Adaptive promising zone design for cancer immunotherapy with heterogeneous delayed treatment effect.

Indirect mechanisms of cancer immunotherapies result in delayed treatment effects that vary among patients. Consequently, the use of the log-rank test in trial design and analysis can lead to significant power loss and pose additional challenges for interim decisions in adaptive designs. In this paper, we describe patients' survival using a piecewise proportional hazard model with random lag time and propose an adaptive promising zone design for cancer immunotherapy with heterogeneous delayed effects. We provide solutions for calculating conditional power and adjusting the critical value for the log-rank test with interim data. We divide the sample space into three zones - unfavourable, promising, and favourable -based on re-estimations of the survival parameters, the log-rank test statistic at the interim analysis, and the initial and maximum sample sizes. If the interim results fall into the promising zone, the sample size is increased; otherwise, it remains unchanged. We show through simulations that our proposed approach has greater overall power than the fixed sample design and similar power to the matched group sequential trial. Furthermore, we confirm that critical value adjustment effectively controls the type I error rate inflation. Finally, we provide recommendations on the implementation of our proposed method in cancer immunotherapy trials.

Associations of global biomarkers of oxidative stress with osteoporosis, bone microstructure and bone turnover: Evidence from human and animal studies.

PURPOSE: Human evidence on the association between oxidative stress and osteoporosis is inconsistent. Fluorescent Oxidation Products (FlOPs) are global biomarkers of oxidative stress. We examined the associations of FlOPs (excitation/emission wavelengths 320/420 nm for FlOP_320, 360/420 nm for FlOP_360, and 400/475 nm for FlOP_400) with osteoporosis, bone microstructure, and bone turnover markers in humans and rats. METHODS: In humans, we conducted a 1:2 age, sex, hospital, and specimen-matched case-control study to test the association between FlOPs and osteoporosis diagnosed from dual-energy X-ray absorptiometry. In eight-week-old male Wistar rats, we administrated D-galactose and 0.9 % saline for 90 days in treatment and control groups (n = 8/group); micro-CT was used to determine bone microstructure. RESULTS: In humans, higher levels of FlOP_320 (OR for per 1 SD increase = 1.49, 95 % CI: 1.01-2.20) and FlOP_360 (OR for per 1 SD increase = 1.59, 95 % CI: 1.07-2.37) were associated with increased odds of osteoporosis. FlOP_400 were not associated with osteoporosis. D-galactose treated rats, as compared with control rats, showed higher levels of FlOP_320 and MDA, and lower P1NP levels during 90 days of experiment (all P < 0.05). The D-galactose group had lower trabecular bone volume fraction (0.07 ± 0.03 vs. 0.13 ± 0.05; P = 0.008) and volumetric BMD (225.4 ± 13.8 vs. 279.1 ± 33.2 mg HA/cm3; P = 0.001) than the control group. CONCLUSION: In conclusion, higher FlOP_320 levels were associated with increased odds of osteoporosis, impaired bone microstructure and decreased bone formation.

Community ambulation in older adults and people with OA - a model verification using Canadian Longitudinal Study on Aging (CLSA) data.

BACKGROUND: There are health and well-being benefits of community ambulation; however, many older adults do not regularly walk outside of their home. Objectives were to estimate the associations between latent constructs related to community ambulation in older adults aged 65-85 (65+), and in adults with osteoarthritis (OA) aged 45-85. METHODS: Secondary data analysis of the comprehensive baseline and maintaining contact questionnaire data from the Canadian Longitudinal Study of Aging (CLSA) was completed. Based on a previous model of community ambulation post-stroke, structural equation modeling (SEM) was used to develop measurement and structural models for two groups: older adults 65+ and people with OA. Multi-group SEM was conducted to test measurement invariance across sex and age groups. Measurement models were developed for the following latent factors: ambulation (frequency of walking outside/week, hours walked/day, ability to walk without help, frequency and aids used in different settings); health perceptions (general health, pain frequency/intensity); timed functional mobility (gait speed, timed up-and-go, sit-to-stand, balance). Variables of depression, falls, age, sex, and fear of walking alone at night were covariates in the structural models. RESULTS: Data were used from 11,619 individuals in the 65+ group (mean age 73 years ±6, 49% female) and 5546 individuals in the OA group (mean age 67 ± 10, 60% female). The final 65+ model had a close fit with RMSEA (90% CI) = 0.018 (0.017, 0.019), CFI = 0.91, SRMR = 0.09. For the OA group, RMSEA (90% CI) = 0.021 (0.020, 0.023), CFI = 0.92, SRMR = 0.07. Health perceptions and timed functional mobility had a positive association with ambulation. Depression was associated with ambulation through negative associations with health perceptions and timed functional mobility. Multi-group SEM results reveal the measurement model was retained for males and females in the 65+ group, for males and females and for age groups (65+, < 65) in the OA group. CONCLUSIONS: The community ambulation model post-stroke was verified with adults aged 65+ and for those with OA. The models of community ambulation can be used to frame and conceptualize community ambulation research and clinical interventions.

Verification of a comprehensive framework for mobility using data from the Canadian Longitudinal Study on Aging: a structural equation modeling analysis.

BACKGROUND: Mobility within and between life spaces is fundamental for health and well-being. Our objective was to verify a comprehensive framework for mobility. METHODS: This was a cross-sectional study. We used structural equation modeling to estimate associations between latent factors with data from the Canadian Longitudinal Study on Aging for participants 65-85 years of age (65+, n = 11,667) and for adults with osteoarthritis (OA) aged 45-85 (n = 5,560). Latent factors included life space mobility, and physical, psychosocial, environmental, financial, and cognitive elements. Personal variables (age, sex, education) were covariates. RESULTS: The models demonstrated good fit (65+: CFI = 0.90, RMSEA (90% CI) = 0.025 (0.024, 0.026); OA: CFI = 0.90, RMSEA (90% CI) = 0.032 (0.031, 0.033)). In both models, better psychosocial and physical health, and being less afraid to walk after dark (observed environmental variable) were associated with greater life space mobility. Greater financial status was associated with better psychosocial and physical health. Higher education was related to better cognition and finances. Older age was associated with lower financial status, cognition, and physical health. Cognitive health was positively associated with greater mobility only in the 65 + model. Models generated were equivalent for males and females. CONCLUSIONS: Associations between determinants described in the mobility framework were verified with adults 65-85 years of age and in an OA group when all factors were considered together using SEM. These results have implications for clinicians and researchers in terms of important outcomes when assessing life space mobility; findings support interdisciplinary analyses that include evaluation of cognition, depression, anxiety, environmental factors, and community engagement, as well as physical and financial health. Public policies that influence older adults and their abilities to access communities beyond their homes need to reflect the complexity of factors that influence life space mobility at both individual and societal levels.

The safety and immunogenicity to inactivated COVID-19 vaccine in patients with hyperlipemia.

It is of urgent need to understand the safety and effectiveness of novel coronavirus (COVID-19)-inactivated vaccine in patients with hyperlipidemia (HLD). However, data on the safety and immune response of SARS-CoV-2-inactivated vaccine in HLD patients are limited. In this prospective study, 105 patients with HLD and 74 healthy controls (HCs) were selected. Within 16-168 days after inoculation-inactivated vaccine, the anti-receptor-binding domain (RBD) IgG and SARS-CoV-2 neutralizing antibodies (NAbs) were evaluated, respectively. Flow cytometry was performed to evaluate RBD-specific B cells and memory B cells. There was no significant difference between HLD patients and HCs in adverse events (AEs) within 7 days after vaccination, and no serious AEs occurred. The seropositivity rates and titers of two Abs (anti-RBD IgG and CoV-2 NAbs) were lower in HLD patients than in HCs (all, p < 0.05). HLD showed significantly lower frequencies of RBD-specific B cells than HCs (p = 0.040). However, in high cholesterol, high triglyceride, mixed (MiX), and lipid control (HC) subgroups, there was no significant difference in the seropositivity rates and titers of the both Abs. Through mixed factor analysis shows that days between the second dose and sample collection/antibody measurement were associated with the lower anti-RBD IgG antibody levels. In conclusion, inactivated COVID-19 vaccine is safe and well tolerated for HLD patients, but the humoral immune may be limited.

Impact of sarcosine on diabetic retinopathy: Findings based on weighted gene co-expression network analysis and machine learning techniques.

AIM: To quantify the association between serum sarcosine and diabetic retinopathy (DR) using weighted gene co-expression network analysis (WGCNA). METHODS: We measured serum metabolites in 69 pairs of type 2 diabetes (T2D) patients with and without DR matched by age, gender, body mass index（BMI and HbA1c, using a propensity score matching-based approach. To identify modules and metabolites linked to DR, pathway analysis was performed using WGCNA, the Kyoto Encyclopedia of Genes and Genomes and Small-Molecule Pathway Database. The association of sarcosine with DR was estimated by restricted cubic spline and conditional logistic regression models. Its joint effects with covariates on DR were also extensively examined. RESULTS: With per interquartile range elevation of sarcosine, the adjusted odds ratio (AOR) of DR significantly decreased by 67% (AOR: 0.33, 95% confidence interval [CI]: 0.19-0.58). Similar results were also found in the tertile analysis. Compared with those in the first tertile of sarcosine, the AOR significantly decreased by 54% (AOR: 0.46, 95% CI: 0.18-1.17) and 78% (AOR: 0.22, 95% CI: 0.08-0.59) for subjects in the second and third tertiles, respectively. Compared with subjects with lower sarcosine and lower HDL-C levels, those with higher sarcosine and lower HDL-C levels had the lowest odds of DR (OR: 0.13, 95% CI: 0.04, 0.43). CONCLUSIONS: Serum sarcosine was inversely related to DR, especially in T2D patients with insufficient HDL-C. This study provides insights on a possible novel target for DR precision prevention and control, as well as a better understanding of the DR mechanism.

Global trends of interstitial lung diseases from 1990 to 2019: an age-period-cohort study based on the Global Burden of Disease study 2019, and projections until 2030.

Background: Interstitial lung diseases (ILDs) are indispensable components of chronic respiratory diseases and global health challenges. We aimed to explore the global long-term changes in the prevalence, mortality, and disability-adjusted life years (DALYs) of ILDs; investigate the independent effect of age, period, and cohort; and project the disease burden over the next decade. Methods: Data were retrieved from the Global Burden of Disease (GBD) database 2019. The joinpoint regression model was used to calculate the average annual percent change (AAPC). An age-period-cohort (APC) analysis was employed to measure the independent effect of age, period, and cohort. The Bayesian age-period-cohort (BAPC) model was used to project the global epidemiological trends until 2030. Results: From 1990 to 2019, the age-standardized prevalence rate (ASPR), age-standardized mortality rate (ASMR), and age-standardized disability-adjusted life years (DALYs) rate (ASDR) of interstitial lung disease and pulmonary sarcoidosis (ILD) slightly increased from 52.66 per 100,000 [95% uncertainty interval (UI) 44.49 to 61.07] to 57.62 per 100,000 (95% UI 49.42 to 65.67), from 1.76 per 100,000 (95% UI 1.41 to 2.22) to 2.17 per 100,000 (95% UI 1.5 to 2.62), and from 41.57 per 100,000 (95% UI 33.93 to 51.92) to 46.45 per 100,000 (95% UI 35.12 to 54.98), whereas the ASPR, ASMR, and ASDR of pneumoconiosis decreased. High social-demographic index (SDI) regions possessed the highest ASPR, whereas low-middle SDI regions had the highest ASMR and ASDR, followed by low-SDI regions in ILD. Middle-SDI regions reported the highest ASPR, ASMR, and ASDR in pneumoconiosis. The age effect showed that the rate ratio (RR) was high in older adults. Period effect indicated that the RR of prevalence increased over time, whereas the RR of mortality and DALYs decreased in men but increased in women. The cohort effect exhibited that the more recent birth cohort had a higher RR than the previous cohort in prevalence. We projected that ASPR, ASMR, and ASDR would stabilize with little variation over the next decade. Conclusion: The global burden of ILDs remains relatively severe, especially among older adults, in low- and middle-SDI regions. Effective measurements are expected to improve this situation.

Immune responses to inactivated COVID-19 vaccine were decreased in Chinese patients with chronic respiratory diseases.

Purpose: The effectiveness of inactivated vaccines against acute respiratory syndrome coronavirus 2 (SARS­CoV­2), the causative agent of coronavirus disease 2019 (COVID-19), has become a global concern. Hence, the aim of this study was to evaluate vaccine safety and to assess immune responses in individuals with chronic respiratory disease (CRD) following a two-dose vaccination. Methods: The study cohort included 191 participants (112 adult CRD patients and 79 healthy controls [HCs]) at least 21 (range, 21-159) days after a second vaccination. Frequencies of memory B cells (MBCs) subsets and titers of SARS-CoV-2 neutralizing antibodies (NAbs) and anti-receptor binding domain (RBD) IgG antibodies (Abs) were analyzed. Results: As compared to the HCs, CRD patients had lower seropositivity rates and titers of both anti-RBD IgG Abs and NAbs, in addition to lower frequencies of RBD-specific MBCs (all, p < 0.05). At 3 months, CRD patients had lower seropositivity rates and titers of anti-RBD IgG Abs than the HCs (p < 0.05). For CoronaVac, the seropositivity rates of both Abs were lower in patients with old pulmonary tuberculosis than HCs. For BBIBP-CorV, the seropositivity rates of CoV-2 NAbs were lower in patients with chronic obstructive pulmonary disease than HCs (all, p < 0.05). Meanwhile, there was no significant difference in overall adverse events between the CRD patients and HCs. Univariate and multivariate analyses identified the time interval following a second vaccination as a risk factor for the production of anti-RBD IgG Abs and CoV-2 NAbs, while the CoronaVac had a positive effect on the titers of both Abs. Female was identified as a protective factor for CoV-2 NAb levels. Conclusion: Inactivated COVID-19 vaccines were safe and well tolerated by CRD patients but resulted in lower Ab responses and the frequencies of RBD-specific MBCs. Therefore, CRD patients should be prioritized for booster vaccinations.

Electrochemiluminescence imaging of a membrane carcinoembryonic antigen at single tissue sections.

Histopathological molecular testing of tissue sections is an essential step in tumor diagnosis; however, the commonly used immunohistochemical methods have problems such as low specificity and the subjective bias of the observer. Here, we report an electrochemiluminescence (ECL) imaging method to detect a membrane carcinoembryonic antigen (CEA) at the single tissue sections of cancer patients. By permeabilizing the tissue attached to a glassy carbon electrode, Ru(bpy)32+ tagged at the membrane CEA of the tissue could electrochemically react with TPrA in solution to emit ECL that has near-zero background and an extremely high signal-to-background ratio. Using the established ECL method, the expression differences and distribution characteristics of the CEA protein in the carcinoma and paracancerous tissues of pancreatic ductal carcinoma (PDAC) and lung adenocarcinoma (LUAD) patients are investigated. The images reveal that CEA proteins are mostly distributed in the acini and surrounding areas both in PDAC and LUAD tissues. Therefore, the presented approach could be able to provide a new molecular recognition method for the diagnosis of adenocarcinoma and other tumors.

Associations of estrogen therapy and non-estrogen anti-resorptive therapy with diabetes mellitus risk: A classical and Bayesian meta-analysis.

Anti-resorptive therapy (AT) increases insulin resistance and decrease insulin secretion through reduced undercarboxylated osteocalcin in mice. However, there are inconsistent findings regarding the impact of AT use on the risk of diabetes mellitus in humans. We examined the association between AT and incident diabetes mellitus using classical and Bayesian meta-analysis. We searched Pubmed, Medline, Embase, Web of Science, Cochrane, and Google Scholar for studies listed from database inception to 25 February 2022. Randomized controlled trials (RCTs) and cohort studies reporting associations of estrogen therapy (ET) and non-estrogen anti-resorptive therapy (NEAT) with incident diabetes mellitus were included. Two reviewers independently extracted research data such as ET and NEAT, diabetes mellitus, risk ratios (RRs), and 95 % confidence intervals (CIs) for incident diabetes mellitus associated with ET and NEAT from individual studies. This meta-analysis included data from nineteen original studies, consisting of fourteen ET and five NEAT studies. ET was associated with reduced risk of diabetes mellitus in the classical meta-analysis (RR: 0.90; 95 % CI: 0.81-0.99). Slightly stronger results were found in the meta-analysis of RCTs (RR: 0.83; 95 % CI: 0.77-0.89). The probability that RR < 1.0 was 95 % in the overall analysis and 99 % in RCTs under weakly informative prior. Although NEAT was associated with reduced risk of diabetes mellitus overall (RR: 0.80; 95 % CI: 0.67-0.97), this was not found in the RCT meta-analysis (RR: 0.90; 95 % CI: 0.75-1.10). Under weakly informative prior, the probabilities that NEAT reduces diabetes mellitus by >0 % were 99 %, and 73 % in the overall and RCT meta-analysis, respectively. In conclusion, meta-analysis provided consistent evidence against the hypothesis that AT increases diabetes risk. ET may reduce the risk of diabetes mellitus. Whether NEAT reduces the risk of diabetes mellitus is uncertain and requires additional evidence from RCTs.

The safety and immunogenicity of inactivated COVID-19 vaccine in old pulmonary tuberculosis patients.

The immunogenicity and safety of vaccines against coronavirus disease 2019 (COVID-19) remain unknown in patients with a history of pulmonary tuberculosis (OPTB). Therefore, the safety and effectiveness of inactivated vaccines against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) were assessed in patients with a history of PTB. The study cohort included 106 healthy controls and 93 adult patients with OPTB who received a two-dose vaccination. The study period was 21 to 105 days. Concentrations of antibodies (Abs) against receptor-binding domain (RBD) IgG and SARS-CoV-2 neutralizing Abs (NAbs) were measured, in addition to the frequencies of SARS-CoV-2-specific B and a portion T cells. The incidence of adverse events was similar between the OPTB patients and healthy controls. No severe adverse events occurred. Concentrations of Abs against RBD-IgG and CoV-2 neutralizing Abs in addition to the frequencies of RBD-specific memory B cells proportions were lower in OPTB patients than the healthy controls (all, p < 0.05), while the frequencies of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4+) cells were higher (p = 0.023). There was no obvious correlation between age and blood concentrations of Abs against RBD-IgG and CoV-2 neutralizing Abs, while immune responses were similar in the fibrosis and calcification groups. The period of time following full-course vaccination and lymphocyte counts were associated to anti-RBD-IgG responses. Inactivated COVID-19 vaccinations were well tolerated in OPTB patients, although immunogenicity was limited in this population. This study has been registered at ClinicalTrials.gov (NCT05043246).

Nanokit coupled electrospray ionization mass spectrometry for analysis of angiotensin converting enzyme 2 activity in single living cell.

Angiotensin-converting enzyme 2 (ACE2) is not only an enzyme but also a functional receptor on cell membrane for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, the activity of ACE2 in single living cell is firstly determined using a nanokit coupled electrospray ionization mass spectrometry (nanokit-ESI-MS). Upon the insertion of a micro-capillary into the living hACE2-CHO cell and the electrochemical sorting of the cytosol, the target ACE2 enzyme hydrolyses angiotensin II inside the capillary to generate angiotensin 1-7. After the electrospray of the mixture at the tip of the capillary, the product is differentiated from the substrate in molecular weight to achieve the detection of ACE2 activity in single cells. The further measurement illustrates that the inflammatory state of cells does not lead to the significant change of ACE2 catalytic activity, which elucidates the relationship between intracellular ACE2 activity and inflammation at single cell level. The established strategy will provide a specific analytical method for further studying the role of ACE2 in the process of virus infection, and extend the application of nanokit based single cell analysis.

Risk of waning humoral responses after inactivated or subunit recombinant SARS-CoV-2 vaccination in patients with chronic diseases: Findings from a prospective observational study in China.

Heterogeneity of antibody responses has been reported in SARS-CoV-2 vaccination recipients with underlying diseases. We investigated the impact of the presence of comorbidities on the humoral response to SARS-CoV-2 vaccination in patients with chronic disease (PWCD) and assessed the effect of the number of comorbidities on the humoral response to vaccination. In this study, neutralizing antibodies (NAbs) and IgG antibodies against the receptor-binding domain (RBD-IgG) were monitored following a full-course vaccination. In total, 1400 PWCD (82.7%, inactivated vaccines; 17.3%, subunit recombinant vaccine) and 245 healthy controls (65.7% inactivated vaccines, 34.3% subunit recombinant vaccine) vaccinated with inactivated or subunit recombinant SARS-CoV-2 vaccines, were included. The seroconversion and antibody levels of the NAbs and RBD-IgG were different in the PWCD group compared with those in the control group. Chronic hepatitis B (odds ratio [OR]: 0.65; 95% confidence interval [CI]: 0.46-0.93), cancer (OR: 0.65; 95% CI: 0.42-0.99), and diabetes (OR: 0.50; 95% CI: 0.28-0.89) were associated with lower seroconversion of NAbs. Chronic kidney disease (OR: 0.29; 95% CI: 0.11-0.76), cancer (OR: 0.38; 95% CI: 0.23-0.62), and diabetes (OR: 0.37; 95% CI: 0.20-0.69) were associated with lower seroconversion of RBD-IgG. Only the presence of autoimmune disease showed significantly lower NAbs and RBD-IgG titers. Patients with most types of chronic diseases showed similar responses to the controls, but humoral responses were still significantly associated with the presence of ≥2 coexisting diseases. Our study suggested that humoral responses following SARS-CoV-2 vaccination are impaired in patients with certain chronic diseases.

Analysis of the uptake and associated factors for virtual crisis care during the pandemic at a 24-h mental health crisis centre in Manitoba, Canada.

BACKGROUND: The coronavirus pandemic necessitated the rapid transition to virtual care. At a 24-h walk-in mental health Crisis Response Centre (CRC) in Winnipeg, Canada we adapted crisis mental health assessments to be offered virtually while the crisis centre also remained open to in person visits. Little is known about the sustainability of virtual visits in the presence of comparable in person care, and which visits are more likely to be done virtually, particularly in the crisis setting. METHODS: An analysis of visits to the CRC from the first local lockdown on March 19, 2020 through the third local wave with heightened public health restrictions in June 2021. Analysis of Variance was used to compare the proportion of visits occurring virtually (telephone or videoconference) during the first wave of heightened public health restrictions (lockdown 1) and subsequent lockdowns as well as the in-between periods. A binary logistic regression examined visit, sociodemographic and clinical factors associated with receipt of a virtual visit compared to an in person visit over the first year of the pandemic. RESULTS: Out of 5,357 visits, 993 (18.5%) occurred virtually. There was a significant difference in proportion of virtual visits across the pandemic time periods (F(4, 62) = 8.56, p < .001). The proportion of visits occurring virtually was highest during lockdown 1 (mean 32.6% by week), with no differences between the other time periods. Receipt of a virtual visit was significantly associated with daytime weekday visits, age, non-male gender, living further away from the CRC, no prior year contact with the CRC, and visits that did not feature suicidal behaviour, substance use, psychosis or cognitive impairment. CONCLUSIONS: A large proportion of virtual care occurring at the outset of the pandemic reflects public anxiety and care avoidance paired with health system rapid transformation. The use of virtual visits reduced over subsequent pandemic periods but was sustained at a meaningful level. Specific visit, sociodemographic and clinical characteristics are more likely to be present in visits occurring virtually compared to those in person. These results can help to inform the future planning and delivery of virtual crisis care.

Frequency of data collection and estimation of trajectories of physical functioning and their associations with survival in older men: analyses of longitudinal data from the Manitoba Follow-Up Study.

OBJECTIVE: In studies of trajectories of physical functioning among older people, the data cannot be measured continuously, but only at certain time points in prespecified cycles. We examine how data collection cycles can affect the estimation of trajectories and their associations with survival. STUDY DESIGN AND SETTING: Longitudinal data from the Manitoba Follow-Up Study (MFUS), with 12 measurements collected annually from 2004 to 2015, are analysed using a summary measures of physical functioning from the Short Form-36 questionnaire. Based on the joint models of the functioning trajectories and risk of death, we compare the estimations among models using different frequency of data collection (annually, biennially and triennially). RESULTS: Our 2004 baseline includes 964 men who were survivors from the original MFUS cohort with mean age of 84 years and range between 75 and 94 years. Results from analysis of annual data indicate that the mean physical functioning is significantly decreasing over time. Further, the rate of decline is increasing over time. The current value of physical functioning is significantly associated with the hazard of death (p<0.001), whereas the association between the change rate and mortality is marginally significant (p<0.10). Results from analysis of biennial and triennial data reveal similar trajectory patterns of physical functioning, but could not reveal the association between the change rate of physical functioning and mortality. The frequency of data collection also impacts substantially on the estimation of heterogeneity of functioning trajectory. The prediction of mortality risk obtained using annual measurements of physical functioning are better than using biennial or triennial measurements, while the predictions obtained using biennial or triennial measurements are almost equivalent. CONCLUSION: The impact of frequency of data collection depends on the shape of functional trajectories and its linking structure to survival outcome.

Comparison of CRP, Procalcitonin, Neutrophil Counts, Eosinophil Counts, sTREM-1, and OPN between Pneumonic and Nonpneumonic Exacerbations in COPD Patients.

Introduction: The patients with community-acquired pneumonia (CAP) and acute exacerbations of COPD (AECOPD) could have a higher risk of acute and severe respiratory illness than those without CAP in AECOPD. Consequently, early identification of pneumonia in AECOPD is quite important. Methods. 52 subjects with AECOPD + CAP and 93 subjects with AECOPD from two clinical centers were enrolled in this prospective observational study. The values of osteopontin (OPN), soluble triggering receptor expressed on myeloid cells-1 (sTREM-1), C-reactive protein (CRP), procalcitonin (PCT), eosinophil (EOS) counts, and neutrophil (Neu) counts in blood on the first day of admission and clinical symptoms were compared in AECOPD and AECOPD + CAP. In addition, subgroup analyses of biomarker difference were conducted based on the current use of inhaled glucocorticoids (ICS) or systemic corticosteroids (SCS). Results: Patients with AECOPD + CAP had increased sputum volume, sputum purulence, diabetes mellitus, and longer hospital stays than AECOPD patients (p < 0.05). A clinical logistic regression model showed among the common clinical symptoms, purulent sputum can independently predict pneumonia in AECOPD patients after adjusting for a history of diabetes. At day 1, AECOPD + CAP patients had higher values of Neu, CRP, PCT, and OPN, while serum sTREM-1 levels and EOS counts were similar in the two groups. CRP fared best at predicting AECOPD with CAP (p < 0.05 for the test of difference), while OPN had similar accuracy with Neu, PCT, and purulent sputum (p > 0.05 for the test of difference). Multivariate analysis, including clinical symptoms and biomarkers, suggested that CRP ≥15.8 mg/dL at day 1 was a only promising predictor of pneumonia in AECOPD. CRP and OPN were not affected by ICS or SCS. Conclusions: CRP ≥15.8 mg/dL is an ideal promising predictor of pneumonia in AECOPD, and its plasma level is not affected by ICS or SCS. The diagnostic performance of CRP is not significantly improved when combined with clinical symptoms or other markers (OPN, PCT, and Neu).

High-Coverage Serum Metabolomics Reveals Metabolic Pathway Dysregulation in Diabetic Retinopathy: A Propensity Score-Matched Study.

Background: Diabetic retinopathy (DR) is a major diabetes-related disease linked to metabolism. However, the cognition of metabolic pathway alterations in DR remains scarce. We aimed to corroborate alterations of metabolic pathways identified in prior studies and investigate novel metabolic dysregulations that may lead to new prevention and treatment strategies for DR. Methods: In this case-control study, we tested 613 serum metabolites in 69 pairs of type 2 diabetic patients (T2DM) with DR and propensity score-matched T2DM without DR via ultra-performance liquid chromatography-tandem mass spectrometry system. Metabolic pathway dysregulation in DR was thoroughly investigated by metabolic pathway analysis, chemical similarity enrichment analysis (ChemRICH), and integrated pathway analysis. The associations of ChemRICH-screened key metabolites with DR were further estimated with restricted cubic spline analyses. Results: A total of 89 differentially expressed metabolites were identified by paired univariate analysis and partial least squares discriminant analysis. We corroborated biosynthesis of unsaturated fatty acids, glycine, serine and threonine metabolism, glutamate and cysteine-related pathways, and nucleotide-related pathways were significantly perturbed in DR, which were identified in prior studies. We also found some novel metabolic alterations associated with DR, including the disturbance of thiamine metabolism and tryptophan metabolism, decreased trehalose, and increased choline and indole derivatives in DR. Conclusions: The results suggest that the metabolism disorder in DR can be better understood through integrating multiple biological knowledge databases. The progression of DR is associated with the disturbance of thiamine metabolism and tryptophan metabolism, decreased trehalose, and increased choline and indole derivatives.

Multimorbidity Patterns in US Adults with Subjective Cognitive Decline and Their Relationship with Functional Difficulties.

OBJECTIVES: This study identified different multimorbidity patterns among adults with subjective cognitive decline (SCD) and examined their association with SCD-related functional difficulties. METHODS: Data were obtained from the 2019 Behavioral Risk Factor Surveillance System. Latent class analysis was applied to identify different patterns of chronic conditions. Logistic regression was implemented to examine relationships between multimorbidity patterns and risk of SCD-related functional difficulties. RESULTS: Five multimorbidity patterns were identified: severely impaired (14.6%), respiratory/depression (18.2%), obesity/diabetes (18.6%), age-associated (22.3%), and minimal chronic conditions group (26.3%). Compared with minimal chronic conditions group, severely impaired group was most likely to report SCD-related functional difficulties, followed by respiratory/depression and obesity/diabetes group. DISCUSSIONS: Individuals in the three multimorbidity groups had elevated risk of SCD-related functional difficulties compared with minimal chronic conditions group. Characteristics of the high-risk groups identified in this study may help in development and implementation of interventions to prevent serious consequences of having multiple chronic conditions.

Electrochemically Imaging the Response of Ion-Selective Membranes with an Ultralow Detection Limit.

The development of ion-selective membranes for the selective response of a particular ion has been studied for many years; however, imaging the response of the membrane with a low detection limit is challenging. Here, high spatial-resolution electrochemical imaging of this response down to picomolar is achieved using scanning ion conductive microscopy. The detection strategy relies on the exclusion of a small amount of counter ions from the membrane in the presence of a low concentration of target ions in the solution. These excluded counter ions are adsorbed at the membrane-solution interface, leading to more positive charges at the surface. The resultant elevation of the ionic current in the approach curve behaves as the response for the target ions down to 10-11 M, which is much more sensitive than that using potentiometric measurement. The constant-current scanning of the membrane exhibits the fluctuation of the apparent surface height that is correlated with the ionic concentration, permitting the imaging of the response at the nanoscale. The achievement of highly sensitive and spatial-resolution imaging for the ionic response enable the collection of spatial response at the ion-selective membrane, which will greatly advance the study of ion-selective electrodes.

Control charts for chronic disease surveillance: testing algorithm sensitivity to changes in data coding.

BACKGROUND: Algorithms used to identify disease cases in administrative health data may be sensitive to changes in the data over time. Control charts can be used to assess how variations in administrative health data impact the stability of estimated trends in incidence and prevalence for administrative data algorithms. We compared the stability of incidence and prevalence trends for multiple juvenile diabetes algorithms using observed-expected control charts. METHODS: Eighteen validated algorithms for juvenile diabetes were applied to administrative health data from Manitoba, Canada between 1975 and 2018. Trends in disease incidence and prevalence for each algorithm were modelled using negative binomial regression and generalized estimating equations; model-predicted case counts were plotted against observed counts. Control limits were set as predicted case count ±0.8*standard deviation. Differences in the frequency of out-of-control observations for each algorithm were assessed using McNemar's test with Holm-Bonferroni adjustment. RESULTS: The proportion of out-of-control observations for incidence and prevalence ranged from 0.57 to 0.76 and 0.45 to 0.83, respectively. McNemar's test revealed no difference in the frequency of out-of-control observations across algorithms. A sensitivity analysis with relaxed control limits (2*standard deviation) detected fewer out-of-control years (incidence 0.19 to 0.33; prevalence 0.07 to 0.52), but differences in stability across some algorithms for prevalence. CONCLUSIONS: Our study using control charts to compare stability of trends in incidence and prevalence for juvenile diabetes algorithms found no differences for disease incidence. Differences were observed between select algorithms for disease prevalence when using wider control limits.