Optimizing SARS-CoV-2 vaccine responses in kidney transplant recipients: an urgent need.

Kidney transplant recipients (KTRs) have been identified as a population at increased risk for severe SARS-CoV-2 infection outcomes. This study focused on understanding the immune response of KTRs post-vaccination, specifically examining both serological and cellular responses to the SARS-CoV-2 vaccine. Thirteen individuals, including seven KTRs and six healthy donors, were evaluated for antibody levels and T cell responses post-vaccination. The study revealed that KTRs had significantly lower serological responses, including reduced anti-receptor binding domain (RBD) binding antibodies and neutralizing antibodies against the Wuhan, Delta, and Omicron BA.2 strains. Additionally, KTRs demonstrated weaker CD8 T cell cytotoxic responses and lower Th1 cytokine secretion, particularly IFN-γ, after stimulation with variant spike peptide pools. These findings highlight the compromised immunity in KTRs post-vaccination and underscore the need for tailored strategies to bolster immune responses in this vulnerable group. Further investigations are warranted into the mechanisms underlying reduced vaccine efficacy in KTRs and potential therapeutic interventions. IMPORTANCE: Some studies have revealed that KTRs had lower serological response against SARS-CoV-2 than healthy people. Nevertheless, limited studies investigate the cellular response against SARS-CoV-2 in KTRs receiving SARS-CoV-2 vaccines. Here, we found that KTRs have lower serological and cellular responses. Moreover, we found that KTRs had a significantly lower IFN-γ secretion than healthy individuals when their PBMCs were stimulated with SARS-CoV-2 spike peptide pools. Thus, our findings suggested that additional strategies are needed to enhance KTR immunity triggered by the vaccine.

Trial characteristics and treatment effect estimates in randomized controlled trials of Chinese herbal medicine: A meta-epidemiological study.

BACKGROUND: Previously published meta-epidemiological studies focused on Western medicine have identified some trial characteristics that impact the treatment effect of randomized controlled trials (RCTs). Nevertheless, it remains unclear if similar associations exist in RCTs on Chinese herbal medicine (CHM). Further, Chinese medicine-related characteristics have not been explored yet. OBJECTIVE: To investigate trial characteristics related to treatment effect estimates on CHM RCTs. SEARCH STRATEGY: This meta-epidemiological study searched 5 databases for systematic reviews on CHM treatment published between January 2011 and July 2021. INCLUSION CRITERIA: An eligible systematic review should only include RCTs of CHM and conduct at least one meta-analysis. DATA EXTRACTION AND ANALYSIS: Two reviewers independently conducted data extraction on general characteristics of systematic reviews, meta-analyses and included RCTs. They also assessed the risk of bias of RCTs using the Cochrane risk of bias tool. A two-step approach was used for data analyses. The ratio of odds ratios (ROR) and difference in standardized mean differences (dSMD) with 95% confidence interval (CI) were applied to present the difference in effect estimates for binary and continuous outcomes, respectively. RESULTS: Ninety-one systematic reviews, comprising 1338 RCTs were identified. For binary outcomes, RCTs incorporated with syndrome differentiation (ROR: 1.23; 95 % CI: [1.07, 1.39]), adopting Chinese medicine formula (ROR: 1.19; 95% CI: [1.03, 1.34]), with low risk of bias on incomplete outcome data (ROR: 1.29; 95% CI: [1.06, 1.52]) and selective outcome reporting (ROR: 1.12; 95% CI: [1.01, 1.24]), as well as a trial size ≥ 100 (ROR: 1.23; 95% CI: [1.04, 1.42]) preferred to show larger effect estimates. As for continuous outcomes, RCTs with Chinese medicine diagnostic criteria (dSMD: 0.23; 95% CI: [0.06, 0.41]), judged as high/unclear risk of bias on allocation concealment (dSMD: -0.70; 95% CI: [-0.99, -0.42]), with low risk of bias on incomplete outcome data (dSMD: 0.30; 95% CI: [0.18, 0.43]), conducted at a single center (dSMD: -0.33; 95% CI: [-0.61, -0.05]), not using intention-to-treat analysis (dSMD: -0.75; 95% CI: [-1.43, -0.07]), and without funding support (dSMD: -0.22; 95% CI: [-0.41, -0.02]) tended to show larger effect estimates. CONCLUSION: This study provides empirical evidence for the development of a specific critical appraisal tool for risk of bias assessments on CHM RCTs. Please cite this article as: Wang BH, Lin YL, Gao YY, Song JL, Qin L, Li LQ, et al. Trial characteristics and treatment effect estimates in randomized controlled trials of Chinese herbal medicine: A meta-epidemiological study. J Integr Med. 2024; Epub ahead of print.

A Frequent Diagnostic Pitfall: Dermatological Clinical Features and Pathological Results in Diagnosing Pagetoid Squamous Cell Carcinoma in situ (Case Series).

Squamous cell carcinoma (SCC) in situ can occur on any skin or mucus surface and is more commonly found in elderly patients on areas of skin that have been sunburnt. Most previous case reports are from dermatologists, with few published reports from pathologists. In this study, three patients underwent pathological routine and auxiliary immunohistochemical (IHC) examination and were ultimately diagnosed with pagetoid SCC in situ - a different diagnosis from the initial clinical assessment. All three patients received a complete resection of the skin mass. After follow-up, as of June 2023, the patients had no tumour recurrence or metastasis. Pagetoid SCC in situ is a particular type of SCC in situ that has no specific features in clinical manifestations, gross diagnosis or histopathological sections. The final diagnosis depends on IHC staining. Pagetoid SCC in situ expresses EMA, CK5/6 and p63 but not CEA, CK8 or S-100, which are expressed in extramammary Paget's disease. Pagetoid SCC in situ is usually only locally invasive, and the main treatment is complete surgical resection. The prognosis is related to human papillomavirus infection, surgical margin closure, disease location, tumour thickness and other factors.

Overcome the Limitation of Phenome-Wide Association Studies (PheWAS): Extension of PheWAS to Efficient and Robust Large-Scale ICD Codes Analysis.

The Phenome-wide association studies (PheWAS) have become widely used for efficient, high-throughput evaluation of relationship between a genetic factor and a large number of disease phenotypes, typically extracted from a DNA biobank linked with electronic medical records (EMR). Phecodes, billing code-derived disease case-control status, are usually used as outcome variables in PheWAS and logistic regression has been the standard choice of analysis method. Since the clinical diagnoses in EMR are often inaccurate with errors which can lead to biases in the odds ratio estimates, much effort has been put to accurately define the cases and controls to ensure an accurate analysis. Specifically in order to correctly classify controls in the population, an exclusion criteria list for each Phecode was manually compiled to obtain unbiased odds ratios. However, the accuracy of the list cannot be guaranteed without extensive data curation process. The costly curation process limits the efficiency of large-scale analyses that take full advantage of all structured phenotypic information available in EMR. Here, we proposed to estimate relative risks (RR) instead. We first demonstrated the desired nature of RR that overcomes the inaccuracy in the controls via theoretical formula. With simulation and real data application, we further confirmed that RR is unbiased without compiling exclusion criteria lists. With RR as estimates, we are able to efficiently extend PheWAS to a larger-scale, phenome construction agnostic analysis of phenotypes, using ICD 9/10 codes, which preserve much more disease-related clinical information than Phecodes.

Endoplasmic reticulum targeted fluorescent probe for real-time monitoring the viscosity changes induced by calcium homeostasis disruption.

The endoplasmic reticulum (ER) acts as the major storage site for calcium ions, which are messenger ions for intracellular signaling. Disruption of calcium ion homeostasis can significantly affect the viscosity, polarity and pH of the ER. However, it is still unclear the relationship between the viscosity changes in ER and the imbalance of calcium ion homeostasis. Herein, we developed a novel fluorescent probe, named TPA, for monitoring viscosity changes that specifically targets the endoplasmic reticulum rather than mitochondria or lysosomes. TPA probe displayed good stability, as well as high responsiveness and selectivity to viscosity. The fluorescence intensity of TPA was significantly enhanced with the increased concentration or incubation time of the stimulating agents(i.e., tunicamycin), showing high responsiveness to the viscosity changes in ER. Furthermore, the TPA probe successfully demonstrated that an increase in intracellular calcium ion concentration leads to an increase in ER viscosity, whereas a decrease in calcium ion concentration leads to a decrease viscosity in ER. Both in vitro and in vivo experiments demonstrated that TPA probe successfully detected the viscosity changes in ER, especially the effects of calcium ion homeostasis disruption on ER. Overall, the TPA probe represents an efficient method for studying the relationship between calcium ion homeostasis and ER viscosity.

A new species and a replacement name in Cynanchum (Apocynaceae, Asclepiadeae) from China.

Cynanchumpingtaoi S.Jin Zeng, G.D.Tang & Miao Liao, sp. nov. (Apocynaceae) from Yunnan Province, China, is described and illustrated based on morphological and molecular evidence. Its deeply cordate to reniform leaves and campanulate, large flowers show that it is a member of former Raphistemma Wall., which has been included in Cynanchum L.. It is different from all former Raphistemma species by the broadly ovate corolla lobes, purple-red corolla and connivent corona tip slightly exceeding the corolla throat. Meanwhile, Cynanchumlonghushanense G.D.Tang & Miao Liao, nom. nov. is proposed as replacement name for Raphistemmabrevipedunculatum Y.Wan, which was considered a synonym of Cynanchumhooperianum (Blume) Liede & Khanum but is here reinstated as a distinct species because of significant morphological differences.

Enhanced acrylic gauge with five eccentric circles for optimizing CT angiography spatial resolution via Taguchi's methodology.

BACKGROUND: Cerebral examination via CTA is always the first choice for patients with unexpected brain injury or different types of brain lesions to detect ruptured hemangiomas, vascular infarcts, or other brain tissue lesions. OBJECTIVE: This study innovated the acrylic gauge with five eccentric circles for computed tomography angiography (CTA) analysis to optimize the spatial resolution via Taguchi's methodology. METHODS: The customized gauge was revised from the V-shaped slit gauge and transferred into five eccentric circles' slit gauge. The gauge was assembled with another six acrylic layers to simulate the human head. Taguchi's L18 orthogonal array was adopted to optimize the spatial resolution of CTA imaging quality. In doing so, six essential factors of CTA are kVp, mAs, spiral rotation pitch, FOV, rotation time of the CT and reconstruction filter, and each factor has either two or three levels to organize into eighteen combinations to simulate the full factor combination of 486 (21 × 35 = 486) times according to Taguchi's recommendation. Three well-trained radiologists ranked the gauge's 18 CTA scanned imaging qualities according to contrast, sharpness, and spatial resolution and derived the unique fish-bone-plot of six factors for further analysis. The optimal factor combination of CTA was proven by follow-up verification and ANOVA to obtain this study's dominant or minor factor. RESULTS: The optimal factor combination of CTA was A2 (120 kVp), B3 (200 mAs), C1 (Pitch 0.6), D2 (FOV 220 mm2), E1 (rotation time 0.33 s), and F3 (Brain sharp, UC). Furthermore, deriving a quantified MDD (minimum detectable difference) to imply the spatial resolution of CTA, a semiauto profile analysis program run in MATLAB and OriginPro was recommended to evaluate the MDD and to suppress the manual error in calculation. Eventually, the derived MDDs of the conventional and optimal factor combinations of CTA were 2.35 and 2.26 mm, respectively, in this study. CONCLUSION: Taguchi's methodology was found applicable for quantifying the CTA imaging quality in practical applications.

Effect of various different pretreatment methods on infrared combined hot air impingement drying behavior and physicochemical properties of strawberry slices.

In current work, the effect of freezing (F), ultrasound (U), and freeze- ultrasound (FU) pretreatment on infrared combined with hot air impingement drying kinetics, cell ultrastructure, enzyme activity, and physicochemical properties of strawberry slices were explored. Results showed that FU pretreatment enhanced cell membrane permeability via forming micropores, altered water status by transforming bound water into free water and thus promoted moisture diffusivity and decreased drying time by 50% compared to the control group. FU pretreatment also extensively decreased pectin methylesterase enzyme activity and maintained quality. The contents of total phenols, anthocyanins, vitamin C, antioxidant activity, and a* value of dried strawberries pretreated by FU were extensively increased compared to the control group. U and FU pretreatments were beneficial for retaining aromatic components and organic sulfides according to e-nose analyses. The findings indicate that FU is a promising pretreatment technique as it enhances drying process and quality of strawberry slices.

First Report of 'Candidatus Phytoplasma asteris'-related Strain (16SrI group) Associated with Small Leaves, Leaf Yellowing, and Shoot Proliferation of Morning Glory (Ipomoea biflora) in Taiwan.

Ipomoea biflora L., commonly known as morning glory, is an herbaceous vine plant in the Convolvulaceae family and is widespread at low elevations in Taiwan and other East Asian countries. In September 2023, six I. biflora plants exhibiting small leaves, leaf yellowing, and shoot proliferation were observed in a vacant lot in Taiwan Agricultural Research Institute (TARI), Wufeng District, Taichung, Taiwan, representing 100% disease incidence in the area. All the symptomatic morning glory climbed onto Murraya paniculata L. (common jasmine orange) which however showed no similar symptoms. The total DNA (two samples for each plant) from leaf tissues of three symptomatic morning glory plants, two asymptomatic morning glory plants, and one asymptomatic common jasmine orange was isolated by the CTAB method (Fulton et al. 1995) and used for PCR with the universal primers, P1 (Deng and Hiruki 1991)/P7 (Schneider et al. 1995), to amplify a fragment containing partial 16S rDNA. Expected 1.8-kb bands were amplified from DNA extracted from all symptomatic plants, whereas no PCR product was detected from that of the asymptomatic I.biflora and M. paniculata plants. Six PCR products were cloned and sequenced in the Biotechnology Center DNA-sequencing facility at National Chung Hsing University, and one representative sequence was selected and deposited in GenBank. BLAST analysis revealed that the obtained 16S rDNA sequence (PP230905) shared 99.92% identity with the following phytoplasma strains: rapeseed phyllody phytoplasma (CP055264), plumbago auriculata leaf yellowing phytoplasma (MN239503), and aster yellows phytoplasma (MK992774), which all belong to the 16SrI subgroup. The query 16S rDNA sequence shares 99.84% identity with that of the 'Candidatus Phytoplasma asteris' reference strain (M30790), suggesting that the phytoplasma is a 'Ca. Phytoplasma asteris'-related strain. A virtual restriction fragment length polymorphism (RFLP) analysis was conducted using iPhyClassifier tool (Zhao et al. 2009), and the pattern derived from the 16S rDNA fragment of the I. biflora phytoplasma was identical (similarity coefficient 1.00) to the reference pattern of 16SrI, subgroup B (onion yellows phytoplasma OY-M; AP006628). Six total DNA samples from symptomatic plants were used as templates to amplify 842 bp secA sequences with SecAfor1 and SecArev3 primers (Hodgetts et al. 2008), and one representative sequence was deposited in GenBank. The partial secA sequence (PP263636) showed 98.22% identity with that of Trema levigatum witches'-broom phytoplasma (MW032212) that also belongs to the 16SrI group (Wan et al. 2021). Phylogenetic analysis of both 16S rDNA and secA confirmed I. biflora phytoplasma as 16SrI, subgroup B. Taken together, we concluded that the morning glory phytoplasma in this study was a 'Ca. Phytoplasma asteris'-related strain belonging to the 16SrI group. To the best of our knowledge, this is the first report of a phytoplasma-infected I. biflora in Taiwan, suggesting morning glory as a new natural host of 16SrI phytoplasmas, alongside other plants like roselle and citrus (Tseng et al. 2014; Feng et al. 2015).

Fostering relational autonomy in end-of-life care: a procedural approach and three-dimensional decision-making model.

Respect for patient autonomy is paramount in resolving ethical tensions in end-of-life care. The concept of relational autonomy has contributed to this debate; however, scholars often use this concept in a fragmented manner. This leads to partial answers on ascertaining patients' true wishes, meaningfully engaging patients' significant others, balancing interests among patients and significant others, and determining clinicians' obligations to change patients' unconventional convictions to enhance patient autonomy. A satisfactory solution based on relational autonomy must incorporate patients' competence (apart from decisional capacity), authenticity (their true desires or beliefs) and the involvement level of their significant others. To that end, we argue that John Christman's procedural approach to relational autonomy provides critical insights, such as the diachronic or socio-historical personhood, sustained critical reflection and his recent explication of the nature of asymmetrical relationships and helpful interlocutors. This study reviews Christman's account, proposes minor modifications and advocates for an integrated three-dimensional model for medical decision-making. Clarifying the relationship among the three elements promotes an ethical framework with a coherent understanding of relational autonomy. This model not only provides a descriptive and normative framework for end-of-life care practice but also reconsiders the nature of the clinician-patient relationship and its normative implications. We further present a case study to illustrate the merits of our proposed model. Altogether, our proposal will help navigate complex medical decision-making, foster trust and negotiate shared values between patients and their significant others, particularly in end-of-life care.

[Effects of coal mine waste dump on soil seed bank and vegetation distribution pattern]. / ç ¤çŸ¿æŽ’çŸ¸åœºå¯¹å‘¨è¾¹åœŸå£¤ç§å­åº“åŠæ¤è¢«åˆ†å¸ƒæ ¼å±€çš„å½±å“.

Long-term occupation of coal gangue dumping sites (CGDS) may destroy ecological environment of nearby area. However, how the CGDS affects the distribution pattern of soil seed banks and vegetation in the nearby area is not clear. In this study, we investigated soil seed bank and vegetation at different distances from the second CGDS of Yangchangwan in Ningdong mining area, Lingwu, Ningxia. The results showed that soil seed bank was mainly distributed in 0-10 cm layer and decreased with increasing soil depth. Species richness of soil seed bank and vegetation first increased and then tended to be stable with increasing distance to the CGDS. The influence range of CGDS on soil seed banks was 300-500 m and was 100-300 m on aboveground vegetation. The CGDS did not affect the vertical distribution pattern of soil seed bank, but significantly affected the horizontal distribution pattern of soil seed banks and aboveground vegetation. The key area of vegetation restoration around the CGDS was between 100 m and 300 m.

Effect of transcutaneous electrical acupoint stimulation based on the theory of "qi ascending and descending movement" on autonomic nervous system and gastrointestinal function in patients after general anesthesia laparoscopic cholecystectomy. / 基于"气机升降"ç†è®ºç»çš®ç©´ä½ç”µåˆºæ¿€å¯¹å ¨éº»è ¹è ”é•œèƒ†å›Šåˆ‡é™¤æœ¯åŽæ‚£è€ è‡ªä¸»ç¥žç»å’Œèƒƒè‚ åŠŸèƒ½çš„å½±å“.

OBJECTIVES: To observe the therapeutic effect of transcutaneous electrical acupoint stimulation (TEAS) based on the theory of "qi ascending and descending movement" in patients after general anesthesia laparoscopic cholecystectomy, so as to explore the impact of TEAS on the autonomic nervous system and gastrointestinal function of patients. METHODS: A total of 204 patients scheduled to undergo general anesthesia laparoscopic cholecystectomy were selected and randomly divided into control, double acupoints and multiple acupoints groups, with 68 cases in each group. For patients in the multiple acupoints group, TEAS was applied at Zusanli (ST36), Tiantu (CV22), Danzhong (CV17), Zhongwan (CV12), Taichong (LR3), and Neiguan (PC6) 30 min before anesthesia induction until the end of the surgery. In the double acupoints group, TEAS was applied only at ST36 and PC6. No electrical stimulation was applied in the control group. The postoperative bloating, bowel sound recovery time, first farting time, first defecation time, length of hospital stay, nausea and vomiting were compared among the three groups. Heart rate variability was monitored by twelve-lead electrocardiogram to evaluate the autonomic nervous function of the patients, including the low frequency power/high frequency power ratio (LF/HF), the standard deviation of all sinus RR intervals (SDNN), and the root mean square of difference between successive normal RR intervals (RMSSD). RESULTS: At 6 h and 24 h after surgery, the symptoms of bloating, nausea and vomiting in the multiple acupoints group and double acupoints group were significantly improved compared to the control group (P<0.05), and the multiple acupoints group was superior to the double acupoints group (P<0.05). Compared with the control group, the bowel sound recovery time, first farting time, first defecation time, and length of hospital stay were significantly shorter (P<0.05) in the multiple acupoints group and double acupoints group, and the multiple acupoints group was superior to the double acupoints group (P<0.05). At 1 d and 2 d after surgery, compared with the control group, LF/HF was decreased (P<0.05) while SDNN and RMSSD were increased (P<0.05) in the multiple acupoints group and double acupoints group, and there was a significant difference between the two groups (P<0.05). CONCLUSIONS: TEAS treatment based on the theory of "qi ascending and descending movement" can relieve gastrointestinal dysfunction, reduce early postoperative sympathetic nerve excitement and maintain parasympathetic nerve tension in patients after general anesthesia laparoscopic cholecystectomy, thereby promoting gastrointestinal function recovery.

Predictive value of NT-proBNP and hs-TnT for outcomes after pediatric congenital cardiac surgery.

BACKGROUND: The available evidence regarding the predictive value of troponins and natriuretic peptides for early postoperative outcomes in pediatrics is limited, controversial, and based on small sample sizes. We aimed to investigate the association of N-terminal pro B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hs-TnT) with the in-hospital adverse outcomes after congenital cardiac surgeries. METHODS: A secondary analysis based on a prospective study of pediatric congenital heart disease (CHD) patients was conducted to investigate the association of NT-proBNP and hs-TnT tested within 6 hours postoperatively with in-hospital adverse events. A multivariate logistic regression analysis with a minimum P value approach was used to identify the optimal thresholds of NT-proBNP and hs-TnT for risk stratification. RESULTS: NT-proBNP and hs-TnT are positively correlated with cardiopulmonary bypass time, mechanical ventilation duration, and pediatric intensive care unit stay. The predictive performance of NT-proBNP is excellent for adverse events in both patients younger than 1 year [area under the curve (AUC): 0.771, 0.693-0.850] and those older than 1 year (AUC: 0.839, 0.757-0.922). However, hs-TnT exhibited a satisfactory predictive value solely in patients aged over 1 year. (AUC: 0.784, 0.717-0.852). NT-proBNP levels of 2000 to 10000 ng/L [Odds Ratio (OR): 3.79, 1.47-9.76) and exceeding 10000 ng/L (OR: 12.21, 3.66-40.80) were associated with a higher risk of postoperative adverse events in patients younger than 1 year. Patients older than 1 year, with NT-proBNP higher than 500 ng/L (OR: 15.09, 6.05-37.66) or hs-TnT greater than 1200 ng/L (OR: 5.50, 1.47-20.59), had a higher incidence of postoperative adverse events. CONCLUSIONS: NT-proBNP and hs-TnT tested within postoperative 6 hours demonstrated significant predictive value for postoperative adverse events in CHD patients older than 1 year. However, among CHD patients younger than 1 year, only NT-proBNP exhibited commendable predictive performance for postoperative adverse events.

CONTACT-01: A Randomized Phase III Trial of Atezolizumab + Cabozantinib Versus Docetaxel for Metastatic Non-Small Cell Lung Cancer After a Checkpoint Inhibitor and Chemotherapy.

PURPOSE: Although checkpoint inhibitors have improved first-line treatment for non-small cell lung cancer (NSCLC), a therapeutic need remains for patients whose disease does not respond or who experience disease progression after anti-PD-L1/PD-1 immunotherapy. CONTACT-01 (ClinicalTrials.gov identifier: NCT04471428) evaluated atezolizumab plus cabozantinib versus docetaxel in patients with metastatic NSCLC who developed disease progression after concurrent or sequential treatment with anti-PD-L1/PD-1 and platinum-containing chemotherapy. METHODS: This multicenter, open-label, phase III trial randomly assigned patients 1:1 to atezolizumab 1,200 mg intravenously once every 3 weeks (q3w) plus cabozantinib 40 mg orally once daily or docetaxel 75 mg/m2 intravenously once every 3 weeks. The primary end point was overall survival (OS). RESULTS: One hundred eighty-six patients were assigned atezolizumab plus cabozantinib, and 180 docetaxel. Minimum OS follow-up was 10.9 months. Median OS was 10.7 months (95% CI, 8.8 to 12.3) with atezolizumab plus cabozantinib and 10.5 months (95% CI, 8.6 to 13.0) with docetaxel (stratified hazard ratio [HR], 0.88 [95% CI, 0.68 to 1.16]; P = .3668). Median progression-free survival was 4.6 months (95% CI, 4.1 to 5.6) and 4.0 months (95% CI, 3.1 to 4.4), respectively (stratified HR, 0.74 [95% CI, 0.59 to 0.92]). Serious adverse events (AEs) occurred in 71 (38.4%) patients receiving atezolizumab plus cabozantinib and 58 (34.7%) receiving docetaxel. Grade 3/4 treatment-related AEs occurred in 73 (39.5%) patients receiving atezolizumab plus cabozantinib and 58 (34.7%) receiving docetaxel. Grade 5 AEs occurred in 14 (7.6%) and 10 (6.0%) patients in the atezolizumab plus cabozantinib and docetaxel arms, respectively (treatment-related in four [2.2%] and one [0.6%], respectively). CONCLUSION: Atezolizumab plus cabozantinib after disease progression following anti-PD-L1/PD-1 immunotherapy and platinum-containing chemotherapy for metastatic NSCLC did not improve OS compared with docetaxel. Safety was consistent with known profiles of these agents.

Association Between Long-Term Exposure to Ambient Air Pollution and the Risk of Mild Cognitive Impairment in a Chinese Urban Area: A Case-Control Study.

Background: As a prodromal stage of dementia, significant emphasis has been placed on the identification of modifiable risks of mild cognitive impairment (MCI). Research has indicated a correlation between exposure to air pollution and cognitive function in older adults. However, few studies have examined such an association among the MCI population inChina. Objective: We aimed to explore the association between air pollution exposure and MCI risk from the Hubei Memory and Aging Cohort Study. Methods: We measured four pollutants from 2015 to 2018, 3 years before the cognitive assessment of the participants. Logistic regression models were employed to calculate odds ratios (ORs) to assess the relationship between air pollutants and MCI risk. Results: Among 4,205 older participants, the adjusted ORs of MCI risk for the highest quartile of PM2.5, PM10, O3, and SO2 were 1.90 (1.39, 2.62), 1.77 (1.28, 2.47), 0.56 (0.42, 0.75), and 1.18 (0.87, 1.61) respectively, compared with the lowest quartile. Stratified analyses indicated that such associations were found in both males and females, but were more significant in older participants. Conclusions: Our findings are consistent with the growing evidence suggesting that air pollution increases the risk of mild cognitive decline, which has considerable guiding significance for early intervention of dementia in the older population. Further studies in other populations and broader geographical areas are warranted to validate these findings.

Association Between Use of Sodium-Glucose Cotransporter-2 Inhibitors or Angiotensin Receptor-Neprilysin Inhibitor and the Risk of Atherosclerotic Cardiovascular Disease With Coexisting Diabetes and Heart Failure.

PURPOSE: This study was to investigate the association between the use of Sodium-glucose Cotransporter-2 inhibitors (SGLT2i) or angiotensin receptor-neprilysin inhibitor (ARNI; ie, Sacubitril + valsartan, Product name ENTRESTO) and the risk of atherosclerotic cardiovascular disease (ASCVD) in patients with coexisting diabetes and heart failure. Specifically, the study compared outcomes between patients using SGLT2i or valsartan + sacubitril and those not using these medications. METHODS: This study utilized data from the National Health Insurance Research Database (NHIRD) from 2017 to 2018. The case group consisted of 8691 patients with coexisting diabetes and heart failure who did not use SGLT2i or Entresto, while the control group consisted of 8691 patients with coexisting diabetes and heart failure who used SGLT2i or Entresto. The primary outcome was ASCVD, including a composite of cardiovascular death and hospitalization for worsening heart failure. Secondary outcomes included all-cause death, cause of cardiovascular death, and recurrence of heart failure, non-fatal myocardial infarction, non-fatal stroke (including ischemic stroke and hemorrhagic stroke) and new renal replacement therapy. RESULTS: The study found that the use of SGLT2 inhibitors or ARNI was associated with a lower risk of ASCVD in patients with coexisting diabetes and heart failure. CONCLUSION: The study suggests that the use of SGLT2 inhibitors, alone or in combination with Entresto, may be effective in reducing the risk of ASCVD and its associated adverse outcomes in patients with diabetes and heart failure. This finding has important implications for the management of these conditions.

Circulating tumor DNA methylation: a promising clinical tool for cancer diagnosis and management.

Cancer continues to pose significant challenges to the medical community. Early detection, accurate molecular profiling, and adequate assessment of treatment response are critical factors in improving the quality of life and survival of cancer patients. Accumulating evidence shows that circulating tumor DNA (ctDNA) shed by tumors into the peripheral blood preserves the genetic and epigenetic information of primary tumors. Notably, DNA methylation, an essential and stable epigenetic modification, exhibits both cancer- and tissue-specific patterns. As a result, ctDNA methylation has emerged as a promising molecular marker for noninvasive testing in cancer clinics. In this review, we summarize the existing techniques for ctDNA methylation detection, describe the current research status of ctDNA methylation, and present the potential applications of ctDNA-based assays in the clinic. The insights presented in this article could serve as a roadmap for future research and clinical applications of ctDNA methylation.

Volumetric brain MRI signatures of heart failure with preserved ejection fraction in the setting of dementia.

Heart failure with preserved ejection fraction (HFpEF) is an important, emerging risk factor for dementia, but it is not clear whether HFpEF contributes to a specific pattern of neuroanatomical changes in dementia. A major challenge to studying this is the relative paucity of datasets of patients with dementia, with/without HFpEF, and relevant neuroimaging. We sought to demonstrate the feasibility of using modern data mining tools to create and analyze clinical imaging datasets and identify the neuroanatomical signature of HFpEF-associated dementia. We leveraged the bioinformatics tools at Vanderbilt University Medical Center to identify patients with a diagnosis of dementia with and without comorbid HFpEF using the electronic health record. We identified high resolution, clinically-acquired neuroimaging data on 30 dementia patients with HFpEF (age 76.9 ± 8.12 years, 61% female) as well as 301 age- and sex-matched patients with dementia but without HFpEF to serve as comparators (age 76.2 ± 8.52 years, 60% female). We used automated image processing pipelines to parcellate the brain into 132 structures and quantify their volume. We found six regions with significant atrophy associated with HFpEF: accumbens area, amygdala, posterior insula, anterior orbital gyrus, angular gyrus, and cerebellar white matter. There were no regions with atrophy inversely associated with HFpEF. Patients with dementia and HFpEF have a distinct neuroimaging signature compared to patients with dementia only. Five of the six regions identified in are in the temporo-parietal region of the brain. Future studies should investigate mechanisms of injury associated with cerebrovascular disease leading to subsequent brain atrophy.

Identifying the role of MTHFD1L in prostate cancer progression from genetic analysis and experimental validation.

One-carbon metabolism plays a crucial role in tumorigenesis as it supplies the one-carbon units necessary for nucleotide synthesis, epigenetic regulation, and redox metabolism, ensuring the rapid proliferation of cancer cells. However, their roles in prostate cancer progression remain poorly understood. In this study, we investigated the association between genetic variants in the one-carbon metabolism pathway and clinical outcomes in patients receiving androgen deprivation therapy for prostate cancer. The associations of 130 single-nucleotide polymorphisms located within 14 genes involved in the one-carbon metabolism pathway with cancer-specific survival (CSS), overall survival, and progression-free survival were assessed using Cox regression in 630 patients with prostate cancer. Subsequently, functional studies were performed using prostate cancer cell lines. After adjusting for covariates and multiple testing, MTHFD1L rs2073190 was found to be significantly associated with CSS (P = 0.000184). Further pooled analysis of multiple datasets demonstrated that MTHFD1L was upregulated in prostate cancer and increased MTHFD1L expression was positively correlated with tumor aggressiveness and poor patient prognosis. Functionally, MTHFD1L knockdown suppressed prostate cancer cell proliferation and colony formation. RNA sequencing and pathway analysis revealed that differentially expressed genes were predominantly enriched in the cell cycle pathway. In conclusion, genetic variants in MTHFD1L of one-carbon metabolism may serve as promising predictors, and our findings offer valuable insights into the underlying genetic mechanisms of prostate cancer progression.

Hypothalamic NPFFR2 attenuates central insulin signaling and its knockout diminishes metabolic dysfunction in mouse models of diabetes mellitus.

BACKGROUND: The hypothalamus is a crucial brain region that mediates the effects of insulin and leptin signals on peripheral metabolic functions. Previous research has shown that insulin signals in the hypothalamus act via multiple neuronal circuits and anabolic/catabolic pathways that converge on the vagus nerve and sympathetic fibers to coordinate energy metabolism in peripheral organs. Additionally, neuropeptide FF (NPFF) has been identified as a regulator of feeding behaviors and energy homeostasis in the hypothalamus, but the mechanisms underlying its involvement in metabolic control remain unclear. This study aims to explore the underlying mechanisms of NPFF in modulating metabolic disorders. METHODS: In this study, we investigated the physiological role of NPFF in insulin-related energy homeostasis and metabolic health. First, we evaluated the effects of NPFF and its receptors on central insulin signaling using mouse hypothalamic cell lines and Npffr2-overexpressing mice. To further explore the effects of NPFFR2 on insulin-related metabolic disorders, such as diabetes mellitus, we used Npffr2-deleted mice in combination with the streptozotocin (STZ)-induced type 1 diabetes and high-fat diet/STZ-induced type 2 diabetic mouse models. The impacts of central NPFFR2 were demonstrated specifically through Npffr2 overexpression in the hypothalamic arcuate nucleus, which subsequently induced type 2 diabetes. RESULTS: We found that stimulating NPFFR2 in the hypothalamus blocked hypothalamic insulin activity. Npffr2 deletion improved central and peripheral metabolic symptoms in both mouse models of diabetes mellitus, exerting effects on central and systemic insulin resistance, feeding behaviors, glucose and insulin intolerance, lipid metabolism, liver steatosis, and inflammation of white adipose tissues. The overexpression of ARC Npffr2 augmented the metabolic dysregulation in the mouse model of type 2 diabetes. CONCLUSIONS: Our findings demonstrate that hypothalamic NPFFR2 negatively regulates insulin signaling in the central nervous system and plays an important role in maintaining systemic metabolic health, thereby providing valuable insights for potential clinical interventions targeting these health challenges.