bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessment of rehabilitation following subarachnoid haemorrhage in China: findings from the Chinese Stroke Center Alliance
Authors: Chen Yi-Tong , Wu Mei-Ru , Li Zi-Xiao , Gu Hong-Qiu , Zhou Qi , Wang Dan-Dan , Wang Yong-Jun , Xing-Quan Zhao
Published: August 2023

Background

Rehabilitation improves functional recovery in subarachnoid hemorrhage (SAH) patients, and assessing patients for rehabilitation is the first step in this process. However, little is known about clinical practice in China regarding the assessment and provision of rehabilitation for patients with SAH.

Methods

To identify patients hospitalized with SAH and to analyze rehabilitation assessment rates, we used data for 11,234 SAH patients admitted to 861 hospitals from the China Stroke Center Alliance from August 2015 to July 2019. We examined factors for rehabilitation assessment and analyzed the relationship between rehabilitation assessment and outcomes in these patients.

Results

Among 11,234 patients with SAH, 6,513 (58.0%) were assessed for rehabilitation. Assessed patients had an increased length of stay (mean ± SD days: 17.3 ± 12.5 versus 11.6 ± 10.5, P = 49.4), a higher Glasgow Coma Scale (GCS) score on admission (mean ± SD GCS score: 12.3 ± 3.8 versus 11.8 ± 4.4, P = 12.2), and were more likely to be admitted to the stroke unit (19.6% versus 13.8%, P = 15.6). In multivariable analysis, factors associated with an increased likelihood of a rehabilitation assessment (p < 0.05) included a longer length of stay (odds ratio [OR], 1.04; 95% confidence interval (CI), 1.04 to 1.05) and care such as dysphagia screening (OR, 1.88; 95% CI, 1.73 to 2.04), DVT prophylaxis (OR, 1.56; 95% CI, 1.41 to 1.72) and vessel evaluation (OR, 1.80; 95% CI, 1.63 to 1.98). For the multivariate analysis of outcomes, patients undergoing rehabilitation assessment had a longer length of stay (OR, 1.96; 95% CI, 1.81 to 2.12), a higher modified Rankin Scale (mRS) score at discharge (OR, 1.49; 95% CI, 1.36 to 1.64), and higher rates of discharge to a rehabilitation center (OR, 3.23; 95% CI, 1.81-5.75).

Conclusion

More than two-fifths of SAH patients were not assessed for rehabilitation. Rates vary considerably among hospital grades, and there is a need to improve adherence to recommended care for SAH patients.
The association between labor companionship and obstetric violence during childbirth in health facilities in five facilities in the occupied Palestinian territory
Authors: Wahdan Yasmeen , Abu-Rmeileh Niveen M. E.
Published: August 2023

Background

Studies show that the presence of companionship during childbirth leads to positive outcomes for women. This study investigates the protective effect of having a labor companion on obstetric violence in the health facilities of the Occupied Palestinian Territory.

Methods

A secondary analysis of a cross-sectional study of women who gave birth in five health centers in the occupied Palestinian territory up to 8 weeks following childbirth was performed. The presence of a labor companion was examined in relation to socioeconomic variables and physical abuse, verbal abuse or stigma or discrimination, failure to achieve professional standards, vaginal examinations, and pain relief.

Results

According to the findings, the total number of women with a labor partner or a birth companion present at any stage during the labor process was 92% in the West Bank, and 77.4% in the Gaza Strip. According to the timing of support, 23.5% of women had a labor companion present during labor, childbirth, and after childbirth whilst in the hospital. Women who did not have labor companions were more likely than women who did to report at least one sort of mistreatment, such as unconsented procedures. Women with a labor companion were less likely to report abuse (16%) compared to women without labor companion. In terms of informed permission for procedures, 75% of women who did not have a labor companion had unconsented episiotomy.

Conclusion

Labor companionship assists women by providing them with companions who are less likely to be mistreated during labor. Efforts should be made to best implement the presence of labor companions, including the duration of the labor companionship and women's preferences.
A novel metabolic subtype with S100A7 high expression represents poor prognosis and immuno-suppressive tumor microenvironment in bladder cancer
Authors: Cai Yun , Cheng Yifei , Wang Ziyu , Li Lu , Qian Zhengtao , Xia Wei , Yu Weiwei
Published: August 2023

Background

Bladder cancer (BLCA) represents a highly heterogeneous disease characterized by distinct histological, molecular, and clinical features, whose tumorigenesis and progression require aberrant metabolic reprogramming of tumor cells. However, current studies have not expounded systematically and comprehensively on the metabolic heterogeneity of BLCA.

Methods

The UCSC XENA portal was searched to obtain the expression profiles and clinical annotations of BLCA patients in the TCGA cohort. A total of 1,640 metabolic-related genes were downloaded from the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Then, consensus clustering was performed to divide the BLCA patients into two metabolic subtypes according to the expression of metabolic-related genes. Kaplan-Meier analysis was used to measure the prognostic values of the metabolic subtypes. Subsequently, comparing the immune-related characteristics between the two metabolic subtypes to describe the immunological difference. Then, the Scissor algorithm was applied to link the metabolic phenotypes and single-cell transcriptome datasets to determine the biomarkers associated with metabolic subtypes and prognosis. Finally, the clinical cohort included 63 BLCA and 16 para-cancerous samples was used to validate the prognostic value and immunological correlation of the biomarker.

Results

BLCA patients were classified into two heterogeneous metabolic-related subtypes (MRSs) with distinct features: MRS1, the subtype with no active metabolic characteristics but an immune infiltration microenvironment; and MRS2, the lipogenic subtype with upregulated lipid metabolism. These two subtypes had distinct prognoses, molecular subtypes distributions, and activations of therapy-related pathways. MRS1 BLCAs preferred to be immuno-suppressive and up-regulated immune checkpoints expression, suggesting the well-therapeutic response of MRS1 patients to immunotherapy. Based on the Scissor algorithm, we found that S100A7 both specifically up-regulated in the MRS1 phenotype and MRS1-tumor cells, and positively correlated with immunological characteristics. In addition, in the clinical cohort included 63 BLCA and 16 para-cancerous samples, S100A7 was obviously associated with poor prognosis and enhanced PD-L1 expression.

Conclusions

The metabolic subtype with S100A7 high expression recognizes the immuno-suppressive tumor microenvironment and predicts well therapeutic response of immunotherapy in BLCA. The study provides new insights into the prognostic and therapeutic value of metabolic heterogeneity in BLCA.
Randomised phase II trial of trifluridine/tipiracil (FTD/TPI) plus ramucirumab (RAM) versus trifluridine/tipiracil for previously treated patients with advanced gastric or esophagogastric junction adenocarcinoma (RETRIEVE study, WJOG15822G)
Authors: Takahashi Naoki , Hara Hiroki , Nagashima Kengo , Hirata Kenro , Masuishi Toshiki , Matsumoto Toshihiko , Kawakami Hisato , Yamazaki Kentaro , Hironaka Shuichi , Boku Narikazu , Muro Kei
Published: August 2023

Background

Trifluridine/tipiracil (FTD/TPI) prolongs survival in the third- or later-line treatment for advanced gastric cancer (GC), esophagogastric junction (EGJ) adenocarcinoma, and colorectal cancer. While single-arm phase II trials showed promising outcomes of FTD/TPI plus ramucirumab (RAM) as third- or later-line treatments for advanced GC or EGJ cancer, there have been no clinical trials to directly compare FTD/TPI plus RAM with FTD/TPI monotherapy. Therefore, we have started a randomised phase II trial to evaluate the efficacy and safety of FTD/TPI plus RAM compared with FTD/TPI monotherapy as third- or later-line treatments in patients with advanced GC and EGJ adenocarcinoma.

Methods

This RETREVE trial (WJOG15822G) is a prospective, open-label, randomised, multicentre phase II trial comparing FTD/TPI plus RAM versus FTD/TPI monotherapy in a third- or later-line setting. Eligibility criteria include age of > 20 years; performance status of 0 or 1; unresectable or recurrent gastric or EGJ adenocarcinoma; confirmed HER2 status; refractory or intolerant to fluoropyrimidine, taxane or irinotecan; refractory to RAM (not intolerant); and at least a measurable lesion per RECIST 1.1. FTD/TPI (35 mg/m2 twice daily, evening of day 1 to morning of day 6 and evening of day 8 to morning of day 13) was administered orally every 4 weeks, and RAM (8 mg/kg) was administered intravenously every 2 weeks. The primary endpoint is progression-free survival (PFS), and the secondary endpoints are overall survival, objective response rate, disease control rate, and safety. The expected hazard ratio of PFS is set as 0.7, assuming 4-month PFS rate of 27% in FTD/TPI monotherapy and 40% in FTD/TPI plus RAM. The number of subjects was 110, with a one-sided alpha error of 0.10 and power of 0.70.

Discussion

This study will clarify the additional effect of RAM continuation beyond disease progression on FTD/TPI in the third- or later-line setting for patients with advanced GC or EGJ cancer.

Trial registration

jRCTs041220120.
Treatment strategy for acute myocarditis in pediatric patients requiring emergency intervention
Authors: Murakoshi Yuka , Hoshino Kenji
Published: August 2023

Background

Patients with acute myocarditis present with a wide range of symptoms. Treatment strategies for pediatric patients with circulatory failure comprise extracorporeal membrane oxygenation (ECMO), emergency temporary pacing, and pharmacotherapy. However, they remain controversial. ECMO is an effective treatment but gives rise to several complications; the goal is therefore to avoid excessive treatment as much as possible. We aimed to evaluate the importance of electrocardiogram findings in differentiating severity and establish an appropriate treatment strategy in pediatric patients with acute myocarditis who required emergency interventions.

Methods

This retrospective study enrolled pediatric patients admitted to and treated in our hospital for acute myocarditis between April 1983 and December 2021. Patients were retrospectively divided into whether circulatory failure occurred (ECMO or temporary pacing was needed; emergency intervention group) or not (pharmacotherapy alone).

Results

Of the 26 pediatric patients, 11 experienced circulatory failure while 15 did not. In the circulatory failure group, six patients were treated with ECMO (ECMO group) and five patients with temporary pacing (pacing group). In the pacing group, all patients were diagnosed with complete and/or advanced atrioventricular block (CAVB and/or advanced AVB) and narrow QRS. Furthermore, these patients improved only with temporary pacing and pharmacotherapy, without requiring ECMO. Wide QRS complexes (QRS ≥ 0.12 ms) with ST-segment changes were detected on admission in five of six patients in the ECMO group and none in the pacing group (P = 0.015). Although all patients in the ECMO group experienced complications, none did in the pacing group (P < 0.008).

Conclusions

Regarding emergency intervention for acute myocarditis, ECMO or temporary pacing could be determined based on electrocardiogram findings, particularly wide QRS complexes with ST-segment changes on admission. It is important to promptly introduce ECMO in patients with wide QRS complexes with ST-segment changes, however, patients with CAVB and/or advanced AVB and narrow QRS could improve without undergoing ECMO. Therefore, excessive treatment should be avoided by separating ECMO from temporary pacing based on electrocardiogram findings on admission.
Transgender women in Kenya experience greater stigma, depressive symptoms, alcohol and drug use and risky sexual practices than cis-gendered men who have sex with men
Authors: Mehta Supriya D. , Otieno Fredrick O. , Kimani Joshua , Wahome Elizabeth , Okal Duncan , Roy Abhishikta , van der Elst Elise , Graham Susan M. , Sanders Eduard J. , Bailey Robert C.
Published: August 2023

Background

Worldwide, sexual and gender minority individuals have disproportionate burden of HIV. There are limited quantitative data from sub-Saharan Africa on the intersection of risks experienced by transgender women (TGW) in comparison to cis-men who have sex with men (MSM). This analysis addresses this gap by comparing reported stigma, psychosocial measures of health, and sexual risk practices between TGW and cis-MSM in Kenya.

Methods

We analyzed data from the baseline visit of an ongoing prospective cohort study taking place in three diverse metropolitan areas. Eligible participants were HIV-negative, assigned male at birth, ages 18–29 years, and reported anal intercourse in the past 3 months with a man or TGW. Data collected by audio computer assisted self-interview included sociodemographic measures, and sexual practices occurring in the past 3 months. Multivariable regressions assessed differences between TGW and cis-MSM in selected sexual practices, depressive symptoms, alcohol and drug use, and stigma.

Results

From September, 2019, through May, 2021, 838 participants were enrolled: 108 (12.9%) TGW and 730 (87.1%) cis-MSM. Adjusting for sociodemographic variables, TGW were more likely than cis-MSM to report: receptive anal intercourse (RAI; adjusted prevalence ratio [aPR] = 1.59, 95% CI: 1.32 – 1.92), engaging in group sex (aPR = 1.15, 95% CI: 1.04 – 1.27), 4 or more male sex partners (aPR = 3.31, 95% CI: 2.52 – 4.35), and 3 or more paying male sex partners (aPR = 1.58, 95% CI: 1.04 – 2.39). TGW were also more likely to report moderate to severe depressive symptoms (aPR = 1.42, 95% CI: 1.01 – 1.55), and had similar alcohol and drug abuse scores as cis-MSM. In sensitivity analysis, similar to TGW, male-identifying individuals taking feminizing gender affirming therapy had an increased likelihood of reporting RAI and group sex, and greater numbers of male sex partners and paying male sex partners relative to cis-MSM.

Conclusions

Across three metropolitan areas in Kenya, TGW were more likely to report depressive symptoms and increased sexual risk taking. We identified a need for research that better characterizes the range of gender identities. Our analysis affirms the need for programmatic gender-affirming interventions specific to transgender populations in Kenya and elsewhere in Africa.
Comparative analysis of two navigation techniques based on augmented reality technology for the orthodontic mini-implants placement
Authors: Riad Deglow Elena , Zubizarreta-Macho Álvaro , González Menéndez Héctor , Lorrio Castro Juan , Galparsoro Catalán Agustín , Tzironi Georgia , Lobo Galindo Ana Belén , Alonso Ezpeleta Luis Óscar , Hernández Montero Sofía
Published: August 2023

To analyze and compare the accuracy and root contact prevalence, comparing a conventional freehand technique and two navigation techniques based on augmented reality technology for the orthodontic self-drilling mini-implants placement.

Methods Two hundred and seven orthodontic self-drilling mini-implants were placed using either a conventional freehand technique (FHT) and two navigation techniques based on augmented reality technology (AR TOOTH and AR SCREWS). Accuracy across different dental sectors was also analyzed. CBCT and intraoral scans were taken both prior to and following orthodontic self-drilling mini-implants placement. The deviation angle and horizontal were then analyzed; these measurements were taken at the coronal entry point and apical endpoint between the planned and performed orthodontic self-drilling mini-implants. In addition, any complications resulting from mini-implant placement, such as spot perforations, were also analyzed across all dental sectors.

Results The statistical analysis showed significant differences between study groups with regard to the coronal entry-point (p < 0.001), apical end-point(p < 0.001) and angular deviations (p < 0.001). Furthermore, statistically significant differences were shown between the orthodontic self-drilling mini-implants placement site at the coronal entry-point (p < 0.0001) and apical end-point (p < 0.001). Additionally, eight root perforations were observed in the FHT group, while there were no root perforations in the two navigation techniques based on augmented reality technology.

Conclusions The navigation techniques based on augmented reality technology has an effect on the accuracy of orthodontic self-drilling mini-implants placement and results in fewer intraoperative complications, comparing to the conventional free-hand technique. The AR TOOTH augmented reality technique showed more accurate results between planned and placed orthodontic self-drilling mini-implants, comparing to the AR SCREWS and conventional free-hand techniques. The navigation techniques based on augmented reality technology showed fewer intraoperative complications, comparing to the conventional free-hand technique.
Designing and psychometric properties of the hospitalized patients’ spiritual needs questionnaire (HPSNQ) in the medical-surgical hospital setting
Authors: Hosseini Fahimeh Alsadat , Momennasab Marzieh , Guàrdia-Olmos Joan , Yektatalab Shahrzad , Shaygan Maryam , Zareiyan Armin
Published: August 2023

Background

The evaluation of spiritual requirements in patients can facilitate the delivery of spiritual care as an essential element of holistic healthcare. The objective of this research was to develop and evaluate the psychometric properties of a questionnaire on patients’ spiritual needs in medical-surgical hospital settings.

Methods

This research utilized an exploratory sequential design, involving the creation of a pool of items through both inductive and deductive methods. The questionnaire’s psychometric properties were then assessed using various techniques, such as face and content validity, item analysis, construct validity, internal consistency, stability, confirmatory factor analysis, and the Gradual Response Model of Samejima. The data analysis was conducted using MPLUS software, version 5.1.

Results

The study’s results showed that a four-factor structure (interpersonal connectedness, relationship with God, transcendence, and peaceful environment) with 43 items was successfully extracted through exploratory factor analysis. The confirmatory factor analysis supported the findings of the exploratory factor analysis. The Cronbach’s alpha coefficients for the scale and factors ranged between 0.83 and 0.95. Furthermore, the interclass correlation coefficients for the scale and factors were between 0.89 and 0.96.

Conclusions

The questionnaire designed in this study is a reliable and valid instrument that can be utilized by healthcare, educational, and research institutions to evaluate the spiritual needs of patients in medical-surgical hospital settings.
Association between hospital competition and quality of prostate cancer care
Authors: Jayadevappa Ravishankar , Malkowicz S. Bruce , Vapiwala Neha , Guzzo Thomas J. , Chhatre Sumedha
Published: August 2023

Background

Hospitals account for approximately 6% of United States’ gross domestic product. We examined the association between hospital competition and outcomes in elderly with localized prostate cancer (PCa). We also assessed if race moderated this association.

Methods

Retrospective study using Surveillance, Epidemiology, and End Results (SEER) – Medicare database. Cohort included fee-for-service, African American and white men aged ≥ 66, diagnosed with localized PCa between 1998 and 2011 and their claims between 1997 and 2016.

We used Hirschman-Herfindahl index (HHI) to measure of hospital competition. Outcomes were emergency room (ER) visits, hospitalizations, Medicare expenditure and mortality assessed in acute survivorship phase (two years post-PCa diagnosis), and long-term mortality. We used Generalized Linear Models for analyzing expenditure, Poisson models for ER visits and hospitalizations, and Cox models for mortality. We used propensity score to minimize bias.

Results

Among 253,176 patients, percent change in incident rate of ER visit was 17% higher for one unit increase in HHI (IRR: 1.17, 95% CI: 1.15–1.19). Incident rate of ER was 24% higher for whites and 48% higher for African Americans. For one unit increase in HHI, hazard of short-term all-cause mortality was 7% higher for whites and 11% lower for African Americans. The hazard of long-term all-cause mortality was 10% higher for whites and 13% higher for African Americans.

Conclusions

Lower hospital competition was associated with impaired outcomes of localized PCa care. Magnitude of impairment was higher for African Americans, compared to whites. Future research will explore process through which competition affects outcomes and racial disparity.
Validation of clinical-radiological scores for prognosis of mortality in acute pulmonary embolism
Authors: Surov Alexey , Thormann Maximilian , Bär Caroline , Wienke Andreas , Borggrefe Jan
Published: August 2023

Introduction

Acute pulmonary embolism (APE) is a hazardous disorder with a high mortality. Combination of clinical, radiological, and serological parameters can improve risk stratification of APE. Most of the proposed combined scores were not validated in independent cohorts. Our aim was to validate the proposed clinical-radiological scores for prognosis of 7- and 30-day mortality in APE.

Materials and methods

Our sample comprised 531 patients with APE, mean age 64.8 ± 15.6 years, 221 (41.6%) females and 310 (58.4%) males. The following parameters were collected: Age and sex of the patients, mortality within the observation time of 30 days, simplified pulmonary embolism severity index (sPESI), pH troponin level (pg/ml), minimal systolic and diastolic blood pressures (mmHg), heart rate, O2 saturation, episodes of syncope, and need for vasopressors. On CT pulmonary angiography (CTPA), short axis ratio right ventricle/left ventricle (RV/LV), and reflux of contrast medium into the inferior vena cava were obtained. The following clinical-radiological scores were calculated: BOVA score, pulmonary embolism mortality score (PEMS), European Society of Cardiology (ESC) score, Kumamaru score, and Calgary acute pulmonary embolism (CAPE) score.

Results

Overall, 31 patients (5.8%) died within seven and 64 patients (12%) within 30 days. All scores showed high negative prognostic values ranging from 89.0 to 99.0%. PEMS and CAPE score demonstrated the highest specificity for 7-day mortality (93.4% and 85.0%), PEMS and BOVA for 30-day mortality (94.2% and 90.4%). The highest sensitivity was observed for ESC 2019 (96.8% and 95.3%). Kumamaru and CAPE scores had low sensitivity. All scores had low positive and high negative predictive values.

Conclusion

For prognosis of 7- and 30-day mortality in APE, PEMS score has the highest specificity. ESC 2019 shows the highest sensitivity. All scores had low positive and high negative predictive values.
Strategies for improving the production of bio-based vanillin
Authors: Liu Ying , Sun Lichao , Huo Yi-Xin , Guo Shuyuan
Published: August 2023

Vanillin (4-hydroxy-3-methoxybenzaldehyde) is one of the most popular flavors with wide applications in food, fragrance, and pharmaceutical industries. However, the high cost and limited yield of plant extraction failed to meet the vast market demand of natural vanillin. Vanillin biotechnology has emerged as a sustainable and cost-effective alternative to supply vanillin. In this review, we explored recent advances in vanillin biosynthesis and highlighted the potential of vanillin biotechnology. In particular, we addressed key challenges in using microorganisms and provided promising approaches for improving vanillin production with a special focus on chassis development, pathway construction and process optimization. Future directions of vanillin biosynthesis using inexpensive precursors are also thoroughly discussed.
BRAF(V600E) mutation together with loss of Trp53 or pTEN drives the origination of hairy cell leukemia from B-lymphocytes
Authors: Yap Jiajun , Yuan Jimin , Ng Wan Hwa , Chen Gao Bin , Sim Yuen Rong M. , Goh Kah Chun , Teo Joey , Lim Trixie Y. H. , Goay Shee Min , Teo Jia Hao Jackie , Lao Zhentang , Lam Paula , Sabapathy Kanaga , Hu Jiancheng
Published: August 2023

Hairy cell leukemia (HCL) is a B-lymphoma induced by BRAF(V600E) mutation. However, introducing BRAF(V600E) in B-lymphocytes fails to induce hematological malignancy, suggesting that BRAF(V600E) needs concurrent mutations to drive HCL ontogeny. To resolve this issue, here we surveyed human HCL genomic sequencing data. Together with previous reports, we speculated that the tumor suppressor TP53, P27, or PTEN restrict the oncogenicity of BRAF(V600E) in B-lymphocytes, and therefore that their loss-of-function facilitates BRAF(V600E)-driven HCL ontogeny. Using genetically modified mouse models, we demonstrate that indeed BRAF(V600E)KI together with Trp53KO or pTENKO in B-lymphocytes induces chronic lymphoma with pathological features of human HCL. To further understand the cellular programs essential for HCL ontogeny, we profiled the gene expression of leukemic cells isolated from BRAF(V600E)KI and Trp53KO or pTENKO mice, and found that they had similar but different gene expression signatures that resemble that of M2 or M1 macrophages. In addition, we examined the expression signature of transcription factors/regulators required for germinal center reaction and memory B cell versus plasma cell differentiation in these leukemic cells and found that most transcription factors/regulators essential for these programs were severely inhibited, illustrating why hairy cells are arrested at a transitional stage between activated B cells and memory B cells. Together, our study has uncovered concurrent mutations required for HCL ontogeny, revealed the B cell origin of hairy cells and investigated the molecular basis underlying the unique pathological features of the disease, with important implications for HCL research and treatment.
Anlotinib plus icotinib as a potential treatment option for EGFR-mutated advanced non-squamous non-small cell lung cancer with concurrent mutations: final analysis of the prospective phase 2, multicenter ALTER-L004 study
Authors: Zhang Linlin , Wang Liuchun , Wang Jingya , Chen Jinliang , Meng Zhaoting , Liu Zhujun , Jiang Xiangli , Wang Xinyue , Huang Chun , Chen Peng , Liang Yan , Jiang Richeng , Wang Jing , Zhong Diansheng , Shang Yanhong , Zhang Yan , Zhang Cuiying , Huang Dingzhi
Published: August 2023

Background

Non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation and concurrent mutations have a poor prognosis. This study aimed to examine anlotinib plus icotinib as a first-line treatment option for advanced NSCLC carrying EGFR mutation with or without concurrent mutations.

Methods

This phase 2, single-arm, multicenter trial (ClinicalTrials.gov NCT03736837) was performed at five hospitals in China from December 2018 to November 2020. Non-squamous NSCLC cases with EGFR-sensitizing mutations were treated with anlotinib and icotinib. The primary endpoint was progression-free survival (PFS). Secondary endpoints included the objective response rate (ORR), disease control rate (DCR), overall survival (OS), and toxicity.

Results

Sixty participants were enrolled, including 31 (52%) and 29 (48%) with concurrent mutations and pathogenic concurrent mutations, respectively. The median follow-up was 26.9 (range, 15.0-38.9) months. ORR and DCR were 68.5% and 98.2%, respectively. Median PFS was 15.1 (95%CI: 12.6–17.6) months which met the primary endpoint, median DoR was 13.5 (95%CI: 10.0-17.1) months, and median OS was 30.0 (95%CI: 25.5–34.5) months. Median PFS and OS in patients with pathogenic concurrent mutations were 15.6 (95%CI: 12.5–18.7) months and not reached (95%CI: 17.46 months to not reached), respectively. All patients experienced TRAEs, including 26 (43%) and 1 (1.7%) who had grade ≥ 3 and serious treatment-related adverse events (TRAEs).

Conclusions

Anlotinib combined with icotinib was effective and well-tolerated as a first-line treatment option for EGFR mutation-positive advanced NSCLC with or without concurrent mutations.

Trial registration

ClinicalTrials.gov identifier: NCT03736837.
Serum proteomic identification and validation of two novel atherosclerotic aortic aneurysm biomarkers, profilin 1 and complement factor D
Authors: Murakami Yusuke , Nishigori Mitsuhiro , Yagi Hiroaki , Osaki Tsukasa , Wakabayashi Masaki , Shirai Manabu , Son Cheol , Iba Yutaka , Minatoya Kenji , Kusano Kengo , Tomita Tsutomu , Ishibashi-Ueda Hatsue , Matsuda Hitoshi , Minamino Naoto
Published: August 2023

Background

Effective diagnostic biomarkers for aortic aneurysm (AA) that are detectable in blood tests are required because early detection and rupture risk assessment of AA can provide insights into medical therapy and preventive treatments. However, known biomarkers for AA lack specificity and reliability for clinical diagnosis.

Methods

We performed proteome analysis of serum samples from patients with atherosclerotic thoracic AA (TAA) and healthy control (HC) subjects to identify diagnostic biomarkers for AA. Serum samples were separated into low-density lipoprotein, high-density lipoprotein, and protein fractions, and the major proteins were depleted. From the proteins identified in the three fractions, we narrowed down biomarker candidates to proteins uniformly altered in all fractions between patients with TAA and HC subjects and evaluated their capability to discriminate patients with TAA and those with abdominal AA (AAA) from HC subjects using receiver operating characteristic (ROC) analysis. For the clinical validation, serum concentrations of biomarker candidates were measured in patients with TAA and AAA registered in the biobank of the same institute, and their capability for the diagnosis was evaluated.

Results

Profilin 1 (PFN1) and complement factor D (CFD) showed the most contrasting profiles in all three fractions between patients with TAA and HC subjects and were selected as biomarker candidates. The PFN1 concentration decreased, whereas the CFD concentration increased in the sera of patients with TAA and AAA when compared with those of HC subjects. The ROC analysis showed that these proteins could discriminate patients with TAA and AAA from HC subjects. In the validation study, these candidates showed significant concentration differences between patients with TAA or AAA and controls. PFN1 and CFD showed sufficient area under the curve (AUC) in the ROC analysis, and their combination further increased the AUC. The serum concentrations of PFN1 and CFD also showed significant differences between patients with aortic dissection and controls in the validation study.

Conclusion

PFN1 and CFD are potential diagnostic biomarkers for TAA and AAA and measurable in blood samples; their diagnostic performance can be augmented by their combination. These biomarkers may facilitate the development of diagnostic systems to identify patients with AA.
Three-dimensional visualization and evaluation of hilar cholangiocarcinoma resectability and proposal of a new classification
Authors: Zhang Jun-Zhe , Yang Chuan-Xin , Gao Si , Bu Jun-Feng , Li Qin-Qin , Wang Hao-Lu , Yang Kai-Ni , Tong Shan-Shi , Qian Li-Jun , Zhang Jin , Hua Rong , Sun Yong-Wei , Yan Jia-Yan , Chen Wei
Published: August 2023

Background

As digital medicine has exerted profound influences upon diagnosis and treatment of hepatobiliary diseases, our study aims to investigate the accuracy of three-dimensional visualization and evaluation (3DVE) system in assessing the resectability of hilar cholangiocarcinoma (hCCA), and explores its potential clinical value.

Materials and methods

The discovery cohort, containing 111 patients from April 2013 to December 2019, was retrospectively included to determine resectability according to revised criteria for unresectability of hCCA. 3D visualization models were reconstructed to evaluate resectability parameters including biliary infiltration, vascular involvement, hepatic atrophy and metastasis. Evaluation accuracy were compared between contrast-enhanced CT and 3DVE. Logistic analysis was performed to identify independent risk factors of R0 resection. A new comprehensive 3DVE classification of hCCA based on factors influencing resectability was proposed to investigate its role in predicting R0 resection and prognosis. The main outcomes were also analyzed in cohort validation, including 34 patients from January 2020 to August 2022.

Results

3DVE showed an accuracy rate of 91% (95%CI 83.6–95.4%) in preoperatively evaluating hCCA resectability, significantly higher than 81% (95%CI 72.8–87.7%) of that of CT (p = 0.03). By multivariable analysis, hepatic artery involvement in 3DVE was identified an independent risk factor for R1 or R2 resection (OR = 3.5, 95%CI 1.4,8.8, P < 0.01). New 3DVE hCCA classification was valuable in predicting patients’ R0 resection rate (p < 0.001) and prognosis (p < 0.0001). The main outcomes were internally validated.

Conclusions

3DVE exhibited a better efficacy in evaluating hCCA resectability, compared with contrast-enhanced CT. Preoperative 3DVE demonstrated hepatic artery involvement was an independent risk factor for the absence of R0 margin. 3DVE classification of hCCA was valuable in clinical practice.
Spatial tumour gene signature discriminates neoplastic from non-neoplastic compartments in colon cancer: unravelling predictive biomarkers for relapse
Authors: Sallinger Katja , Gruber Michael , Müller Christin-Therese , Bonstingl Lilli , Pritz Elisabeth , Pankratz Karin , Gerger Armin , Smolle Maria Anna , Aigelsreiter Ariane , Surova Olga , Svedlund Jessica , Nilsson Mats , Kroneis Thomas , El-Heliebi Amin
Published: August 2023

Background

Opting for or against the administration of adjuvant chemotherapy in therapeutic management of stage II colon cancer remains challenging. Several studies report few survival benefits for patients treated with adjuvant therapy and additionally revealing potential side effects of overtreatment, including unnecessary exposure to chemotherapy-induced toxicities and reduced quality of life. Predictive biomarkers are urgently needed. We, therefore, hypothesise that the spatial tissue composition of relapsed and non-relapsed colon cancer stage II patients reveals relevant biomarkers.

Methods

The spatial tissue composition of stage II colon cancer patients was examined by a novel spatial transcriptomics technology with sub-cellular resolution, namely in situ sequencing. A panel of 176 genes investigating specific cancer-associated processes such as apoptosis, proliferation, angiogenesis, stemness, oxidative stress, hypoxia, invasion and components of the tumour microenvironment was designed to examine differentially expressed genes in tissue of relapsed versus non-relapsed patients. Therefore, FFPE slides of 10 colon cancer stage II patients either classified as relapsed (5 patients) or non-relapsed (5 patients) were in situ sequenced and computationally analysed.

Results

We identified a tumour gene signature that enables the subclassification of tissue into neoplastic and non-neoplastic compartments based on spatial expression patterns obtained through in situ sequencing. We developed a computational tool called Genes-To-Count (GTC), which automates the quantification of in situ signals, accurately mapping their position onto the spatial tissue map and automatically identifies neoplastic and non-neoplastic tissue compartments. The GTC tool was used to quantify gene expression of biological processes upregulated within the neoplastic tissue in comparison to non-neoplastic tissue and within relapsed versus non-relapsed stage II colon patients. Three differentially expressed genes (FGFR2, MMP11 and OTOP2) in the neoplastic tissue compartments of relapsed patients in comparison to non-relapsed patients were identified predicting recurrence in stage II colon cancer.

Conclusions

In depth spatial in situ sequencing showed potential to provide a deeper understanding of the underlying mechanisms involved in the recurrence of disease and revealed novel potential predictive biomarkers for disease relapse in colon cancer stage II patients. Our open-access GTC-tool allowed us to accurately capture the tumour compartment and quantify spatial gene expression in colon cancer tissue.
Machine learning algorithms to predict risk of postoperative pneumonia in elderly with hip fracture
Authors: Guo Jiale , He Qionghan , Peng Caiju , Dai Ru , Li Wei , Su Zhichao , Li Yehai
Published: August 2023

Background

Hip fracture (HF) is one of the most common fractures in the elderly and is significantly associated with high mortality and unfavorable prognosis. Postoperative pneumonia (POP), the most common postoperative complication of HF, can seriously affect patient prognosis and increase the burden on the healthcare system. The aim of this study was to develop machine learning models for identifying elderly patients at high risk of pneumonia after hip fracture surgery.

Methods

From May 2016 to November 2022, patients admitted to a single central hospital for HF served as the study population. We extracted data that could be collected within 24 h of patient admission. The dataset was divided into training and validation sets according to 70:30. Based on the screened risk factors, prediction models were developed using seven machine learning algorithms, namely CART, GBM, KNN, LR, NNet, RF, and XGBoost, and their performance was evaluated.

Results

Eight hundred five patients were finally included in the analysis and 75 (9.3%) patients suffered from POP. Age, CI, COPD, WBC, HB, GLU, STB, GLOB, Ka+ which are used as features to build machine learning models. By evaluating the model's AUC value, accuracy, sensitivity, specificity, Kappa value, MCC value, Brier score value, calibration curve, and DCA curve, the model constructed by XGBoost algorithm has the best and near-perfect performance.

Conclusion

The machine learning model we created is ideal for detecting elderly patients at high risk of POP after HF at an early stage.
RNA-binding protein CCDC137 activates AKT signaling and promotes hepatocellular carcinoma through a novel non-canonical role of DGCR8 in mRNA localization
Authors: Tao Shuang , Xie Shu-Juan , Diao Li-Ting , Lv Guo , Hou Ya-Rui , Hu Yan-Xia , Xu Wan-Yi , Du Bin , Xiao Zhen-Dong
Published: August 2023

Background

RNA binding proteins (RBPs)—regulated gene expression play a vital role in various pathological processes, including the progression of cancer. However, the role of RBP in hepatocellular carcinoma (HCC) remains much unknown. In this study, we aimed to explore the contribution of RBP CCDC137 in HCC development.

Methods

We analyzed the altered expression level and clinical significance of CCDC137 in database and HCC specimens. In vitro cell assays and in vivo spontaneous mouse models were used to assess the function of CCDC137. Finally, the molecular mechanisms of how CCDC137 regulates gene expression and promotes HCC was explored.

Results

CCDC137 is aberrantly upregulated in HCC and correlates with poor clinical outcomes in HCC patients. CCDC137 markedly promoted HCC proliferation and progression in vitro and in vivo. Mechanistically, CCDC137 binds with FOXM1, JTV1, LASP1 and FLOT2 mRNAs, which was revealed by APOBEC1-mediated profiling, to increase their cytoplasmic localization and thus enhance their protein expressions. Upregulation of FOXM1, JTV1, LASP1 and FLOT2 subsequently synergistically activate AKT signaling and promote HCC. Interestingly, we found that CCDC137 binds with the microprocessor protein DGCR8 and DGCR8 has a novel non-canonical function in mRNA subcellular localization, which mediates the cytoplasmic distribution of mRNAs regulated by CCDC137.

Conclusions

Our results identify a critical proliferation-related role of CCDC137 and reveal a novel CCDC137/DGCR8/mRNA localization/AKT axis in HCC progression, which provide a potential target for HCC therapy.
Novel corticotropin-releasing hormone receptor genes (CRHR1 and CRHR2) linkage to and association with polycystic ovary syndrome
Authors: Amin Mutaz , Horst Nicholas , Wu Rongling , Gragnoli Claudia
Published: August 2023

Background

Women with polycystic ovarian syndrome (PCOS) have increased hypothalamic–pituitary–adrenal (HPA) axis activation, pro-inflammatory mediators, and psychological distress in response to stressors. In women with PCOS, the corticotropin-releasing hormone (CRH) induces an exaggerated HPA response, possibly mediated by one of the CRH receptors (CRHR1 or CRHR2). Both CRHR1 and CRHR2 are implicated in insulin secretion, and variants in CRHR1 and CRHR2 genes may predispose to the mental-metabolic risk for PCOS.

Methods

We phenotyped 212 Italian families with type 2 diabetes (T2D) for PCOS following the Rotterdam diagnostic criteria. We analyzed within CRHR1 and CRHR2 genes, respectively, 36 and 18 microarray-variants for parametric linkage to and/or linkage disequilibrium (LD) with PCOS under the recessive with complete penetrance (R1) and dominant with complete penetrance (D1) models. Subsequentially, we ran a secondary analysis under the models dominant with incomplete penetrance (D2) and recessive with incomplete penetrance (R2).

Results

We detected 22 variants in CRHR1 and 1 variant in CRHR2 significantly (p < 0.05) linked to or in LD with PCOS across different inheritance models.

Conclusions

This is the first study to report CRHR1 and CRHR2 as novel risk genes in PCOS. In silico analysis predicted that the detected CRHR1 and CRHR2 risk variants promote negative chromatin activation of their related genes in the ovaries, potentially affecting the female cycle and ovulation. However, CRHR1- and CRHR2-risk variants might also lead to hypercortisolism and confer mental-metabolic pleiotropic effects. Functional studies are needed to confirm the pathogenicity of genes and related variants.
Large-scale reference-free analysis of flavivirus sequences in Aedes aegypti whole genome DNA sequencing data
Authors: Spadar Anton , Phelan Jody E. , Clark Taane G. , Campino Susana
Published: August 2023

Flaviviruses are a diverse group of RNA viruses, which include the etiological agents of Zika, dengue and yellow fever that are transmitted by mosquitoes. Flaviviruses do not encode reverse transcriptase and cannot reverse transcribe into DNA, yet DNA sequences of flaviviruses are found both integrated in the chromosomes of Aedes aegypti mosquitoes and as extrachromosomal sequences. We have previously examined the Ae. aegypti reference genome to identify flavivirus integrations and analyzed conservation of these sequences among whole-genome data of 464 Ae. aegypti collected across 10 countries globally. Here, we extended this analysis by identifying flavivirus sequences in these samples independently of the Ae. aegypti reference assembly. Our aim was to identify the complete set of viral sequences, including those absent in the reference genome, and their geographical distribution. We compared the identified sequences using BLASTn and applied machine learning methods to identify clusters of similar sequences. Apart from clusters of sequences that correspond to the four viral integration events that we had previously described, we identified 19 smaller clusters. The only cluster with a strong geographic association consisted of Cell-fusing agent virus-like sequences specific to Thailand. The remaining clusters did not have a geographic association and mostly consisted of near identical short sequences without strong similarity to any known flaviviral genomes. The short read sequencing data did not permit us to determine whether identified sequences were extrachromosomal or integrated into Ae. aegypti chromosomes. Our results suggest that Liverpool strain and field Ae. aegypti mosquitoes have a similar variety of conserved flaviviral DNA, whose functional role should be investigated in follow-up studies.

Graphical Abstract
Post-infectious inflammatory response syndrome in an HIV-negative patient after Cryptococcus gattii meningoencephalitis: a case report and review of the literature
Authors: Lan Jianhua , Lv Luyi , Ye Ling , Wang Tao , Wu Zhiyu , Wu Shugen , Peng Chunxian , Lu Weili , Lu Tao
Published: August 2023

Background

Cryptococcal meningitis (CM) is an inflammatory mycosis of the central nervous system caused by meninge infection or brain parenchyma with Cryptococcus species. It is associated with high morbidity and mortality, and patients with acquired immune deficiency syndrome are particularly susceptible. There have been increasing reports of CM in HIV-negative patients in China over the last few years.

Case presentation

A 31-year-old healthy Chinese male presented with fever and gradually developed headache, projectile vomiting, and other manifestations that were later confirmed as Cryptococcus gattii meningoencephalitis. However, multiple disease changes occurred during the course of treatment, and the regimen was accordingly modified after the diagnosis of post-infectious inflammatory response syndrome (PIIRS). The patient eventually recovered.

Conclusion

There has been a growing trend in the incidence of C. gattii meningoencephalitis in HIV-negative patients. It shows rapid onset and severe prognosis. This case report can provide a reference to treat PIIRS following CM in HIV-negative patients.
Regulation of serotonin production by specific microbes from piglet gut
Authors: Liu Ziyu , Ling Yidan , Peng Yu , Han Shuibing , Ren Yuting , Jing Yujia , Fan Wenlu , Su Yong , Mu Chunlong , Zhu Weiyun
Published: August 2023

Background

Serotonin is an important signaling molecule that regulates secretory and sensory functions in the gut. Gut microbiota has been demonstrated to affect serotonin synthesis in rodent models. However, how gut microbes regulate intestinal serotonin production in piglets remains vague. To investigate the relationship between microbiota and serotonin specifically in the colon, microbial composition and serotonin concentration were analyzed in ileum-cannulated piglets subjected to antibiotic infusion from the ileum when comparing with saline infusion. Microbes that correlated positively with serotonin production were isolated from piglet colon and were further used to investigate the regulation mechanisms on serotonin production in IPEC-J2 and a putative enterochromaffin cell line RIN-14B cells.

Results

Antibiotic infusion increased quantities of Lactobacillus amylovorus (LA) that positively correlated with increased serotonin concentrations in the colon, while no effects observed for Limosilactobacillus reuteri (LR). To understand how microbes regulate serotonin, representative strains of LA, LR, and Streptococcus alactolyticus (SA, enriched in feces from prior observation) were selected for cell culture studies. Compared to the control group, LA, LR and SA supernatants significantly up-regulated tryptophan hydroxylase 1 (TPH1) expression and promoted serotonin production in IPEC-J2 cells, while in RIN-14B cells only LA exerted similar action. To investigate potential mechanisms mediated by microbe-derived molecules, microbial metabolites including lactate, acetate, glutamine, and γ-aminobutyric acid were selected for cell treatment based on computational and metabolite profiling in bacterial supernatant. Among these metabolites, acetate upregulated the expression of free fatty acid receptor 3 and TPH1 while downregulated indoleamine 2,3-dioxygenase 1. Similar effects were also recapitulated when treating the cells with AR420626, an agonist targeting free fatty acid receptor 3.

Conclusions

Overall, these results suggest that Lactobacillus amylovorus showed a positive correlation with serotonin production in the pig gut and exhibited a remarkable ability to regulate serotonin production in cell cultures. These findings provide evidence that microbial metabolites mediate the dialogue between microbes and host, which reveals a potential approach using microbial manipulation to regulate intestinal serotonin biosynthesis.