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The expansion evolution law of internal fractures of coal under external load is of great significance to coalbed methane production and to control coal and gas outburst disasters. The coal body is in a three-dimensional (3D) stress state under the action of original in-situ stress. It is necessary to study the fracture evolution law of a loaded coal-containing gas under triaxial compression. The industrial computed tomographic (CT) scanning test of a loaded coal-containing gas under triaxial loading was carried out using the industrial micro-CT scanning system for the loaded coal-containing gas. The CT images and stress–strain curves of coal samples were obtained at each deformation stage. The 3D digital reconstruction of CT scanning data was carried out using image analysis software. Next, 3D visualization and quantitative characterization of coal sample internal fractures were realized. Based on the gray level co-occurrence matrix (GLCM) theory, the fracture dynamic expansion characteristics and laws of the loaded coal-containing gas were analyzed. The results show that the existence of gas pressure weakens the mechanical properties of the loaded coal-containing gas and accelerates the expansion of cracks. The two-dimensional fractures of the loaded coal-containing gas first close and then expand, and then expand rapidly after the peak, forming a connected two-dimensional fracture network. The 3D fracture volume and fracture density first show a decreasing and then an increasing trend, which can be divided into three stages: fracture compaction and closure, new fracture initiation and expansion, and main fracture accelerated expansion and penetration. In the GLCM analysis, the contrast first decreases and then increases, the energy and homogeneity first increase and then decrease, and the correlation presents a monotonic decreasing trend. The analysis results accurately describe the overall development law of the internal cracks of the loaded coal-containing gas changing with stress increase.

Abstract Aims This study aimed to assess the effect of blood pressure (BP) index, in terms of level and variability, on the progression of cardiovascular and renal diseases in patients with both heart failure (HF) and chronic kidney disease (CKD). Methods and results The study involved patients with HF and CKD from the database of the Chronic Renal Insufficiency Cohort (CRIC) study. The study endpoint includes the following: (i) primary endpoint, including cardiovascular disease (CVD) events, renal events, and all‐cause death; (ii) CVD events; (iii) renal events; and (iv) all‐cause death. Among 3939 participants in the CRIC study, a total of 382 patients were included. The duration of the follow‐up was 6.3 ± 2.7 years, the age was 60.2 ± 8.9 years, and 57.6% were male. BP index included 20 indicators in relation to BP level and variability, 4 of which were analysed including baseline systolic BP (SBP), standard deviation of SBP, coefficient of variation of diastolic BP (DBP CV), and average real variability of pulse pressure. In the Cox regression analysis after adjustment, baseline SBP was significant for the risk of primary endpoint [hazard ratio (HR) 1.22, 95% confidence interval (CI) 1.03–1.44, P = 0.02] and renal events (HR 1.54, 95% CI 1.22–1.95, P

ABSTRACTThe objective of this research was to investigate quality properties of Chinese Sichuan-style (CSS) sausages treated with Chinese red wine (RW), yellow rice wine (YR) and Chinese beer (CB). The CSS sausages treated with 13% Chinese liquor as the control, and other three groups treated with 6.5% Chinese red wine as the RW group, 6.5% Chinese yellow rice wine as the YR group, and 6.5% Chinese beer as the CB group on the basis of 6.5% Chinese liquor addition were prepared. Results showed that RW, YR and CB group CSS sausages displayed higher L⁎(39.46–43.44) and Aw, lower pH (5.78–5.91) and protein content (33.75–37.44%) compared with those of the control. The YR group sausages had higher b⁎ value (23.25), total area% of aldehydes (3.09%) as well as flavor score (6.72), while the CB group CSS sausages showed higher a* value (24.29), total area% of aldehydes (3.94%) and kenones (2.13%), as well as lower free thiol groups (10.88 nmol/mg protein) relative to those of the control group. No significant difference in overall quality scores were detected between YR and CB group CSS sausages. The PCA showed that RW group CSS sausages achieved similar effects as CB group for volatile, color and sensory properties, which could separate CB/YR group CSS sausages from those of the other two groups. The results of this study indicated that it was applicable to improve quality properties of CSS sausages by using 6.5% Chinese yellow rice wine or beer on the basis of adding 6.5% Chinese liquor during processing.

Abstract Purpose To investigate the association of subjects with refractive error and diabetic retinopathy (DR) in the United States comparing results between different race groups. Methods All data were derived from National Health and Nutrition Examination Survey (NHANES) from 2005 to 2008. The data were divided into four groups (emmetropia, mild myopia, high myopia, hypertropia) according to the spherical equivalent (SE), and those who met the enrollment conditions were selected as the study subjects. Multivariable logistic regression analysis was used to evaluate the relationship between refractive error and diabetic retinopathy risk. Results A total of 1317 participants were included in the study, including 331 participants with diabetic retinopathy, and 986 without diabetic retinopathy. After adjustment for potential confounders, subjects with high myopia were associated with a lower risk of diabetic retinopathy. The odds ratio (OR) was 0.44, 95% confidence interval (CI): (0.20–0.96), P-value = 0.040 in the multivariate regression analysis. Subgroup analyses showed that subjects with high myopia in the non-Hispanic Black group were associated with decreased odds of diabetic retinopathy. (OR was 0.20, and 95% CI: 0.04–0.95, P-value = 0.042). Conclusion The results show that high myopia is associated with diabetic retinopathy in diabetic patients.

Introduction: Pulmonary fibrosis is a major cause of the poor prognosis of acute respiratory distress syndrome (ARDS). While mechanical ventilation (MV) is an indispensable life-saving intervention for ARDS, it may cause the remodeling process in lung epithelial cells to become disorganized and exacerbate ARDS-associated pulmonary fibrosis. Piezo1 is a mechanosensitive ion channel that is known to play a role in regulating diverse physiological processes, but whether Piezo1 is necessary for MV-exacerbated ARDS-associated pulmonary fibrosis remains unknown. Objectives: This study aimed to explore the role of Piezo1 in MV-exacerbated ARDS-associated pulmonary fibrosis. Methods: Human lung epithelial cells were stimulated with hydrochloric acid (HCl) followed by mechanical stretch for 48 h. A two-hit model of MV after acid aspiration-induced lung injury in mice was used. Mice were sacrificed after 14 days of MV. Pharmacological inhibition and knockout of Piezo1 were used to delineate the role of Piezo1 in MV-exacerbated ARDS-associated pulmonary fibrosis. In some experiments, ATP or the ATP-hydrolyzing enzyme apyrase was administered. Results: The stimulation of human lung epithelial cells to HCl resulted in phenotypes of epithelial-mesenchymal transition (EMT), which were enhanced by mechanical stretching. MV exacerbated pulmonary fibrosis in mice exposed to HCl. Pharmacological inhibition or knockout of Piezo1 attenuated the MV-exacerbated EMT process and lung fibrosis in vivo and in vitro. Mechanistically, the observed effects were mediated by Piezo1-dependent Ca2+ influx and ATP release in lung epithelial cells. Conclusions: Our findings identify a key role for Piezo1 in MV-exacerbated ARDS-associated pulmonary fibrosis that is mediated by increased ATP release in lung epithelial cells. Inhibiting Piezo1 may constitute a novel strategy for the treatment of MV-exacerbated ARDS-associated pulmonary fibrosis.

The time-sequenced damage behavior of the reactive projectile impacting double-layer plates is discussed. The analytical model considering the combined effect of kinetic and chemical energy is developed to reveal the damage mechanism. The influences of impact velocity and reactive projectile chemical characteristics on the damage effect are decoupled analyzed based on this model. These analyses indicate that the high energy releasing efficiency and fast reaction propagation velocity of the reactive projectile are conducive to enhancing the damage effect. The experiments with various reactive projectiles impact velocity increasing from 702 to 1385 m/s were conducted to verify this model. The experimental results presented that, the damage hole radius of the rear-plate increases with the increase of impact velocity. At the impact velocity of 1350 m/s, the radius of damage hole formed by PTFE/Al/Bi2O3, PTFE/Al/MoO3, PTFE/Al/Fe2O3 projectile on the rear-plate become smaller in sequence. These results are consistent with the analytical model prediction, demonstrating that this model can predict the damage effect quantitatively. This work is of constructive significance to the application of reactive projectiles.

Abstract Background The innovative combination of all‐trans retinoic acid (ATRA) and arsenic trioxide (ATO) has established a new chapter of curative approach in acute promyelocytic leukemia (APL). The disease characteristics and prognostic influence of additional cytogenetic abnormalities (ACA) in APL with modern therapeutic strategy need to be elucidated. Methods In the present study, we retrospectively investigated disease features and prognostic power of ACA in 171 APL patients treated with ATRA‐ATO‐containing regimens. Results Patients with ACA had markedly decreased hemoglobin levels than that without ACA (p = 0.021). Risk stratification in the ACA group was significantly worse than that in the non‐ACA group (p = 0.032). With a median follow‐up period of 62.0 months, worse event‐free survival (EFS) was demonstrated in patients harboring ACA. Multivariate analysis showed that ACA was an independent adverse factor for EFS (p = 0.033). By further subgroup analysis, in CD34 and CD56 negative APL, patients harboring ACA had inferior EFS (p = 0.017; p = 0.037). Conclusions To sum up, ACA remains the independent prognostic value for EFS, we should build risk‐adapted therapeutic strategies in the long‐term management of APL when such abnormalities are detected.

Abstract This study aimed to explore sex differences in the relationship between thyroid function indicators and suicide attempts in first-episode and drug-naïve young major depressive disorder (MDD) patients with comorbid anxiety (MDA). A total of 917 MDD patients (aged 18–35 years) were recruited. The Hamilton depression rating scale (HAMD-17), Hamilton anxiety rating scale (HAMA), positive and negative syndrome scale (PANSS) positive subscale and clinical global impression of severity scale (CGI-S) were used. 467 patients were classified as MDA. The prevalence of suicide attempts was 31.3% in MDA patients, which was significantly higher than that (7.3%) in MDD patients without anxiety. Compared with MDA patients without suicide attempts, MDA patients with suicide attempts were older, had a later age of onset, higher HAMD-17, HAMA, and PANSS positive symptom subscale scores, as well as higher TSH, TgAb and TPOAb levels. For male patients, TSH and TPOAb levels were independently associated with suicide attempts. For female patients, HAMA, PANSS positive symptom scores, CGI-S score and TPOAb levels were independently associated with suicide attempts. Our results suggest that the indicators of thyroid function which can predict suicide attempts in male and female MDA patients have sex differences.

Abstract Background Rat sarcoma viral oncogene homolog (RAS) gene mutation is a common molecular event in colorectal cancer (CRC). The prognosis of mCRC (metastatic colorectal cancer) patients with RAS mutation is poor and capecitabine and oxaliplatin (CapeOx) plus bevacizumab has shown to be one of the standard therapeutic regimens as first line for these patients with objective response rate (ORR) of ~ 50% and median progression-free survival (mPFS) of 8–9 months. Immunotherapy, especially anti-programmed death 1 (PD-1) monoclonal antibody has demonstrated ground-breaking results in deficient mismatch repair (dMMR) / microsatellite instability-high (MSI-H) mCRC patients. However, the response rate of in microsatellite stable (MSS) patients is extremely low. In addition, preclinical studies have demonstrated that anti-Vascular endothelial growth factor (VEGF) agents, such as bevacizumab, can induce tumor vascular normalization and enhance antitumor immunity. Previous study indicated the combination of chemotherapy, anti-VEGF agents (bevacizumab) with immune checkpoint inhibitors may have promising clinical activity in RAS mutant, MSS refractory mCRC patients. Based on these evidences, we will explore the combination of CapeOx with bevacizumab and sintilimab (anti-PD-1 monoclonal antibody) in RAS mutant, MSS mCRC patients as first-line therapy. Methods This is a randomized, open-label, multicentric clinical trial. In the sintilimab arm, patients will receive sintilimab in combination with CapeOx and bevacizumab. In the control arm, patients will receive CapeOx and bevacizumab. This trial will recruit 494 patients from 20 centers and randomly (1:1) disseminated into two groups. The primary endpoint is the PFS. The secondary endpoints include overall survival, safety, ORR, and disease control rate. Discussion This study may provide new ideas for optimizing oncology treatment planning for RAS mutant, MSS mCRC patients in the first-line set. Trial registration This study is short for BBCAPX and has been registered at clinicaltrials.gov registry with identifier NCT05171660.

Objective:. Acitretin is a widely used systemic retinoid that is to treat psoriasis but has significant variations in efficacy and adverse events (AEs) among individuals. This study aimed to determine the impact of AEs associated with acitretin treatment of moderate-to-severe plaque psoriasis on the Dermatology Life Quality Index (DLQI) and Hospital Anxiety and Depression Scale (HADS) scores. Methods:. This prospective, observational, single-center study was conducted from March 2021 to June 2022 and analyzed 116 patients with moderate-to-severe plaque psoriasis treated with acitretin who were followed up for 12 weeks. The primary outcome was the incidence of AEs related to acitretin, and the secondary objective was to investigate the effect of AEs on the DLQI and HADS scores. The generalized linear models were used to assess the association between AEs related to acitretin and DLQI scores or HADS scores, and the association between the involved system/tissue and DLQI scores or HADS scores. Results:. A final total of 45 patients were included in the analysis, and a total of 157 treatment-related AEs involving nine organs or systems were reported in 41 patients. The most common AE was skin- or mucosa-related, with 72 cumulative events in 31 patients. AEs also commonly affected the endocrine, digestive, and genitourinary systems. Compared with the group with 0–2 AEs, the group with 3–5 AEs had a significantly increased DLQI score by 5.49 points (95% CI, 1.47–9.51) (P = 0.0089). Compared with AEs involving 0 to 1 system, AEs affecting 2 to 3 systems resulted in a significant increase in the DLQI score by 5.75 points (95% CI, 1.67–9.83) (P = 0.0071). Generalized linear models showed no statistically significant associations between AEs and the HADS scores. Conclusion:. Our study demonstrates a high incidence of acitretin-related AEs. These AEs may affect quality of life but rarely cause psychological problems such as anxiety and depression.

Abstract High performance imaging in parallel cameras is a worldwide challenge in computational optics studies. However, the existing solutions are suffering from a fundamental contradiction between the field of view (FOV), resolution and bandwidth, in which system speed and FOV decrease as system scale increases. Inspired by the compound eyes of mantis shrimp and zoom cameras, here we break these bottlenecks by proposing a deep learning-based parallel (DLBP) camera, with an 8-μrad instantaneous FOV and 4 × computational zoom at 30 frames per second. Using the DLBP camera, the snapshot of 30-MPs images is captured at 30 fps, leading to orders-of-magnitude reductions in system complexity and costs. Instead of directly capturing photography with large scale, our interactive-zoom platform operates to enhance resolution using deep learning. The proposed end-to-end model mainly consists of multiple convolution layers, attention layers and deconvolution layer, which preserves more detailed information that the image reconstructs in real time compared with the famous super-resolution methods, and it can be applied to any similar system without any modification. Benefiting from computational zoom without any additional drive and optical component, the DLBP camera provides unprecedented-competitive advantages in improving zoom response time (~ 100 ×) over the comparison systems. Herein, with the experimental system described in this work, the DLBP camera provides a novel strategy to solve the inherent contradiction among FOV, resolution and bandwidth.

Since the 1990s, researchers have been seeking approaches for applying artificial intelligence (AI) to prenatal ultrasound. With the breakthrough of cloud computing technology and the development of deep learning technology, AI in prenatal ultrasound has already entered the clinical application stage in recent years. How does AI combine with clinical prenatal ultrasound? Is the clinical application of AI in prenatal ultrasound effective? What can we expect from AI in prenatal ultrasound? This review introduces the latest developments in this field and explores the challenges and opportunities brought by AI to prenatal ultrasound.

AbstractBackground Septic shock is the development of sepsis to refractory circulatory collapse and metabolic derangements, characterized by persistent hypotension and increased lactate levels. Anisodamine hydrobromide (Ani HBr) is a Chinese medicine used to improve blood flow in circulatory disorders. The purpose of this study was to determine the therapeutic efficacy of Ani HBr in the treatment of patients with septic shock.Methods This was a prospective, multicenter, randomized controlled trial focusing on patients with septic shock in 16 hospitals in China. Patients were randomly assigned in a 1:1 ratio to either the treatment group or the control group. The primary endpoint was 28-day mortality. The secondary outcomes included 7-day mortality, hospital mortality, hospital length of stay, vasopressor-free days within 7 days, etc. These indicators were measured and collected at 0, 6h, 24h, 48h, 72h and 7d after the diagnosis.Results Between September 2017 and March 2021, 404 subjects were enrolled. 203 subjects received Ani HBr and 201 subjects were assigned to the control group. The treated group showed lower 28-day mortality than the control group. Stratified analysis further showed significant differences in 28-day mortality between the two groups for patients with a high level of illness severity. We also observed significant differences in 7-day mortality, hospital mortality and some other clinical indicators between the two groups.Conclusion Ani HBr might be an important adjuvant to conventional treatment to reduce 28-day mortality in patients with septic shock. A large-scale prospective randomized multicenter trial is warranted to confirm our results.

AbstractBackground Occupational-related cancers are a substantial global health issue. The largest proportion of occupational-related cancers is tracheal, bronchus, and lung (TBL) cancer. This study aimed to explore the geographical and temporal trends in occupational carcinogens related to TBL cancer.Methods Data on TBL cancer attributable to occupational carcinogens were collected from the Global Burden of Disease Study 2019. Numbers and age-standardized rates (ASRs) of deaths, disability-adjusted life years (DALYs), and corresponding average annual percentage change (AAPC) were evaluated and stratified by geographic location, socio-demographic index (SDI) quintiles, age, and sex.Results Globally, ASRs of deaths and DALYs in TBL cancer attributable to occupational carcinogens showed a downward trend (AAPC = − 0.69%, − 1.01%) while increases were observed in the low, low-middle, and middle SDI quintiles. Although males accounted for 82.4% and 81.5% of deaths and DALYs in 2019, respectively, it showed an upward trend of ASRs in females (AAPC = 0.33%, 0.02%). Occupational exposure to asbestos, silica and diesel engine exhaust were the top three causes of age-standardized TBL cancer deaths and DALYs. Over the past three decades, the percentage of age-standardized TBL cancer deaths and DALYs attributable to occupational asbestos and silica exposure decreased by 18.24, 6.71 and 20.52%, 4.00% globally, but increased significantly in lower SDI regions, while the burden attributable to occupational diesel engine exhaust exposure increased by 32.76, 37.23% worldwide.Conclusions Occupational exposure remains an important risk factor for TBL cancer. The burden of TBL cancer attributable to occupational carcinogens showed obvious heterogeneity which decreased in higher SDI but increased in lower SDI regions. The burden of males was significantly higher than females, but the females showed an increasing trend. Occupational exposure to asbestos was the main causes of the burden. Therefore, effective prevention and control measures tailored to local conditions are necessary.

Abstract Homogeneity and heterogeneity of the cytopathological mechanisms in different etiology-induced acute kidney injury (AKI) are poorly understood. Here, we performed single-cell sequencing (scRNA) on mouse kidneys with five common AKI etiologies (CP-Cisplatin, IRI-Ischemia-reperfusion injury, UUO-Unilateral ureteral obstruction, FA-Folic acid, and SO-Sodium oxalate). We constructed a potent multi-model AKI scRNA atlas containing 20 celltypes with 80,689 high-quality cells. The data suggest that compared to IRI and CP-AKI, FA- and SO-AKI exhibit injury characteristics more similar to UUO-AKI, which may due to tiny crystal-induced intrarenal obstruction. Through scRNA atlas, 7 different functional proximal tubular cell (PTC) subtypes were identified, we found that Maladaptive PTCs and classical Havcr1 PTCs but not novel Krt20 PTCs affect the pro-inflammatory and pro-fibrotic levels in different AKI models. And cell death and cytoskeletal remodeling events are widespread patterns of injury in PTCs. Moreover, we found that programmed cell death predominated in PTCs, whereas apoptosis and autophagy prevailed in the remaining renal tubules. We also identified S100a6 as a novel AKI-endothelial injury biomarker. Furthermore, we revealed that the dynamic and active immune (especially Arg1 Macro_2 cells) -parenchymal cell interactions are important features of AKI. Taken together, our study provides a potent resource for understanding the pathogenesis of AKI and early intervention in AKI progression at single-cell resolution.

Abstract Background Apatinib, a highly selective VEGFR2 inhibitor, significantly improved efficacy versus placebo as a third- and later-line treatment for advanced gastric cancer in phase 2 and 3 trials. This prospective, single-arm, multicenter phase IV AHEAD study was conducted to verify the safety and efficacy of apatinib in patients with advanced or metastatic gastric or gastroesophageal adenocarcinoma after at least two lines of systematic therapy in clinical practice settings. Methods Patients with advanced gastric cancer who had previously failed at least two lines of chemotherapy received oral apatinib until disease progression, death or unacceptable toxicity. The primary endpoint was safety. The secondary endpoints included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). Adverse events were summarized by the incidence rate. Median OS and PFS were estimated using the Kaplan–Meier method. ORR, DCR, OS at 3 and 6 months, and PFS at 3 and 6 months were calculated, and their 95% CIs were estimated according to the Clopper-Pearson method. Results Between May 2015 and November 2019, a total of 2004 patients were enrolled, and 1999 patients who received at least one dose of apatinib were assessed for safety. In the safety population, 87.9% of patients experienced treatment-related adverse events (TRAEs), with the most common hypertension (45.2%), proteinuria (26.5%), and white blood cell count decreased (25.3%). Additionally, 51% of patients experienced grade ≥ 3 TRAEs. Fatal TRAEs occurred in 57 (2.9%) patients. No new safety concerns were reported. Among the 2004 patients included in the intention-to-treat population, the ORR was 4.4% (95% CI, 3.6–5.4%), and DCR was 35.8% (95% CI, 33.7–38.0%). The median PFS was 2.7 months (95% CI 2.2–2.8), and the median OS was 5.8 months (95% CI 5.4–6.1). Conclusions The findings in the AHEAD study confirmed the acceptable and manageable safety profile and clinical benefit of apatinib in patients with advanced gastric cancer as a third- or later-line of treatment. Trial registration This study was registered with ClinicalTrials.gov NCT02426034. Registration date was April 24, 2015.

Direct RNA sequencing using nanopore platform can be used to detect N6-methyladenosine (m6A) modifications on mRNAs. Here the authors systematically compare tools used for m6A detection from nanopore direct sequencing.

Objective: The superiority of segmentectomy over lobectomy with regard to preservation of pulmonary function is controversial. This study aimed to examine changes in pulmonary function after uniportal video-assisted thoracoscopic surgery (VATS) according to the number of resected segments. Methods: We retrospectively reviewed 135 consecutive patients who underwent anatomical lung resection via uniportal VATS from April 2015 to December 2020. Pulmonary function loss was evaluated using forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1). Patients were grouped according to number of resected segments: one-segment (n = 33), two segments (n = 22), three segments (n = 40), four segments (n = 15), and five segments (n = 25). Results: Clinical characteristics did not significantly differ between groups, except for tumor size. Mean follow-up was 8.96 ± 3.16 months. FVC loss was significantly greater in five-segment resection (10.8%) than one-segment (0.97%, p = 0.008) and two-segment resections (2.44%, p = 0.040). FEV1 loss was significantly greater in five-segment resection (15.02%) than one-segment (3.83%, p

Abstract Objective The KEYNOTE‐590 trial showed that individuals with advanced esophageal cancer who received Pembrolizumab in combination with chemotherapy as a first‐line regimen achieved a significant extension of survival. However, this treatment option increases the financial burden on patients and the economic benefits remain to be further evaluated. Methods A Markov model was used to simulate 10‐year survival of patients with esophageal cancer from the perspective of United States (US) Medicare payers. We evaluated the economics of Pembrolizumab plus chemotherapy in the PD‐L1 positive score (CPS ≥10) and any PD‐L1 expression groups, respectively. We estimated total costs, quality‐adjusted life years (QALYs), and calculated incremental cost effectiveness ratios (ICERs). Sensitivity analyses were conducted to explore the impact of uncertainties on the results. Subgroup analysis was also performed. Results The analysis results showed that the ICER for pembrolizumab plus chemotherapy versus chemotherapy alone was $293,513.17/QALYs in the any PD‐L1 expression group. This exceeded the threshold of willingness to pay ($150,000/QALYs). ICERs were most sensitive to the cost of pembrolizumab and the ICERs exceeded $150,000/QALYs in all subgroups. Conclusions Evidence suggests that first‐line pembrolizumab in combination with chemotherapy is not a cost‐effective option for advanced esophageal cancer in the US, regardless of PD‐L1 expression status.

Background: Tyrosine kinase inhibitors (TKIs) have altered the therapeutic landscape of multiple hematological and solid malignancies. FDA approved starting doses of TKIs are based on the recommended phase 2 dose (RP2D) in clinical trials. However, patients are started on lower doses in practice. We assessed the dosing, drug reduction rates, and drug discontinuation rates among FDA approved TKIs and observed the disparity among study populations to understand if there was adequate representation of diversity in race. Methods: We established a database of all FDA approved TKIs from the FDA online label repository. We extracted descriptive data for indications and usage, type of approval, approval dosage, dose reduction recommendation, median age, race, dose reduction rates, drug discontinuation rates, dose modification, warnings, adverse reactions, clinical trial experience, and geriatric use above 65 yrs and 75 yrs. Results: Among all TKIs, median dose was 200 mg and average dose was 307.7 mg; 36 (24%) were approved bid vs 107 (72%) qd. Among approved indications, median rates of dose reduction rate (DRR), drug interruption rate (DIR), and drug discontinuations rate (DDR) were 31%, 52%, and 10% respectively. Reasons for DRR, DIR, and DDR were diarrhea, fatigue, nausea, vomiting, hepatotoxicity, rash, and hypertension. Black and Hispanic races are consistently underrepresented among the TKI studies. Conclusions: TKIs have a variable dose reduction and drug discontinuation rate but these studies were done mostly in White individuals. Clinical trials should evaluate multiple dosing regimens and schedules to lessen the toxicity burden and improve QOL in patients while broadening the study population so that the studies will be generalizable to patients in clinical practice. Future studies are warranted to increase representation in the studies to address these disparities.

Colorectal cancer (CRC) is one of the most common malignancies, and at the initial visit, most patients are diagnosed with metastatic CRC (mCRC). However, immunotherapy is only and highly effective in a very small proportion of patients with mCRC having mismatch repair defect (dMMR)/high microsatellite instability, and the majority of the patients with mCRC having mismatch repair proficient (pMMR)/microsatellite stability (MSS) cannot benefit from it. At present, many clinical studies of immunotherapy combined with tyrosine kinase inhibitors (TKIs) are trying to regulate the immune microenvironment of pMMR/MSS mCRC, transforming a “cold tumor” into a “hot tumor,” which has not only surprising effects but also certain limitations, i.e., the response could not be specific to metastasis. Therefore, regarding the bottleneck encountered by immunotherapy in patients with patients pMMR/MSS mCRC, this study summarized current research and possible mechanisms of immunotherapy combined with local therapy for metastasis, including radiotherapy, ablation, and transcatheter arterial chemoembolization.

BackgroundTraditional drug susceptibility testing cannot be performed in clinical laboratories due to the slow-growing characteristics of Mycoplasma genitalium when cultured in vitro. Sanger sequencing is the standard method for detecting drug resistance-associated mutations. It has been used in some laboratories to guide the choice of macrolide antibiotics for Mycoplasma genitalium infected patients. Furthermore, resistance to fluoroquinolone has become another emerging clinical challenge.ObjectiveSequencing analysis can detect unknown mutations, but it is time-consuming, requires professional analytical skills and the appropriate testing equipment. The main objective of this study was to establish a nested real-time PCR method for the simultaneous detection of 23S rRNA and parC genotypes in relation to the macrolide and fluoroquinolone resistance.Results105 MG-positive samples and 27 samples containing other pathogens were used for validation. The limit of the nested real-time PCR detection was 500 copies/reaction and there was no cross-reaction with Ureaplasma urealyticum, Mycoplasma hominis, Chlamydia trachomatis, Neisseria gonorrhoeae, Human papillomavirus, Herpes simplex virus, Candida albicans and Ureaplasma parvum, but the 23S rRNA assay cross-reacted with Mycoplasma pneumoniae. Compared with sequencing results, the sensitivity of 23S rRNA was 100% (95% CI; 93.3 -100), the specificity was 94.3% (95% CI; 79.4 - 99.0), the overall consistency was 98% (95% CI; 92.5 - 99.7) and kappa value was 0.96 (P < 0.001); the sensitivity of parC was 100% (95% CI; 93.4 - 100), the specificity was 89.7% (95% CI; 71.5 - 97.3) and the overall consistency was 96.9% (95% CI; 90.7 - 99.2) with a kappa value of 0.92 (P < 0.001).ConclusionsThe results of this sensitive and rapid alternative for identifying resistant genotypes of Mycoplasma genitalium are intuitive and easy to interpret, especially for mixed MG populations. Although the relevant 23S rRNA primers need further adjustment, this reliable method would provide an effective diagnostic tool for the selection of antibiotics in clinical practice.

Eperisone hydrochloride is a central muscle relaxant used to treat osteoporosis. Seizures are rare side effects of eperisone hydrochloride and have been previously reported in the medical literature in overdose situations but not at regular doses. This case report describes a 42-year-old male painter who developed severe bilateral tonic seizures after the initiation of eperisone hydrochloride at regular doses for low back pain. Symptoms gradually eased in the days following the discontinuation of eperisone hydrochloride and antiepileptic treatment, with no recurrence. This rare adverse drug reaction warrants clinical awareness; however, the mechanisms underlying these adverse reactions remain to be clarified.

Urban and building morphologies, usually determined at the design stage, have been proven as important determinants of energy usage at later operational stages. However, questions remain regarding the identification of the key determinants that influence urban building energy usage. To address this, in this study, an urban building dataset of 539 residential buildings and 153 public buildings was used to extract the building morphology factors as the determinants. A principal component analysis was performed to identify the key determinants for three buildings groups—residential buildings, residential blocks, and public buildings. The results show that the key determinants for residential buildings are their orientation, ratio of obstruction height to the canyon width from the south and west directions, shape coefficient, perimeter-to-area ratio, and building aspect ratio. The key determinants for public buildings are similar to those for residential buildings with the exception of the ratio of the obstruction height to the canyon width from the south direction. The key determinants for residential blocks are the ratio of the obstruction height to the canyon width from the south and west directions, mass space proportion, building aspect ratio, and floor area ratio. The findings of this study provide insights into the key drivers of urban building energy usage and the strategies that could be used to improve urban energy planning.

Introduction: We aimed to identify clinical, pathologic, and treatment factors that are predictive of response and survival in patients with cervical cancer referred to phase I clinical trials. Methods: Patients with cervical cancer who received at least one dose of a phase I investigational agent at our institution between 2014 and 2022 were included. The log-rank test was used to analyze differences in progression-free survival (PFS) and overall survival (OS), and multivariable regression analysis was performed. Results: We included 65 patients with a median age of 41 years (range, 20–74), 3 prior therapies (range, 1–7), and 67.7% squamous carcinoma. The rate of distant metastasis at trial entry was 84.6%. The most common molecular alterations included PIK3CA (46.5%), PD-L1+ (46.2%), EPH (30.0%), and CREBBP (23.1%); 23.1% had received a prior checkpoint inhibitor. Phase I trials were for immunotherapy (58.5%) or targeted therapy (41.5%). The rate of biomarker matching was 21.5%. For all patients, median PFS was 3.6 months (95% CI, 2.0–5.2) and OS was 9.3 months (95% CI, 7.0–10.6). Factors at study entry associated with worse survival were presence of bone metastasis (PFS 1.6 vs 4.4 months: hazard ratio [HR], 2.8; p = 0.001; OS 3.8 vs 10.0 months: HR, 3.9; p < 0.0001) and absolute lymphocyte count below 1000/μL (PFS 1.8 vs 5.2 months: HR, 2.9; p = 0.0004; OS 7.0 vs 10.6 months: HR, 3.2; p = 0.0009). Factors associated only with worse OS were absolute neutrophil count above 4700/μL, hemoglobin below 10.5 g/dL, and smoking status. Grade 3+ treatment-related adverse events were seen in 16.9% of cases. Conclusion: Bone metastasis and absolute lymphocyte count below normal range at phase I study entry portend poor survival in patients with recurrent or metastatic cervical cancer.

Abstract RAS genes are the most frequently mutated oncogenes and play critical roles in the development and progression of malignancies. The mutation, isoform (KRAS, HRAS, and NRAS), position, and type of substitution vary depending on the tissue types. Despite decades of developing RAS‐targeted therapies, only small subsets of these inhibitors are clinically effective, such as the allele‐specific inhibitors against KRASG12C. Targeting the remaining RAS mutants would require further experimental elucidation of RAS signal transduction, RAS‐altered metabolism, and the associated immune microenvironment. This study reviews the mechanisms and efficacy of novel targeted therapies for different RAS mutants, including KRAS allele‐specific inhibitors, combination therapies, immunotherapies, and metabolism‐associated therapies.