGROUND: Substantial effort has been directed toward demonstrating uses of predictive models in health care. However, implementation of these models into clinical practice may influence patient outcomes, which in turn are captured in electronic health record data. As a result, deployed models may affect the predictive ability of current and future models. OBJECTIVE: To estimate changes in predictive model performance with use through 3 common scenarios: model retraining, sequentially implementing 1 model after another, and intervening in response to a model when 2 are simultaneously implemented. DESIGN: Simulation of model implementation and use in critical care settings at various levels of intervention effectiveness and clinician adherence. Models were either trained or retrained after simulated implementation. SETTING: Admissions to the intensive care unit (ICU) at Mount Sinai Health System (New York, New York) and Beth Israel Deaconess Medical Center (Boston, Massachusetts). PATIENTS: 130 000 critical care admissions across both health systems. INTERVENTION: Across 3 scenarios, interventions were simulated at varying levels of clinician adherence and effectiveness. MEASUREMENTS: Statistical measures of performance, including threshold-independent (area under the curve) and threshold-dependent measures. RESULTS: At fixed 90% sensitivity, in scenario 1 a mortality prediction model lost 9% to 39% specificity after retraining once and in scenario 2 a mortality prediction model lost 8% to 15% specificity when created after the implementation of an acute kidney injury (AKI) prediction model; in scenario 3, models for AKI and mortality prediction implemented simultaneously, each led to reduced effective accuracy of the other by 1% to 28%. LIMITATIONS: In real-world practice, the effectiveness of and adherence to model-based recommendations are rarely known in advance. Only binary classifiers for tabular ICU admissions data were simulated. CONCLUSION: In simulated ICU settings, a universally effective model-updating approach for maintaining model performance does not seem to exist. Model use may have to be recorded to maintain viability of predictive modeling. PRIMARY FUNDING SOURCE: National Center for Advancing Translational Sciences.

Interpreting Randomized Controlled Trials.

This article describes rationales and limitations for making inferences based on data from randomized controlled trials (RCTs). We argue that obtaining a representative random sample from a patient population is impossible for a clinical trial because patients are accrued sequentially over time and thus comprise a convenience sample, subject only to protocol entry criteria. Consequently, the trial's sample is unlikely to represent a definable patient population. We use causal diagrams to illustrate the difference between random allocation of interventions within a clinical trial sample and true simple or stratified random sampling, as executed in surveys. We argue that group-specific statistics, such as a median survival time estimate for a treatment arm in an RCT, have limited meaning as estimates of larger patient population parameters. In contrast, random allocation between interventions facilitates comparative causal inferences about between-treatment effects, such as hazard ratios or differences between probabilities of response. Comparative inferences also require the assumption of transportability from a clinical trial's convenience sample to a targeted patient population. We focus on the consequences and limitations of randomization procedures in order to clarify the distinctions between pairs of complementary concepts of fundamental importance to data science and RCT interpretation. These include internal and external validity, generalizability and transportability, uncertainty and variability, representativeness and inclusiveness, blocking and stratification, relevance and robustness, forward and reverse causal inference, intention to treat and per protocol analyses, and potential outcomes and counterfactuals.

Assessment of Risk Factors for Postoperative Delirium in Older Adults Who Underwent Spinal Surgery and Identifying Associated Biomarkers Using Exosomal Protein.

PURPOSE: With an increase in the aging population, the number of patients with degenerative spinal diseases undergoing surgery has risen, as has the incidence of postoperative delirium. This study aimed to investigate the risk factors affecting postoperative delirium in older adults who had undergone spine surgery and to identify the associated biomarkers. METHODS: This study is a prospective study. Data of 100 patients aged ≥ 70 years who underwent spinal surgery were analyzed. Demographic data, medical history, clinical characteristics, cognitive function, depression symptoms, functional status, frailty, and nutritional status were investigated to identify the risk factors for delirium. The Confusion Assessment Method, Delirium Rating Scale-R-98, and Nursing Delirium Scale were also used for diagnosing delirium. To discover the biomarkers, urine extracellular vesicles (EVs) were analyzed for tau, ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), neurofilament light, and glial fibrillary acidic protein using digital immunoassay technology. RESULTS: Nine patients were excluded, and data obtained from the remaining 91 were analyzed. Among them, 18 (19.8%) developed delirium. Differences were observed between participants with and without delirium in the contexts of a history of mental disorder and use of benzodiazepines (p = .005 and p = .026, respectively). Tau and UCH-L1-concentrations of urine EVs-were comparatively higher in participants with severe delirium than that in participants without delirium (p = .002 and p = .001, respectively). CONCLUSION: These findings can assist clinicians in accurately identifying the risk factors before surgery, classifying high-risk patients, and predicting and detecting delirium in older patients. Moreover, urine EV analysis revealed that postoperative delirium following spinal surgery is most likely associated with brain damage.