bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of early clinical outcome in carpal tunnel release - mini-open technique with palmar incision vs. endoscopic technique with wrist crease incision-
Authors: Nakamichi Ryo , Saito Taichi , Shimamura Yasunori , Hamada Masanori , Nishida Keiichiro , Ozaki Toshifumi
Published: April 2024

Background

The purpose of this study was to examine two techniques for Carpal Tunnel Syndrome, mini-Open Carpal Tunnel Release (mini-OCTR) and Endoscopic Carpal Tunnel Release (ECTR), to compare their therapeutic efficacy.

Methods

Sixteen patients who underwent mini-OCTR in palmar incision and 17 patients who underwent ECTR in the wrist crease incision were included in the study. All patients presented preoperatively and at 1, 3, and 6 months postoperatively and were assessed with the Visual Analogue Scale (VAS) and the Disabilities of Arm, Shoulder and Hand Score (DASH). We also assessed the pain and cosmetic VAS of the entire affected hand or surgical wound, and the patient’s satisfaction with the surgery.

Results

In the objective evaluation, both surgical techniques showed improvement at 6 months postoperatively. The DASH score was significantly lower in the ECTR group (average = 3 months: 13.6, 6 months: 11.9) than in the mini-OCTR group (average = 3 months: 27.3, 6 months: 20.6) at 3 and 6 months postoperatively. Also, the pain VAS score was significantly lower in the ECTR group (average = 17.1) than in the mini-OCTR group (average = 36.6) at 3 months postoperatively. The cosmetic VAS was significantly lower in the ECTR group (average = 1 month: 15.3, 3 months: 12.2, 6 months: 5.41) than in the mini-OCTR group (average = 1 month: 33.3, 3 months: 31.2, 6 months: 24.8) at all time points postoperatively. Patient satisfaction scores tended to be higher in the ECTR group (average = 3.3) compared to the mini-OCTR group (average = 2.7).

Conclusions

ECTR in wrist increase incision resulted in better pain and cosmetic recovery in an early postoperative phase compared with mini-OCTR in palmar incision. Our findings suggest that ECTR is an effective technique for patient satisfaction.
Specific lipid magnetic sphere sorted CD146-positive bone marrow mesenchymal stem cells can better promote articular cartilage damage repair
Authors: Ren Hanru , Zhang Lele , Zhang Xu , Yi Chengqing , Wu Lianghao
Published: April 2024

Background

The characteristics and therapeutic potential of subtypes of bone marrow mesenchymal stem cells (BMSCs) are largely unknown. Also, the application of subpopulations of BMSCs in cartilage regeneration remains poorly characterized. The aim of this study was to explore the regenerative capacity of CD146-positive subpopulations of BMSCs for repairing cartilage defects.

Methods

CD146-positive BMSCs (CD146 + BMSCs) were sorted by self-developed CD146-specific lipid magnetic spheres (CD146-LMS). Cell surface markers, viability, and proliferation were evaluated in vitro. CD146 + BMSCs were subjected to in vitro chondrogenic induction and evaluated for chondrogenic properties by detecting mRNA and protein expression. The role of the CD146 subpopulation of BMSCs in cartilage damage repair was assessed by injecting CD146 + BMSCs complexed with sodium alginate gel in the joints of a mouse cartilage defect model.

Results

The prepared CD146-LMS had an average particle size of 193.7 ± 5.24 nm, an average potential of 41.9 ± 6.21 mv, and a saturation magnetization intensity of 27.2 Am2/kg, which showed good stability and low cytotoxicity. The sorted CD146 + BMSCs highly expressed stem cell and pericyte markers with good cellular activity and cellular value-added capacity. Cartilage markers Sox9, Collagen II, and Aggrecan were expressed at both protein and mRNA levels in CD146 + BMSCs cells after chondrogenic induction in vitro. In a mouse cartilage injury model, CD146 + BMSCs showed better function in promoting the repair of articular cartilage injury.

Conclusion

The prepared CD146-LMS was able to sort out CD146 + BMSCs efficiently, and the sorted subpopulation of CD146 + BMSCs had good chondrogenic differentiation potential, which could efficiently promote the repair of articular cartilage injury, suggesting that the sorted CD146 + BMSCs subpopulation is a promising seed cell for cartilage tissue engineering.
The employment of art therapy to develop empathy and foster wellbeing for junior doctors in a palliative medicine rotation - a qualitative exploratory study on acceptability
Authors: Ong Eng-Koon , Tan U-Tong Emily , Chiam Min , Sim Wen Shan
Published: April 2024

Background

The interdisciplinary realm of medical humanities explores narratives and experiences that can enhance medical education for physicians through perspective-taking and reflective practice. However, there is a gap in comprehension regarding its appropriateness at the postgraduate level, especially when utilising art therapists as faculty. This study aims to assess the acceptability of an innovative art therapy-focused educational initiative among junior doctors during a palliative care rotation, with the goal of cultivating empathy and promoting well-being.

Methods

A qualitative research project was conducted at the Division of Supportive and Palliative Care (DSPC) in the National Cancer Centre Singapore (NCCS). The study involved the recruitment of junior doctors who had successfully completed a three-month palliative care rotation program, spanning from January 2020 to April 2021. In a single small-group session lasting 1.5 h, with 3 to 4 participants each time, the individuals participated in activities such as collage making, group reflection, and sharing of artistic creations. These sessions were facilitated by an accredited art therapist and a clinical psychologist, focusing on themes related to empathy and wellbeing. To assess the acceptability of the program, two individual interviews were conducted three months apart with each participant. An independent research assistant utilised a semi-structured question guide that considered affective attitude, burden, perceived effectiveness, coherence, and self-efficacy. Thematic analysis of the transcribed data was then employed to scrutinise the participants’ experiences.

Results

A total of 20 individual interviews were completed with 11 participants. The three themes identified were lack of pre-existing knowledge of the humanities, promotors, and barriers to program acceptability.

Conclusions

The participants have mixed perceptions of the program’s acceptability. While all completed the program in its entirety, the acceptability of the program is impeded by wider systemic factors such as service and manpower needs. It is vital to address these structural limitations as failing to do so risks skewing current ambivalence towards outright rejection of future endeavours to integrate humanities programs into medical education.
Providing holistic end-of-life care for people with a history of problem substance use: a mixed methods cohort study of interdisciplinary service provision and integrated care
Authors: Webb Lucy , Yarwood Gemma , Witham Gary , Wright Sam , Galvani Sarah
Published: April 2024

Harmful use of illicit drugs and/or alcohol is linked to life-limiting illness and complex health and social care needs, but people who use substances and have complex needs do not receive timely palliative care and fail to achieve quality standards for a good death. They and their families often require support from multiple health and social care services which are shown to be poorly integrated and fail to deliver interdisciplinary care. This study aimed to identify the existing barriers and facilitators within and between services in providing this population with a good death. Using a mixed methods approach of survey, focus groups and semi-structured interviews, we explored the perspectives of practitioner and management staff across a range of health and social disciplines and organisations in one combined authority in a large city in the north west of England. Our findings indicate that practitioners want to provide better care for this client group, but face structural, organisational and professional boundary barriers to delivering integrated and shared care. Differences in philosophy of care, piecemeal commissioning and funding of services, and regulatory frameworks for different services, lead to poor and inequitable access to health and social care services. Ways forward for improving care are suggested as bespoke hostel-based accommodation for palliative care for this client group, and specialist link workers who can transcend professional and organisational boundaries to support co-ordination of services and support. We conclude that it is no longer adequate to call for more training, better communication and improved joint working. Complex care at the end of life requires creative and cohesive systemic responses that enable multi-disciplinary practitioners to provide the care they wish to give and enables individuals using substances to get the respect and quality service they deserve.
Effects of hysteroscopic septum incision versus expectant management on IVF outcomes in women with complete septate uterus: a retrospective study
Authors: Zhang Jiajia , Kang Jia , Song Xueling , Yang Shuo , Yang Yan , Qiao Jie , Ma Caihong
Published: March 2024

Objective

This retrospective study aimed to assess the impact of hysteroscopic septum incision on in vitro fertilization (IVF) outcomes among infertile women diagnosed with a complete septate uterus and no history of recurrent pregnancy loss.

Methods

The study was conducted at a tertiary reproductive center affiliated with a university hospital and involved 78 women with a complete septate uterus. Among them, 34 women underwent hysteroscopic septum incision, while 44 women opted for expectant management. The primary outcome measure was the live birth rate, while secondary outcomes included clinical pregnancy rate, preterm birth rate, miscarriage rate, and ongoing pregnancy rate.

Results

Women who underwent hysteroscopic septum incision demonstrated a comparable likelihood of achieving a live birth compared to those managed expectantly (25% vs. 25%, Relative Risk (RR): 1.000, 95% Confidence Interval (CI): 0.822 to 1.216). No preterm births occurred in either group. The clinical pregnancy rate, ongoing pregnancy rate, and miscarriage rate showed no significant differences between the surgical group and the expectant management group. Subgroup analyses based on the type of embryo transferred also revealed no significant differences in outcomes.

Conclusions

Hysteroscopic septum incision does not appear to yield improved IVF outcomes compared to expectant management in infertile women with a complete septate uterus and no history of recurrent pregnancy loss.
Relationship between depression and burnout among nurses in Intensive Care units at the late stage of COVID-19: a network analysis
Authors: Zhang Yinjuan , Wu Chao , Ma Jin , Liu Fang , Shen Chao , Sun Jicheng , Ma Zhujing , Hu Wendong , Lang Hongjuan
Published: April 2024

Background

Mental health problems are critical and common in medical staff working in Intensive Care Units (ICU) even at the late stage of COVID-19, particularly for nurses. There is little research to explore the inner relationships between common syndromes, such as depression and burnout. Network analysis (NA) was a novel approach to quantified the correlations between mental variables from the perspective of mathematics. This study was to investigate the interactions between burnout and depression symptoms through NA among ICU nurses.

Method

A cross-sectional study with a total of 616 Chinese nurses in ICU were carried out by convenience sampling from December 19, 2022 to January19, 2023 via online survey. Burnout symptoms were measured by Maslach Burnout Inventory-General Survey (MBI-GS) (Chinese version), and depressive symptoms were assessed by the 9-item Patient Health Questionnaire (PHQ-9). NA was applied to build interactions between burnout and depression symptoms. We identified central and bridge symptoms by R package qgraph in the network model. R package bootnet was used to examined the stability of network structure.

Results

The prevalence of burnout and depressive symptoms were 48.2% and 64.1%, respectively. Within depression-burnout network, PHQ4(Fatigue)-MBI2(Used up) and PHQ4(Fatigue)-MBI5(Breakdown) showed stronger associations. MBI2(Used up) had the strongest expected influence central symptoms, followed by MBI4(Stressed) and MBI7 (Less enthusiastic). For bridge symptoms. PHQ4(Fatigue), MBI5(Breakdown) and MBI2(Used up) weighed highest. Both correlation stability coefficients of central and bridge symptoms in the network structure were 0.68, showing a high excellent level of stability.

Conclusion

The symptom of PHQ4(Fatigue) was the bridge to connect the emotion exhaustion and depression. Targeting this symptom will be effective to detect mental disorders and relieve mental syndromes of ICU nurses at the late stage of COVID-19 pandemic.
Genetic toolbox for Photorhabdus and Xenorhabdus: pSEVA based heterologous expression systems and CRISPR/Cpf1 based genome editing for rapid natural product profiling
Authors: Rill Alexander , Zhao Lei , Bode Helge B.
Published: April 2024

Background

Bacteria of the genus Photorhabdus and Xenorhabdus are motile, Gram-negative bacteria that live in symbiosis with entomopathogenic nematodes. Due to their complex life cycle, they produce a large number of specialized metabolites (natural products) encoded in biosynthetic gene clusters (BGC). Genetic tools for Photorhabdus and Xenorhabdus have been rare and applicable to only a few strains. In the past, several tools have been developed for the activation of BGCs and the deletion of individual genes. However, these often have limited efficiency or are time consuming. Among the limitations, it is essential to have versatile expression systems and genome editing tools that could facilitate the practical work.

Results

In the present study, we developed several expression vectors and a CRISPR-Cpf1 genome editing vector for genetic manipulations in Photorhabdus and Xenorhabdus using SEVA plasmids. The SEVA collection is based on modular vectors that allow exchangeability of different elements (e.g. origin of replication and antibiotic selection markers with the ability to insert desired sequences for different end applications). Initially, we tested different SEVA vectors containing the broad host range origins and three different resistance genes for kanamycin, gentamycin and chloramphenicol, respectively. We demonstrated that these vectors are replicative not only in well-known representatives, e.g. Photorhabdus laumondii TTO1, but also in other rarely described strains like Xenorhabdus sp. TS4. For our CRISPR/Cpf1-based system, we used the pSEVA231 backbone to delete not only small genes but also large parts of BGCs. Furthermore, we were able to activate and refactor BGCs to obtain high production titers of high value compounds such as safracin B, a semisynthetic precursor for the anti-cancer drug ET-743.

Conclusions

The results of this study provide new inducible expression vectors and a CRISPR/CPf1 encoding vector all based on the SEVA (Standard European Vector Architecture) collection, which can improve genetic manipulation and genome editing processes in Photorhabdus and Xenorhabdus.
“Metabolic burden” explained: stress symptoms and its related responses induced by (over)expression of (heterologous) proteins in Escherichia coli
Authors: Snoeck Sofie , Guidi Chiara , De Mey Marjan
Published: March 2024

Background

Engineering bacterial strains to redirect the metabolism towards the production of a specific product has enabled the development of industrial biotechnology. However, rewiring the metabolism can have severe implications for a microorganism, rendering cells with stress symptoms such as a decreased growth rate, impaired protein synthesis, genetic instability and an aberrant cell size. On an industrial scale, this is reflected in processes that are not economically viable.

Main text

In literature, most stress symptoms are attributed to “metabolic burden”, however the actual triggers and stress mechanisms involved are poorly understood. Therefore, in this literature review, we aimed to get a better insight in how metabolic engineering affects Escherichia coli and link the observed stress symptoms to its cause. Understanding the possible implications that chosen engineering strategies have, will help to guide the reader towards optimising the envisioned process more efficiently.

Conclusion

This review addresses the gap in literature and discusses the triggers and effects of stress mechanisms that can be activated when (over)expressing (heterologous) proteins in Escherichia coli. It uncovers that the activation of the different stress mechanisms is complex and that many are interconnected. The reader is shown that care has to be taken when (over)expressing (heterologous) proteins as the cell’s metabolism is tightly regulated.
Circulating ceramide levels and ratios in Emirati youth under 18 years: associations with cardiometabolic risk factors
Authors: Shalaby Youssef M. , Al-Zohily Bashar , Raj Anjana , Yasin Javed , Al Hamad Sania , Antoniades Charalambos , Akawi Nadia , Aburawi Elhadi H.
Published: April 2024

Background

Circulating ceramide (Cer) drives various pathological processes associated with cardiovascular diseases, liver illness, and diabetes mellitus. Although recognized as predictors of cardiometabolic diseases (CMD) in research and clinical settings, their potential for predicting CMD risk in individuals under 18 remains unexplored.

Objectives

This study was designed to utilize Liquid Chromatography-Mass Spectrometry (LC-MS/MS) methodology to determine the biological reference ranges for Cer in plasma samples of Emirati children and develop a risk assessment score (CERT-1) based on Cer concentrations.

Methods

Using LC-MS/MS, we developed a method to measure five Cer species in plasma samples of 582 Emirati participants aged 5–17. We used the circulating concentrations of these Cer to determine their reference intervals in this population. We employed traditional statistical analyses to develop a risk score (CERT-1) and assess the association between Cer levels and conventional biomarkers of CMD.

Results

We validated a high-throughput methodology using LC–MS/MS to quantify five Cer species in human plasma. Reference values for this population (n = 582) were quantified: CerC16:0 (0.12–0.29 µmol/L), CerC18:0 (0.019–0.067 µmol/L), CerC22:0 (0.102–0.525 µmol/L), CerC24:0 (0.65–1.54 µmol/L) and CerC24:1 (0.212–0.945 µmol/L). We devised a risk assessment score (CERT-1) based on plasma Cer content in the study participants, showing that 72.5% have low to moderate risk and 9.3% are at a higher risk of developing CMD. Our analyses also revealed a significant correlation (P < 0.05) between this score and the conventional risk factors linked to CMD, indicating its potential clinical implication.

Conclusion

This study presents a clinical-scaled LC–MS/MS methodology for assessing clinically relevant Cer, setting reference ranges, and developing a risk score (CERT-1) for young Emirati individuals. Our findings can enhance primary risk prediction and inform the management and follow-up of CMD from an early age.
Acceptability of a pilot motivational interviewing intervention at public health facilities to improve the HIV treatment cascade among people who inject drugs in Indonesia
Authors: Wongso Lydia V. , Rahadi Arie , Sukmaningrum Evi , Handayani Miasari , Wisaksana Rudi
Published: April 2024

Background

HIV-positive people who inject drugs (PWID) experience challenges in initiating and adhering to antiretroviral treatment (ART). Counselling using motivational interviewing (MI) techniques may help them formulate individualised strategies, and execute actions to address these challenges collaboratively with their providers. We evaluated the acceptability of MI from a pilot implementation at three public health facilities in Indonesia.

Methods

Adapting the acceptability constructs developed by Sekhon (2017) we assessed the acceptability to HIV-positive PWID clients (n = 12) and providers (n = 10) in four synthesised constructs: motivation (attributes that inspire engagement); cost consideration (sacrifices made to engage in MI); learned understanding (mechanism of action); and outcomes (ability to effect change with engagement). We included all providers and clients who completed ≥ 2 MI encounters. Qualitative analysis with an interpretive paradigm was used to extract and categorise themes by these constructs.

Results

In motivation, clients valued the open communication style of MI, while providers appreciated its novelty in offering coherent structure with clear boundaries. In cost consideration, both groups faced a challenge in meeting MI encounters due to access or engagement in other health care areas. In learned understanding, clients understood that MI worked to identify problematic areas of life amenable to change to support long-term ART, with reconciliation in family life being the most targeted change. By contrast, providers preferred targeting tangible health outcomes to such behavioural proxies. In outcomes, clients were confident in their ability to develop behaviours to sustain ART uptakes, whereas providers doubted the outcome of MI on younger PWID or those with severe dependence.

Conclusions

There is broad acceptability of MI in motivating engagement for both actors. Relative to providers, clients were more acceptable in its mechanism and had greater confidence to perform behaviours conducive to ART engagement. Design innovations to improve the acceptability of MI for both actors are needed.
MicroRNA-21a-5p inhibition alleviates systemic sclerosis by targeting STAT3 signaling
Authors: Park Jin-Sil , Kim Chongtae , Choi JeongWon , Jeong Ha Yeon , Moon Young-Mee , Kang Hoin , Lee Eun Kyung , Cho Mi-La , Park Sung-Hwan
Published: April 2024

Background

MicroRNA (miRNA)-21-5p participates in various biological processes, including cancer and autoimmune diseases. However, its role in the development of fibrosis in the in vivo model of systemic sclerosis (SSc) has not been reported. This study investigated the effects of miRNA-21a-5p overexpression and inhibition on SSc fibrosis using a bleomycin-induced SSc mouse model.

Methods

A murine SSc model was induced by subcutaneously injecting 100 μg bleomycin dissolved in 0.9% NaCl into C57BL/6 mice daily for 5 weeks. On days 14, 21, and 28 from the start of bleomycin injection, 100 μg pre-miRNA-21a-5p or anti-miRNA-21a-5p in 1 mL saline was hydrodynamically injected into the mice. Fibrosis analysis was conducted in lung and skin tissues of SSc mice using hematoxylin and eosin as well as Masson’s trichrome staining. Immunohistochemistry was used to examine the expression of inflammatory cytokines, phosphorylated signal transducer and activator of transcription-3 (STAT3) at Y705 or S727, and phosphatase and tensin homologue deleted on chromosome-10 (PTEN) in skin tissues of SSc mice.

Results

MiRNA-21a-5p overexpression promoted lung fibrosis in bleomycin-induced SSc mice, inducing infiltration of cells expressing TNF-α, IL-1β, IL-6, or IL-17, along with STAT3 phosphorylated cells in the lesional skin. Conversely, anti-miRNA-21a-5p injection improved fibrosis in the lung and skin tissues of SSc mice, reducing the infiltration of cells secreting inflammatory cytokines in the skin tissue. In particular, it decreased STAT3-phosphorylated cell infiltration at Y705 and increased the infiltration of PTEN-expressing cells in the skin tissue of SSc mice.

Conclusion

MiRNA-21a-5p promotes fibrosis in an in vivo murine SSc model, suggesting that its inhibition may be a therapeutic strategy for improving fibrosis in SSc.
Bilateral juvenile osteochondrosis dissecans in monozygotic twins: a case report
Authors: Bausch Luca , Probst Monika , Fritsch Lorenz , Mehl Julian , Siebenlist Sebastian , Willinger Lukas
Published: April 2024

Introduction

The etiology of osteochondrosis dissecans (OCD), a chondropathy associated with detachment of the subchondral bone and the overlaying cartilage, is not yet fully understood. While repetitive physical exercise-related stress is usually assumed to be the main risk factor for the occurrence of OCD, genetic predisposition could have an underestimated influence on the development of the disease.

Case report

We report a case of monozygotic twins with almost identical stages of bilateral osteochondrosis dissecans of the knee joint. In both patients, initially, a unilateral lesion occurred; despite restricted physical exercise, in the further course of the disease a lesion also developed on the contralateral side. While the lesion found most recently demonstrated an ongoing healing process at a 6-month follow-up, the other three lesions showed a natural course of healing under conservative treatment with significant clinical as well as radiological improvements after one year and complete consolidation in magnetic resonance imaging (MRI) after 2 years.

Conclusion

There could be a genetic component to the development of OCD, although this has not yet been proven. Based on a two-year MRI follow-up, we were able to show the self-limiting characteristics of juvenile osteochondrosis dissecans.
Experimental assessment of pelvis slipping during postless traction for orthopaedic applications
Authors: Daghero Marco , Borrelli Simone , Vieira Taian M. , Cannito Francesco , Aprato Alessandro , Audisio Andrea , Bignardi Cristina , Terzini Mara
Published: April 2024

Background

The application of lower limb traction during hip arthroscopy and femur fractures osteosynthesis is commonplace in orthopaedic surgeries. Traditional methods utilize a perineal post on a traction table, leading to soft tissue damage and nerve neuropraxia. A postless technique, using high-friction pads, has been considered as a potential damage-free alternative. However, whether these pads sufficiently prevent patient displacement remains unknown. Thus, this study systematically assesses the efficacy of commercial high-friction pads (PinkPad and CarePad) in restraining subject displacement, for progressively increasing traction loads and different Trendelenburg angles.

Methods

Three healthy male subjects were recruited and tested in supine and Trendelenburg positions (5° and 10°), using a customized boot-pulley system. Ten load disks (5 kg) were dropped at 15s intervals, increasing gradually the traction load up to 50 kg. Pelvis displacement along the traction direction was measured with a motion capture system. The displacement at 50 kg of traction load was analyzed and compared across various pads and bed inclinations. Response to varying traction loads was statistically assessed with a quadratic function model.

Results

Pelvis displacement at 50 kg traction load was below 60 mm for all conditions. Comparing PinkPad and CarePad, no significant differences in displacement were observed. Finally, similar displacements were observed for the supine and Trendelenburg positions.

Conclusions

Both PinkPad and CarePad exhibited nearly linear behavior under increasing traction loads, limiting displacement to 60 mm at most for 50 kg loads. Contrary to expectations, placing subjects in the Trendelenburg position did not increase adhesion.
An attachment-based pilot program to promote adolescent adjustment to parental divorce
Authors: Tay-Karapas Karla , Guzmán-González Mónica , Gómez Fabiola , Comino Priscila , Salaberria Karmele , Bahamondes Joaquín
Published: March 2024

The study aimed to assess the impact of an attachment-based intervention on adolescent adaptation to parental divorce. The Adolescent Adjustment Pilot Program to Parental Divorce (AAPPD) employed an experimental group format, targeting improvements in various adaptation indicators (life satisfaction, positive affect, and negative affect). The sample comprised 30 Chilean adolescents aged 12 to 16 (M = 13.6, SD = 1.35), with 60% females and 40% males. After the intervention, the adolescents showed a decrease in negative affect at 6 and 12 months. However, no differences were identified in other dimensions of subjective well-being considered as indicators of divorce adaptation. The findings prompt discussion on theoretical and clinical implications.
Identification of genetic modifiers enhancing B7-H3-targeting CAR T cell therapy against glioblastoma through large-scale CRISPRi screening
Authors: Li Xing , Sun Shiyu , Zhang Wansong , Liang Ziwei , Fang Yitong , Sun Tianhu , Wan Yong , Ma Xingcong , Zhang Shuqun , Xu Yang , Tian Ruilin
Published: April 2024

Background

Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with a poor prognosis. Current treatment options are limited and often ineffective. CAR T cell therapy has shown success in treating hematologic malignancies, and there is growing interest in its potential application in solid tumors, including GBM. However, current CAR T therapy lacks clinical efficacy against GBM due to tumor-related resistance mechanisms and CAR T cell deficiencies. Therefore, there is a need to improve CAR T cell therapy efficacy in GBM.

Methods

We conducted large-scale CRISPR interference (CRISPRi) screens in GBM cell line U87 MG cells co-cultured with B7-H3 targeting CAR T cells to identify genetic modifiers that can enhance CAR T cell-mediated tumor killing. Flow cytometry-based tumor killing assay and CAR T cell activation assay were performed to validate screening hits. Bioinformatic analyses on bulk and single-cell RNA sequencing data and the TCGA database were employed to elucidate the mechanism underlying enhanced CAR T efficacy upon knocking down the selected screening hits in U87 MG cells.

Results

We established B7-H3 as a targetable antigen for CAR T therapy in GBM. Through large-scale CRISPRi screening, we discovered genetic modifiers in GBM cells, including ARPC4, PI4KA, ATP6V1A, UBA1, and NDUFV1, that regulated the efficacy of CAR T cell-mediated tumor killing. Furthermore, we discovered that TNFSF15 was upregulated in both ARPC4 and NDUFV1 knockdown GBM cells and revealed an immunostimulatory role of TNFSF15 in modulating tumor-CAR T interaction to enhance CAR T cell efficacy.

Conclusions

Our study highlights the power of CRISPR-based genetic screening in investigating tumor-CAR T interaction and identifies potential druggable targets in tumor cells that confer resistance to CAR T cell killing. Furthermore, we devised targeted strategies that synergize with CAR T therapy against GBM. These findings shed light on the development of novel combinatorial strategies for effective immunotherapy of GBM and other solid tumors.
Critical period of oxygen supplementation and invasive ventilation: implications for severe retinopathy of prematurity
Authors: Choi Ho Jung , Shin Baek Sup , Shin Seung Han , Kim Ee-Kyung , Kim Han-Suk
Published: April 2024

Background

Several studies have identified graded oxygen saturation targets to prevent retinopathy of prematurity (ROP), a serious complication in preterm infants. We aimed to analyze the critical period of oxygen supplementation and/or invasive ventilation associated with severe ROP.

Methods

This retrospective case-control study included neonates with a gestational age (GA) < 29 weeks. Participants were divided into two groups: treated retinopathy and untreated/no retinopathy. Time-weighted average FiO2 (TWAFiO2) and weekly invasive ventilation were compared between groups by postnatal age (PNA) and postmenstrual age (PMA). The association of treated retinopathy with TWAFiO2 and invasive ventilation was analyzed.

Results

Data from 287 neonates were analyzed; 98 were treated for ROP and had lower GAs (25.5 vs. 27.4 weeks, p < 0.01) and lower birthweights (747.6 vs. 1014 g, p < 0.001) than those with untreated/no ROP. TWAFiO2 was higher from PMA 26–34 weeks, except for PMA 31 weeks in treated ROP, and higher in the first nine weeks of life in treated ROP. On multiple logistic regression, TWAFiO2 and invasive ventilation were associated with ROP treatment during the first seven weeks PNA. Invasive ventilation was associated with ROP treatment from PMA 26–31 weeks; no association was found for TWAFiO2 and PMA.

Conclusions

Amount of oxygen supplementation and/or invasive ventilation during the first 7 weeks of life or up to 31 weeks PMA was associated with development of severe ROP. This period might be candidate timing for strict oxygen supplementation strategies in preterm infants, while concerns of mortality with low oxygen supplementation should be further explored.
Hereditary or acquired? Comprehensive genetic testing assists in stratifying angioedema patients
Authors: Rozevska Marija , Kanepa Adine , Purina Signe , Gailite Linda , Nartisa Inga , Farkas Henriette , Rots Dmitrijs , Kurjane Natalja
Published: March 2024

Hereditary angioedema (HAE) poses diagnostic challenges due to its episodic, non-specific symptoms and overlapping conditions. This study focuses on the genetic basis of HAE, particularly focusing on unresolved cases and those with normal C1-inhibitor levels (nC1-INH HAE). This study reveals that conventional testing identified pathogenic variants in only 10 patients (n = 32), emphasizing the necessity for an integrative approach using genome, exome, and transcriptome sequencing. Despite extensive genetic analyses, the diagnostic yield for nC1-INH HAE remains low in our study, the pathogenic variant for nC1-INH HAE was identified in only 1 patient (n = 21). Investigation into candidate genes yielded no pathogenic variants, prompting a re-evaluation of patients’ diagnoses. This study advocates for a nuanced approach to genetic testing, recognizing its limitations and emphasizing the need for continuous clinical assessment. The complex genetic landscape of nC1-INH HAE necessitates further research for a more comprehensive understanding. In conclusion, this study contributes valuable insights into the genetic intricacies of HAE, highlighting the challenges in diagnosis and the evolving nature of the disease. The findings underscore the importance of advanced sequencing techniques and an integrated diagnostic strategy in unravelling the complexities of HAE, particularly in nС1-INH HAE cases.
The role of goblet cells in Crohn’ s disease
Authors: Wang Zichen , Shen Jun
Published: April 2024

The prevalence of Crohn’s disease (CD), a subtype of inflammatory bowel disease (IBD), is increasing worldwide. The pathogenesis of CD is hypothesized to be related to environmental, genetic, immunological, and bacterial factors. Current studies have indicated that intestinal epithelial cells, including columnar, Paneth, M, tuft, and goblet cells dysfunctions, are strongly associated with these pathogenic factors. In particular, goblet cells dysfunctions have been shown to be related to CD pathogenesis by direct or indirect ways, according to the emerging studies. The mucus barrier was established with the help of mucins secreted by goblet cells. Not only do the mucins mediate the mucus barrier permeability and bacterium selection, but also, they are closely linked with the endothelial reticulum stress during the synthesis process. Goblet cells also play a vital role in immune response. It was indicated that goblet cells take part in the antigen presentation and cytokines secretion process. Disrupted goblet cells related immune process were widely discovered in CD patients. Meanwhile, dysbiosis of commensal and pathogenic microbiota can induce myriad immune responses through mucus and goblet cell-associated antigen passage. Microbiome dysbiosis lead to inflammatory reaction against pathogenic bacteria and abnormal tolerogenic response. All these three pathways, including the loss of mucus barrier function, abnormal immune reaction, and microbiome dysbiosis, may have independent or cooperative effect on the CD pathogenesis. However, many of the specific mechanisms underlying these pathways remain unclear. Based on the current understandings of goblet cell’s role in CD pathogenesis, substances including butyrate, PPARγagonist, Farnesoid X receptor agonist, nuclear factor-Kappa B, nitrate, cytokines mediators, dietary and nutrient therapies were all found to have potential therapeutic effects on CD by regulating the goblet cells mediated pathways. Several monoclonal antibodies already in use for the treatment of CD in the clinical settings were also found to have some goblet cells related therapeutic targets. In this review, we introduce the disease-related functions of goblet cells, their relationship with CD, their possible mechanisms, and current CD treatments targeting goblet cells.
Exploring pre-MRI imaging tests: patient survey reveals potential implications for healthcare efficiency in Israel
Authors: Kaim Arielle , Singer Clara , Bergovoy-Yellin Lucia , Luxenburg Osnat , Vaknin Sharona , Boldor Noga , Wilf-Miron Rachel , Myers Vicki
Published: April 2024

Background

Medical imaging tests are vital in healthcare but can be costly, impacting national health expenditures. Magnetic resonance imaging (MRI) is a crucial diagnostic tool for assessing medical conditions. However, the rising demand for MRI scans has frequently strained available resources. This study aimed to estimate the prevalence of different imaging tests in individuals who eventually had an MRI, in the Israeli public health system.

Methods

An online survey of patient experience of scheduling an MRI was conducted in January–February 2023, among 557 Israeli adults, representing all four health maintenance organizations (HMOs). All participants had undergone an MRI in the public health system within the past year.

Results

Results showed that 60% of participants underwent other imaging tests before their MRI scan. Of those, computed tomography (CT) scans (43%), X-rays (39%), and ultrasounds (32%) were the most common additional imaging procedures. In addition, of the 60% of participants, 23% had undergone more than one prior imaging examination.

Conclusions

These findings highlight the high prevalence of preliminary imaging tests prior to MRI, with many patients undergoing multiple tests for the same problem. The health system may need to evaluate whether current clinical guidelines defining the use of various imaging tests are cost-effective.
Capillary refill time response to a fluid challenge or a vasopressor test: an observational, proof-of-concept study
Authors: Hernández Glenn , Valenzuela Emilio Daniel , Kattan Eduardo , Castro Ricardo , Guzmán Camila , Kraemer Alicia Elzo , Sarzosa Nicolás , Alegría Leyla , Contreras Roberto , Oviedo Vanessa , Bravo Sebastián , Soto Dagoberto , Sáez Claudia , Ait-Oufella Hafid , Ospina-Tascón Gustavo , Bakker Jan
Published: April 2024

Background

Several studies have validated capillary refill time (CRT) as a marker of tissue hypoperfusion, and recent guidelines recommend CRT monitoring during septic shock resuscitation. Therefore, it is relevant to further explore its kinetics of response to short-term hemodynamic interventions with fluids or vasopressors. A couple of previous studies explored the impact of a fluid bolus on CRT, but little is known about the impact of norepinephrine on CRT when aiming at a higher mean arterial pressure (MAP) target in septic shock. We designed this observational study to further evaluate the effect of a fluid challenge (FC) and a vasopressor test (VPT) on CRT in septic shock patients with abnormal CRT after initial resuscitation. Our purpose was to determine the effects of a FC in fluid-responsive patients, and of a VPT aimed at a higher MAP target in chronically hypertensive fluid-unresponsive patients on the direction and magnitude of CRT response.

Methods

Thirty-four septic shock patients were included. Fluid responsiveness was assessed at baseline, and a FC (500 ml/30 mins) was administered in 9 fluid-responsive patients. A VPT was performed in 25 patients by increasing norepinephrine dose to reach a MAP to 80–85 mmHg for 30 min. Patients shared a multimodal perfusion and hemodynamic monitoring protocol with assessments at at least two time-points (baseline, and at the end of interventions).

Results

CRT decreased significantly with both tests (from 5 [3.5–7.6] to 4 [2.4–5.1] sec, p = 0.008 after the FC; and from 4.0 [3.3–5.6] to 3 [2.6 -5] sec, p = 0.03 after the VPT. A CRT-response was observed in 7/9 patients after the FC, and in 14/25 pts after the VPT, but CRT deteriorated in 4 patients on this latter group, all of them receiving a concomitant low-dose vasopressin.

Conclusions

Our findings support that fluid boluses may improve CRT or produce neutral effects in fluid-responsive septic shock patients with persistent hypoperfusion. Conversely, raising NE doses to target a higher MAP in previously hypertensive patients elicits a more heterogeneous response, improving CRT in the majority, but deteriorating skin perfusion in some patients, a fact that deserves further research.
Multi-rate modulation encoding via unsupervised learning for audio event detection
Authors: Kothinti Sandeep Reddy , Elhilali Mounya
Published: April 2024

Technologies in healthcare, smart homes, security, ecology, and entertainment all deploy audio event detection (AED) in order to detect sound events in an audio recording. Effective AED techniques rely heavily on supervised or semi-supervised models to capture the wide range of dynamics spanned by sound events in order to achieve temporally precise boundaries and accurate event classification. These methods require extensive collections of labeled or weakly labeled in-domain data, which is costly and labor-intensive. Importantly, these approaches do not fully leverage the inherent variability and range of dynamics across sound events, aspects that can be effectively identified through unsupervised methods. The present work proposes an approach based on multi-rate autoencoders that are pretrained in an unsupervised way to leverage unlabeled audio data and ultimately learn the rich temporal dynamics inherent in natural sound events. This approach utilizes parallel autoencoders that achieve decompositions of the modulation spectrum along different bands. In addition, we introduce a rate-selective temporal contrastive loss to align the training objective with event detection metrics. Optimizing the configuration of multi-rate encoders and the temporal contrastive loss leads to notable improvements in domestic sound event detection in the context of the DCASE challenge.
Intelligent code search aids edge software development
Authors: Zhang Fanlong , Li Mengcheng , Wu Heng , Wu Tao
Published: April 2024

The growth of multimedia applications poses new challenges to software facilities in edge computing. Developers must effectively develop edge computing software to accommodate the rapid expansion of multimedia applications. Code search has become a prevalent practice to enhance the efficiency of the construction of edge software infrastructure. Researchers have proposed lots of approaches for code search, and employed deep learning technology to extract features from program representations, such as token, AST, graphs, method name, and API. Nevertheless, two prominent issues remain: 1) there are only a few studies on the effective use of graph representation for code search (especially in Java language), and 2) there is a lack of empirical study on the contributions of different program representations. To address these issues, we conduct an empirical study to explore program representations, especially program graphs. To the best of our knowledge, this is the first attempt to conduct code search with mixed graphs representation for Java language, containing the control flow graph and the program dependence graph. We also present a hybrid approach to capture and fuse the features of a program with representations of Token, AST, and Mixed Graphs (TAMG). The results of our experiment show that our approach possesses the best ability (R@1 with 37% and R@10 with 67.1%). Our graph representation exhibits a positive effect, and the token and AST also have a significant contribution to the code search. Our findings can aid developers in efficiently searching for the desired code while constructing the software infrastructure for edge computing, which is crucial for the rapid expansion of multimedia applications.
A methodological protocol for the development of a national guideline on perioperative management of gastrointestinal tumors in Germany
Authors: Willis M. A. , Post S. , Nothacker M. , Follmann M. , Langer T. , Vilz T. O.
Published: April 2024

Background

The success of abdominal cancer surgery depends not only on the surgery itself but is influenced by the overall perioperative management. Given the multitude of perioperative measures and the ever-increasing number of studies on perioperative management, it is difficult to keep track and provide evidence-based perioperative management. The planned guideline on perioperative management will review the existing evidence and derive treatment recommendations.

Methods

The processing of the evidence is carried out by 6 working groups according to an 8-step scheme: after drafting the guideline questions in PICO format (1), a systematic literature search is carried out (2), and the records found are screened by two independent reviewers from the coordination team. Subsequently, the full texts of the potentially relevant articles are made available to the working groups for full text screening (3). All articles to be included are reviewed for methodological quality (4) before summary of findings tables are generated (5). In line with the GRADE approach, confidence in the evidence is assessed (6) before a recommendation is derived from the evidence, using a modified GRADE Evidence to Decision Framework (7). Finally, all recommendations are compiled and agreed within the guideline group (8).

Discussion

Guidelines serve as foundation for therapy decisions in everyday clinical practice and should therefore be based on up-to-date research results. However, while primary studies and systematic reviews are critically reviewed for their methodological quality, the process of guideline development is often not comprehensible. A protocol with predefined methodology should therefore create transparency and strengthen confidence in the recommendations.

Trial registration

The guideline is registered in the AWMF (Association of the Scientific Medical Societies) Guideline Register (088—010OL).