bluuebunny/crossref_metadata_2025 huggingface dataset:
Multimorbidity in patients with atrial fibrillation and community controls: A population-based study
Authors: Chamberlain Alanna M. , Alonso Alvaro , Noseworthy Peter A. , Siontis Konstantinos C. , Gersh Bernard J. , Killian Jill M. , Weston Susan A. , Vaughan Lisa E. , Manemann Sheila M. , Roger Véronique L. , Ryu Euijung
Published: December 2024

Background

Multimorbidity is common in patients with atrial fibrillation (AF), yet comorbidity patterns are not well documented.

Methods

The prevalence of 18 chronic conditions (6 cardiometabolic, 7 other somatic, 5 mental health) was obtained in patients with new-onset AF from 2013-2017 from a 27-county region and controls matched 1:1 on age, sex, and county of residence. For AF patients and controls separately, clustering of conditions and co-occurrence beyond chance was estimated (using the asymmetric Somers’ D statistic), overall and for ages <65, 65-74, 75-84, and ≥85 years.

Results

Among 16,509 patients with AF (median age 76 years, 57% men), few (4%) did not have any of the 18 chronic conditions, whereas nearly one-quarter of controls (23%) did not have any chronic conditions. Clustering of cardiometabolic conditions was common in both AF patients and controls, but clustering of other somatic conditions was more common in AF. Although the prevalence of most condition pairs was higher in AF patients, controls had a larger number of condition pairs occurring together beyond chance. In persons aged <65 years, AF patients more frequently exhibited concordance of condition pairs that included either pairs of somatic conditions or a combination of conditions from different condition groups. In persons aged 65-74 years, AF patients more frequently had pairs of other somatic conditions.

Conclusion

Patterns of co-existing conditions differed between patients with AF and controls, particularly in younger ages. A better understanding of the clinical consequences of multimorbidity in AF patients, including those diagnosed at younger ages, is needed.
A Case Series: Is the Use of Acetaminophen Still Safe in Pregnancy?
Authors: Boctor Carol , Watson HangYu , Ray Chaudhuri Nita , Hoda Mehar , Gendi Salwa
Published: December 2024

Acetaminophen is a common over-the-counter medication taken for fever and pain relief, during pregnancy. However, concerns have emerged regarding its potential to induce constriction of the ductus arteriosus, which is an essential fetal vessel. This case series investigated the potential association between acetaminophen usage during pregnancy and fetal ductus arteriosus constriction. This study is based on four pregnant patients who took acetaminophen at different stages of pregnancy and experienced premature constriction of the ductus arteriosus, in the fetus. The cases were identified on fetal echocardiograms, and pertinent details such as maternal acetaminophen usage, gestational age, ductus arteriosus characteristics, and clinical outcomes were gathered from medical records. All cases demonstrated ductus arteriosus constriction, with improvement seen in ductal velocities in two of the cases, after acetaminophen cessation. The additional case had sustained elevated velocities, with a stable outcome. The final case had progression of ductal constriction, leading to right ventricular dilation, and cesarean delivery at 36 weeks. Maternal acetaminophen use varied across the three trimesters. This case series underscores a potential link between acetaminophen use, during pregnancy, and premature constriction of the ductus arteriosus. Further research is needed to examine the correlation between acetaminophen exposure and premature constriction of the ductus arteriosus.
Evaluation of the effects of fenestration in Fontan circulation using a lumped parameter model
Authors: Horio Naohiro , Shimizu Shuji , Kotani Yasuhiro , Miyahara Yoshinori , Kasahara Shingo
Published: December 2024

Fenestration has been reported to enhance Fontan hemodynamics in several cases of Fontan circulation. However, the indication criteria for fenestration remain under discussion. To assess the effectiveness of fenestration in Fontan circulation, we conducted a theoretical analysis using a computational model of the fenestrated Fontan circulation. The cardiac chambers and vascular systems were modeled using the time-varying elastance model and the modified Windkessel model, respectively. When the pulmonary vascular resistance index was 4.01 Wood units m2, fenestration significantly reduced central venous pressure from 18.0 to 16.1 mmHg and decreased stressed blood volume from 610 to 555 ml. However, in the models with reduced ventricular end-systolic elastance, increased ventricular stiffness constant, or heightened systemic vascular resistance, the advantages of fenestration were diminished. Thus, fenestration may effectively improve the hemodynamics of Fontan circulation in patients with elevated pulmonary vascular resistance.
The profound impact of COVID-19 on the control and care of diabetic patients: a comprehensive retrospective cohort study
Authors: Al Rashdi Fakhria , Al Harrasi Salwa , Al Ismaili Mohammed , Yaaqubi AL-Ghaliya AL , Atwan Zeenah , Tabche Celine
Published: December 2024

Background

The COVID-19 pandemic has led to a significant shift in healthcare services, focusing on pandemic response and emergency preparedness. The Oman Ministry of Health implemented various measures to combat and control COVID-19. However, this shift disrupted routine outpatient appointments, particularly for chronic diseases such as diabetes mellitus (DM) and hypertension (HTN). This study aims to assess the pandemic’s effect on diabetes control, by examining glycated haemoglobin (HbA1c), blood pressure (BP), lipid values (particularly low-density lipoprotein (LDL), body weight/ body mass index (BMI), and comparing these measures to pre-pandemic levels.

Methods

A retrospective cohort study of 223 people with diabetes (PwD), aged 20–95 years who underwent a blood workup in 2019 and 2020 and were registered in Al-Khuwair Health Centre from March to December 2020. Data was extracted from the Al Shifa 3plus System and National Diabetic Register (NDR), and analyzed using SPSS.

Results

Out of 260 PwD identified, 223 met the inclusion criteria, while 37 were excluded due to recent diagnoses or missing follow-up in 2019. Significant changes were observed in HbA1C, systolic blood pressure (SBP), and BMI from 2019 to 2020. Mean HbA1c increased from 6.9% in 2019 to 7.2% in 2020. Mean SBP rose from 131.22 mmHg in 2019 to 134.84 mmHg in 2020, while mean BMI increased from 30.49 to 30.80. No significant changes were found in LDL levels or diastolic BP.

Conclusion

The COVID-19 pandemic disrupted healthcare systems globally, and the consequences on health and mortality were not only due to the direct impact of the virus, but also to the modifications in priorities. These interruptions in inconsistent care, had consequences for non-communicable diseases (NCDs) like diabetes. Future strategic plans should be prepared and implemented to manage NCD cases in case of pandemics.
Incidence of primary care chest pain consultations during the COVID-19 pandemic: an interrupted time series analysis with routine care data
Authors: van den Bulk Simone , van Egeraat Jasper W. A. , Petrus Annelieke H. J. , Numans Mattijs E. , Bonten Tobias N.
Published: December 2024

Background

The COVID-19 lockdown had profound effects on society and healthcare. Cardiology departments reported declines in chest pain evaluations and acute coronary syndrome (ACS) diagnoses. However, the pattern of chest pain in primary care is not clear yet. This study aims to assess the impact of the COVID-19 lockdown on the number of patients presenting with chest pain in primary care.

Methods

Routine primary care data from the Extramural LUMC (Leiden University Medical Center) Academic Network (ELAN) in the Netherlands were used. Chest pain consultations from January 2017 to December 2020 were included. An interrupted time series analysis was performed to compare the incidence rate (IR) of chest pain consultations during the COVID-19 lockdown to the expected IR. Secondary outcomes were the type of consultations, referral proportions, and the IR of registered ACS diagnoses.

Results

In total 9,908 chest pain consultations were included. During the COVID-19 lockdown the IR was 6.16 per 1000 person-years while the expected IR was 7.55 (95% CI 7.03–8.12). The immediate effect of the lockdown yielded an incidence rate ratio (IRR) of 0.62 (95% CI 0.50–0.77). A similar decrease was seen for ACS diagnoses (IRR 0.62, 95% CI 0.48–0.79), with no compensatory increase after the lockdown (IRR 1.04, 95% CI 0.89–1.21). Face-to-face consultations shifted to telephone consultations (p < 0.001) and hospital referrals decreased (9.9% vs. 19.0% (p < 0.001)).

Conclusions

During the COVID-19 lockdown the number of chest pain consultations and registered ACS diagnoses in primary care decreased significantly. In addition, fewer patients were assessed face-to-face and fewer patients were referred to the hospital.
Providing ‘professionalism with compassion’; how the time for caring communication can improve experiences at the end-of-life at home, findings from a realist evaluation
Authors: McEwan Kathryn , Atkinson Joanne , Clarke Amanda , Bate Angela , Jeffery Caroline , Dalkin Sonia
Published: December 2024

Background

For many patients and caregivers, attending to dying and death at home will be a new and fearful experience. This research brings new evidence on the central support of the Rapid Response Service (RRS), provided to those who chose to die at home. RRS’s are variable, although all seek to avoid unwanted hospital admissions and to respond flexibly to suit individual preferences for support. Staffed by specialist palliative and end-of-life care nurses, the RRS works alongside primary and acute care, but little is known on their impact.

Methods

Realist evaluation is a theory driven approach which identifies patterns of generative causation; this approach ascertains what works, for who, why, and in what circumstances. In this study, initial theories were developed by the research team and subsequently tested through semi-structured realist interviews with patients, caregivers, RRS staff, and other health practitioners. Iterative rounds of data analysis were undertaken to tease out contexts, mechanisms and outcomes, testing and revising the theories, including the application of substantive theory. Finally, we produced refined programme theories (PTs) which provide the basis for wider application of findings.

Results

Overall, 36 participants contributed, and six areas of inquiry were developed. This paper sets out the data from one area, PT Skilled Communication. Several benefits arose from RRS staff having the time to talk to and with patients and caregivers: specifically, that this communication improved knowledge in a tailored and compassionate manner. These exchanges allayed fears and reduced uncertainty, improving confidence to care. This was particularly embedded in one RRS because of their holistic approach.

Conclusions

Supporting death and dying at home is a novel and difficult experience for many; skilled communication, provided by specialist palliative care staff, can make a positive difference. Through their provision of compassionate support, RRS staff can help caregivers to recognise and respond to different symptoms and situations, reducing fear. By responding rapidly, only on request, they also meet individual preferences for contact. Together, this improves the opportunity for the last days and hours of life to be experienced, at home, in as affirmative a manner as possible.
Ethical implications of AI-driven clinical decision support systems on healthcare resource allocation: a qualitative study of healthcare professionals’ perspectives
Authors: Elgin Cansu Yüksel , Elgin Ceyhun
Published: December 2024

Background

Artificial intelligence-driven Clinical Decision Support Systems (AI-CDSS) are increasingly being integrated into healthcare for various purposes, including resource allocation. While these systems promise improved efficiency and decision-making, they also raise significant ethical concerns. This study aims to explore healthcare professionals’ perspectives on the ethical implications of using AI-CDSS for healthcare resource allocation.

Methods

We conducted semi-structured qualitative interviews with 23 healthcare professionals, including physicians, nurses, administrators, and medical ethicists in Turkey. Interviews focused on participants’ views regarding the use of AI-CDSS in resource allocation, potential ethical challenges, and recommendations for responsible implementation. Data were analyzed using thematic analysis.

Results

Participant responses are clustered around five pre-determined thematic areas: (1) balancing efficiency and equity in resource allocation, (2) the importance of transparency and explicability in AI-CDSS, (3) shifting roles and responsibilities in clinical decision-making, (4) ethical considerations in data usage and algorithm development, and (5) balancing cost-effectiveness and patient-centered care. Participants acknowledged the potential of AI-CDSS to optimize resource allocation but expressed concerns about exacerbating healthcare disparities, the need for interpretable AI models, changing professional roles, data privacy, and maintaining individualized care.

Conclusions

The integration of AI-CDSS into healthcare resource allocation presents both opportunities and significant ethical challenges. Our findings underscore the need for robust ethical frameworks, enhanced AI literacy among healthcare professionals, interdisciplinary collaboration, and rigorous monitoring and evaluation processes. Addressing these challenges proactively is crucial for harnessing the potential of AI-CDSS while preserving the fundamental values of equity, transparency, and patient-centered care in healthcare delivery.
Patient cost analysis of a community-based teledermatology service versus conventional outpatient appointments in East Kent: a retrospective study through a societal lens to reduce health inequalities
Authors: Nizar Nurul Ain , Farooki Roopa , Mahapatra Piyush , Halpern Saul , Hoogenboom Tim C. H.
Published: December 2024

Background

The UK's National Health Service (NHS) is grappling with rising demand and limited dermatologists, leading to longer waiting times. This is particularly concerning for conditions like malignant melanoma, where early diagnosis is crucial. Teledermatology is being introduced to address these issues, but its impact on patients’ monetary and time costs, especially in deprived areas, is under-researched. This study investigates the impact of a community-based teledermatology model in East Kent, a coastal region with high cross-regional health inequalities.

Methods

We analysed the financial costs and time invested by patients undergoing community-based teledermatology versus if they were to attend traditional appointments. Data were gathered from 1368 referrals, from May 2022 to January 2024 at a secondary care provider in the region. We considered the diagnosis method, appointments, travel, monetary cost of time, parking costs and Index of Multiple Deprivation Deciles (IMDD).

Results

Our study showed the community teledermatology model significantly reduced the active patient’s time and cost to obtain a diagnosis. Average time was 38.1 min, compared to 96.7 min in traditional clinics, saving 58.4 min (95% CI -62.3 to -54.5, p < 0.001). Patients saved £17.9 per diagnosis with this model (95% CI -£19.2 to -£16.6, p < 0.001). Time savings were more substantial for patients from more deprived regions (IMDD 1–3).

Conclusion

The community-based teledermatology model proves to be cheaper for patients, providing a convenient alternative to traditional clinics, particularly benefiting patients from deprived backgrounds by improving healthcare accessibility and offering flexible consultation options.
Factor structure of the HIV-SM LMIC self-management questionnaire for people living with HIV in low- and middle-income countries
Authors: Dadi Tegene Legese , Medhin Girmay , Spigt Mark
Published: December 2024

Introduction

Despite the need for reliable questionnaires to monitor self-management in chronic disease patients, such tools are lacking in developing countries. This study aims to pilot and assess the construct validity of the HIV-SM LMIC questionnaire.

Method

The validation of the HIV-SM LMIC questionnaire involved two cross-sectional studies in Ethiopia. The first round, for exploratory factor analysis (EFA), included 261 patients, while the second round, for confirmatory factor analysis (CFA), included 300 patients. Data was collected using the Kobo Collect electronic data entry template.

Result

The sample adequacy test showed a good value of 0.82. In the first round, 6 of the 32 items were not loaded, forming three factors in the EFA. Four of these items were dropped, but two (PSMB2 and PSMB12) were retained for their content. In the second round, CFA on the remaining 28 items led to dropping 8 more items due to conceptual overlap, resulting in a 20-item questionnaire. The final items were structured into three dimensions: awareness and well-being (4 items), self-regulation (6 items), and self-management practices (10 items).

Conclusion

The study refined the original 32-item HIV-SM LMIC questionnaire to a validated 20-item, three-dimensional tool with an acceptable goodness of fit. The authors recommend further cross-cultural and predictive validation and adaptation for newly diagnosed HIV patients, those with poor treatment outcomes.
Effectiveness of dolutegravir-based regimens compared to raltegravir-, elvitegravir-, bictegravir, and darunavir-based regimens among older adults with HIV in the Veterans Aging Cohort Study (VACS)
Authors: Yan Lei , Henegar Cassidy E. , Marconi Vincent C. , Gordon Kirsha S. , Hicks Charles , Vannappagari Vani , Justice Amy C. , Aslan Mihaela
Published: December 2024

Background

Real-world data on treatment patterns and clinical outcomes for newer drugs, including integrase strand transfer inhibitors, among older people with human immunodeficiency virus (PWH) are limited.

Methods

This cohort study included PWH enrolled in the Veterans Aging Cohort Study (VACS) who were prescribed a standard 3-drug antiretroviral therapy (ART) regimen containing dolutegravir (DTG), bictegravir (BIC), cobicistat boosted elvitegravir (EVG), raltegravir (RAL), or darunavir/ritonavir (DRV) plus 2 nucleoside reverse transcriptase inhibitors between January 1, 2014, and March 31, 2020, and who were ≥50 years at regimen initiation. The association between regimen and virologic effectiveness or discontinuation was assessed using logistic regression models with inverse probability of treatment weights. Pairwise comparisons were made between DTG-based regimen and each of the other 3-drug regimens, stratified by ART experience.

Results

Among 15,702 PWH (across treatment groups, median age 58–62 years; 94–98% male; 5–11% Hispanic; 44–60% Black; 29–42% White), 5,800 received DTG-based regimens, 2,081 BIC-based regimens, 4,159 EVG-based regimens, 1,607 RAL-based regimens, and 2,055 received DRV-based regimens. Among ART-naïve PWH, there were no statistical differences in the odds of virologic suppression, and 6- and 12-month discontinuations were higher in those on DRV. Among ART-experienced PWH, compared to DTG, those on RAL and DRV were less likely to be suppressed at 6 months (RAL vs DTG: aOR 0.64, 95% CI 0.51–0.81; DRV vs DTG: aOR 0.63, 95% CI 0.51–0.76) and those on EVG and DRV were less likely suppressed at 12 months (EVG vs DTG: aOR 0.82, 95% CI 0.68–0.99; DRV vs DTG: aOR 0.64, 95% CI 0.52–0.80). Those on DRV were more likely to have virologic failure within 12 months (aOR 1.96, 95% CI 1.30–2.97). Six- and 12-month discontinuations were higher in those on RAL and DRV, but less likely for BIC-based regimens.

Conclusions

DTG-based regimens demonstrated higher levels of effectiveness and durability compared to DRV- or RAL-based regimens and had similar treatment responses as BIC- and EVG-based regimens among ART-experienced older PWH.
Upper extremity function and disability recovery with vibration therapy after stroke: a systematic review and meta-analysis of RCTs
Authors: Lu Yueh-Hsun , Chen Hung-Ju , Liao Chun-De , Chen Po-Jung , Wang Xin-Miao , Yu Chieh-Hsiang , Chen Po-Yin , Lin Chueh-Ho
Published: December 2024

Background

This study aimed to investigate the therapeutic effects of vibration therapy for improving upper extremity motor impairment, function, and disability recovery in people with stroke.

Design

We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. PubMed, EMBASE, the Cochrane Library Database, Physiotherapy Evidence Database (PEDro), China Knowledge Resource Integrated Database, and Google Scholar were searched from inception to May 31, 2024. Randomized controlled trials (RCTs) that evaluated the effects of vibration therapy on upper extremity motor impairment, function, and disability recovery post-stroke were analyzed.

Setting and participants

Participants with a diagnosis of stroke with hemiplegia (or hemiparesis) were recruited.

Methods

Methodological quality assessment was performed using the PEDro quality score. Upper extremity motor impairment, function, and disability were the primary outcomes. Upper extremity motor impairment was measured using the Fugl-Meyer Assessment scale and other methods. Upper extremity functions were evaluated using the Wolf Motor Function test or other tools assessing manipulative activities. Disability was assessed using the Functional Independence Measure, Barthel index, and other methods.

Results

Overall, 30 RCTs including 1621 people with stroke were selected. Compared with the control, vibration therapy exerted significant effects on upper extremity motor impairment [standardized mean difference (SMD) = 1.19; p < 0.00001)], function (SMD = 0.62; p < 0.00001), and disability recovery (SMD = 1.01; p < 0.00001). The subgroup analysis revealed that focal vibration therapy (SMD = 2.14) had favorable effects on disability recovery compared with whole-body vibration therapy (SMD = 2.0). Interventions lasting 4–8 weeks showed significant improvements in motor impairment (SMD = 1.19), motor function (SMD = 0.57), and disability (SMD = 0.84); additionally, the effects of vibration therapy combined with conventional rehabilitation (SMD = 1.03) were superior to those of vibration therapy alone (SMD = 0.21).

Conclusions

Vibration therapy may be a reliable rehabilitation program to improve upper extremity motor functions and disabilities. Furthermore, vibration therapy should be performed at the earliest possibility after stroke for at least 4–8 weeks.

Trial registration The protocol of this study was registered with PROSPERO (Registration number: CRD42022301119).
The current troubled state of the global pathology workforce: a concise review
Authors: Walsh Elizabeth , Orsi Nicolas M
Published: December 2024

The histopathology workforce is a cornerstone of cancer diagnostics and is essential to the delivery of cancer services and patient care. The workforce has been subject to significant pressures over recent years, and this review considers them in the UK and internationally. These pressures include declining pathologist numbers, the increasing age of the workforce, and greater workload volume and complexity. Forecasts of the workforce’s future in numerous countries are also not favourable – although this is not universal. Some in the field suggest that the effects of these pressures are already coming to bear, such as the financial costs of the additional measures needed to maintain clinical services. There is also some evidence of a detrimental impact on service delivery, patient care and pathologists themselves. Various solutions have been considered, including increasing the number of training places, enhancing recruitment, shortening pathology training and establishing additional support roles within pathology departments. A few studies have examined the effect of some of these solutions. However, the broader extent of their implementation and impact, if any, remains to be determined. In this regard, it is critical that future endeavours should focus on gaining a better understanding of the benefits of implemented workforce solutions, as well as obtaining more detailed and updated pathology workforce numbers. With a concentrated effort in these areas, the future of the pathology workforce could become brighter in the face of the increased demands on its services.
Targeted long-read sequencing to quantify methylation of the C9orf72 repeat expansion
Authors: Udine Evan , Finch NiCole A. , DeJesus-Hernandez Mariely , Jackson Jazmyne L. , Baker Matthew C. , Saravanaperumal Siva Arumugam , Wieben Eric , Ebbert Mark T.W. , Shah Jaimin , Petrucelli Leonard , Rademakers Rosa , Oskarsson Björn , van Blitterswijk Marka
Published: December 2024

Background

The gene C9orf72 harbors a non-coding hexanucleotide repeat expansion known to cause amyotrophic lateral sclerosis and frontotemporal dementia. While previous studies have estimated the length of this repeat expansion in multiple tissues, technological limitations have impeded researchers from exploring additional features, such as methylation levels.

Methods

We aimed to characterize C9orf72 repeat expansions using a targeted, amplification-free long-read sequencing method. Our primary goal was to determine the presence and subsequent quantification of observed methylation in the C9orf72 repeat expansion. In addition, we measured the repeat length and purity of the expansion. To do this, we sequenced DNA extracted from blood for 27 individuals with an expanded C9orf72 repeat.

Results

For these individuals, we obtained a total of 7,765 on-target reads, including 1,612 fully covering the expanded allele. Our in-depth analysis revealed that the expansion itself is methylated, with great variability in total methylation levels observed, as represented by the proportion of methylated CpGs (13 to 66%). Interestingly, we demonstrated that the expanded allele is more highly methylated than the wild-type allele (P-Value = 2.76E-05) and that increased methylation levels are observed in longer repeat expansions (P-Value = 1.18E-04). Furthermore, methylation levels correlate with age at collection (P-Value = 3.25E-04) as well as age at disease onset (P-Value = 0.020). Additionally, we detected repeat lengths up to 4,088 repeats (~ 25 kb) and found that the expansion contains few interruptions in the blood.

Conclusions

Taken together, our study demonstrates robust ability to quantify methylation of the expanded C9orf72 repeat, capturing differences between individuals harboring this expansion and revealing clinical associations.
Accuracy of POC testing systems for HPV screening: the importance of disease prevalence and characteristics of the screened population
Authors: Giorgi Rossi Paolo , Ronco Guglielmo
Published: December 2024

Infectious Agents and Cancer journal has recently launched a new collection of papers about “Point-of-Care (POC) for HPV-related genital cancers” putting together some interesting works on the accuracy of HPV tests for screening. This editorial initiative gave us the opportunity to reflect on the relations between accuracy measures, prevalence and characteristics of the tested population in the case of HPV-based screening. In screening test evaluation, we look at the clinical accuracy of the test as an intrinsic characteristic of the assay, which interacts with the characteristics of the population, the result being the screening performance. In the case of HPV testing, the clinical accuracy should be conceptualized in two steps, the analytical accuracy of the assay for HPV infection and the biological link between HPV infection and the target disease, i.e. the high-grade cervical intraepithelial neoplasia (hgCIN). This approach highlights that just a few false positive cases result from a lack of analytical specificity while most derive from women who have the infection but it did not progress to hgCIN. In addition, increasing prevalence of hgCIN results in relevant increases of PPV only if due or associated with exposures which increase the progression from infection to hgCIN or the duration of the latter; while an increase due to a higher prevalence of HPV infection would only marginally affect PPV. This approach may help in modelling the performance of HPV-based cervical screening.
Glutathione peroxidase 4 overexpression induces anomalous subdiffusion and impairs glioblastoma cell growth
Authors: Teferi Nahom , Ekanayake Akalanka , Owusu Stephenson B. , Moninger Thomas O. , Sarkaria Jann N. , Tivanski Alexei V. , Petronek Michael S.
Published: December 2024

Glioblastoma tumors are the most common and aggressive adult central nervous system malignancy. Nearly all patients experience disease progression, which significantly contributes to disease mortality. Recently, it has been suggested that recurrent tumors may be characterized by a ferroptosis-prone phenotype with a significant decrease in glutathione peroxidase 4 (GPx4) expression. This led to the hypothesis that GPx4 expression negatively influences GBM cell growth. This study utilizes a doxycycline inducible GPx4 overexpression model to test this hypothesis. Consistently, the overexpression of GPx4 significantly impairs cell growth and colony formation while also causing an accumulation of cells in G1/G0 phase of the cell cycle. From a biophysical perspective, GPx4 overexpressing cells have significantly greater surface area, increased Young’s modulus, and experience anomalous sub-diffusion as opposed to normal diffusion associated with Brownian motion. Moreover, analysis of patient derived GBM cells reveal that cell growth rates, plating efficiency, and Young’s modulus are all inversely proportional to GPx4 expression. Therefore, GPx4 appears to be a biophysical regulator of GBM cell growth that warrants further mechanistic investigation in its role in GBM progression.
Ecteinascidin synthetic analogues: a new class of selective inhibitors of transcription, exerting immunogenic cell death in refractory malignant pleural mesothelioma
Authors: Salaroglio I. C. , Aviles P. , Kopecka J. , Merlini A. , Napoli F. , Righi L. , Novello S. , Sullivan H. , Cuevas C. , Scagliotti G. V. , Riganti C.
Published: December 2024

Background

Malignant pleural mesothelioma (MPM) is a highly chemo-refractory and immune-evasive tumor that presents a median overall survival of 12–14 months when treated with chemotherapy and immunotherapy. New anti-tumor therapies as well as the concomitant reactivation of immune destruction are urgently needed to treat patients with this tumor. The aim of this work is to investigate the potential effect of ecteinascidin derivatives as lurbinectedin as new first-line treatment option in MPM, alone and in combination with immunotherapy.

Methods

The antitumor activity of ecteinascidin synthetic analogues: lurbinectedin, ecubectedin and PM54 was evaluated in an array of patient-derived MPM cells in terms of cell proliferation, cell cycle, apoptosis, DNA damage and repair. Immunoblot was used to assess the cGAS/STING pathway. ELISA and flow cytometry-based assays were used to evaluate immunogenic cell death parameters and the effect on the immunophenotype in autologous peripheral blood monocyte-MPM cells co-cultures. Patient-derived xenografts (PDX) in humanized mice were used to evaluate the efficacy of ecteinascidins in vivo.

Results

Lurbinectedin, ecubectedin, and PM54 were effective in reducing cell proliferation and migration, as well as inducing S-phase cell cycle arrest and DNA damage in malignant pleural mesothelioma cells. These effects were more pronounced compared to the standard first-line treatment (platinum-based plus pemetrexed). Mechanistically, the drugs downregulated DNA repair genes, activated the cGAS/STING pathway, and promoted the release of pro-inflammatory cytokines. They also induced immunogenic cell death of mesothelioma cells, enhancing the activation of anti-tumor CD8+T-cells and natural killer cells while reducing tumor-tolerant T-regulatory cells and myeloid-derived suppressor cells in ex vivo co-cultures. These promising results were also observed in humanized patient-derived xenograft models, where the drugs were effective in reducing tumor growth and increasing the ratio anti-tumor/pro-tumor infiltrating immune populations, either alone or combined with the anti-PD-1L atezolizumab.

Conclusions

Collectively, these findings reveal a previously unknown mechanism of action of ecteinascidins that merits further investigation for potential clinical applications in the treatment of MPM, as new first line treatment in monotherapy or in association with immunotherapy.
Implementation of a parent training intervention (SPARCK) to prevent childhood mental health problems: study protocol for a pragmatic implementation trial in Norwegian municipalities
Authors: Grønlie Anette Arnesen , Backer-Grøndahl Agathe , Nes Ragnhild Bang , Gomez Maria Begoña , Tømmerås Truls
Published: December 2024

Background

Effective evidence-based interventions (EBI) are necessary to prevent and avoid negative life trajectories for children with mental health problems. Even though many EBIs prove effective when tested, few are successfully implemented and used in real-world clinical practice. As a result, many children and families do not receive the best care in due time or at all. To reduce this research-practice gap, a combined RCT and implementation study of Supportive Parents—Coping Kids (SPARCK), a parent training intervention to prevent childhood mental health problems, will be performed. This study protocol concerns the implementation part of the larger effectiveness-implementation project.

Methods

The study is a correlational multi-site implementation study of SPARCK performed alongside a two-armed RCT, in 24 Norwegian municipalities. A quantitative three-wave longitudinal web-based data collection will be conducted among SPARCK practitioners and leaders in relevant services. We will investigate the relations between theory-driven and empirical implementation determinants and implementation outcomes, measured by fidelity, acceptability, appropriateness, and feasibility. In addition, we will examine how these implementation determinants and outcomes are associated with the clinical outcomes of SPARCK.

Discussion

The current study will investigate implementation determinants and their relation to indicators of implementation success, while simultaneously investigating effectiveness of an intervention optimized to the needs of both the target group and relevant stakeholders. Together, this may improve clinical effect, contextual fit, implementation success, and reduce the time lag between research findings and application in real-world settings.

Trial registration

ClinicalTrials.gov NCT05800522. Registered on 2023.03.23.
Acoustic scene classification using inter- and intra-subarray spatial features in distributed microphone array
Authors: Kawamura Takao , Kinoshita Yuma , Ono Nobutaka , Scheibler Robin
Published: December 2024

In this study, we investigate the effectiveness of spatial features in acoustic scene classification using distributed microphone arrays. Under the assumption that multiple subarrays, each equipped with microphones, are synchronized, we investigate two types of spatial feature: intra- and inter-generalized cross-correlation phase transforms (GCC-PHATs). These are derived from channels within the same subarray and between different subarrays, respectively. Our approach treats the log-Mel spectrogram as a spectral feature and intra- and/or inter-GCC-PHAT as a spatial feature. We propose two integration methods for spectral and spatial features: (a) middle integration, which fuses embeddings obtained by spectral and spatial features, and (b) late integration, which fuses decisions estimated using spectral and spatial features. The evaluation experiments showed that, when using only spectral features, employing all channels did not markedly improve the F1-score compared with the single-channel case. In contrast, integrating both spectral and spatial features improved the F1-score compared with using only spectral features. Additionally, we confirmed that the F1-score for late integration was slightly higher than that for middle integration.
Multiband in-band full-duplexing using fractal concentric circular antenna arrays
Authors: Elsanousi Geili , Abbas Mohammed , Hirtenfelder Franz , AbdAlhameed Raed , Yang Xin-She , Le Tuan , Nguyen Huan X.
Published: December 2024

In this work, we present an innovative approach to enhance multiband communication systems by enabling the antenna subsystems to simultaneously transmit and receive across multiple independent in-band full-duplex (IBFD) channels, i.e. multiband-IBFD (MIBFD). This capability is powered by fractal antenna arrays, specifically using hexagonal star array (HSA) geometry. The approach provides a unique self-interference cancellation (SIC) capability across multiple bands (MB-SIC), achieved through translation or rotational transformations of self-similar or self-affine array structures. Simulation results demonstrate significantly enhanced SIC bandwidth for three signals at sub-frequencies near 5 GHz, with the integration of subbands’ SIC bandwidths achieving 1.4 GHz across these subbands. Further enhancements include combining this method with a technique involving the elevation of the central receiving element, significantly broadening the SIC bandwidth compared to traditional methods. Additionally, the multiband functionality is validated with pilot signals at 2.68 and 5.2 GHz, showing effective SIC in these narrow bands. This research presents a promising path for optimising radio resources in multiband communication systems.
Promoting hand hygiene in a chemotherapy day center: the role of a robot
Authors: Wong Shuk-Ching , Ip Stephen Chun-Yat , Kwok Monica Oi-Tung , Siu Crystal Yuen-Ki , Chen Jonathan Hon-Kwan , So Simon Yung-Chun , Chiu Kelvin Hei-Yeung , Yuen Kwok-Keung , Cheng Vincent Chi-Chung
Published: December 2024

Background

Hand hygiene is a critical component of infection prevention in healthcare settings. Innovative strategies are required to enhance hand hygiene practices among patients and healthcare workers (HCWs).

Methods

This study was conducted at the Chemotherapy Day Center of Queen Mary Hospital, Hong Kong. It comprised three phases: phase 1 involved observational audits of hand hygiene practices among patients and HCWs by infection control nurse (ICN); phase 2 included the installation of 53 pressure sensors on alcohol-based hand rub (AHR) bottles at designated sites to monitor usage; phase 3 introduced the robot named Temi Medic to promote hand hygiene through video broadcasts at strategic locations in the center. The mean counts of pressure sensor-equipped AHR per 100 attendances per day (hereafter referred to as the mean count) across phases 2 and 3 were analyzed.

Results

A total of 2580 patient attended the center from April to September 2023. The ICN observed a significant increase in hand hygiene practices among patients at the entrance and reception area, rising from phase 1 (0.2%, 1/583) and phase 2 (0.5%, 3/656) to phase 3 (5.0%, 33/654) (p < 0.001). Meanwhile, the overall hand hygiene compliance among HCWs was 74.1% (1341/1810) throughout the study period. From phase 2 to phase 3, the mean counts of 7 AHR bottles designated for patient use (P1–P7) significantly increased (35 ± 17 vs. 64 ± 24, p < 0.001), as did the 33 AHR bottles shared by both patients and HCWs (207 ± 104 vs. 267 ± 113, p = 0.027). In contrast, there was no significant change in the mean count among the 13 AHR bottles designated for HCWs (H1–H13). The mean count of H1–H13 was significantly higher than that of P1–P7 throughout phases 2 and 3 (214 ± 93 vs. 49 ± 25, p < 0.001), indicating a 4.4-fold difference.

Conclusions

While HCWs maintained stable hand hygiene compliance, the introduction of the robot significantly improved hand hygiene practices among patients in the chemotherapy day center. This underscores the importance of integrating technology into routine practices to promote infection prevention and control in healthcare settings.
Myocardial mRNA expression of interleukin-6 and hypoxia inducible factor-1α in neonates with congenital cardiac defects
Authors: Farhat Nesrine , Vazquez-Jimenez Jaime , Heying Ruth , Seghaye Marie-Christine
Published: December 2024

Background

In neonates with congenital heart disease (CHD), myocardial remodelling involves activation of inflammatory pathways. The role of hypoxemia related pathways is however unknown. This study was therefore designed to investigate myocardial mRNA expression of interleukin (IL)-6 and hypoxia-inducible factor (HIF)-1α in neonates with CHD and analyse its influence on post-operative outcome.

Results

14 neonates with CHD scheduled for open cardiac surgery were studied. In group 1 (n = 5), pre-operative transcutaneous arterial oxygen saturation (SaO2) was ≤ 85% and in group 2 (n = 9) > 85%. Expression of IL-6- and HIF-1α-mRNA was studied on right atrial biopsy by RT-PCR and corelated to post-operative (po) outcome. Group 1 patients showed higher mean arterial blood pressure (MAP) and lower glycaemia 4 h po (p = 0.047 and p = 0.021, respectively). In the whole cohort, SaO2 correlated negatively with MAP (Pearson R: -0.662, p = 0.010). mRNA coding for IL-6 and HIF-1α was detected in the myocardium of all neonates independently of age, gender, or type of CHD. IL6-mRNA expression was not influenced by pre-operative hypoxemia but was associated with higher lactate levels in early po period (Pearson R: 0,611, p = 0,020). HIF-1α-mRNA expression correlated negatively with pre-operative SaO2 (Pearson R: -0.551, p = 0.04) and with aspartate aminotransferase levels 4 h po (Pearson R: 0.625, p = 0.017).

Conclusion

Our study shows that besides inflammatory pathways, hypoxemia related pathways are activated in the myocardium of neonates with CHD. Myocardial expression of both IL-6-mRNA and HIF-1α-mRNA relates to biological markers of a worse po outcome.
CHMP2B promotes CHMP7 mediated nuclear pore complex injury in sporadic ALS
Authors: Keeley Olivia , Mendoza Emma , Menon Druv , Coyne Alyssa N.
Published: December 2024

Alterations to the composition and function of neuronal nuclear pore complexes (NPCs) have been documented in multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis (ALS). Moreover, recent work has suggested that injury to the NPC can at least in part contribute to TDP-43 loss of function and mislocalization, a pathological hallmark of ALS and related neurodegenerative diseases. Collectively, these studies highlight a role for disruptions in NPC homeostasis and surveillance as a significant pathophysiologic event in neurodegeneration. The ESCRT-III nuclear surveillance pathway plays a critical role in the surveillance and maintenance of NPCs and the surrounding nuclear environment. Importantly, pathologic alterations to this pathway and its protein constituents have been implicated in neurodegenerative diseases such as ALS. However, the mechanism by which this pathway contributes to disease associated alterations in the NPC remains unknown. Here we use an induced pluripotent stem cell (iPSC) derived neuron (iPSN) model of sALS to demonstrate that CHMP7/ESCRT-III nuclear maintenance/surveillance is overactivated in sALS neurons. This overactivation is dependent upon the ESCRT-III protein CHMP2B and sustained CHMP2B dependent “activation” is sufficient to contribute to pathologic CHMP7 nuclear accumulation and POM121 reduction. Importantly, partial knockdown of CHMP2B was sufficient to alleviate NPC injury and downstream TDP-43 dysfunction in sALS neurons thereby highlighting CHMP2B as a potential therapeutic target in disease.
Prognostic value of metabolic tumor volume on [18F]FDG PET/CT in addition to the TNM classification system of locally advanced non-small cell lung cancer
Authors: Brose Alexander , Miederer Isabelle , König Jochem , Gkika Eleni , Sahlmann Jörg , Schimek-Jasch Tanja , Schreckenberger Mathias , Nestle Ursula , Kappes Jutta , Miederer Matthias
Published: December 2024

Purpose

Staging of non-small cell lung cancer (NSCLC) is commonly based on [18F]FDG PET/CT, in particular to exclude distant metastases and guide local therapy approaches like resection and radiotherapy. Although it is hoped that PET/CT will increase the value of primary staging compared to conventional imaging, it is generally limited to the characterization of TNM. The first aim of this study was to evaluate the PET parameter metabolic tumor volume (MTV) above liver background uptake as a prognostic marker in lung cancer. The second aim was to investigate the possibility of incorporating MTV into the TNM classification system for disease prognosis in locally advanced NSCLC treated with chemoradiotherapy.

Methods

Retrospective evaluation of 235 patients with histologically proven, locally advanced NSCLC from the multi-centre randomized clinical PETPLAN trial and a clinical cohort from a hospital registry. The PET parameters SUVmax, SULpeak, MTV and TLG above liver background uptake were determined. Kaplan-Meier curves and stratified Cox proportional hazard regression models were used to investigate the prognostic value of PET parameters and TNM along with clinical variables. Subgroup analyses were performed to compare hazard ratios according to TNM, MTV, and the two variables combined.

Results

In the multivariable Cox regression analysis, MTV was associated with significantly worse overall survival independent of stage and other prognostic variables. In locally advanced disease stages treated with chemoradiotherapy, higher MTV was significantly associated with worse survival (median 17 vs. 32 months). Using simple cut-off values (45 ml for stage IIIa, 48 ml for stage IIIb, and 105 ml for stage IIIc), MTV was able to further predict differences in survival for stages IIIa-c. The combination of TNM and MTV staging system showed better discrimination for overall survival in locally advanced disease stages, compared to TNM alone.

Conclusion

Higher metabolic tumor volume is significantly associated with worse overall survival and combined with TNM staging, it provides more precise information about the disease prognosis in locally advanced NSCLC treated with chemoradiotherapy compared to TNM alone. As a PET parameter with volumetric information, MTV represents a useful addition to TNM.