bluuebunny/crossref_metadata_2025 huggingface dataset:
Targeting NLRP3 signaling reduces myocarditis-induced arrhythmogenesis and cardiac remodeling
Authors: Chin Chye-Gen , Chen Yao-Chang , Lin Fong-Jhih , Lin Yung-Kuo , Lu Yen-Yu , Cheng Tzu-Yu , Chen Shih-Ann , Chen Yi-Jen
Published: April 2024

Background

Myocarditis substantially increases the risk of ventricular arrhythmia. Approximately 30% of all ventricular arrhythmia cases in patients with myocarditis originate from the right ventricular outflow tract (RVOT). However, the role of NLRP3 signaling in RVOT arrhythmogenesis remains unclear.

Methods

Rats with myosin peptide–induced myocarditis (experimental group) were treated with an NLRP3 inhibitor (MCC950; 10 mg/kg, daily for 14 days) or left untreated. Then, they were subjected to electrocardiography and echocardiography. Ventricular tissue samples were collected from each rat’s RVOT, right ventricular apex (RVA), and left ventricle (LV) and examined through conventional microelectrode and histopathologic analyses. In addition, whole-cell patch-clamp recording, confocal fluorescence microscopy, and Western blotting were performed to evaluate ionic currents, intracellular Ca2+ transients, and Ca2+-modulated protein expression in individual myocytes isolated from the RVOTs.

Results

The LV ejection fraction was lower and premature ventricular contraction frequency was higher in the experimental group than in the control group (rats not exposed to myosin peptide). Myocarditis increased the infiltration of inflammatory cells into cardiac tissue and upregulated the expression of NLRP3; these observations were more prominent in the RVOT and RVA than in the LV. Furthermore, experimental rats treated with MCC950 (treatment group) improved their LV ejection fraction and reduced the frequency of premature ventricular contraction. Histopathological analysis revealed higher incidence of abnormal automaticity and pacing-induced ventricular tachycardia in the RVOTs of the experimental group than in those of the control and treatment groups. However, the incidences of these conditions in the RVA and LV were similar across the groups. The RVOT myocytes of the experimental group exhibited lower Ca2+ levels in the sarcoplasmic reticulum, smaller intracellular Ca2+ transients, lower L-type Ca2+ currents, larger late Na+ currents, larger Na+–Ca2+ exchanger currents, higher reactive oxygen species levels, and higher Ca2+/calmodulin-dependent protein kinase II levels than did those of the control and treatment groups.

Conclusion

Myocarditis may increase the rate of RVOT arrhythmogenesis, possibly through electrical and structural remodeling. These changes may be mitigated by inhibiting NLRP3 signaling.
Association between diabetes mellitus and primary restenosis following endovascular treatment: a comprehensive meta-analysis of randomized controlled trials
Authors: Sun Xiaolei , Zhang Cheng , Ma Yarong , He Yanzheng , Zhang Xiaodong , Wu Jianbo
Published: April 2024

Importance

Diabetes mellitus (DM) is thought to be closely related to arterial stenotic or occlusive disease caused by atherosclerosis. However, there is still no definitive clinical evidence to confirm that patients with diabetes have a higher risk of restenosis.

Objective

This meta-analysis was conducted to determine the effect of DM on restenosis among patients undergoing endovascular treatment, such as percutaneous transluminal angioplasty (PTA) or stenting.

Data sources and study selection

The PubMed/Medline, EMBASE and Cochrane Library electronic databases were searched from 01/1990 to 12/2022, without language restrictions. Trials were included if they satisfied the following eligibility criteria: (1) RCTs of patients with or without DM; (2) lesions confined to the coronary arteries or femoral popliteal artery; (3) endovascular treatment via PTA or stenting; and (4) an outcome of restenosis at the target lesion site. The exclusion criteria included the following: (1) greater than 20% of patients lost to follow-up and (2) a secondary restenosis operation.

Data extraction and synthesis

Two researchers independently screened the titles and abstracts for relevance, obtained full texts of potentially eligible studies, and assessed suitability based on inclusion and exclusion criteria.. Disagreements were resolved through consultation with a third researcher. Treatment effects were measured by relative ratios (RRs) with 95% confidence intervals (CIs) using random effects models. The quality of the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria.

Main outcomes and measures

The main observation endpoint was restenosis, including > 50% stenosis at angiography, or TLR of the primary operation lesion during the follow-up period.

Results

A total of 31,066 patients from 20 RCTs were included. Patients with DM had a higher risk of primary restenosis after endovascular treatment (RR = 1.43, 95% CI: 1.25–1.62; p = 0.001).

Conclusions and relevance

This meta-analysis of all currently available RCTs showed that patients with DM are more prone to primary restenosis after endovascular treatment.
Unravelling immune microenvironment features underlying tumor progression in the single-cell era
Authors: Du Qilian , An Qi , Zhang Jiajun , Liu Chao , Hu Qinyong
Published: April 2024

The relationship between the immune cell and tumor occurrence and progression remains unclear. Profiling alterations in the tumor immune microenvironment (TIME) at high resolution is crucial to identify factors influencing cancer progression and enhance the effectiveness of immunotherapy. However, traditional sequencing methods, including bulk RNA sequencing, exhibit varying degrees of masking the cellular heterogeneity and immunophenotypic changes observed in early and late-stage tumors. Single-cell RNA sequencing (scRNA-seq) has provided significant and precise TIME landscapes. Consequently, this review has highlighted TIME cellular and molecular changes in tumorigenesis and progression elucidated through recent scRNA-seq studies. Specifically, we have summarized the cellular heterogeneity of TIME at different stages, including early, late, and metastatic stages. Moreover, we have outlined the related variations that may promote tumor occurrence and metastasis in the single-cell era. The widespread applications of scRNA-seq in TIME will comprehensively redefine the understanding of tumor biology and furnish more effective immunotherapy strategies.
Remnant cholesterol is an effective biomarker for predicting survival in patients with breast cancer
Authors: Shi Jinyu , Liu Tong , Liu Chenan , Zhang Heyang , Ruan Guotian , Xie Hailun , Lin Shiqi , Zheng Xin , Chen Yue , Zhang Qi , Zhang Xiaowei , Li Xiangrui , Liu Xiaoyue , Deng Li , Shi Han-Ping
Published: April 2024

Background

Breast cancer is the most common malignancy in women worldwide. The relationship between remnant cholesterol (RC) and the prognosis of patients with breast cancer has not been clearly reported. This study investigated the prognostic value of RC in predicting mortality in patients with breast cancer.

Methods

This study prospectively analysed 709 women patients with breast cancer from the Investigation on Nutrition Status and Clinical Outcome of Common Cancers (INSCOC) project. Restricted cubic splines were used to analyse the dose-response relationship between RC and breast cancer mortality. The Kaplan–Meier method was used to evaluate the overall survival of patients with breast cancer. A Cox regression analyses was performed to assess the independent association between RC and breast cancer mortality. Inverse probability of treatment weighting (IPTW) using the propensity score was used to reduce confounding. Sensitivity analysis was performed after excluding patients with underlying diseases and survival times shorter than one year.

Results

A linear dose-response relationship was identified between RC and the risk of all-cause mortality in patients with breast cancer (p = 0.036). Kaplan–Meier survival analysis and log-rank test showed that patients with high RC levels had poorer survival than those with low RC levels (p = 0.007). Univariate and multivariate Cox regression analyses showed that RC was an independent risk factor for mortality in women patients with breast cancer. IPTW-adjusted analyses and sensitivity analyses showed that CR remained a prognostic factor.

Conclusions

RC is an independent risk factor for the prognosis of patients with breast cancer, and patients with higher RC levels have poorer survival.
Water, sanitation, and hygiene access among people who inject drugs in Tijuana and San Diego in 2020–2021: a cross-sectional study
Authors: Calderón-Villarreal Alhelí , Avelar Portillo Lourdes Johanna , Abramovitz Daniela , Goldenberg Shira , Flanigan Shawn , Quintana Penelope J. E. , Harvey-Vera Alicia , Vera Carlos F. , Rangel Gudelia , Strathdee Steffanie A. , Kayser Georgia L.
Published: April 2024

Background

Water, sanitation, and hygiene (WASH) access is critical to public health and human dignity. People who inject drugs (PWID) experience stigma and structural violence that may limit WASH access. Few studies have assessed WASH access, insecurity, and inequities among PWID. We describe WASH access, social and geographic inequalities, and factors associated with WASH insecurity among PWID in the Tijuana-San Diego metropolitan area.

Methods

In this cross-sectional binational study, we interviewed PWID (age 18+) in 2020–2021 about WASH access and insecurity. City of residence (Tijuana/San Diego) and housing status were considered as independent variables to describe key WASH access outcomes and to assess as factors associated with WASH insecurity outcomes. Measures of association between outcomes and independent variables were assessed using log modified-Poisson regression models adjusting for covariates.

Results

Of 586 PWID (202 Tijuana; 384 San Diego), 89% reported basic access to drinking water, 38% had basic hand hygiene, 28% basic sanitation, and 46% access to bathing, and 38% reported recent open defecation. Participants residing in Tijuana reported significantly higher insecurity in accessing basic drinking water (aRR: 1.68, 95%CI: 1.02–2.76), basic hygiene (aRR: 1.45, 95%CI: 1.28–1.64), and bathing (aRR: 1.21, 95%CI: 1.06–1.39) than those living in San Diego. Participants experiencing unsheltered homelessness experienced significantly higher insecurity in accessing basic drinking water (aRR: 2.03, 95%CI: 1.07–3.86), basic sanitation (aRR: 1.68, 95%CI: 1.48, 1.92), bathing (aRR: 1.84, 95%CI: 1.52–2.22), and improved water sources for cleaning wounds (aRR: 3.12, 95%CI: 1.55–6.29) and for preparing drugs (aRR: 2.58, 95%CI: 1.36–4.89) than participants living in permanent housing.

Conclusion

WASH access among PWID in the Tijuana-San Diego metropolitan area was low by international standards and lower than the national averages in both countries. Homelessness was significantly associated with WASH insecurity in this population. Concentrated efforts are needed to guarantee continuously available WASH services for PWID—especially those who are unsheltered.
Prognostic and predictive value of tumor deposits in advanced signet ring cell colorectal cancer: SEER database analysis and multicenter validation
Authors: Li Fuchao , Liu Lei , Feng Qingzhao , Wang Xiaohong , Liu Fang , Yang Li , Miao Lin , Wang Weiming , Ji Guozhong , Yu Chenggong
Published: April 2024

Background

Colorectal signet-ring cell carcinoma (SRCC) is a rare cancer with a bleak prognosis. The relationship between its clinicopathological features and survival remains incompletely elucidated. Tumor deposits (TD) have been utilized to guide the N staging in the 8th edition of American Joint Committee on Cancer (AJCC) staging manual, but their prognostic significance remains to be established in colorectal SRCC.

Patients and methods

The subjects of this study were patients with stage III/IV colorectal SRCC who underwent surgical treatment. The research comprised two cohorts: a training cohort and a validation cohort. The training cohort consisted of 631 qualified patients from the SEER database, while the validation cohort included 135 eligible patients from four independent hospitals in China. The study assessed the impact of TD on Cancer-Specific Survival (CSS) and Overall Survival (OS) using Kaplan-Meier survival curves and Cox regression models. Additionally, a prognostic nomogram model was constructed for further evaluation.

Results

In both cohorts, TD-positive patients were typically in the stage IV and exhibited the presence of perineural invasion (PNI) (P < 0.05). Compared to the TD-negative group, the TD-positive group showed significantly poorer CSS (the training cohort: HR, 1.87; 95% CI, 1.52–2.31; the validation cohort: HR, 2.43; 95% CI, 1.55–3.81; all P values < 0.001). This association was significant in stage III but not in stage IV. In the multivariate model, after adjusting for covariates, TD maintained an independent prognostic value (P < 0.05). A nomogram model including TD, N stage, T stage, TNM stage, CEA, and chemotherapy was constructed. Through internal and external validation, the model demonstrated good calibration and accuracy. Further survival curve analysis based on individual scores from the model showed good discrimination.

Conclusion

TD positivity is an independent factor of poor prognosis in colorectal SRCC patients, and it is more effective to predict the prognosis of colorectal SRCC by building a model with TD and other clinically related variables.
Lifestyle behaviors and risk of cardiovascular disease and prognosis among individuals with cardiovascular disease: a systematic review and meta-analysis of 71 prospective cohort studies
Authors: Wu Jian , Feng Yifei , Zhao Yuanyuan , Guo Zhiping , Liu Rongmei , Zeng Xin , Yang Fan , Liu Bei , Gu Jianqing , Tarimo Clifford Silver , Shao Weihao , Guo Xinghong , Li Quanman , Zhao Lipei , Ma Mingze , Shen Zhanlei , Zhao Qiuping , Miao Yudong
Published: April 2024

Background

Healthy lifestyle behaviors (LBs) have been widely recommended for the prevention and management of cardiovascular disease (CVD). Despite a large number of studies exploring the association between combined LBs and CVD, a notable gap exists in integration of relevant literatures. We conducted a systematic review and meta-analysis of prospective cohort studies to analyze the correlation between combined LBs and the occurrence of CVD, as well as to estimate the risk of various health complications in individuals already diagnosed with CVD.

Methods

Articles published up to February 10, 2023 were sourced through PubMed, EMBASE and Web of Science. Eligible prospective cohort studies that reported the relations of combined LBs with pre-determined outcomes were included. Summary relative risks (RRs) and 95% confidence intervals (CIs) were estimated using either a fixed or random-effects model. Subgroup analysis, meta-regression, publication bias, and sensitivity analysis were as well performed.

Results

In the general population, individuals with the healthiest combination of LBs exhibited a significant risk reduction of 58% for CVD and 55% for CVD mortality. For individuals diagnosed with CVD, adherence to the healthiest combination of LBs corresponded to a significant risk reduction of 62% for CVD recurrence and 67% for all-cause mortality, when compared to those with the least-healthy combination of LBs. In the analysis of dose-response relationship, for each increment of 1 healthy LB, there was a corresponding decrease in risk of 17% for CVD and 19% for CVD mortality within the general population. Similarly, among individuals diagnosed with CVD, each additional healthy LB was associated with a risk reduction of 27% for CVD recurrence and 27% for all-cause mortality.

Conclusions

Adopting healthy LBs is associated with substantial risk reduction in CVD, CVD mortality, and adverse outcomes among individuals diagnosed with CVD. Rather than focusing solely on individual healthy LB, it is advisable to advocate for the adoption of multiple LBs for the prevention and management of CVD.

Trial registration

PROSPERO: CRD42023431731.
Assessment of cephalometric parameters and correlation with the severity of the obstructive sleep apnea syndrome
Authors: Garofalo Eugenio , Neri Giuseppe , Perri Lucilla Maria , Lombardo Nicola , Piazzetta Giovanna , Antonelli Alessandro , Biamonte Eugenio , Bosco Vincenzo , Battaglia Caterina , Pelaia Corrado , Manti Francesco , Pitino Annalisa , Tripepi Giovanni , Bruni Andrea , Morelli Michele , Giudice Amerigo , Longhini Federico ,   The OSAS Study authors, Barone Selene , Caroleo Antonio , Corea Angela , Guzzi Giusy , Lentini Lucia , Macheda Sebastiano , Maglio Pietro , Mastrangelo Helenia , Pasqua Alessandra , Salviati Marianna , Tescione Marco
Published: April 2024

Background

In individuals diagnosed with obstructive sleep apnea syndrome (OSAS), variations in craniofacial structure have been inconsistently documented, showing differing degrees of alteration between obese and nonobese patients. In addition, sleep disturbance has also been shown to induce disequilibrium in this population of patients. This pilot observational study aimed to assess craniofacial values in obese and nonobese subpopulations of patients with OSAS and their correlation and association with the severity of OSAS. We also assessed whether OSAS patients are characterized by an impaired equilibrium in relation to and associated with the severity of OSAS.

Methods

We included all consecutive adult patients with OSAS. Through cephalometry, we assessed the upper (UPa-UPp) and lower (LPa-LPp) pharynx diameters, superior anterior facial height (Sor-ANS), anterior facial height (ANS-Me), anterior vertical dimension (Sor-Me), posterior facial height (S-Go) and craniovertebral angle (CVA). Furthermore, we analyzed postural equilibrium through a stabilometric examination.

Results

Forty consecutive OSAS patients (45% female with a mean age of 56 ± 8.2 years) were included. The subgroup of nonobese patients had a reduced UPa-UPp (p = 0.02). Cephalometric measurements were correlated with the severity of OSAS in nonobese patients, whereas only Sor-ANS was correlated with the severity of OSAS in the obese subpopulation. In the overall population, altered craniofacial values are associated with severe OSAS. Although there are differences in equilibrium between obese and nonobese OSAS patients, the stabilometric measurements were not correlated or associated with OSAS severity.

Conclusion

Altered craniofacial values and compromised equilibrium in OSAS patients are linked to OSAS severity. Therefore, the management of OSAS should be tailored not only to weight management but also to craniofacial and postural rehabilitation to enhance patient outcomes.
High uptake of menstrual health information, products and analgesics within an integrated sexual reproductive health service for young people in Zimbabwe
Authors: Tembo Mandikudza , Simms Victoria , Weiss Helen A. , Bandason Tsitsi , Redzo Nicol , Larsson Leyla , Dauya Ethel , Nzanza Tafadzwa , Ishumael Pauline , Gweshe Nancy , Nyamwanza Rangarirai , Ndlovu Precious , Bernays Sarah , Chikwari Chido Dziva , Mavodza Constancia Vimbayi , Renju Jenny , Francis Suzanna C. , Ferrand Rashida A. , Mackworth-Young Constance
Published: April 2024

Background

Despite being integral to women’s well-being, achieving good menstrual health (MH) remains a challenge. This study examined MH services uptake (including information, analgesics, and a choice of MH products - the menstrual cup and reusable pads) and sustained use of MH products within an integrated sexual and reproductive health intervention for young people in Zimbabwe.

Methods

This mixed-methods study was nested within a cluster randomised trial of integrated sexual and reproductive health services (CHIEDZA) for youth in three provinces (Harare, Mashonaland East, and Bulawayo). The study collected qualitative and quantitative data from 27,725 female clients aged 16–24 years, who accessed CHIEDZA from April 2019 – March 2022. Using a biometric (fingerprint recognition) identification system, known as SIMPRINTS, uptake of MH information, products, and analgesics and other services was tracked for each client. Descriptive statistics and logistic regression were used to investigate MH service uptake and product choice and use over time, and the factors associated with these outcomes. Thematic analysis of focus group discussions and interviews were used to further explore providers’ and participants’ experiences of the MH service and CHIEDZA intervention.

Results

Overall, 36,991 clients accessed CHIEDZA of whom 27,725 (75%) were female. Almost all (n = 26,448; 95.4%) took up the MH service at least once: 25433 took up an MH product with the majority (23,346; 92.8%) choosing reusable pads. The uptake of cups varied across province with Bulawayo province having the highest uptake (13.4%). Clients aged 20–24 years old were more likely to choose cups than reusable pads compared with those aged 16–19 years (9.4% vs 6.0%; p < 0.001). Over the implementation period, 300/1819 (16.5%) of clients swapped from the menstrual cup to reusable pads and 83/23346 (0.4%) swapped from reusable pads to the menstrual cup. Provision of the MH service encouraged uptake of other important SRH services. Qualitative findings highlighted the provision of free integrated SRH and MH services that included a choice of MH products and analgesics in a youth-friendly environment were key to high uptake and overall female engagement with SRH services.

Conclusions

High uptake demonstrates how the MH service provided much needed access to MH products and information. Integration of MH within an SRH intervention proved central to young women accessing other SRH services.
Prognostic analysis of radiation-induced liver damage following carbon-ion radiotherapy for hepatocellular carcinoma
Authors: Hayashi Kazuhiko , Suzuki Osamu , Wakisaka Yushi , Ichise Koji , Uchida Hirofumi , Anzai Makoto , Hasegawa Azusa , Seo Yuji , Shimizu Shinichi , Ishii Takayoshi , Teshima Teruki , Fujimoto Jiro , Ogawa Kazuhiko
Published: April 2024

Background

Radiation-induced liver damage (RILD) occasionally occurs following carbon-ion radiotherapy (CIRT) for liver tumors, such as hepatocellular carcinoma (HCC), in patients with impaired liver function disease. However, the associated risk factors remain unknown. The present study aimed to determine the risk factors of RILD after CIRT.

Methods

We retrospectively analyzed 108 patients with HCC treated with CIRT at the Osaka Heavy Ion Therapy Center between December 2018 and December 2022. RILD was defined as a worsening of two or more points in the Child–Pugh score within 12 months following CIRT. The median age of the patients was 76 years (range 47–95 years), and the median tumor diameter was 41 mm (range 5–160 mm). Based on the pretreatment liver function, 98 and 10 patients were categorized as Child–Pugh class A and B, respectively. We analyzed patients who received a radiation dose of 60 Gy (relative biological effectiveness [RBE]) in four fractions. The median follow-up period was 9.7 months (range 2.3–41.1 months), and RILD was observed in 11 patients (10.1%).

Results

Multivariate analysis showed that pretreatment Child–Pugh score B (p = 0.003, hazard ratio [HR] = 6.90) and normal liver volume spared from < 30 Gy RBE (VS30 < 739 cm3) (p = 0.009, HR = 5.22) were significant risk factors for RILD. The one-year cumulative incidences of RILD stratified by Child–Pugh class A or B and VS30 < 739 cm3 or ≥ 739 cm3 were 10.3% or 51.8% and 39.6% or 9.2%, respectively.

Conclusion

In conclusion, the pretreatment Child–Pugh score and VS30 of the liver are significant risk factors for RILD following CIRT for HCC.
The value of knowing: preferences for genetic testing to diagnose rare muscle diseases
Authors: Mansfield Carol , Boeri Marco , Coulter Josh , Baranowski Eileen , Sparks Susan , An Haack Kristina , Hamed Alaa
Published: April 2024

Background

Genetic testing can offer early diagnosis and subsequent treatment of rare neuromuscular diseases. Options for these tests could be improved by understanding the preferences of patients for the features of different genetic tests, especially features that increase information available to patients.

Methods

We developed an online discrete-choice experiment using key attributes of currently available tests for Pompe disease with six test attributes: number of rare muscle diseases tested for with corresponding probability of diagnosis, treatment availability, time from testing to results, inclusion of secondary findings, necessity of a muscle biopsy, and average time until final diagnosis if the first test is negative. Respondents were presented a choice between two tests with different costs, with respondents randomly assigned to one of two costs. Data were analyzed using random-parameters logit.

Results

A total of 600 online respondents, aged 18 to 50 years, were recruited from the U.S. general population and included in the final analysis. Tests that targeted more diseases, required less time from testing to results, included information about unrelated health risks, and were linked to shorter time to the final diagnosis were preferred and associated with diseases with available treatment. Men placed relatively more importance than women on tests for diseases with available treatments. Most of the respondents would be more willing to get a genetic test that might return unrelated health information, with women exhibiting a statistically significant preference. While respondents were sensitive to cost, 30% of the sample assigned to the highest cost was willing to pay $500 for a test that could offer a diagnosis almost 2 years earlier.

Conclusion

The results highlight the value people place on the information genetic tests can provide about their health, including faster diagnosis of rare, unexplained muscle weakness, but also the value of tests for multiple diseases, diseases without treatments, and incidental findings. An earlier time to diagnosis can provide faster access to treatment and an end to the diagnostic journey, which patients highly prefer.
Engineering water exchange is a safe and effective method for magnetic resonance imaging in diverse cell types
Authors: Miller Austin D.C. , Chowdhury Soham P. , Hanson Hadley W. , Linderman Sarah K. , Ghasemi Hannah I. , Miller Wyatt D. , Morrissey Meghan A. , Richardson Chris D. , Gardner Brooke M. , Mukherjee Arnab
Published: April 2024

Aquaporin-1 (Aqp1), a water channel, has garnered significant interest for cell-based medicine and in vivo synthetic biology due to its ability to be genetically encoded to produce magnetic resonance signals by increasing the rate of water diffusion in cells. However, concerns regarding the effects of Aqp1 overexpression and increased membrane diffusivity on cell physiology have limited its widespread use as a deep-tissue reporter. In this study, we present evidence that Aqp1 generates strong diffusion-based magnetic resonance signals without adversely affecting cell viability or morphology in diverse cell lines derived from mice and humans. Our findings indicate that Aqp1 overexpression does not induce ER stress, which is frequently associated with heterologous expression of membrane proteins. Furthermore, we observed that Aqp1 expression had no detrimental effects on native biological activities, such as phagocytosis, immune response, insulin secretion, and tumor cell migration in the analyzed cell lines. These findings should serve to alleviate any lingering safety concerns regarding the utilization of Aqp1 as a genetic reporter and should foster its broader application as a noninvasive reporter for in vivo studies.
Noninvasive prenatal testing for the detection of fetal chromosome 17 microduplication: clinical implications and findings
Authors: Shi Ye , Zheng Fang-xiu , Wang Jing , Zhou Qin , Chen Ying-ping , Zhang Bin
Published: April 2024

Background

 Noninvasive prenatal testing (NIPT) is widely used to screen for fetal aneuploidies. However, there are few reports of using NIPT for screening chromosomal microduplications and microdeletions. This study aimed to investigate the application efficiency of NIPT for detecting chromosomal microduplications.

Methods

Four cases of copy number gains on the long arm of chromosome 17 (17q12) were detected using NIPT and further confirmed using copy number variation (CNV) analysis based on chromosome microarray analysis (CMA).

Results

The prenatal diagnosis CMA results of the three cases showed that the microduplications in 17q12 (ranging from 1.5 to 1.9 Mb) were consistent with the NIPT results. The karyotypic analysis excluded other possible unbalanced rearrangements. The positive predictive value of NIPT for detecting chromosomal 17q12 microduplication was 75.0%.

Conclusions

 NIPT has a good screening effect on 17q12 syndrome through prenatal diagnosis, therefore it could be considered for screening fetal CNV during the second trimester. With the clinical application of NIPT, invasive prenatal diagnoses could be effectively reduced while also improving the detection rate of fetal CNV.
Efficacy and safety of bendamustine for lymphodepletion before lisocabtagene maraleucel
Authors: Ghilardi Guido , Paruzzo Luca , Patel Vrutti , Svoboda Jakub , Chong Emeline R. , Fardella Eugenio , Chong Elise A. , Gabrielli Giulia , Nasta Sunita D. , Landsburg Daniel J. , Carter Jordan , Pajarillo Raymone , Barta Stefan K. , White Griffin , Weber Elizabeth , Napier Ellen , Porter David L. , Garfall Alfred L. , Schuster Stephen J. , Ruella Marco
Published: April 2024

Bendamustine has been retrospectively shown to be an effective and safe lymphodepletion regimen prior to the anti-CD19 chimeric antigen receptor T cell (CART) products tisagenlecleucel and axicabtagene ciloleucel, as well as the anti-BCMA CART products idecabtagene vicleucel and ciltacabtagene autoleucel. However, bendamustine as lymphodepletion prior to lisocabtagene maraleucel (liso-cel), a 4-1BB co-stimulated, fixed CD4:CD8 ratio anti-CD19 CART product, has not been described yet. Thus, we studied a cohort of sequentially-treated patients with large B-cell lymphomas who received bendamustine lymphodepletion before liso-cel at the University of Pennsylvania between 5/2021 and 12/2023 (n = 31). Patients were evaluated for toxicities and responses. Of note, 7 patients (22.6%) would have dnot met the inclusion criteria for the registrational liso-cel clinical trials, mostly due to older age. Overall and complete response rates were 76.9% and 73.1%, respectively. At a median follow-up of 6.3 months, the 6-month progression-free and overall survival were 59.9% and 91.1%, respectively. Rates of cytokine-release syndrome (CRS) and neurotoxicity (ICANS) of any grade were 9.7% and 9.7%, respectively, with no grade ≥ 3 events. No infections were reported during the first 30 days following liso-cel infusion. Neutropenia ≥ grade 3 was observed in 29.0% of patients; thrombocytopenia ≥ grade 3 occurred in 9.7%. In conclusion, bendamustine lymphodepletion before liso-cel appears to be a strategy that can drive tumor responses while ensuring a mild toxicity profile.
Two cases of diquat poisoning in adolescent children
Authors: Duan Mengtao , Yang Baowang , Cheng Xiaohang , Shen Fuhui , Lu Xia , Wang Fan
Published: April 2024

Diquat (DQ) is among the most widely used herbicides, and its intake can cause severe systemic toxicity that manifests rapidly. The resultant symptoms can cause the dysfunction of a range of tissues and organs,. As there is no specific antidote for diquat poisoning and the efficacy of extant treatments is suboptimal, physicians must acquire a more comprehensive understanding of the most effective approaches to managing affected patients. Relative few studies have been published to date focused on diquat poisoning in pediatric patients. In this report, we compare two similar cases of juvenile diquat poisoning with dynamic changes in clinical manifestations, laboratory values, and imaging results. For the first time, the difference in whether to perform blood flow perfusion and the time difference of initiation of hemoperfusion had a clear clinical difference in the subsequent effects of diquat poisoning in children with diquat poisoning. Limited evidence is available regarding the efficacy of early hemoperfusion for diquat poisoning; however, the differences in clinical outcomes articulated here highlight the benefits of early and timely hemoperfusion therapy in the treatment of DQ toxicity in children, in conjunction with primary supportive care in the management of DQ poisoning in children.
Mutations in the NUP93, NUP107 and NUP160 genes cause steroid-resistant nephrotic syndrome in Chinese children
Authors: Han Yanxinli , Sha Hongyu , Yang Yuan , Yu Zhuowei , Zhou Lanqi , Wang Yi , Yang Fengjie , Qiu Liru , Zhang Yu , Zhou Jianhua
Published: April 2024

Background

The variants of nucleoporins are extremely rare in hereditary steroid-resistant nephrotic syndrome (SRNS). Most of the patients carrying such variants progress to end stage kidney disease (ESKD) in their childhood. More clinical and genetic data from these patients are needed to characterize their genotype–phenotype relationships and elucidate the role of nucleoporins in SRNS.

Methods

Four patients of SRNS carrying biallelic variants in the NUP93, NUP107 and NUP160 genes were presented. The clinical and molecular genetic characteristics of these patients were summarized, and relevant literature was reviewed.

Results

All four patients in this study were female and initially presented with SRNS. The median age at the onset of the disease was 5.08 years, ranging from 1 to 10.5 years. Among the four patients, three progressed to ESKD at a median age of 7 years, ranging from 1.5 to 10.5 years, while one patient reached stage 3 chronic kidney disease (CKD3). Kidney biopsies revealed focal segmental glomerulosclerosis in three patients. Biallelic variants were detected in NUP93 in one patient, NUP107 in two patients, as well as NUP160 in one patient respectively. Among these variants, five yielded single amino acid substitutions, one led to nonsense mutation causing premature termination of NUP107 translation, one caused a single nucleotide deletion resulting in frameshift and truncation of NUP107. Furthermore, one splicing donor mutation was observed in NUP160. None of these variants had been reported previously.

Conclusion

This report indicates that biallelic variants in NUP93, NUP107 and NUP160 can cause severe early-onset SRNS, which rapidly progresses to ESKD. Moreover, these findings expand the spectrum of phenotypes and genotypes and highlight the importance of next-generation sequencing in elucidating the molecular basis of SRNS and allowing rational treatment for affected individuals.
The translocator protein 18kDa ligand etifoxine in the treatment of depressive disorders—a double-blind, randomized, placebo-controlled proof-of-concept study
Authors: Brunner Lisa-Marie , Riebel Marco , Wein Simon , Koller Michael , Zeman Florian , Huppertz Gunnar , Emmer Tanja , Eberhardt Yvonne , Schwarzbach Jens , Rupprecht Rainer , Nothdurfter Caroline
Published: April 2024

Background

Recent developments suggest that neurosteroids may achieve rapid antidepressant effects. As such, neurosteroidogenesis mediated by the translocator protein 18 kDa (TSPO) might constitute a promising option for the treatment of depression. Therefore, the current clinical trial aims to get the first evidence of whether TPSO ligands promote rapid antidepressant effects. Furthermore, we study which mechanisms of action, e.g., modulation of distinct neuronal networks, neurosteroidogenesis, endocrinological mechanisms, TSPO expression or microbiome composition, contribute to their putative antidepressant effects.

Methods

This is a randomized, placebo-controlled, double-blind single-center trial of 2-week treatment with the TSPO ligand etifoxine versus placebo in depressive patients. Main eligibility criteria: male or female individuals aged 18 to 65 years with unipolar/bipolar depressive disorder with no other psychiatric main diagnosis or acute neurological/somatic disorder or drug/alcohol dependence during their lifetime.

The primary endpoint is the time point at which 50% of the maximal effect has occurred (ET50) estimated by the scores of the Hamilton Depression Scale (HAMD-21). A total of 20 patients per group are needed to detect changes of therapeutic efficacy about 5% and changes of ET50 about 10% with a power of 70%. Assuming a drop-out rate of 10–20%, 50 patients will be randomized in total. The study will be conducted at the Department of Psychiatry and Psychotherapy of the University of Regensburg.

Discussion

This study will provide a first proof-of-concept on the potential of the TSPO ligand etifoxine in the treatment of depressive disorders.

Trial registration

Clinical Trials Register (EudraCT number: 2021-006773-38, registration date: 14 September 2022) and German Register of Clinical Studies (DRKS number: DRKS00031099, registration date: 23 January 2023).
Impact of the COVID-19 pandemic on utilization and cost for care of pediatric and young adult ALL
Authors: Hoover Alex , Watson Dave , Reimche Paige , Tanner Lynn , Gilchrist Laura , Finch Mike , Messinger Yoav H , Turcotte Lucie M.
Published: April 2024

Objective

Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy and among the most common malignancies in young adults and requires a unique pattern of healthcare utilization including an acute/emergent presentation and an intensive initial 8 months of therapy followed by two years of outpatient treatment. The COVID-19 pandemic caused massive global disruptions in healthcare use and delivery. This report aims to examine the effects of the COVID-19 pandemic on the presentation, diagnosis and continued management of childhood and young adult ALL in regard to utilization and cost of care among commercially insured individuals in the United States.

Results

Utilizing a commercial insurance claims database, 529 pediatric and young adult patients were identified who were diagnosed with ALL between January 2016 and March 2021. New diagnoses were evaluated by era and demographics. Utilization was measured by COVID-related era as number of inpatient and outpatient encounters, inpatient days, and cumulative cost during the initial 8 months of therapy. None of these cost or utilization factors changed significantly during or shortly after the pandemic. These findings reinforce that the necessary care for pediatric and young adult ALL was unwavering despite the massive shifts in the healthcare system caused by the COVID-19 pandemic. This provides a valuable benchmark as we further examine the factors that influence the pandemic’s impact on health equity and access to care, especially in vulnerable pediatric and young adult populations. This is the first investigation of the effect of the COVID-19 pandemic on utilization and cost of care in pediatric and young adult cancer.
Fixed point results for Geraghty–Ćirić-type contraction mappings in b-metric space with applications
Authors: Kalo Albray Gebremariam , Tola Kidane Koyas , Yesuf Haider Ebrahim
Published: April 2024

In this study, we manifest a new class of mappings that satisfy Geraghty–Ćirić-type contractive conditions in the context of b-metric spaces and prove a theorem on the existence and uniqueness of fixed points. Our results unify and generalize the results of Geraghty; Ćirić; Dukic, Kadelburg, and Radenović; and Shu-fang Li, Fei Hi, and Ning Lu in the setting of b-metric spaces. Furthermore, we provide examples to verify the correctness and applicability of our results. We also utilize our findings to show the existence of a unique solution for a nonlinear integral equation.
Unveilling genetic profiles and correlations of biofilm-associated genes, quorum sensing, and antibiotic resistance in Staphylococcus aureus isolated from a Malaysian Teaching Hospital
Authors: Chan Yun Li , Chee Chin Fei , Tang Soo Nee , Tay Sun Tee
Published: April 2024

Background

Staphylococcus aureus is a notorious multidrug resistant pathogen prevalent in healthcare facilities worldwide. Unveiling the mechanisms underlying biofilm formation, quorum sensing and antibiotic resistance can help in developing more effective therapy for S. aureus infection. There is a scarcity of literature addressing the genetic profiles and correlations of biofilm-associated genes, quorum sensing, and antibiotic resistance among S. aureus isolates from Malaysia.

Methods

Biofilm and slime production of 68 methicillin-susceptible S. aureus (MSSA) and 54 methicillin-resistant (MRSA) isolates were determined using a a plate-based crystal violet assay and Congo Red agar method, respectively. The minimum inhibitory concentration values against 14 antibiotics were determined using VITEK® AST-GP67 cards and interpreted according to CLSI-M100 guidelines. Genetic profiling of 11 S. aureus biofilm-associated genes and agr/sar quorum sensing genes was performed using single or multiplex polymerase chain reaction (PCR) assays.

Results

In this study, 75.9% (n = 41) of MRSA and 83.8% (n = 57) of MSSA isolates showed strong biofilm-forming capabilities. Intermediate slime production was detected in approximately 70% of the isolates. Compared to MSSA, significantly higher resistance of clindamycin, erythromycin, and fluoroquinolones was noted among the MRSA isolates. The presence of intracellular adhesion A (icaA) gene was detected in all S. aureus isolates. All MSSA isolates harbored the laminin-binding protein (eno) gene, while all MRSA isolates harbored intracellular adhesion D (icaD), clumping factors A and B (clfA and clfB) genes. The presence of agrI and elastin-binding protein (ebpS) genes was significantly associated with biofilm production in MSSA and MRSA isolates, respectively. In addition, agrI gene was also significantly correlated with oxacillin, cefoxitin, and fluoroquinolone resistance.

Conclusions

The high prevalence of biofilm and slime production among MSSA and MRSA isolates correlates well with the detection of a high prevalence of biofilm-associated genes and agr quorum sensing system. A significant association of agrI gene was found with cefoxitin, oxacillin, and fluoroquinolone resistance. A more focused approach targeting biofilm-associated and quorum sensing genes is important in developing new surveillance and treatment strategies against S. aureus biofilm infection.
Blocking group 2 innate lymphoid cell activation and macrophage M2 polarization: potential therapeutic mechanisms in ovalbumin-induced allergic asthma by calycosin
Authors: Tian Chunyan , Liu Qi , Zhang Xiaoyu , Li Zhuying
Published: April 2024

Background

Calycosin, a flavonoid compound extracted from Astragalus membranaceus, has shown anti-asthma benefits in house dust mite-induced asthma. Recent studies have suggested that innate-type cells, including group 2 innate lymphoid cells (ILC2s) and macrophages, serve as incentives for type 2 immunity and targets for drug development in asthma. This work focuses on the effects of calycosin on the dysregulated ILC2s and macrophages in allergic asthma.

Methods

In vivo, the asthmatic mouse model was established with ovalbumin (OVA) sensitization and challenge, and calycosin was intraperitoneally administered at doses of 20 and 40 mg/kg. In vivo, mouse primary ILC2s were stimulated with interleukin (IL)-33 and mouse RAW264.7 macrophages were stimulated with IL-4 and IL-13 to establish the cell models. Cells were treated with calycosin at doses of 5 and 10 µM.

Results

In vivo, we observed significantly reduced numbers of eosinophils, neutrophils, monocyte macrophages and lymphocytes in the bronchoalveolar lavage fluid (BALF) of OVA-exposed mice with 40 mg/kg calycosin. Histopathological assessment showed that calycosin inhibited the airway inflammation and remodeling caused by OVA. Calycosin markedly decreased the up-regulated IL-4, IL-5, IL-13, IL-33, and suppression tumorigenicity 2 (ST2) induced by OVA in BALF and/or lung tissues of asthmatic mice. Calycosin repressed the augment of arginase 1 (ARG1), IL-10, chitinase-like 3 (YM1) and mannose receptor C-type 1 (MRC1) levels in the lung tissues of asthmatic mice. In vivo, calycosin inhibited the IL-33-induced activation as well as the increase of IL-4, IL-5, IL-13 and ST2 in ILC2s. Calycosin also repressed the increase of ARG1, IL-10, YM1 and MRC1 induced by IL-4 and IL-13 in RAW264.7 macrophages. In addition, we found that these changes were more significant in 40 mg/kg calycosin treatment than 20 mg/kg calycosin.

Conclusions

Collectively, this study showed that calycosin might attenuate OVA-induced airway inflammation and remodeling in asthmatic mice via preventing ILC2 activation and macrophage M2 polarization. Our study might contribute to further study of asthmatic therapy.
Knowledge, attitudes, and practices related to dietary salt among older adults in Abha, Saudi Arabia
Authors: Alhazmi Amani , Hawash Manal Mohammed , Ali Haroon , Narapureddy Bayapa Reddy , Aziz Farah
Published: April 2024

The need to foster successful aging has intensified with the aging of the global population. This study aimed to assess the knowledge, attitudes, and practices (KAP) concerning dietary salt consumption and to investigate the correlations between sociodemographic variables and salt-related KAP. A structured interview was administered to a cohort of 200 older adults in Abha City, Saudi Arabia, recruited through a convenience sampling approach. The evaluation of salt-related KAP revealed widespread low knowledge (91.5%) as participants scored less than 3, negative attitudes (85.5%) scored less than 12, and predominantly unsatisfactory practices (69.5%) with scores less than 26. Noteworthy differences emerged between participants with poor overall KAP (81.5%) and those with good KAP (18.5%). Significantly weak negative correlations were found between age (r=-0.212), marital status (-0.236), and body mass index (-0.243) with overall KAP. Further examination revealed a significantly weak positive correlation between attitude and practice (r = 0.141). KAP scores show a highly significant positive correlation with overall KAP scores (r = 0.169, 0.352, 0.969). The uncovered correlations contribute to a valuable understanding of the complex dynamics surrounding salt-related KAP. This understanding guides the design of targeted interventions, such as health education programs, promoting successful aging and public health outcomes.
Comparison of canine colostrum and milk using a multi-omics approach
Authors: Cohen Alisa , Turjeman Sondra , Levin Rachel , Tal Smadar , Koren Omry
Published: April 2024

Background

A mother’s milk is considered the gold standard of nutrition in neonates and is a source of cytokines, immunoglobulins, growth factors, and other important components, yet little is known about the components of canine milk, specifically colostrum, and the knowledge related to its microbial and metabolic profiles is particularly underwhelming. In this study, we characterized canine colostrum and milk microbiota and metabolome for several breeds of dogs and examined profile shifts as milk matures in the first 8 days post-whelping.

Results

Through untargeted metabolomics, we identified 63 named metabolites that were significantly differentially abundant between days 1 and 8 of lactation. Surprisingly, the microbial compositions of the colostrum and milk, characterized using 16S rRNA gene sequencing, were largely similar, with only two differentiating genera. The shifts observed, mainly increases in several sugars and amino sugars over time and shifts in amino acid metabolites, align with shifts observed in human milk samples and track with puppy development.

Conclusion

Like human milk, canine milk composition is dynamic, and shifts are well correlated with developing puppies’ needs. Such a study of the metabolic profile of canine milk, and its relation to the microbial community, provides insights into the changing needs of the neonate, as well as the ideal nutrition profile for optimal functionality. This information will add to the existing knowledge base of canine milk composition with the prospect of creating a quality, tailored milk substitute or supplement for puppies.