Pulmonary artery denervation versus conventional therapies for PAH: a systematic review and updated network meta-analysis.

AIMS: A recent guideline presented by the ESC Congress in 2022 had indicated a novel therapy targeted at pulmonary artery hypertension, known as pulmonary artery denervation (PADN), which get inspired from a laboratorial trial that could lowering the pulmonary artery pressure through the intervention on the animals. Our aim is to conduct a network meta-analysis to compare the efficacy and safety of PADN from six aspects with the current conventional therapies. METHODS AND RESULTS: According to the PRISMA guidance, databases including Ovid, ClinicalTrials.gov, Medline, Embase, and PubMed were searched from inception to 22 August 2023, along with a full assessment of the previous five meta-analyses. Data were extracted and curated for Bayesian network meta-analysis. The primary outcome was the change in the 6-min walking distance (6MWD) from baseline with a secondary outcome called change in mean pulmonary artery pressure (mPAP) from baseline. The four safety outcomes included risk of clinical worsening, hospitalization, mortality and severe adverse events (SAEs). The comparison is structured on a contrast model based on 65 randomized controlled trials (RCTs) on PADN and the other conventional mainstream drugs. PADN had a better effect in improving 6MWD than Placebo (-77.76 m, 95% CI: -102.04 to -54.34 m), Macitentan (-65.32 m, 95% CI: -95.34 to -36.1 m), Bosentan (-64.5 m, 95% CI: -94.7 to -35.07 m), Iloprost (-62.66 m, 95% CI: -99.48 to -27.13 m), Oxygen (-62.42 m, 95% CI: -100.01 to -25.78 m), Treprostinil (-62.01 m, 95% CI: -89.04 to -35.61 m), Riociguat (-60.59 m, 95% CI: -86.11 to -35.98 m), Selexipag (-47.2 m, 95% CI: -85.61 to -10.19 m), Sildenafil (-44.92 m, 95% CI: -74.43 to -16.15 m), or Sitaxsentan (-39.53 m, 95% CI: -78.99 to -0.76 m). PADN had a better antihypertensive effect than placebo and showed statistical significant lower risks to induce clinical worsening and re-hospitalization than treprostinil, riociguat, and placebo groups. No statistically significant difference in risk of mortality and severe adverse events was observed between PADN versus the other interventions. CONCLUSIONS: Compared with 16 types of conventional therapies and Placebo, PADN has advantage over nine single therapies and Placebo in improving 6MWD and appears to be better than two types of dual-drug combined therapies while with no statistical significance. PADN shows a favourable antihypertensive effect on mPAP and has a lower risk to trigger clinical worsening or hospitalization, while its risk on mortality and severe adverse events is still inconclusive.

Characterization of zinc finger protein 536, a neuroendocrine regulator, using pan-cancer analysis.

BACKGROUND: Previous studies suggested that zinc finger protein 536 (ZNF536) was abundant in the central brain and regulated neuronal differentiation. However, the role of ZNF536 in cancer has remained unclear. METHODS: ZNF536 mutation, copy number alteration, DNA methylation, and RNA expression were explored using public portals. Data from The Cancer Genome Atlas (TCGA) were utilized to analyze pathways and tumor microenvironment (TME), with a focus on prognosis in both TCGA and immunotherapy pan-cancer cohorts. Methylated ZNF536 from small cell lung cancer (SCLC) cell lines were utilized to train with probes for conducting enrichment analysis. Single-cell RNA profile demonstrated the sublocalization and co-expression of ZNF536, and validated its targets by qPCR. RESULTS: Genetic alterations in ZNF536 were found to be high-frequency and a single sample could harbor different variations. ZNF536 at chromosome 19q12 exerted a bypass effect on CCNE1, supported by CRISPR data. For lung cancer, ZNF536 mutation was associated with longer survival in primary lung adenocarcinoma (LUAD), but its prognosis was poor in metastatic LUAD and SCLC. Importantly, ZNF536 mutation and amplification had opposite prognoses in Stand Up To Cancer-Mark Foundation (SU2C-MARK) LUAD cohort. ZNF536 mutation altered the patterns of genomic alterations in tumors, and had distinct impacts on the signaling pathways and TME compared to ZNF536 amplification. Additionally, ZNF536 expression was predominantly in endocrine tumors and brain tissues. High-dimensional analysis supported this finding and further revealed regulators of ZNF536. Considering that the methylation of ZNF536 was involved in the synaptic pathway associated with neuroendocrine neoplasms, demonstrating both diagnostic and prognostic value. Moreover, we experimentally verified ZNF536 upregulated neuroendocrine markers. CONCLUSIONS: Our results showed that ZNF536 alterations in cancer, including variations in copy number, mutation, and methylation. We proved the involvement of ZNF536 in neuroendocrine regulation, and identified highly altered ZNF536 as a potential biomarker for immunotherapy.

Clinical application of reserved gastric tube in neuroendoscopic endonasal surgery for pituitary tumor.

BACKGROUND: The neuroendoscopic approach has the advantages of a clear operative field, convenient tumor removal, and less damage, and is the development direction of modern neurosurgery. At present, transnasal surgery for sphenoidal pituitary tumor is widely used. But it has been found in clinical practice that some patients with this type of surgery may experience post-operative nausea and vomiting and other discomforts. AIM: To explore the effect of reserved gastric tube application in the neuroendoscopic endonasal resection of pituitary tumors. METHODS: A total of 60 patients who underwent pituitary adenoma resection via the endoscopic endonasal approach were selected and randomly divided into the experimental and control groups, with 30 in each group. Experimental group: After anesthesia, a gastric tube was placed through the mouth under direct vision using a visual laryngoscope, and the fluid accumulated in the oropharynx was suctioned intermittently with low negative pressure throughout the whole process after nasal disinfection, during the operation, and when the patient recovered from anesthesia. Control group: Given the routine intraoperative care, no gastric tube was left. The number of cases of nausea/vomiting/aspiration within 24 h post-operation was counted and compared between the two groups; the scores of pharyngalgia after waking up, 6 h post-operation, and 24 h post-operation. The frequency of postoperative cerebrospinal fluid leakage and intracranial infection were compared. The hospitalization days of the two groups were statistically compared. RESULTS: The times of postoperative nausea and vomiting in the experimental group were lower than that in the control group, and the difference in the incidence of nausea was statistically significant (P < 0.05). After the patient woke up, the scores of sore throat 6 h after the operation and 24 h after operation were lower than those in the control group, and the difference was statistically significant (P < 0.05). The number of cases of postoperative cerebrospinal fluid leakage and intracranial infection was higher than that of the control group, but there was no statistically significant difference from the control group (P > 0.05). The hospitalization days of the experimental group was lower than that of the control group, and the difference was statistically significant (P < 0.05). CONCLUSION: Reserving a gastric tube in the endoscopic endonasal resection of pituitary tumors, combined with intraoperative and postoperative gastrointestinal decompression, can effectively reduce the incidence of nausea, reduce the number of vomiting and aspiration in patients, and reduce the complications of sore throat The incidence rate shortened the hospitalization days of the patients.

High-resolution transcriptomics analysis of CXCL13+ EPSTI1+ CDK1+ cells with a specific focus on lung adenocarcinoma.

Background: Programmed cell death ligand 1 (PD-L1) blocking therapy has transformed the treatment of lung adenocarcinoma (LUAD), which has significantly changed the landscape of immunotherapy. We aimed to explore specific cell subpopulations to understand tumor progression and identify markers of response to PD-L1 blocking therapy. Methods: Bulk, fluorescence-activated cell sorting (FACS), and single-cell RNA (scRNA) sequencing were used to profile CXCL13, EPSTI1, and CDK1. The gene set variation analysis (GSVA) R package was utilized for score calculation, and prognostic analyses included receiver operating characteristic (ROC) curves, Cox proportional hazard models, and meta-analysis. Additionally, we analyzed tumor microenvironment (TME), genomics, compound perturbations, and clinical indicators. The high-dimensional analysis captured the intrinsic characteristics of the subpopulation. Furthermore, subpopulation differential genes were used for enrichment analysis of transcription factors and compounds. Results: Literature and website analyses supported the essential role of CXCL13, CDK1, and EPSTI1 in immunotherapy. This led us to focus specifically on LUAD by representing a pan-cancer profile of immune-sensitive genes. Logically, the high-characteristic population may consist of samples positive for CXCL13, EPSTI1, and CDK1. The three-gene signature was a favorable indicator of immunotherapy response in the Stand Up to Cancer-Mark Foundation (SU2C-MARK) LUAD cohort but showed a poor prognosis before treatment in the Lung Cancer Explorer (LCE) database. Further mechanistic exploration revealed specific mutations associated with the three-gene signature in SU2C-MARK LUAD, such as STK11. In The Cancer Genome Atlas (TCGA)-LUAD cohort, the high-scoring group exhibited a higher tumor mutational burden (TMB) and global methylation but a lower fraction genome altered (FGA) and estimated tumor purity. Moreover, dasatinib demonstrated sensitivity in the high-scoring group. The co-localization of the CXCL13, EPSTI1, and CDK1 subpopulation was validated through spatial transcriptome and immunohistochemical databases. Assessment of the subpopulation depicted high-resolution intercellular communication. Maintenance of specific pathways, such as TNF, CD74, and CD44, contributed to immunotherapy sensitivity. Finally, the subpopulation-enriched targets and drugs were confirmed through ConnectivityMap (CMAP) analysis and multi-omics, respectively. Conclusions: In this study, positive samples for CXCL13, EPSTI1, and CDK1 exhibited poor prognostic significance in treatment-naïve LUAD cases but demonstrated benefits from PD-L1 blockade and dasatinib therapies.

Does Walking Have an Association with Osteoarthritis? A Two-Sample Mendelian Randomization Analysis.

Objective: Osteoarthritis (OA) is one of the major disabling human diseases. The related studies indicate a potential correlation between walking and OA. However, there is still a lack of evidence in genetics to support the correlation between walking and OA. Therefore, this study aimed to explore the relationship between walking and OA at the genetic level. Methods: The publicly available Genome Wide Association Study (GWAS) data were used, with inverse variance weighting (IVW, the random-effects model) as the main analysis method, whereas MR-Egger, Weighted median, Simple mode, and Weighted mode as the secondary analysis methods. In addition, Cochran's Q test, pleiotropy test, and MR-Egger intercept test were conducted to examine the heterogeneity and pleiotropy of the outcome. Results: In the MR analysis, IVW results showed a negative correlation between types of physical activity in last 4 weeks: Walking for pleasure (not as a means of transport) and OA (KOA or HOA) (odds ratio (OR) = 0.3224, 95% confidence interval (CI): 0.1261 to 0.8243), and the difference was of statistical significance (P = 0.0181). Moreover, IVW results also revealed a negative correlation between types of physical activity in last 4 weeks: Walking for pleasure (not as a means of transport) and KOA (OR = 0.1396, 95% CI: 0.0484 to 0.4026), and the difference was statistically significant (P = 0.0003). However, IVW results did not demonstrate any statistical significance types of physical activity in last 4 weeks: Walking for pleasure (not as a means of transport) and HOA (OR = 1.2075, 95% CI: 0.1978 to 7.3727, P = 0.8381). Conclusion: From genetic studies, types of physical activity in last 4 weeks: Walking for pleasure (not as a means of transport) is negatively correlated with knee osteoarthritis (KOA), but there is no clear evidence supporting its correlation with hip osteoarthritis (HOA).

Evidence for Genetic Causal Relationships Between Multiple Immune-Mediated Inflammatory Diseases and Age-Related Macular Degeneration: A Univariable and Multivariable Mendelian Randomization Study.

INTRODUCTION: With the global aging population on the rise, age-related macular degeneration (AMD) poses a growing healthcare burden. Prior research hints at immune-mediated inflammatory diseases (IMIDs) potentially elevating AMD risk via diverse mechanisms. However, causality remains disputed as a result of confounding factors. Hence, our Mendelian randomization (MR) study aims to untangle this link, mitigating confounding effects to explore the IMID-AMD causal relationship. This study aims to investigate the causal relationship between IMIDs and AMD, providing new strategies for the prevention and treatment of AMD in clinical practice. METHODS: This study was registered with PROSPERO, CRD42023469815. We obtained data on IMIDs and AMD from Genome-Wide Association Studies (GWAS) summary statistics and the FinnGen consortium. Rigorous selection steps were applied to screen for eligible instrumental single nucleotide polymorphisms (SNPs). We conducted univariate Mendelian randomization, inverse variance-weighted (IVW), weighted median, Mendelian randomization-Egger (MR-Egger), and multivariate Mendelian randomization (MVMR) analyses. Various sensitivity analysis methods were employed to assess pleiotropy and heterogeneity. The aim was to explore the causal relationships between IMIDs and AMD. RESULTS: The MR analysis revealed that Crohn's disease (CD) (IVW: odd ratios (OR) 1.05, 95% CI (confidence interval) 1.01-1.10, p = 0.007), rheumatoid arthritis (RA) (IVW: OR 1.09, 95% CI 1.04-1.15, p = 0.0001), and type 1 diabetes (T1D) (IVW: OR 1.05, 95% CI 1.02-1.09, p = 0.001) were correlated with an elevated risk of AMD, while multiple sclerosis (MS) (IVW: OR 2.78E-18, 95% CI 2.23E-31 to 3.48E-05, p = 0.008) appeared to be protective against AMD. These findings were supported by an array of MR analysis methodologies and the MVMR approach. CONCLUSION: Our study results, based on MR, provide genetic evidence indicating a causal relationship between specific IMIDs and AMD. CD, RA, and T1D are factors increasing the risk of AMD, while MS may have a protective effect.

"In situ bone flap" combined with vascular pedicled mucous flap to reconstruction of skull base defect.

BACKGROUND: At present, neuroendoscopy technology has made rapid development, and great progress has been made in the operation of lesions in the saddle area of the skull base. However, the complications of cerebrospinal fluid and intracranial infection after the operation are still important and life-threatening complications, which may lead to poor prognosis. AIM: To investigate the method of in situ bone flap combined with nasal septum mucosal flap for reconstruction of enlarged skull base defect by endonasal sphenoidal approach and to discuss its application effect. METHODS: Clinical data of 24 patients undergoing transnasal sphenoidal endoscopic approach in the Department of Neurosurgery, Affiliated 2 Hospital of Nantong University from January 2019 to December 2022 were retrospectively analyzed. All patients underwent multi-layer reconstruction of skull base using in situ bone flap combined with nasal septum mucosa flap. The incidence of intraoperative and postoperative cerebrospinal fluid leakage and intracranial infection were analyzed, and the application effect and technical key points of in situ bone flap combined with nasal septum mucosa flap for skull base bone reconstruction were analyzed. RESULTS: There were 5 cases of high flow cerebrospinal fluid (CSF) leakage and 7 cases of low flow CSF leakage. Postoperative cerebrospinal fluid leakage occurred in 2 patients (8.3%) and intracranial infection in 2 patients (8.3%), which were cured after strict bed rest, continuous drainage of lumbar cistern combined with antibiotic treatment, and no secondary surgical repair was required. The patients were followed up for 8 to 36 months after the operation, and no delayed cerebrospinal fluid leakage or intracranial infection occurred during the follow-up. Computed tomography reconstruction of skull base showed satisfactory reconstruction after surgery. CONCLUSION: The use of in situ bone flap combined with vascular pedicled mucous flap to reconstruction of skull base defect after endonasal sphenoidal approach under neuroendoscopy has a lower incidence of cerebrospinal fluid leakage and lower complications, which has certain advantages and is worthy of clinical promotion.

A Bidirectional Mendelian Randomization Study of Sarcopenia-Related Traits and Knee Osteoarthritis.

Background: With the development of population aging worldwide, sarcopenia and knee osteoarthritis (KOA), two age-related diseases, will continue to impose increasing medical and economic burdens on the society. Previous studies have discovered an association between the two, but the causality remains controversial, and it is difficult to eliminate confounding factors. Therefore, a Mendelian randomization (MR) study was conducted to overcome these confounding factors and investigate the causal relationship between sarcopenia and KOA. Objective: The present work focused on assessing the causality between KOA and sarcopenia, so as to provide new strategies to prevent and treat these two conditions in clinic. Methods: We registered the title with PROSPERO (ID: CRD42023421096). The two-sample bidirectional MR analysis was conducted in two steps, with sarcopenia being the exposure whereas KOA being the outcome in the first step, and vice versa in the second step. Genome-wide association studies (GWAS) data on low hand-grip strength (n=256,523), walking pace (n=459,915), appendicular lean mass (ALM, n=450,243), and KOA (n=403,124) were obtained from the UK Biobank. Methods such as the inverse variance weighted (IVW) and weighted median were utilized for assessing the causality of KOA with sarcopenia, and sensitivity analyses were also conducted. Results: In the main MR analysis using the IVW method, evidence suggested that low hand-grip strength, walking pace, and ALM had adverse effects on KOA (p-value 0.0001, odds ratio (OR) 1.4569, 95% confidence interval (CI) 1.2007-1.7677 for low hand-grip strength; p-value 0.0003, OR 1.1500, 95% CI 1.050-1.183 for ALM; p-value 5.29E-19, OR 0.0932, 95% CI 0.0553-0.1572 for walking pace). However, there was no causality of KOA with sarcopenia in the opposite direction. Conclusion: Our study suggests an obvious unidirectional causality of KOA with sarcopenia, and supports the notion that patients with sarcopenia are more susceptible to the development of KOA.

Case Report: Endoscopic trans-cerebellar medullary fissure approach for the management of brainstem hemorrhage.

Objective: Brainstem hematoma (BSH) is a high-risk condition that can lead to deadly and disabling consequences if not properly managed. However, recent advances in endoscopic techniques, employed for removing supratentorial intracerebral hemorrhage have shown significant improvements in operative morbidity and mortality rates compared to other approaches. In this study, we demonstrate the utility and feasibility of the endoscopic trans-cerebellar medullary fissure approach for the management of brain stem hemorrhage in carefully selected patients. Patients and methods: A 55-year-old man presented to the emergency department in a comatose state with respiratory distress. A CT scan revealed the presence of a brainstem hemorrhage. Given the location of the hemorrhage and the need to quickly manage the associated developmental obstructive hydrocephalus and respiratory distress, an endoscopic trans-cerebellar medullary fissure approach was chosen as the most appropriate method of treatment. Results: Total resection was achieved, and the patient gradually improved postoperatively with no new neurological deficits. He is currently under routine follow-up and is conscious but has partial hemiplegia. Conclusion: This approach provided direct visualization of the lesion and was minimally invasive. The endoscopic trans-cerebellar medullary fissure approach may be considered an alternative to open approaches for brainstem hemorrhage in carefully selected patients.

Positioning and design by computed tomography imaging in neuroendoscopic surgery of patients with chronic subdural hematoma.

BACKGROUND: Neuroendoscopy is a very useful technique to Chronic Subdural Hematoma (CSH). But how to achieve the goal of treatment more minimally invasive? AIM: To develop a simple, fast and accurate preoperative planning method in our way for endoscopic surgery of patients with CSH. METHODS: From June 2018 to May 2020, forty-two patients with CSH, admitted to our hospital, were performed endoscopic minimally invasive surgery; computed tomography (CT) imaging was employed to locate the intracerebral hematoma and select the appropriate endoscopic approach before the endoscopic surgery. The clinical data and treatment efficacy were analyzed. RESULTS: According to the learning of CT scanning images, the surgeon can accurately design the best minimally invasive neuroendoscopic surgical approach and realize the precise positioning and design of the drilling site of the skull and the size of the bone window, so as to provide the most effective operation space with the smallest bone window. In this group, the average operation time was only about 1 h, and the clearance rate of hematoma was about 95%. CONCLUSION: Patients with CSH can achieve good therapeutic effect by using our way to positioning and design to assist the operation of CSH according to CT scan and image, and our way is very useful and necessary.

Self-Assembled Nanodelivery System with Rapamycin and Curcumin for Combined Photo-Chemotherapy of Breast Cancer.

Nanodelivery systems combining photothermal therapy (PTT) and chemotherapy (CT), have been widely used to improve the efficacy and biosafety of chemotherapeutic agents in cancer. In this work, we constructed a self-assembled nanodelivery system, formed by the assembling of photosensitizer (IR820), rapamycin (RAPA), and curcumin (CUR) into IR820-RAPA/CUR NPs, to realize photothermal therapy and chemotherapy for breast cancer. The IR820-RAPA/CUR NPs displayed a regular sphere, with a narrow particle size distribution, a high drug loading capacity, and good stability and pH response. Compared with free RAPA or free CUR, the nanoparticles showed a superior inhibitory effect on 4T1 cells in vitro. The IR820-RAPA/CUR NP treatment displayed an enhanced inhibitory effect on tumor growth in 4T1 tumor-bearing mice, compared to free drugs in vivo. In addition, PTT could provide mild hyperthermia (46.0 °C) for 4T1 tumor-bearing mice, and basically achieve tumor ablation, which is beneficial to improving the efficacy of chemotherapeutic drugs and avoiding damage to the surrounding normal tissue. The self-assembled nanodelivery system provides a promising strategy for coordinating photothermal therapy and chemotherapy to treat breast cancer.

Nanosystems for oxidative stress regulation in the anti-inflammatory therapy of acute kidney injury.

Acute kidney injury (AKI) is a clinical syndrome that results from a rapid decline in renal structure or renal functional impairment with the main pathological feature of sublethal and lethal damage to renal tubular cells. However, many potential therapeutic agents cannot achieve the desired therapeutic effect because of their poor pharmacokinetics and short retention time in the kidneys. With the recent emergence and progress of nanotechnology, nanodrugs with unique physicochemical properties could prolong circulation time, enhance efficient targeted delivery, and elevate the accumulation of therapeutics that can cross the glomerular filtration barrier and indicate comprehensive application prospects in the prevention and treatment of AKI. In this review, various types of nanosystems (such as liposomes, polymeric nanosystems, inorganic nanoparticles and cell-derived extracellular vesicles) are designed and applied to improve the pharmacokinetics of drug formation, which could further relieve the burden on the kidneys caused by the final cumulative dose of drugs in conventional treatments. Moreover, the passive or active targeting effect of nanosystems can also reduce the total therapeutic dose and off-target adverse effects on other organs. Nanodelivery systems for treating AKI that alleviate oxidative stress-induced renal cell damage and regulate the inflammatory kidney microenvironment are summarized.

Retrospective Modeling of the Omicron Epidemic in Shanghai, China: Exploring the Timing and Performance of Control Measures.

BACKGROUND: In late February 2022, the Omicron epidemic swept through Shanghai, and the Shanghai government responded to it by adhering to a dynamic zero-COVID strategy. In this study, we conducted a retrospective analysis of the Omicron epidemic in Shanghai to explore the timing and performance of control measures based on the eventual size and duration of the outbreak. METHODS: We constructed an age-structured and vaccination-stratified SEPASHRD model by considering populations that had been detected or controlled before symptom onset. In addition, we retrospectively modeled the epidemic in Shanghai from 26 February 2022 to 31 May 2022 across four periods defined by events and interventions, on the basis of officially reported confirmed (58,084) and asymptomatic (591,346) cases. RESULTS: According to our model fitting, there were about 785,123 positive infections, of which about 57,585 positive infections were symptomatic infections. Our counterfactual assessment found that precise control by grid management was not so effective and that citywide static management was still needed. Universal and enforced control by citywide static management contained 87.65% and 96.29% of transmission opportunities, respectively. The number of daily new and cumulative infections could be significantly reduced if we implemented static management in advance. Moreover, if static management was implemented in the first 14 days of the epidemic, the number of daily new infections would be less than 10. CONCLUSIONS: The above research suggests that dynamic zeroing can only be achieved when strict prevention and control measures are implemented as early as possible. In addition, a lot of preparation is still needed if China wants to change its strategy in the future.

OWL: an optimized and independently validated machine learning prediction model for lung cancer screening based on the UK Biobank, PLCO, and NLST populations.

BACKGROUND: A reliable risk prediction model is critically important for identifying individuals with high risk of developing lung cancer as candidates for low-dose chest computed tomography (LDCT) screening. Leveraging a cutting-edge machine learning technique that accommodates a wide list of questionnaire-based predictors, we sought to optimize and validate a lung cancer prediction model. METHODS: We developed an Optimized early Warning model for Lung cancer risk (OWL) using the XGBoost algorithm with 323,344 participants from the England area in UK Biobank (training set), and independently validated it with 93,227 participants from UKB Scotland and Wales area (validation set 1), as well as 70,605 and 66,231 participants in the Prostate, Lung, Colorectal, and Ovarian cancer screening trial (PLCO) control and intervention subpopulations, respectively (validation sets 2 & 3) and 23,138 and 18,669 participants in the United States National Lung Screening Trial (NLST) control and intervention subpopulations, respectively (validation sets 4 & 5). By comparing with three competitive prediction models, i.e., PLCO modified 2012 (PLCOm2012), PLCO modified 2014 (PLCOall2014), and the Liverpool Lung cancer Project risk model version 3 (LLPv3), we assessed the discrimination of OWL by the area under receiver operating characteristic curve (AUC) at the designed time point. We further evaluated the calibration using relative improvement in the ratio of expected to observed lung cancer cases (RIEO), and illustrated the clinical utility by the decision curve analysis. FINDINGS: For general population, with validation set 1, OWL (AUC = 0.855, 95% CI: 0.829-0.880) presented a better discriminative capability than PLCOall2014 (AUC = 0.821, 95% CI: 0.794-0.848) (p < 0.001); with validation sets 2 & 3, AUC of OWL was comparable to PLCOall2014 (AUCPLCOall2014-AUCOWL < 1%). For ever-smokers, OWL outperformed PLCOm2012 and PLCOall2014 among ever-smokers in validation set 1 (AUCOWL = 0.842, 95% CI: 0.814-0.871; AUCPLCOm2012 = 0.792, 95% CI: 0.760-0.823; AUCPLCOall2014 = 0.791, 95% CI: 0.760-0.822, all p < 0.001). OWL remained comparable to PLCOm2012 and PLCOall2014 in discrimination (AUC difference from -0.014 to 0.008) among the ever-smokers in validation sets 2 to 5. In all the validation sets, OWL outperformed LLPv3 among the general population and the ever-smokers. Of note, OWL showed significantly better calibration than PLCOm2012, PLCOall2014 (RIEO from 43.1% to 92.3%, all p < 0.001), and LLPv3 (RIEO from 41.4% to 98.7%, all p < 0.001) in most cases. For clinical utility, OWL exhibited significant improvement in average net benefits (NB) over PLCOall2014 in validation set 1 (NB improvement: 32, p < 0.001); among ever smokers of validation set 1, OWL (average NB = 289) retained significant improvement over PLCOm2012 (average NB = 213) (p < 0.001). OWL had equivalent NBs with PLCOm2012 and PLCOall2014 in PLCO and NLST populations, while outperforming LLPv3 in the three populations. INTERPRETATION: OWL, with a high degree of predictive accuracy and robustness, is a general framework with scientific justifications and clinical utility that can aid in screening individuals with high risks of lung cancer. FUNDING: National Natural Science Foundation of China, the US NIH.

How meteorological factors impacting on scrub typhus incidences in the main epidemic areas of 10 provinces, China, 2006-2018.

Scrub typhus, caused by Orientia tsutsugamushi, is a serious public health problem in the Asia-Pacific region, threatening the health of more than one billion people. China is one of the countries with the most serious disease burden of scrub typhus. Previous epidemiological evidence indicated that meteorological factors may affect the incidence of scrub typhus, but there was limited evidence for the correlation between local natural environment factors dominated by meteorological factors and scrub typhus. This study aimed to evaluate the correlation between monthly scrub typhus incidence and meteorological factors in areas with high scrub typhus prevalence using a distributed lag non-linear model (DLNM). The monthly data on scrub typhus cases in ten provinces from 2006 to 2018 and meteorological parameters were obtained from the Public Health Science Data Center and the National Meteorological Data Sharing Center. The results of the single-variable and multiple-variable models showed a non-linear relationship between incidence and meteorological factors of mean temperature (Tmean), rainfall (RF), sunshine hours (SH), and relative humidity (RH). Taking the median of meteorological factors as the reference value, the relative risks (RRs) of monthly Tmean at 0°C, RH at 46%, and RF at 800 mm were most significant, with RRs of 2.28 (95% CI: 0.95-5.43), 1.71 (95% CI: 1.39-2.09), and 3.33 (95% CI: 1.89-5.86). In conclusion, relatively high temperature, high humidity, and favorable rainfall were associated with an increased risk of scrub typhus.

Randomized Trial of Left Bundle Branch vs Biventricular Pacing for Cardiac Resynchronization Therapy.

BACKGROUND: Left bundle branch pacing (LBBP) is the most rapidly growing conduction system pacing technique that is capable of correcting intrinsic left bundle branch block (LBBB). As such, it is potentially an optimal alternative to cardiac resynchronization therapy (CRT) with biventricular pacing (BiVP). OBJECTIVES: The authors sought to compare the efficacy of LBBP-CRT with BiVP-CRT in patients with heart failure and reduced left ventricular ejection fraction (LVEF). METHODS: This is a prospective, randomized trial of patients with nonischemic cardiomyopathy and LBBB with 6-month preplanned follow-up. Crossovers were allowed if LBBP or BiVP were unsuccessful. The primary endpoint was the difference in LVEF improvement between 2 groups. The secondary endpoints included changes in echocardiographic measurements, N-terminal pro-B-type natriuretic peptide (NT-proBNP), New York Heart Association functional class, 6-minute walk distance, QRS duration, and CRT response. RESULTS: The study included 40 consecutive patients (20 males, mean age 63.7 years, LVEF 29.7% ± 5.6%). Crossovers occurred in 10% of LBBP-CRT and 20% of BiVP-CRT. All patients completed follow-up. Intention-to-treat analysis showed significantly higher LVEF improvement at 6 months after LBBP-CRT than BiVP-CRT (mean difference: 5.6%; 95% CI: 0.3-10.9; P = 0.039). LBBP-CRT also appeared to have greater reductions in left ventricular end-systolic volume (-24.97 mL; 95% CI: -49.58 to -0.36 mL) and NT-proBNP (-1,071.80 pg/mL; 95% CI: -2,099.40 to -44.20 pg/mL), and comparable changes in New York Heart Association functional class, 6-minute walk distance, QRS duration, and rates of CRT response compared with BiVP-CRT. CONCLUSIONS: LBBP-CRT demonstrated greater LVEF improvement than BiVP-CRT in heart failure patients with nonischemic cardiomyopathy and LBBB. (Left Bundle Branch Pacing Versus Biventricular Pacing for Cardiac Resynchronization Therapy [LBBP-RESYNC]; NCT04110431).

The Evolution of BRAF Activation in Non-Small-Cell Lung Cancer.

Non-small-cell lung cancer (NSCLC) is the most common subtype of lung cancer, of which approximate 4% had BRAF activation, with an option for targeted therapy. BRAF activation comprises of V600 and non-V600 mutations, fusion, rearrangement, in-frame deletions, insertions, and co-mutations. In addition, BRAF primary activation and secondary activation presents with different biological phenotypes, medical senses and subsequent treatments. BRAF primary activation plays a critical role in proliferation and metastasis as a driver gene of NSCLC, while secondary activation mediates acquired resistance to other targeted therapy, especially for epidermal growth factor tyrosine kinase inhibitor (EGFR-TKI). Treatment options for different activation of BRAF are diverse. Targeted therapy, especially two-drug combination therapy, is an important option. Besides, immune checkpoint inhibitors (ICIs) would be another option since BRAF activation would be a positive biomarker of tumor response of ICIs therapy. To date, no high level evidences support targeted therapy or immunotherapy as prioritized recommendation. After targeted therapy, the evolution of BRAF includes the activation of the upstream, downstream and bypass pathways of BRAF. In this review, therapeutic modalities and post-therapeutic evolutionary pathways of BRAF are discussed, and future research directions are also provided.

NK cells induce hepatic ER stress to promote insulin resistance in obesity through osteopontin production.

High-fat diet (HFD) induced hepatic endoplasmic reticulum (ER) stress drives insulin resistance (IR) and steatosis. NK cells in adipose tissue play an important role in the pathogenesis of IR in obesity. Whether NK cells in the liver can induce hepatic ER stress and thus promote IR in obesity is still unknown. We demonstrate that HFD-fed mice display elevated production of proinflammatory cytokine osteopontin (OPN) in hepatic NK cells, especially in CD49a+ DX5- tissue-resident NK (trNK) cells. Obesity-induced ER stress, IR, and steatosis in the liver are ameliorated by ablating NK cells with neutralizing antibody in HFD-fed mice. OPN treatment enhances the expression of ER stress markers, including p-PERK, p-eIF2, ATF4, and CHOP in both murine liver tissues and HL-7702, a human liver cell line. Pretreatment of HL-7702 cells with OPN promotes hyperactivation of JNK and subsequent decrease of tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1), resulting in impaired insulin signaling, which can be reversed by inhibiting ER stress. Collectively, we demonstrate that hepatic NK cells induce obesity-induced hepatic ER stress, and IR through OPN production.