bluuebunny/crossref_metadata_2025 huggingface dataset:
DNA Methylation Analysis in Monozygotic Twins Discordant for ALS in Blood Cells
Authors: Yazar Volkan , Ruf Wolfgang P , Knehr Antje , Günther Kornelia , Ammerpohl Ole , Danzer Karin M , Ludolph Albert C
Published: May 2023

ALS is a fatal motor neuron disease that displays a broad variety of phenotypes ranging from early fatal courses to slowly progressing and rather benign courses. Such divergence can also be seen in genetic ALS cases with varying phenotypes bearing specific mutations, suggesting epigenetic mechanisms like DNA methylation act as disease modifiers. However, the epigenotype dictated by, in addition to other mechanisms, DNA methylation is also strongly influenced by the individual’s genotype. Hence, we performed a DNA methylation study using EPIC arrays on 7 monozygotic (MZ) twin pairs discordant for ALS in whole blood, which serves as an ideal model for eliminating the effects of the genetic-epigenetic interplay to a large extent. We found one CpG site showing intra-pair hypermethylation in the affected co-twins, which maps to the Glutamate Ionotropic Receptor Kainate Type Subunit 1 gene ( GRIK1). Additionally, we found 4 DMPs which were subsequently confirmed using 2 different statistical approaches. Differentially methylated regions or blocks could not be detected within the scope of this work. In conclusion, we revealed that despite a low sample size, monozygotic twin studies discordant for the disease can bring new insights into epigenetic processes in ALS, pointing to new target loci for further investigations.
Psychographics of Rural-Urban Purchase Behaviour towards Consumer Durables in Punjab
Authors: Thakur Anand , Hundal BS
Published: May 2023

Since 1991, India is going through a transition phase. It has opted for liberalisation and globalisation and reaffirmed its commitment to new economic policies. This will bring about a marked change in rural markets too, as these will now be flooded with a variety of foreign products. The Indian rural market with its vast size and demand base offers a huge opportunity that MNCs cannot afford to ignore. The present study is a comparative examination of various psycho-socio characteristics forming vital part of rural-urban purchase behaviour of the leading & prosperous state of Punjab (India). Present study offers useful implications for various durables manufacturing companies about modifications required in present marketing strategies applied for tapping urban markets and to decide, if possible and to what extent, these strategies can be molded and applied successfully to the rural markets.
Organisational Factors, Fulfilment of the Psychological Contract and Quality of Patient-Care in Public Hospitals
Authors: Agarwal Manisha , Kumar Khanna Ajay , Sharma Abhishek
Published: May 2023

The study examined the impact of hospital organisations structure-related factors, namely, decentralisation, coordination and work autonomy, on perceived levels of psychological contract fulfilment of medical employees and the reported quality of patient care in not-for-profit public hospitals which are (a) attached to a teaching institution and (b) those which are only involved in providing medical services (railways non-teaching). The study was conducted on a sample of paramedical staff in both types of hospitals (N=200) in northern India dirough questionnaire method using five-point Likert-type scales. Responses of participants were statistically analysed through computation of correlation and stepwise regression analysis using SPSS programme. Results highlighted the importance of ‘co-ordination’ as the salient structural factor diat predicted perceived levels of psychological contract fulfilment and reported levels of quality of patient care in both types of hospitals. Mediator effects of perceived psychological contract fulfilment (PCF) on the relationship between the structural factors and quality of patient care through hierarchical regression analysis revealed that PCF mediated die prediction of quality of patient care by decentralisation and work autonomy only in the public (non-teaching) hospital but failed to mediate the prediction of quality of patient care by ‘coordination’ in both types of hospitals. Findings highlighted the significance of co-ordination among various specialities and departments in hospitals as the single factor that can be promoted by hospital administrators for increasing perceived contract fulfilment among their paramedical staff and their quality of patient care.
Eligibility criteria and Enrollment of a Diverse Racial and Ethnic population in Multiple Myeloma Clinical Trials
Authors: Kanapuru Bindu , Fernandes Laura , Baines Andrea C , Ershler Rachel , Bhatnagar Vishal , Pulte Elizabeth , Gwise Thomas , Theoret Marc R. , Pazdur Richard , Fashoyin-Aje Lola A. , Gormley Nicole
Published: May 2023

Narrow eligibility criteria may contribute to underrepresentation of racial and ethnic subgroups in cancer clinical trials. We conducted a retrospective pooled analysis of multicenter, global clinical trials submitted to the U.S. FDA between 2006-2019 to support approval of multiple myeloma (MM) therapies to analyze the rates and reasons for trial ineligibility by race and ethnicity in MM clinical trials. Race and ethnicity were coded per OMB standards. Patients flagged as screen failures were identified as ineligible. Ineligibility rates were calculated as a percentage of patients who were ineligible compared to the screened population within the respective racial and ethnic subgroups. Trial eligibility criteria were grouped into specific categories for analysis of reasons for trial ineligibility. Blacks (25%), and Other (24%) race subgroups had higher ineligibility rates compared to Whites (17%). Asian race had the lowest ineligibility rates (12%) among the racial subgroups. Failure to meet Hematologic Lab Criteria (19%) and failure to meet Treatment Related Criteria (17%) were the most common reasons for ineligibility among Blacks and were more common in Black patients compared to other races. Failure to meet Disease Related Criteria was the most common reason for ineligibility among White (28%) and Asian (29%) participants. Our analysis indicates that specific eligibility criteria may contribute to enrollment disparities for racial and ethnic subgroups in MM clinical trials. However, the small number of screened patients in underrepresented racial and ethnic subgroups limits definitive conclusions.
Transcriptome analysis of thermomorphogenesis in ovules and during early seed development in Brassica napus
Authors: Jedličková Veronika , Hejret Václav , Demko Martin , Jedlička Pavel , Štefková Marie , Robert Hélène S.
Published: May 2023

Background

Plant sexual reproduction is highly sensitive to elevated ambient temperatures, impacting seed development and production. We previously phenotyped this effect on three rapeseed cultivars (DH12075, Topas DH4079, and Westar). This work describes the transcriptional response associated with the phenotypic changes induced by heat stress during early seed development inBrassica napus.

Results

We compared the differential transcriptional response in unfertilized ovules and seeds bearing embryos at 8-cell and globular developmental stages of the three cultivars exposed to high temperatures. We identified that all tissues and cultivars shared a common transcriptional response with the upregulation of genes linked to heat stress, protein folding and binding to heat shock proteins, and the downregulation of cell metabolism. The comparative analysis identified an enrichment for a response to reactive oxygen species (ROS) in the heat-tolerant cultivar Topas, correlating with the phenotypic changes. The highest heat-induced transcriptional response in Topas seeds was detected for genes encoding various peroxidases, temperature-induced lipocalin (TIL1), or protein SAG21/LEA5. On the contrary, the transcriptional response in the two heat-sensitive cultivars, DH12075 and Westar, was characterized by heat-induced cellular damages with the upregulation of genes involved in the photosynthesis and plant hormone signaling pathways. Particularly, theTIFY/JAZgenes involved in jasmonate signaling were induced by stress, specifically in ovules of heat-sensitive cultivars. Using a weighted gene co-expression network analysis (WGCNA), we identified key modules and hub genes involved in the heat stress response in studied tissues of either heat-tolerant or sensitive cultivars.

Conclusions

Our transcriptional analysis complements a previous phenotyping analysis by characterizing the growth response to elevated temperatures during early seed development and reveals the molecular mechanisms underlying the phenotypic response. The results demonstrated that response to ROS, seed photosynthesis, and hormonal regulation might be the critical factors for stress tolerance in oilseed rape.
Omicron BA.1 neutralizing antibody response following Delta breakthrough infection compared with booster vaccination of BNT162b2
Authors: Yamamoto Shohei , Matsuda Kouki , Maeda Kenji , Oshiro Yusuke , Inamura Natsumi , Mizoue Tetsuya , Konishi Maki , Takeuchi Junko S. , Horii Kumi , Ozeki Mitsuru , Sugiyama Haruhito , Mitsuya Hiroaki , Sugiura Wataru , Ohmagari Norio
Published: May 2023

Background

Longitudinal data are lacking to compare booster effects of Delta breakthrough infection versus third vaccine dose on neutralizing antibodies (NAb) against Omicron.

Methods

Participants were the staff of a national research and medical institution in Tokyo who attended serological surveys on June 2021 (baseline) and December 2021 (follow-up); in between, the Delta-dominant epidemic occurred. Of 844 participants who were infection-naïve and had received two doses of BNT162b2 at baseline, we identified 11 breakthrough infections during follow-up. One control matched to each case was selected from boosted and unboosted individuals. We compared live-virus NAb against Wild-type, Delta, and Omicron BA.1 across groups.

Results

Breakthrough infection cases showed marked increases in NAb titers against Wild-type (4.1-fold) and Delta (5.5-fold), and 64% had detectable NAb against Omicron BA.1 at follow-up, although the NAb against Omicron after breakthrough infection was 6.7- and 5.2-fold lower than Wild-type and Delta, respectively. The increase was apparent only in symptomatic cases and as high as in the third vaccine recipients.

Conclusions

Symptomatic Delta breakthrough infection increased NAb against Wild-type, Delta, and Omicron BA.1, similar to the third vaccine. Given the much lower NAb against Omicron BA.1, infection prevention measures must be continued irrespective of vaccine and infection history while the immune evasive variants are circulating.
Effect of intradialytic oral nutritional supplementation on nutritional markers in malnourished chronic hemodialysis patients: prospective randomized trial
Authors: Gharib Mohamed Sary , Nazeih Mariem Shaker , El Said Tamer Wahid
Published: May 2023

Background and objectives

Malnutrition is prevalent in chronic hemodialysis (HD) patients. It increases mortality and negatively affects quality of life. This study aimed to assess the effect of intradialytic oral nutritional supplement (ONS) on nutritional markers in chronic HD patients with protein energy wasting (PEW).

Methods

This 3-month prospective, open-label, randomized controlled trial included 60 chronic HD patients with PEW. The intervention group (30 patients) received intradialytic ONS and dietary counseling, whereas the control group (30 patients) received only dietary counseling. Nutritional markers were measured at the beginning and end of the study.

Results

The mean age of the patients was 54 ± 12.7 years, and that of the HD vintage was 64 ± 49.3 months. Compared to the control group, the intervention group showed a significant increase in serum albumin (p < 0.001), prealbumin (p < 0.001), cholesterol (p = 0.016), body mass index (BMI) (p = 0.019), serum creatinine/body surface area (BSA) (p = 0.016), and composite French PEW score (p = 0.002), as well as a significant decrease in high-sensitivity C-reactive protein (hs-CRP) (p = 0.001). The total iron binding capacity, normalized protein nitrogen appearance, and hemoglobin levels increased significantly in both groups.

Conclusion

Intradialytic ONS and dietary counseling for three months were more effective than dietary counseling alone in terms of improving nutritional status and inflammation in chronic HD patients, as evidenced by increases in serum albumin, prealbumin, BMI, serum creatinine/BSA, composite French PEW score, and a decrease in hs-CRP.
A pilot clinical study of complex rhegmatogenous retinal detachment treatment via foldable capsular buckle scleral buckling
Authors: Li Cheng , Zhang Baike , Tan Xiao , Jia Yong , Guo Lisha , Wang Chunlei , Xing Yaofan , Li Qiaoyun , Tian Xuemin
Published: May 2023

Background

To evaluate the feasibility of and identify problems in treating complex rhegmatogenous retinal detachment using foldable capsular buckle scleral buckling.

Methods

This prospective clinical study enrolled five patients with complex rhegmatogenous retinal detachment treated with foldable capsular buckle scleral buckling at the 988th Hospital of People’s Liberation Army Joint Logistic Force, China. During the 24-week follow-up period, the patients underwent measurements of their best-corrected visual acuity, slit-lamp examination, indirect ophthalmoscopy, and visual field testing. Additionally, B-ultrasound and fundus photography of the patients’ retinal reattachments helped evaluate the treatment’s post-surgery efficacy. We determined the safety of foldable capsular buckle scleral buckling based on infection, eye pain, diplopia, elevated intraocular pressure, and other postoperative severe complications.

Results

All five patients’ complex rhegmatogenous retinal detachments were successfully treated and evaluated via B-ultrasound and fundus photography after surgery. Visual acuity was enhanced in four patients 24 weeks after surgery, while the remaining patients developed diplopia after surgery. No other complications were observed.

Conclusion

This pilot study preliminarily determined that foldable capsular buckle scleral buckling is feasible for efficient and safe treatment of complex rhegmatogenous retinal detachment. These results support this surgery as a potential and novel alternative to current extraocular procedures for treating complex rhegmatogenous retinal detachment.

Trial registration

The prospective observational clinical study protocol was approved by the Institutional Review Board and Ethics Committee and registered at the clinical research center in the 988th Hospital of People’s Liberation Army Joint Logistic Force, China (9,882,019,000).
The effectiveness of blended versus regular Forensic Outpatient Systemic Therapy in the treatment of juvenile antisocial behavior: a study protocol of a randomized controlled trial
Authors: van Cappellen S. Marjolein , Creemers Hanneke E. , Hoogsteder Larissa , van Horn Joan , Dekovic Maja , Asscher Jessica J.
Published: May 2023

Background

Antisocial behavior during adolescence can have long-lasting negative effects and leads to high societal costs. Forensic Outpatient Systemic Therapy (Forensische Ambulante Systeem Therapie; FAST) is a promising treatment for juveniles aged 12–21 showing severe antisocial behavior. The intensity, content and duration of FAST can be adjusted to the needs of the juvenile and their caregiver(s), which is considered crucial for effective treatment. Next to the regular version of FAST (FASTr), a blended version (FASTb) in which face-to-face contacts are replaced by minimally 50% online contacts over the duration of intervention was developed during the Covid-19 pandemic. The current study will investigate whether FASTb is equally effective as FASTr, and through which mechanisms of change, for whom, and under which conditions FASTr and FASTb work.

Methods

A randomized controlled trial (RCT) will be carried out. Participants (N = 200) will be randomly assigned to FASTb (n = 100) or FASTr (n = 100). Data collection will consist of self-report questionnaires and case file analysis, and include a pre-test at the start of the intervention, a post-test immediately after the intervention, and a six month follow-up. Mechanisms of change will be investigated using monthly questionnaires of key variables during treatment. Official recidivism data will be collected at two-year follow-up.

Discussion

This study aims to improve the effectiveness and quality of forensic mental health care for juveniles with antisocial behavior by studying the effectiveness of blended care, which has not been studied before in treatment of externalizing behavior. If found to be at least as effective as face-to-face treatment, blended treatment can help meet the urgent need for more flexible and efficient interventions in this field. In addition, the proposed study aims to unravel what works for whom, knowledge urgently needed in mental health care for juveniles with severe antisocial behavior.

Trial registration

This trial was registered at ClinicalTrials.gov on 07/11/2022, registration number NCT05606978.
Predictors of clinical and surgical characteristics of giant stones of the urinary bladder: a retrospective study
Authors: Gadelkareem Rabea Ahmed , Shalaby Mahmoud Mohamad , Faddan Amr Abou
Published: May 2023

Background

Giant stones of the urinary bladder (GSBs) are rare and usually presented as case reports. We aimed to assess the clinical and surgical characteristics of GSBs and identify their predictors.

Methods

A retrospective study of 74 patients with GSBs who presented between July, 2005 and June, 2020 was performed. Patients’ demographics, clinical presentations, and surgical peculiarities were studied.

Results

Older age and male gender were risk factors for the occurrence of GSBs. The irritative lower urinary tract symptoms (iLUTS) were the main presenting symptoms (97.3%). Most patients were treated with cystolithotomy (90.1%). Univariate analyses showed that solitary (p < 0.001) and rough surface (P = 0.009) stones were significant factors for occurrence of iLUTS as the presenting symptoms. Also, the severity of symptoms (p = 0.021), rough surface (p = 0.010) and size (p < 0.001) of stones, and farmer occupation (p = 0.009) were significantly associated with adherence of the stone to the bladder mucosa at surgery. In multivariate analysis, the rough surface (p = 0.014) and solitary (p = 0.006) stones, and concomitant ureteral stones (p = 0.020) were independently associated with iLUTS as the main presentation. However, the stone size and severity of iLUTS were the independently associated factors for adherence of GSBs to the bladder mucosa.

Conclusions

Solitary GSB, rough surface and the association with ureteral stones are independent risk factors for the occurrence of long-standing iLUTS. The stone size and severity of iLUTS were the independent predictors of adherence of GSBs to the bladder mucosa. Cystolithotomy is the main treatment, but it may be more difficult when there is bladder mucosa adherence.
Phenotypic and genotypic characterization of virulence markers and antifungal susceptibility of oral Candida species from diabetic and non-diabetic hemodialysis patients
Authors: Mohammadi Faezeh , Charkhchian Maliheh , mirzadeh Monirsadat
Published: May 2023

Background

Patients with chronic kidney disease undergoing hemodialysis are often colonized by Candida species with high possibility of fungal infections. The purposes of this study were to determine the prevalence of Candida species, evaluate antifungal susceptibility profile, biofilm formation, proteinase and phospholipase activities, and the frequency of virulence genes in the Candida species isolated from the oral mucosa of hemodialysis diabetic (DM) and non-diabetic (non-DM) patients.

Methods

This study identified several species of Candida isolated from 69 DM and 58 non-DM patients on hemodialysis using phenotypic methods and PCR–RFLP technique. The identification of C. albicans and C. glabrata complex was performed by HWP1 gene and four oligonucleotides (UNI-5.8S, GLA-f, BRA-f, and NIV-f), respectively. Antifungal susceptibility to amphotericin B, fluconazole, itraconazole, voriconazole, and caspofungin was assessed according to CLSI M27-A3/S4. The biomass, metabolic activity of biofilm, proteinase (Prz), phospholipase (Pz), and molecular study for virulence genes were assessed using crystal violet, XTT assay, agar-based hydrolytic enzyme, and PCR technique, respectively.

Results

Candida prevalence was 44.9% with 47.8% and 41.4% among DM and non-DM patients, respectively (P = .045). The species identified were C. albicans (49.5%), C. glabrata (16.5%), C. tropicalis (12%), C. kefyr (8.8%), C. parapsilosis (6.6%), C. dubliniensis (3.3%), and C. lusitaniae (3.3%). The antifungal susceptibility profile showed that all Candida isolates were sensitive to amphotericin B, itraconazole, voriconazole, and caspofungin whereas fluconazole resistance was observed in 6.3% (MIC ≥ 64 μg/mL) of C. albicans and 6.6% of C. glabrata (MIC ≥ 64 μg/mL). The susceptible- dose-dependent rate was found in 10.5% of C. albicans. The Prz values of C. albicans ranged from 0.37 to 0.66 for the DM and 0.44–0.73 for the non-DM group (P < 0.05). The non-albicans Candida (NAC) species produced higher degree of biomass and metabolic activity compared to C. albicans (P < 0.05). Furthermore, significant (p < 0.05) correlations were detected between the biofilm formation with Prz values and fluconazole MICs. The most detected virulence factors were ALS3 and Sap5.

Conclusions

These results showed the importance of prevalence of NAC species in hemodialysis patients. Investigating antifungal susceptibility profile made a better understanding of the role of virulence markers in the pathogenesis of Candida strains.
The role of men’s forgiveness in marital satisfaction and coping strategies of infertile iranian women
Authors: Safari Samaneh , Hasanpoor-Azghady Seyedeh Batool , Amiri-Farahani Leila
Published: May 2023

Background

Infertility and its related problems create tensions in infertile women, which may lead to reduced marital satisfaction and the use of ineffective coping strategies. Considering the important role of forgiveness, marital satisfaction and effective coping strategies in the quality of life of infertile couples, and taking into account the growing number of Iranian infertile couples, this study was conducted to determine the relationship between men’s forgiveness, marital satisfaction, and coping strategies of infertile Iranian women.

Methods

This cross-sectional study included 200 Iranian infertile couples. The research environment was the most equipped infertility center in the west of Iran. Sampling was continuous. Data collection tools used included a self-generated demographic and fertility questionnaire, the Family Forgiveness Scale (FFS), the Index of Marital Satisfaction (IMS), and the Ways of Coping Questionnaire-revised (WOCQ-R).

Results

Husbands’ forgiveness had a significant direct relationship with the marital satisfaction of infertile women (r = -0.27, p < 0.001). However, there was no significant correlation between Husbands’ forgiveness, emotion-focused, and problem-focused coping of infertile women. Among the subscales of forgiveness, only the subscale of recognition had inversely correlated with the emotional coping of infertile women.

Conclusion

The results showed that the higher the forgiveness of husbands, the higher the marital satisfaction of infertile women. Also, with the increase of husbands’ forgiveness in the recognition subscale, the use of emotion-focused coping decreased in infertile women. Based on the results with empowering the husbands of infertile women with forgiveness skills, it is possible to take a step towards marital satisfaction and thus improve the quality of life of infertile women.
Differentiation between fetal and postnatal iron deficiency in altering brain substrates of cognitive control in pre-adolescence
Authors: Hua Mengdi , Shi Donglin , Xu Wenwen , Zhu Liuyan , Hao Xiaoxin , Zhu Bingquan , Shu Qiang , Lozoff Betsy , Geng Fengji , Shao Jie
Published: May 2023

Background

Early iron deficiency (ID) is a common risk factor for poorer neurodevelopment, limiting children’s potential and contributing to global burden. However, it is unclear how early ID alters the substrate of brain functions supporting high-order cognitive abilities and whether the timing of early ID matters in terms of long-term brain development. This study aimed to examine the effects of ID during fetal or early postnatal periods on brain activities supporting proactive and reactive cognitive control in pre-adolescent children.

Methods

Participants were part of a longitudinal cohort enrolled at birth in southeastern China between December 2008 and November 2011. Between July 2019 and October 2021, 115 children aged 8–11 years were invited to participate in this neuroimaging study. Final analyses included 71 children: 20 with fetal ID, 24 with ID at 9 months (postnatal ID), and 27 iron-sufficient at birth and 9 months. Participants performed a computer-based behavioral task in a Magnetic Resonance Imaging scanner to measure proactive and reactive cognitive control. Outcome measures included accuracy, reaction times, and brain activity. Linear mixed modeling and the 3dlme command in Analysis of Functional NeuroImages (AFNI) were separately used to analyze behavioral performance and neuroimaging data.

Results

Faster responses in proactive vs. reactive conditions indicated that all groups could use proactive or reactive cognitive control according to contextual demands. However, the fetal ID group was lower in general accuracy than the other 2 groups. Per the demands of cues and targets, the iron-sufficient group showed greater activation of wide brain regions in proactive vs. reactive conditions. In contrast, such condition differences were reversed in the postnatal ID group. Condition differences in brain activation, shown in postnatal ID and iron-sufficient groups, were not found in the fetal ID group. This group specifically showed greater activation of brain regions in the reward pathway in proactive vs. reactive conditions.

Conclusions

Early ID was associated with altered brain functions supporting proactive and reactive cognitive control in childhood. Alterations differed between fetal and postnatal ID groups. The findings imply that iron supplement alone is insufficient to prevent persisting brain alterations associated with early ID. Intervention strategies in addition to the iron supplement should consider ID timing.
Pulmonary magnetic resonance-guided online adaptive radiotherapy of locally advanced non-small-cell lung cancer: the PUMA trial
Authors: Regnery Sebastian , de Colle Chiara , Eze Chukwuka , Corradini Stefanie , Thieke Christian , Sedlaczek Oliver , Schlemmer Heinz-Peter , Dinkel Julien , Seith Ferdinand , Kopp-Schneider Annette , Gillmann Clarissa , Renkamp C. Katharina , Landry Guillaume , Thorwarth Daniela , Zips Daniel , Belka Claus , Jäkel Oliver , Debus Jürgen , Hörner-Rieber Juliane
Published: May 2023

Background

Patients with locally-advanced non-small-cell lung cancer (LA-NSCLC) are often ineligible for surgery, so that definitive chemoradiotherapy (CRT) represents the treatment of choice. Nevertheless, long-term tumor control is often not achieved. Intensification of radiotherapy (RT) to improve locoregional tumor control is limited by the detrimental effect of higher radiation exposure of thoracic organs-at-risk (OAR). This narrow therapeutic ratio may be expanded by exploiting the advantages of magnetic resonance (MR) linear accelerators, mainly the online adaptation of the treatment plan to the current anatomy based on daily acquired MR images. However, MR-guidance is both labor-intensive and increases treatment times, which raises the question of its clinical feasibility to treat LA-NSCLC. Therefore, the PUMA trial was designed as a prospective, multicenter phase I trial to demonstrate the clinical feasibility of MR-guided online adaptive RT in LA-NSCLC.

Methods

Thirty patients with LA-NSCLC in stage III A-C will be accrued at three German university hospitals to receive MR-guided online adaptive RT at two different MR-linac systems (MRIdian Linac®, View Ray Inc. and Elekta Unity®, Elekta AB) with concurrent chemotherapy. Conventionally fractioned RT with isotoxic dose escalation up to 70 Gy is applied. Online plan adaptation is performed once weekly or in case of major anatomical changes. Patients are followed-up by thoracic CT- and MR-imaging for 24 months after treatment. The primary endpoint is twofold: (1) successfully completed online adapted fractions, (2) on-table time. Main secondary endpoints include adaptation frequency, toxicity, local tumor control, progression-free and overall survival.

Discussion

PUMA aims to demonstrate the clinical feasibility of MR-guided online adaptive RT of LA-NSCLC. If successful, PUMA will be followed by a clinical phase II trial that further investigates the clinical benefits of this approach. Moreover, PUMA is part of a large multidisciplinary project to develop MR-guidance techniques.

Trial registration

ClinicalTrials.gov:NCT05237453.
Health-related quality of life in patients with Kashin–Beck disease is lower than in those with osteoarthritis: a cross-sectional study
Authors: Jin Zhankui , Wu Xueyuan , Sun Zhengming , Chen Ming , Yang Bo , Dong Xianghui , Liu Shizhang , Chang Yanhai , Xu Cuixiang , Yi Zhi , Ling Ming
Published: May 2023

Background

Kashin–Beck disease (KBD) is an endemic deformable bone and joint disease, which affects the quality of life (QOL) of patients. We conducted a cross-sectional study of the QOL of KBD patients by a new KBD quality of life (KBDQOL) questionnaire.

Methods

A total of 252 KBD patients and 248 OA patients came from Northwest China, and 260 healthy people living in the same area as KBD and osteoarthritis (OA) patients served as the controls. KBDQOL questionnaire was used to evaluate the QOL of all objects.

Results

The average scores for physical functions, activity limitations, support of society, mental health and general health were significantly lower in KBD patients than that in OA patients and healthy people except for economics. Monofactor analysis showed that age, height, weight status, education level and grade of KBD had a significant effect on KBDQOL score. Multivariate analysis showed that grade of KBD was the influencing factor of physical function score; gender, age, height, grade of KBD and duration of symptoms were the influencing factors of activity restriction score; age and grade of KBD were factors affecting the general health score.

Conclusion

The QOL of KBD patients was significantly lower than that of OA patients and healthy people. The KBDQOL questionnaire may be a promising tool for assessing the QOL of KBD patients.
Irbesartan overcomes gemcitabine resistance in pancreatic cancer by suppressing stemness and iron metabolism via inhibition of the Hippo/YAP1/c-Jun axis
Authors: Zhou Tianxing , Xie Yongjie , Hou Xupeng , Bai Weiwei , Li Xueyang , Liu Ziyun , Man Quan , Sun Jingyan , Fu Danqi , Yan Jingrui , Zhang Zhaoyu , Wang Yifei , Wang Hongwei , Jiang Wenna , Gao Song , Zhao Tiansuo , Chang Antao , Wang Xiuchao , Sun Hongxia , Zhang Xiufeng , Yang Shengyu , Huang Chongbiao , Hao Jihui , Liu Jing
Published: May 2023

Background

Chemoresistance is the main reason for the poor prognosis of pancreatic ductal adenocarcinoma (PDAC). Thus, there is an urgent need to screen out new targets and compounds to reverse chemotherapeutic resistance.

Methods

We established a bio-bank of human PDAC organoid models, covering a representative range of PDAC tumor subtypes. We screened a library of 1304 FDA-approved compounds to identify candidates efficiently overcoming chemotherapy resistance. The effects of the compounds were evaluated with a CellTiter-Glo-3D assay, organoid apoptosis assay and in vivo patient-derived xenograft (PDX), patient-derived organoid (PDO) and LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx1-Cre (KPC) genetically engineered mouse models. RNA-sequencing, genome editing, sphere formation assays, iron assays and luciferase assays were conducted to elucidate the mechanism.

Results

High-throughput drug screening of chemotherapy-resistant PDOs identified irbesartan, an angiotensin ‖ type 1 (AT1) receptor antagonist, which could synergistically enhance the ability of chemotherapy to kill PDAC cells. In vitro and in vivo validation using PDO, PDX and KPC mouse models showed that irbesartan efficiently sensitized PDAC tumors to chemotherapy. Mechanistically, we found that irbesartan decreased c-Jun expression by inhibiting the Hippo/YAP1 pathway and further overcame chemotherapy resistance in PDAC. We also explored c-Jun, a potential target of irbesartan, which can transcriptionally upregulate the expression of key genes involved in stemness maintenance (SOX9/SOX2/OCT4) and iron metabolism (FTH1/FTL/TFRC). More importantly, we observed that PDAC patients with high levels of c-Jun expression demonstrated poor responses to the current standard chemotherapy regimen (gemcitabine plus nab-paclitaxel). Moreover, patients with PDAC had significant survival benefits from treatment with irbesartan plus a standard chemotherapy regimen in two-center retrospective clinical cohorts and patients with high c-Jun expression exhibited a better response to combination chemotherapy.

Conclusions

Irbesartan could be used in combination with chemotherapy to improve the therapeutic efficacy in PDAC patients with high levels of c-Jun expression. Irbesartan effectively inhibited chemotherapy resistance by suppressing the Hippo/YAP1/c-Jun/stemness/iron metabolism axis. Based on our findings, we are designing an investigator-initiated phase II clinical trial on the efficacy and safety of irbesartan plus a standard gemcitabine/nab-paclitaxel regimen in the treatment of patients with advanced III/IV staged PDAC and are hopeful that we will observe patient benefits.
Heterogeneity in the definition of delirium in ICUs and association with the intervention effect in randomized controlled trials: a meta-epidemiological study
Authors: Collet Lucie , Lanore Aymeric , Alaterre Camille , Constantin Jean-Michel , Martin Guillaume L. , Caille Agnès , James Arthur , Dechartres Agnès
Published: May 2023

Purpose

To evaluate the heterogeneity in the definition of delirium in randomized controlled trials (RCTs) included in meta-analyses of delirium in intensive care units (ICUs) and to explore whether intervention effect depends on the definition used.

Methods

We searched PubMed for meta-analyses including RCTs evaluating prevention or treatment strategies of delirium in ICU. The definition of delirium was collected from RCTs and classified as validated (DSM criteria, CAM-ICU, ICDSC, NEECHAM, DRS-R98) or non-validated (non-validated scales, set of symptoms, physician appreciation or not reported). We conducted a meta-epidemiological analysis to compare intervention effects between trials using or not a validated definition by a two-step method as primary analysis and a multilevel model as secondary analysis. A ratio of odds ratios (ROR) < 1 indicated larger intervention effects in trials using a non-validated definition.

Results

Of 149 RCTs (41 meta-analyses), 109 (73.1%) used a validated definition and 40 (26.8%) did not (including 31 [20.8%] not reporting the definition). The primary analysis of 7 meta-analyses (30 RCTs) found no significant difference in intervention effects between trials using a validated definition and the others (ROR = 0.54, 95% CI 0.27–1.08), whereas the secondary multilevel analysis including 12 meta-analyses (67 RCTs) found significantly larger effects for trials using a non-validated versus a validated definition (ROR = 0.36, 95% CI 0.21–0.62).

Conclusion

The definition of delirium was heterogeneous across RCTs, with one-fifth not reporting how they evaluated delirium. We did not find a significant association with intervention effect in the primary analysis. The secondary analysis including more studies revealed significantly larger intervention effects in trials using a non-validated versus a validated definition.
Development of a hookworm egg hatching assay to determine the ovicidal effects of anthelminthics
Authors: Easland Erin , Biendl Stefan , Keiser Jennifer
Published: May 2023

Background

Few anthelminthics are currently available, manifesting the urgent need for new treatment options. In vitro profiling of current anthelminthics against larval and adult stage helminths displayed varying effects on closely related worm species and between life stages of the same species. Conversely, limited research has been performed on the egg stage of human hookworms, and the effects of investigational compounds on the egg stage are not routinely assessed.

Methods

We profiled the development and hatching of Heligmosomoides polygyrus, Ancylostoma duodenale and Necator americanus eggs isolated from rodent faeces in liquid media with various nutrient levels, osmolar concentrations, and acidities in dependence on incubation temperature and light exposure. Incubation conditions were optimised to allow the study of drug effect on immature and embryonated eggs. We analysed concentration-effect relationships of commercially available anthelminthics over 72 h.

Results

Rapid embryonation and hatching were observed at room temperature with and without light exposure without nutrient supplementation in a wide range of acidities. Hookworms hatched optimally at room temperature in PBS achieving > 75% hatching over 34 h. Developmental delays were seen when eggs were stored at 4 °C with no effect on viability. Similar delays were also seen with increased osmolar concentrations resulting in decreased viability. Benzimidazole anthelminthics effectively reduced the viability and prevented hatching of hookworm eggs, with albendazole and thiabendazole eliciting particularly potent effects at EC50 values below 1 µM. Macrolide anthelminthics as well as emodepside, oxantel pamoate, and pyrantel pamoate were inactive while monepantel, levamisole, and tribendimidine displayed varied potencies among the hookworm species.

Conclusion

The presented egg-hatching assay will complement ongoing anthelminthic drug discovery and allow a full characterisation of drug activity against all life stages. In the development and application of the egg-hatching assay, good accordance was observed between the three hookworm species evaluated. Marketed anthelminthics show differences of drug action compared to larval and adult stages highlighting the importance of profiling drug activity against all life stages.

Graphical Abstract
The impact of epigenetic landscape on ovarian cells in infertile older women undergoing IVF procedures
Authors: Sgueglia Giulia , Longobardi Salvatore , Valerio Domenico , Campitiello Maria Rosaria , Colacurci Nicola , Di Pietro Cinzia , Battaglia Rosalia , D’Hooghe Thomas , Altucci Lucia , Dell’Aversana Carmela
Published: May 2023

The constant decline in fertility and older reproductive age is the major cause of low clinical pregnancy rates in industrialised countries. Epigenetic mechanisms impact on proper embryonic development in women undergoing in vitro fertilisation (IVF) protocols. Here, we describe the main epigenetic modifications that may influence female reproduction and could affect IVF success.

Graphical Abstract
Harmonised culture procedures minimise but do not eliminate mesenchymal stromal cell donor and tissue variability in a decentralised multicentre manufacturing approach
Authors: Calcat-i-Cervera Sandra , Rendra Erika , Scaccia Eleonora , Amadeo Francesco , Hanson Vivien , Wilm Bettina , Murray Patricia , O’Brien Timothy , Taylor Arthur , Bieback Karen
Published: May 2023

Background

Mesenchymal stromal cells (MSCs), commonly sourced from adipose tissue, bone marrow and umbilical cord, have been widely used in many medical conditions due to their therapeutic potential. Yet, the still limited understanding of the underlying mechanisms of action hampers clinical translation. Clinical potency can vary considerably depending on tissue source, donor attributes, but importantly, also culture conditions. Lack of standard procedures hinders inter-study comparability and delays the progression of the field. The aim of this study was A- to assess the impact on MSC characteristics when different laboratories, performed analysis on the same MSC material using harmonised culture conditions and B- to understand source-specific differences.

Methods

Three independent institutions performed a head-to-head comparison of human-derived adipose (A-), bone marrow (BM-), and umbilical cord (UC-) MSCs using harmonised culture conditions. In each centre, cells from one specific tissue source were isolated and later distributed across the network to assess their biological properties, including cell expansion, immune phenotype, and tri-lineage differentiation (part A). To assess tissue-specific function, angiogenic and immunomodulatory properties and the in vivo biodistribution were compared in one expert lab (part B).

Results

By implementing a harmonised manufacturing workflow, we obtained largely reproducible results across three independent laboratories in part A of our study. Unique growth patterns and differentiation potential were observed for each tissue source, with similar trends observed between centres. Immune phenotyping verified expression of typical MSC surface markers and absence of contaminating surface markers. Depending on the established protocols in the different laboratories, quantitative data varied slightly. Functional experiments in part B concluded that conditioned media from BM-MSCs significantly enhanced tubulogenesis and endothelial migration in vitro. In contrast, immunomodulatory studies reported superior immunosuppressive abilities for A-MSCs. Biodistribution studies in healthy mice showed lung entrapment after administration of all three types of MSCs, with a significantly faster clearance of BM-MSCs.

Conclusion

These results show the heterogeneous behaviour and regenerative properties of MSCs as a reflection of intrinsic tissue-origin properties while providing evidence that the use of harmonised culture procedures can reduce but do not eliminate inter-lab and operator differences.
Intelligent computing for WPT–MEC-aided multi-source data stream
Authors: Zheng Xiangdong , Zhu Fusheng , Xia Junjuan , Gao Chongzhi , Cui Tao , Lai Shiwei
Published: May 2023

Due to its low latency and energy consumption, edge computing technology is essential in processing multi-source data streams from intelligent devices. This article investigates a mobile edge computing network aided by wireless power transfer (WPT) for multi-source data streams, where the wireless channel parameters and the characteristic of the data stream are varied. Moreover, we consider a practical communication scenario, where the devices with limited battery capacity cannot support the executing and transmitting of computational data streams under a given latency. Thus, WPT technology is adopted for this considered network to enable the devices to harvest energy from the power beacon. In further, by considering the device’s energy consumption and latency constraints, we propose an optimization problem under energy constraints. To solve this problem, we design a customized particle swarm optimization-based algorithm, which aims at minimizing the latency of the device processing computational data stream by jointly optimizing the charging and offloading strategies. Furthermore, simulation results illustrate that the proposed method outperforms other benchmark schemes in minimizing latency, which shows the proposed method’s superiority in processing the multi-source data stream.
An overview of systems for providing integrated and comprehensive care for older people in Japan
Authors: Sano Junko , Hirazawa Yuzuki , Komamura Kohei , Okamoto Shohei
Published: May 2023

As longevity occurs, people encounter various risks associated with ageing, including economic uncertainty and health issues. Therefore, in addition to extending healthy life expectancy, it is crucial to create an environment where older people can live better even when their intrinsic capacity declines. Additionally, integrated and comprehensive care for older adults is needed to maintain their functional ability and well-being at higher levels. This review provides an overview of the systems and initiatives in Japan, a forerunner of population ageing that supports the quality of life of older people and summarises their remaining challenges. In Japan, with support for access to necessary care available from social welfare councils and community comprehensive support centres, various health and welfare services are provided to respond to the needs of people with different levels of intrinsic capacity, including medical care, preventive care, long-term care, adult guardianship systems, pensions, and social assistance. Nevertheless, there are challenges for the systems, including the gap between life and healthy life expectancy, moderate accumulation and decumulation of retirement assets, lack of human and financial resources for care, and user-unfriendliness and non-covered needs of the current system. Therefore, integrated and comprehensive care beyond health and long-term care is needed to maintain the well-being of older adults, even with their intrinsic capacity declining.
Treating opioid use disorder in veterans with co-occurring substance use: a qualitative study with buprenorphine providers in primary care, mental health, and pain settings
Authors: Frost Madeline C. , Soyer Elena M. , Achtmeyer Carol E. , Hawkins Eric J. , Glass Joseph E. , Hallgren Kevin A. , Williams Emily C.
Published: May 2023

Background

Most people with opioid use disorder (OUD) have co-occurring substance use, which is associated with lower receipt of OUD medications (MOUD). Expanding MOUD provision and care linkage outside of substance use disorder (SUD) specialty settings is a key strategy to increase access. Therefore, it is important to understand how MOUD providers in these settings approach care for patients with co-occurring substance use. This qualitative study of Veterans Health Administration (VA) clinicians providing buprenorphine care in primary care, mental health, and pain settings aimed to understand (1) their approach to addressing OUD in patients with co-occurring substance use, (2) perspectives on barriers/facilitators to MOUD receipt for this population, and (3) support needed to increase MOUD receipt for this population.

Methods

We interviewed a purposive sample of 27 clinicians (12 primary care, 7 mental health, 4 pain, 4 pharmacists) in the VA northwest network. The interview guide assessed domains of the Tailored Implementation for Chronic Diseases Checklist. Interviews were transcribed and qualitatively analyzed using inductive content analysis.

Results

Participants reported varied approaches to identifying co-occurring substance use and addressing OUD in this patient population. Although they reported that this topic was not clearly addressed in clinical guidelines or training, participants generally felt that patients with co-occurring substance use should receive MOUD. Some viewed their primary role as providing this care, others as facilitating linkage to OUD care in SUD specialty settings. Participants reported multiple barriers and facilitators to providing buprenorphine care to patients with co-occurring substance use and linking them to SUD specialty care, including provider, patient, organizational, and external factors.

Conclusions

Efforts are needed to support clinicians outside of SUD specialty settings in providing buprenorphine care to patients with co-occurring substance use. These could include clearer guidelines and policies, more specific training, and increased care integration or cross-disciplinary collaboration. Simultaneously, efforts are needed to improve linkage to specialty SUD care for patients who would benefit from and are willing to receive this care, which could include increased service availability and improved referral/hand-off processes. These efforts may increase MOUD receipt and improve OUD care quality for patients with co-occurring substance use.