bluuebunny/crossref_metadata_2025 huggingface dataset:
Evidence for a relationship between genetic polymorphisms of the L-DOPA transporter LAT2/4F2hc and risk of hypertension in the context of chronic kidney disease
Authors: Crocco Paolina , Dato Serena , Grotta Rossella La , Passarino Giuseppe , Rose Giuseppina
Published: April 2024

Background
Chronic kidney disease (CKD) and hypertension are chronic diseases affecting a large portion of the population, frequently coexistent and interdependent. The inability to produce/use adequate renal dopamine may contribute to the development of hypertension and renal dysfunction. The heterodimeric amino acid transporter LAT2/4F2hc (SLC7A8/SLC3A2 genes) promotes the uptake of L-DOPA, the natural precursor of dopamine. We examined the plausibility that SLC7A8/SLC3A2 gene polymorphisms may contribute to hypertensive CKD by affecting the L-DOPA uptake.
Methods
421 subjects (203 men and 218 women, mean age of 78.9 ± 9.6 years) were recruited and divided in four groups according to presence/absence of CKD, defined as reduced estimated glomerular filtration rate (eGFR < 60 ml/min/m2) calculated using the creatinine-based Berlin Initiative Study–1 (BIS1) equation, and to presence/absence of hypertension (systolic blood pressure ≥ 140 and/or diastolic blood pressure ≥ 90 mmHg). Subjects were analysed for selected SNPs spanning the SLC7A8 and SLC3A2 loci by Sequenom MassARRAY iPLEX platform.
Results
The most significant SNP at the SLC3A2 (4F2hc) locus was rs2282477-T/C, with carriers of the C-allele having a lower chance to develop hypertension among CKD affected individuals [OR = 0.33 (CI 0.14–0.82); p = 0.016]. A similar association with hypertensive CKD was found for the SLC7A8 (LAT2) rs3783436-T/C, whose C-allele resulted associated with decreased risk of hypertension among subjects affected by CKD [OR = 0.56 (95% CI 0.35–0.90; p = 0.017]. The two variants were predicted to be potentially functional.
Conclusions
The association between SLC3A2 and SLC7A8 variants to hypertension development in patients with renal failure could be linked to changes in L-DOPA uptake and consequently dopamine synthesis. Although additional research is needed, our study opens new avenues for future basic and translational research in the field of hypertensive CKD.
Feeding practices, prevalence and factors associated with concurrent wasting and stunting (WaSt) among children under five years attending health facilities in Southwestern Uganda
Authors: Iranezereje Dick , Bernis Melvis Maren , Kumbakulu Patrick Kumbowi , Muhumuza Joshua , Nduwimana Martin
Published: April 2024

Background
Malnutrition remains a significant factor determining health and survival of children in countries with low and middle income. The indicators utilized traditionally to separately assess the magnitude of malnutrition in communities have been reported by recent studies to have ignored the impact of simultaneous anthropometric deficits. This study aimed to determine the feeding practices, prevalence and factors associated with concurrent wasting and stunting (WaSt) among children under 5 years attending health facilities in Southwestern Uganda (Bushenyi district)
Methods
This was a health facility-based, cross sectional study that enrolled 321 patients. The data related to feeding practices and socio demographic factors was collected using interview of caregivers while the weight and length were obtained using a digital weighing scale and an infantometer/stadiometer respectively. Concurrent wasting and stunting (WaSt) was diagnosed if both weight for length and height for age were under − 2SD. Binary logistic regression was used to determine factors associated with concurrent wasting and stunting (WaSt) in SPSS version 26.
Results
The prevalence of WaSt was 4%. Early initiation of breast feeding was done in 85.1%, exclusive breastfeeding in 64.7%, continued breastfeeding in 63.1%, minimum diet diversity received in 33.7% and minimum meal frequency in 78.1%. The factors associated with WaSt were the presentation with diarrhea (aOR = 1.269, CI = 1.138–1.414, P < 0.001), pneumonia (aOR = 1.230, CI = 1.095–1.383, P = 0.001), not receiving minimum diet diversity (aOR = 1.235, CI = 1.052–1.265, P = 0.001), being a child to an unmarried mother, mother's MUAC < 22cm ((aOR = 1.316, CI = 1.144–1.514, P < 0.001) and not receiving nutritional counselling (aOR = 1.061, CI = 1.017–1.107, P = 0.006).
Conclusion
The prevalence of concurrent wasting and stunting (WaSt) among children under five years attending health facilities in Bushenyi district was in global prevalence range (4%). Complementary feeding practices indicators were poor particularly food diversity. Healthcare providers should screen systematically children under five for multiple anthropometric deficits.
Objective Response after Immune Checkpoint Inhibitors in a Chemotherapy-Refractory pMMR/MSS Metastatic Rectal Cancer Patient Primed with Experimental AlloStim® Immunotherapy.
Authors: Hirschfeld Azriel , Gurell Daniel , Har-Noy Michael
Published: April 2024

Background: Immune Checkpoint Inhibitor (ICI) immunotherapy is most effective in immune effector cell infiltrated ‘hot’ tumor lesions, such as occurs in deficient mismatch repair, microsatellite instability high (dMMR/MSI-H) colorectal cancer (CRC). However, most all metastatic CRC tumors are mismatch repair proficient/microsatellite stable (pMMR/MSS) ‘cold’ lesions, without significant immune cell infiltration, and are unresponsive to ICI. AlloStim®, is an experimental, allogeneic immunomodulatory cell therapy designed to convert ‘cold’ metastatic tumor lesions to ‘hot’ inflamed lesions. After AlloStim® immunotherapy, this cold to hot inflammatory mechanism can make it difficult to distinguish between pseudoprogression and actual progression on restaging CT scans, as inflamed metastatic lesions can appear larger and occult disease can appear as new small lesions.Methods: To explore whether radiological progression after AlloStim® immunotherapy is due to immune-flare or disease progression, we administered a short course of a combination ICI therapy to a pMMR/MSS chemotherapy-refractory metastatic colorectal cancer patient enrolled in the StimVax Phase IIb clinical study that presented with radiological progression after AlloStim® immunotherapy. Our rationale was that an accelerated response to ICI should occur if the lesions were inflamed, while if the enlarged lesions were due to disease progression there would not be a response.Results: Here we report a rapid, significant reduction in tumor burden in response to ICI administration in an AlloStim®primed pMMR/MSS mCRC patient with retroperitoneal and lung metastases.Conclusion: This rare objective response to ICIs in a pMMR/MSS mCRC patient supports further evaluation of the combination of AlloStim®with ICI immunotherapy in MSS mCRC and other cold or ICI refractory tumors.Trial registration:National Library of Medicine (NLM) at the National Institutes of Health (NIH). Registered 22 June 2020, https://clinicaltrials.gov/study/NCT04444622
Association of Anaemia with Indoor Air Pollution Among Older Indian Adult Population: Multilevel Modelling Analysis of Nationally Representative Cross-Sectional Study
Authors: Halder Pritam , Verma Madhur , Pal Saumyarup , Mishra Amit Kumar , Deori Trideep Jyoti , Biswas Riya , Tiwari Jaya , Mamgai Anshul , Rathor Shivani , Prabhakar Manish Chandra
Published: April 2024

Introduction- Anaemia is a disease of public health importance with multi-causal pathways. Previous literature suggests the role of indoor air pollution (IAP) on haemoglobin levels, but this has been studied less due to logistic constraints. A high proportion of the population in developing countries, including India, still depends on unclean fuel, which exacerbates IAP. The objective was to study the association between anaemia and IAP among the older Indian adult population (>45 years) as per gender.
Methods- Our study analysed the nationally representative dataset of the Longitudinal Ageing Study in India (LASI 2017–18, Wave-1). Bivariate analysis and logistic regression were used to depict the association of anaemia (outcome variable) with IAP (explanatory variable). Multivariable logistic regression was conducted by adjusting for covariates as per their models. P value<0.05 was considered statistically significant. SATA version 17 was used for analysis.
Results- Almost half (50.38%) of the participants were exposed to IAP (female (52.40%) > male (47.60%)). The adjusted likelihood of having anaemia was 19% higher (aOR 1.19; 1.09-1.31) among participants exposed to unclean/solid fuel. The adjusted odds were significantly higher among participants exposed to pollution-generating sources (aOR 1.30; 1.18-1.43), and household indoor smoking (aOR 1.17 (1.07-1.29. The adjusted odds of having anaemia were significantly higher (aOR 1.27; 1.16-1.39) among participants exposed to IAP, which was higher in males (aOR 1.36; 1.15-1.61) than females (aOR 1.21; 1.09-1.35).
Conclusion- This study established the positive association of anaemia with indoor air pollution among older Indian adults through a nationally representative large dataset. The association was higher among men. Further research is recommended to understand detailed causation and to establish temporality. It is a high time to implement positive intervention nationally to decrease solid/ unclean fuel usage, vulnerable ventilation, indoor smoking, IAP and health hazards associated with these.
Utilization of Preventive Medical Check-Up and Associated Factors Among Public Hospital Workers in Addis Ababa, Ethiopia
Authors: Achamo Tamene , Tumebo Teketel , Woldemariyam Mesay , Woldeyohannes Fikirte
Published: April 2024

Background: The proper utilization of the Preventive Medical checkups (PMC) increases people’s quality of life and life expectancy by identifying treatable health issues and controlling life threatening diseases. Non-communicable diseases account for more than 71% of the overall global burden of diseases. The PMC is effective in preventing illness, promoting health, reducing morbidity and mortality. However, there is a paucity of evidence on the utilization of PMC in Ethiopia. Therefore, we aimed to assess the level of utilization of preventive medical check-ups and associated factors among workers in public hospitals.
Objective: To assess the utilization of preventive medical check-ups and associated factors among public hospital employees in Addis Ababa Ethiopia.
Methods: A Hospital-based cross-sectional study with quantitative approach was conducted in 2019 on 422 subjects selected by systematic random sampling technique among the employees of the public hospitals in Addis Ababa. Data were collected using a structured questionnaire through a face-to-face interview. Data were entered into Epi info version 7.2.2.6 and exported to SPSS version 23 statistical software for analysis. Variables with a p-value of less than 0.20 in bivariate analysis were included in multivariate logistic regression. Finally, variables with a p-value of less than 0.05 in multivariate analysis were considered as significantly associated.
Result: A total of 389 respondents were included in the study with response rate of 92.2%. The estimated utilization of PMC is 118(30.3%) within last twelve months and majority 319(82%) undergo PMC ever in their life. In the study area, respondents’ Age (AOR=6.56, 95%CI [1.87-23.06]), Work experience (AOR=0.75, 95%CI [0.65-0.70]) and NCDs history in respondent’s family (AOR=1.64; 95%CI: [1.70- 3.81]) were significantly associated with the utilization of PMCs.
Conclusion: The estimated utilization of PMC is very low (30.3%). It is critical to raise awareness about the importance of using PMC because, once established, the majority of chronic diseases can have a long-term impact on quality of life and wellness.
Subsequent acute ischemic stroke in a patient with monocular vision loss associated with isolated internal carotid artery occlusion: a case report
Authors: Seetge Jessica , Cséke Balázs , Karádi Zsófia Nozomi , Szalai Eszter , Gaál Valéria , Szapáry László
Published: April 2024

Background
Despite a growing body of evidence and ongoing clinical trials assessing the efficacy of reperfusion therapies in the acute phase, reliable systems capable of rapidly identifying patients with central retinal artery occlusion (CRAO) and evidence-based therapeutic interventions that have been shown to improve visual outcomes, are currently lacking. In this report, we present an exceptional case involving CRAO with concurrent occlusion of the internal carotid artery (ICA), followed by an acute ischemic stroke (AIS) affecting the middle cerebral artery (MCA).
Case presentation
An 83-year-old woman with acute, painless vision loss in her right eye received intravenous thrombolysis (IVT) within 4.5 hours of admission, suspecting CRAO associated with ICA occlusion (ICAO) on CT angiography (CTA). One hour post thrombolysis, perfusion CT (CTP) confirmed MCA occlusion (MCAO), necessitating mechanical thrombectomy (MT). Endovascular intervention proceeded without complications, and the patient exhibited no functional impairments at discharge.
Conclusions
This case study underscores the significance of maintaining a vigilant approach toward stroke management in patients with CRAO. It highlights the diagnostic challenges encountered in clinical practice and advocates for further research regarding the role of IVT in CRAO patients due to ICAO, emphasizing the need for consensus in treatment.
MiR-29a-5p engages in the mechanism of diabetic retinopathy by specifically targeting SIRT3
Authors: He Jianhong , Wei Shu zhen , Liang qing , Lai Duowen , Liao Rifang , Zeng Zhuanping
Published: April 2024

Whether miR-29a-5p is associated with diabetic retinopathy (DR) is still a subject of ongoing discussion. The current research examines the involvement of miR-29a-5p in regulating apoptosis, oxidative stress, and inflammation of retinal ganglion cells (RGCs) generated by high glucose (HG). Additionally, we are interested in analyzing the contribution of miR-29a-5p in developing DR. We obtained peripheral blood samples from 7 people with DR and 14 individuals without DR. Subsequently, we conducted biochemical indices analyses and qRT-PCR. We randomly divided RGCs into low glucose groups, HG groups, HG + inhibitor negative control groups, and HG + miR-29a-5p inhibitor groups. SIRT3 siRNA was transfected into RGCs through lipofectamine 3000 reagent. Cell vitality was detected by MTT; qRT-PCR was applied to identify miR-29a-5p expression; Detection of ROS, SOD, and MDA levels was quantified using the DCFH-DA, WST-1, and colorimetric methods, respectively; IL-6 and TNF-α contents were analyzed utilizing ELISA; Dual-luciferase gene reporter experiment was used to examine if SIRT3 is the specific target gene of miR-29a-5p; Flow cytometry evaluated apoptosis in RGCs; The technique of Western blotting identified the expression of Caspase-3, Bax and Bcl-2 proteins. The expression of miR-29a-5p was markedly elevated in individuals with DR, and it had positive correlations with levels of total cholesterol (TC) and fasting blood glucose (FBG). The combination of miR-29a-5p, total cholesterol, and triglycerides (TG) exhibits significant diagnostic value for DR, demonstrating both high sensitivity and specificity. High glucose stimulated the expression of miR-29a-5p in RGCs and worsened cellular oxidative stress, inflammatory response, and apoptotic levels. Transfection of miR-29a-5p inhibitor protected RGCs against HG-induced oxidative injury, inflammation, and apoptosis. Furthermore, the dual-luciferase reporter experiment provided confirmation that SIRT3 was a target gene of miR-29a-5p, as it negatively regulated SIRT3 expression. Notably, SIRT3 knockdown abolished the protection of miR-29a-5p inhibition on RGCs. Suppression of the miR-29a-5p gene safeguards RGCs against injury caused by high glucose via boosting SIRT3 signaling, which might provide a new prevention and treatment strategy for DR.
Dynamic Vaccine Allocation for Control of Human Transmissible Disease
Authors: Lyu Mingdong , Chang Chang , Liu Kuofu , Hall Randolph
Published: April 2024

During pandemics, such as COVID-19, supplies of vaccines can be insufficient to meet all needs, particularly when vaccines first become available. Our study develops a dynamic methodology for vaccine allo- cation, segmented by region, age, and timeframe, using a time-sensitive, age-structured compartmental model. Based on the objective of mini- mizing a weighted sum of deaths and cases, we used the Sequential Least Squares Quadratic Programming method to search for a locally opti- mal COVID-19 vaccine allocation for the United States, for the period from December 16, 2020, to June 30, 2021, where regions corresponded to the 50 states in the United States (US). We also compared our solu- tion to actual allocations of vaccines. From our model, we estimate that approximately 1.8 million cases and 9 thousand deaths could have been averted in the US with an improved allocation. When case reduction is prioritized over death reduction, we found that young people (17 and younger) should receive priority over old people due to their potential to expose others. However, if death reduction is prioritized over case reduc- tion, we found that more vaccines should be allocated to older people, due to their propensity for severe disease. While we have applied our methodology to COVID-19, our approach generalizes to other human- transmissible diseases, with potential application to future epidemics.
Effect of Changes in Physical Activity on Medical Expenditure among South Korean Adults with Chronic Diseases
Authors: Jeong Wonseok
Published: April 2024

Objectives
Regular physical activity is a cost-effective way to enhance both physical and mental health without any side effects. Yet, among 5,820 Korean adults, 66.0% did not meet any of the physical activity guidelines. Due to the increasing proportion of elderly population and those conducting poor health behaviors, such as lack of exercises, the prevalence of chronic diseases is growing rapidly in South Korea. Nevertheless of the circumstances getting worse and economic burden increasing as a result, lack of researches scrutinized the effects of physical activity of patients with chronic diseases on medical expense. Therefore, this study aimed to examine the effect of changes in physical activity on medical expenses among South Korean adults with chronic diseases.
Methods
Data were included from the 2014, 2015, 2016, 2017 and 2018 Korea Health Panel Survey. The KHPS is conducted by a national institution based on 90% of the 2005 Population and Housing Census data as a sampling frame, and therefore, the national representation was maintained. “Changes in physical activity” was the main independent variable. Physical activity was categorized as one of the four status: increase, decrease, remained active, remained inactive. The dependent variable, medical expenditure, was calculated by the sum of outpatient medical expenses, hospitalization expenses, and emergency medical expenses. Generalized Estimating Equation was performed to examine target effect.
Results
Those who decreased physical activity compared to the previous year presented with a higher estimate of total medical cost compared to those who maintained regular physical activity. (decrease: estimate = 392269.40, p-value = 0.0174). More importantly, those who remained inactive resulted in highest total medical cost (remained inactive: estimate = 476968.60, p-value = 0.0005). Lastly, those started to perform regular physical activity did not show a statistically significant difference between those who always remained active.
Conclusion
This study suggests that every patient with chronic diseases to either start or continue to exercise and the government officials to develop chronic diseases management programs inducing patients to actively participate in physical activity, for both maintaining a healthy quality of life for the individual and minimizing excessive medical expenses.
A landscape of resistance gene analogs in sour cherry (Prunus cerasus L.)
Authors: Wöhner Thomas W. , Emeriewen Ofere F.
Published: April 2024

Objective: This research aims to analyze the presence and distribution of resistance genes in the subgenomes of Prunus cerasus (P. avium and P. fruticosa) through computational methods and bioinformatics tools.
Results: Analysis of genome and transcriptome sequencing data revealed a total of 19,570 transcripts with at least one resistance gene domain in P. avium and 19,142 in P. fruticosa. Key findings include the identification of 804 "complete" resistance gene transcripts in P. avium and 817 in P. fruticosa, with distinct distributions of resistance gene classes observed between the subgenomes. Phylogenetic analysis showed clustering of resistance genes, and unique resistance proteins were identified in each subgenome. Functional annotation comparisons with Arabidopsis thaliana highlighted shared and unique resistance genes, emphasizing the complexity of disease resistance in cherry species. Additionally, a higher diversity of RLKs and RLPs was observed, with 504 transcripts identified and 18 showing similarity to known reference genes.
Clinical Features and Determinants of Disease Severity of Immune Checkpoint Inhibitor-Related Pneumonitis: A Retrospective Study
Authors: Wu Guixian , Qu Jingjing , Zheng Jing , Wu Binggen , Wang Ting , Gan Yuncui , Jiang Nan , Li Yuekang , Zhou Jianying , Zhou Jianya
Published: April 2024

Background
Immune checkpoint inhibitor associated pneumonia(CIP) is the most dangerous adverse reaction of immunecheckpoint inhibitors. Howerer,research on the factors affecting its severity is limited.
Methods
This retrospective study analyzed 2673 patients who underwent immune checkpoint inhibitor(ICI)treatment at the First Affiliated Hospital of Zhejiang University between 2019 and 2023. Of these, 106 cases of immune checkpoint inhibitor associated pneumonia(CIP) were identified, all of which were associated with lung cancer. The clinical manifestations and diagnostic and therapeutic approaches used for these 106 patients were summarized. The patients were also classified into four types based on clinical characteristics and imaging findings, and a detailed analysis was conducted.
Results
It was found that immune checkpoint inhibitor associated pneumonia(CIP) occurred at a median of 5.17 months (95%CI 4.61‒5.72) after the start of immune checkpoint inhibitor(ICI) therapy.Grade 4 was usually the earliest to be identified and had the poorest prognosis, with a median onset of 2.47 months after treatment (95%CI 0, 5.12 months), an incidence rate of 4.7%, a median progression-free survival (mPFS) of 3.83 months, and a median overall survival (mOS) of 4.03 months. The PFS curves for Grades 1–2 and Grades 3–4 CIP showed separation but without statistical significance (mPFS 8.47 m vs. 6.50 m, HR = 3.36, log-rank P = 0.07), while the difference in OS was significant OS (mOS 23.15 m vs. 11.20 m, HR = 8.97, log-rank P = 0.003). Multivariate logistic regression showed that forced vital capacity (FVC) was the only predictive factor linked to 3–4 grades occurrence (OR = 1.00, 95% CI 0.01–0.80, P = 0.03), with decreased forced vital capacity (FVC) an independent risk factor for the grade 3–4 CIP (OR = 1.00, 95% CI 0.01–0.80, P = 0.03).
Conclusions
Forced vital capacity(FVC) was observed to be the only independent risk factor for grade 3–4 immune checkpoint inhibitor associated pneumonia(CIP), reminding us of the importance of assessing baseline pulmonary function testing before immune checkpoint inhibitor use. In addition to forced vital capacity(FVC), active monitoring of radiological examinations and clinical manifestations remains meaningful.
Experimental and Numerical modelling of desiccation of clayey soils
Authors: Cheng Wenqing , Bian Hanbing , Gao Qianfeng , Wang Liang , Xun Fangfang
Published: April 2024

The desiccation of clayey soils is widespread in nature and it significantly affects the mechanical behavior of the soil, which in practice can compromise the sustainability of geotechnical structures. The desiccation of clayey soils should first be studied, as a basis for recherche the mechanism of cracking. In current research, the combined numerical simulation and experiments research were conducted for investigating the desiccation of clayey soils. The desiccation experiments of fully saturated slurry and pre-consolidation clayey soils are analyzed and simulated. The material properties are first introduced. Then, the experiments are introduced and analyzed, the numerical model parameters are identified. The constitutive model of clayey soils is established and the numerical simulation of the desiccation is realized by using finite element method, the approach permitted to estimate how, from the fully saturated state to the completely dry state, both deformations, suction and the stresses developed in the sample. Finally, the proposed numerical approach is validated by reproducing the desiccation experiments. The numerical results show that the numerical simulations are in good agreements with the experimental observations. A deeper understanding of the formation mechanism of desiccation of clayey soils is obtained by using a combination of numerical simulation and experiments.
Mitochondrial associated programmed cell death patterns in predicting the prognosis of non-small cell lung cancer
Authors: Shi Xue-Yan , Han Si-Chong , Wang Gui-Zhen , Zhou Guang-Biao
Published: April 2024

Mitochondrion is the convergence point of multiple pathways that trigger programmed cell death (PCD), and mitochondrial associated PCD (mtPCD) is involved in the pathogenesis of several diseases. However, the roles of mtPCD in cancer pathogenesis and prognosis prediction in many cancers including non-small cell lung cancer (NSCLC), remain to be investigated. Here, 12 mtPCD patterns (necroptosis, autophagy, pyroptosis, ferroptosis, apoptosis, NETotic cell death, alkaliptosis, entotic cell death, cuproptosis, oxeiptosis, parthanatos, and lysosome-dependent cell death) were analyzed in a large number of transcriptomes, genomics, and clinical data collected from The Cancer Genome Atlas (TCGA)-NSCLC, GSE29013, GSE31210, and GSE37745 datasets, and a risk score assessment system was established with 18 genes (AP3S1, CCK, EIF2AK3, ERO1A, KRT8, PEBP1, PIK3CD, PPIA, PPP3CC, RAB39B, RIPK2, RUBCNL, SELENOK, SQLE, STK3, TRIM6, VDAC1, and VPS13D) included in the system. The NSCLC patients were divided into high- and low-risk groups. We found that NSCLC patients with a mtPCD high-risk score had a worse prognosis. A nomogram with high predictive performance on overall survival was constructed by incorporating the risk score with clinical features. Furthermore, the risk score was associated with clinicopathological information, tumor mutation frequency, and key tumor microenvironment components based on bulk transcriptome analysis. NSCLC patients with high-risk score had more Treg cells infiltration; however, these patients had higher tumor microenvironment and tumor mutation burden scores, and might be more sensitive to immunotherapy. These results indicated that mtPCD genes may have important roles in NSCLC carcinogenesis, and ptPCD patterns can predict clinical prognosis of NSCLC patients.
A Global Industry Survey on Post-Approval Change Management and Use of Reliance
Authors: Deavin Andrew , Hossain Aliyah , Colmagne-Poulard Isabelle , Wong Kum Cheun , Perea-Vélez Mónica , Cappellini Sonia , Ausborn Susanne , Meillerais Sylvie , Bourguignon Céline
Published: April 2024

Post-approval changes (PACs) to the control and manufacturing processes of medicines and vaccines are routinely undertaken and critical to enable both innovation and secure sustained supply. In a world of global supply chains, the existence of divergent national PAC requirements (with additional countries introducing new requirements with potential differences) can lead to long delays in approval (of up to 3 to 5 years) increasing the risk of disruption and shortages. We undertook an Industry survey in 2023 to assess implementation of ICH Q12, PAC procedures (change categorisation and review timelines) and use of reliance mechanisms across different international countries (9 selected ICH Members and 19 Observers). Although this survey revealed limited implementation of Q12 in ICH Member countries, when comparing the data collected with those of a previous survey performed in 2020, we observed a broader adoption of risk-based approaches to variation categorisation (in all countries). This, however, was not reflected in improved timelines for approval. With regards to ICH Q12 adoption, the uptake of Post-Approval Change Management Protocols (PACMPs) was unchanged (with only one country reporting in-use) and implementation gaps were evident for Established Conditions (EC) and the Product Life Cycle Management document (PLCM). The survey found greater awareness of ICH Q12 and its tools compared to 2020, potentially illustrating the positive impact of training efforts. This illustrates the challenges being faced to broaden its implementation and use globally. In the same Industry survey, we also assessed PAC processes across different international countries. Long unpredictable timelines were the major concern across the countries surveyed together with limited capacity of the regulators. Four different CMC changes were selected and categorized by the respondents according to current knowledge of national classifications and timelines in the selected countries and compared with a reference classification and timeline from the European Medicines Agency and the World Health Organisation. This highlighted the lack of harmonisation of many countries with EU/WHO requirements, especially within the ICH Observer group. Last, this survey showed that some use of unilateral forms of reliance to Reference Authorities for PACs is starting. This is a mechanism all countries can employ, regardless of convergence of requirements and expertise, to enhance capacity building and reduce duplication of reviews, streamline variations approval, whilst accelerating patient access to innovation and securing supply.
Prolonged use of urinary catheter delays mobilization after a cesarean delivery
Authors: Vihervaara Hanna , Väänänen Antti , Kaijomaa Marja
Published: April 2024

Purpose: Cesarean section is the most common surgery performed on women. According to the enhanced recovery recommendation, early urinary catheter removal and early mobilization are essential elements of postoperative care. The issue of catheter therapy length is still controversial but early mobilization is known to improve the overall postoperative recovery. This study aimed to analyze the possible interaction of these elements and whether the use of urinary catheter itself affects the time of postoperative mobilization.
Methods: This retrospective case-control study consisted of cases enrolled in a study concerning early post-operative catheter removal (8-12 hours) and the subsequent patients not in the study as their controls. Apart from the time of catheter removal, the routine postoperative care by the same personnel was given without any advice on patient mobilization. Data on patient demographics, surgery details, post-operative medication, first upright mobilization, the length of hospital stay, and patient satisfaction were analyzed.
Results: Fifty-two cases and one control for each case comprised the groups. No difference was detected in maternal characteristics or surgical parameters. The regression analysis showed that the length of the catheter therapy was significantly associated with the time of patient mobilization. The need for additional opioid medication in the groups was equal. No difference was detected in the length of hospital stay or patient satisfaction index.
Conclusion: The duration of catheter therapy significantly impacts the timing of postoperative mobilization. It is crucial to understand this relationship and support optimal recovery by avoiding the unwarranted prolongation of catheter therapy after cesarean.
Effects of International Migration on Air Pollution in Developing Countries
Authors: Nourou Mohammadou , Freddy Yamben Harry Michel , Benguellah Wang-laouna , Eric Atangana Ignace
Published: April 2024

The objective of this work is to analyze the effect of international migration on air pollution in a panel of 124 developing countries over the period 1990–2020. Adopting the pollution haven hypothesis as a theoretical framework, we use the IPAT model developed by Ehrlich and Holdren's (1971). We specify and estimate our model in panel data using the Ordinary Least Squares (OLS) and Fixed Effects (FE) methods. Three results emerge: international migration increases air pollution in developing countries. Industrialization slightly reduces air pollution. And the KEC is not verified in the case of our study. We suggest that developing countries consolidate the framework by integrating the environmental factor into their policies in order to improve the situation of migrants in their respective countries.
JEL-Classification: F22, P23, Q53, 011
Numerical modeling of Zn-doped Cu2O used as HTL for CsPbCl3 lead-based perovskite solar cell
Authors: Hachimi Mohamed Amine , Tarbi Amal , El-Mrabet Mariam , Erguig Hassane , Chtouki Tarek
Published: April 2024

In recent years, inorganic perovskite solar cells have emerged as a promising and environment friendly technology for photovoltaics. In this study, an in-depth simulation was carried out using SCAPS-1D software to optimize inorganic perovskite solar cells, with particular emphasis on the use of CsPbCl3 as an absorber material. Various ETL layers such as C60, ZnSe, PCBM, SnO2, and WS2, and an inorganic HTL consisting of zinc-doped Cu2O (7%) were evaluated. The highest performance was achieved by using SnO2 as the ETL layer. This study focused on the impact of critical parameters such as the thickness and defect density of the absorber layer, donor doping density in this layer, series and shunt resistances, and operating temperatures on the overall cell performance. The optimum device configuration, FTO/SnO2/CsPbCl3/Cu2O:Zn(7%)/Au, demonstrated a PCE of 24.23%, FF of 88.45%, a VOC of 1.567 V, and a JSC of 17.48 mA/cm2. These results underline that the use of CsPbCl3 as an absorber material in perovskite solar cells leads to improved performance and notable thermal stability, highlighting the considerable potential of this material.
Learning from Demonstration in Embedded Hardware for the Composition of Micro-Skills in Mobile Robots
Authors: Triana Mario Andres Pastrana , Arboleda Daniel Mauricio Muñoz , de Oliveira Luiz Henrique Nunes
Published: April 2024

Designing mobile robot controllers for non-expert users is a complex task that involves programming abilities and developing accurate mathematical models for representing the robot's kinematics, sensor observations, and parameter estimations. Learning from demonstration (LfD) is a technique that enables robots to autonomously learn and perform new tasks from the observations of human demonstrations. Obtaining models with low computational complexity is of utmost importance for embedded robotics systems. This paper proposes the usage of LfD for learning three simple micro-skills (move forward, turn clockwise, and turn counterclockwise) that can be combined to efficiently perform more complex skills on a mobile robot. An adaptive single-layer perceptron neural network (SLP) and a Particle Swarm Optimization (PSO) training algorithm were implemented using a low-cost System-on-chip (SoC) device, allowing the robot to learn the wheel's speed profile for each demonstrated micro-skill and compose them to navigate around obstacles in complex scenarios. Real-world scenarios were used to statistically analyze the robustness of the proposed methodology, achieving a success rate of 100% for the known scenarios and a success rate of 61.81% for the unknown scenarios. Experimental results demonstrated that the robot correctly moves on several unknown scenarios that compose the three taught micro-skills, avoiding obstacles and correcting deviations from the initial position.
Neighborhood Attention Transformer Multiple Instance Learning for Whole Slide Image Classification
Authors: Aftab Rukhma , Qiang Yan , Zhao Juanjuan , Gao Yong , Yue Huajie
Published: April 2024

Purpose:: : The purpose of the passage is to introduce and describe NATMIL (Neighborhood Attention Transformer Multiple Instance Learning), an innovative deep learning approach aimed at improving the classification of tumor cells and subtypes in whole slide images (WSIs) of tissue section biopsies for diagnosing cancer.
Method:: The method involves leveraging dependencies among WSI tiles using the Neighborhood Attention Transformer, which incorporates contextual constraints as prior knowledge into multiple instance learning models. The approach utilizes weakly supervised methods, classifying WSIs using image parts or tiles along with attention ratings, to address the limitations of traditional methods.
Result:: NATMIL has demonstrated superior performance compared to other weakly supervised algorithms when subtyping non-small cell lung cancer (NSLC) and lymph node (LN) tumors. The accuracy values achieved on the Camelyon dataset reached 89.6\% and 88.1\% for TCGA-LUSC. The introduction of NATMIL presents an effective and scalable sliding window attention technique for vision, known as Neighborhood Attention, which improves performance and reduces the burden on pathologists while making more data available.
Conclusion:: NATMIL's success in improving tumor-level classifications by considering the interdependence of nearby tiles in histopathological pictures highlights its potential to enhance cancer diagnosis. By incorporating contextual constraints and leveraging dependencies among WSI tiles, NATMIL demonstrates promising results in improving accuracy and reducing false positives and negatives, thus advancing the field of cancer diagnosis through deep learning-based approaches.
The soluble ST2 level predicts the risk of atrial fibrillation recurrences in long-term period after radiofrequency ablation
Authors: Gizatulina Tatiana P. , Mamarina Aleksandra V. , Martyanova Leysan U. , Belonogov Denis V. , Kolunin Grigorii V. , Petelina Tatiana I. , Shirokov Nikita E. , Gorbatenko Elena A.
Published: April 2024

Background and Objectives: The hypothesis of the study was the assumption that the serum levels of soluble ST2 (sST2) and growth differentiation factor (GDF-15) can be predictors of atrial fibrillation (AF) recurrence in long-term period after primary radiofrequency catheter ablation (RFA).
Methods: Of the 165 patients (pts) included in the prospective follow-up, the final analysis included 131 pts whose follow-up duration reached 18 months after the end of the blanking period (3 months after the date of RFA). The median age of pts was 59.0 (50.0; 64.0) years, and 80 pts (61%) were men. 103 (79%) pts had paroxysmal and 28 (21%) persistent AF.
All pts underwent transthoracic and transesophageal echocardiography, electroanatomic mapping to assess the area of low-voltage zones (LVZ) and determination of sST2 and GDF-15 levels by ELISA using analytical kits GDF-15/MIC-1 (BioVender, Czech Republic) and Presage ST2 (Critical Diagnostics, USA). After RFA pts had regular follow-up visits at 3-6-9-12-18 months with 12-lead ECG or Holter ECG monitoring and with clinical evaluation. The primary endpoint was the occurrence of the first symptomatic AF recurrence (AFr) lasting >30 seconds, recorded on an ECG or during daily ECG monitoring, after a blanking period.
Results: During follow-up of 18 months, 47 pts (35.9%) had AFr. The groups with and without AFr didn`t differ in the LVZ area. The medians of NT-proBNP, GDF-15 and sST2 also didn`t differ significantly between the groups, but in pts with AFr, the proportion of pts with sST2 ≥36 ng/ml (the border of the lower and middle terziles) was higher (p=0.03). According to the one-factor Cox regression analysis, late AFr were associated with four factors: AF history ≥1 year, early AFr (during the blanking period), left atrial appendage flow velocity (LAAFV) <54 cm/sec and sST2 ≥36 ng/ml. In the multivariate Cox analysis two independent predictors of late AFr were obtained: sST2 ≥36 ng/ml (HR=3.8; 95% CI 1.5-9.8, p=0.006) and LAAFV <54 сm/sec (HR=1.96; 95% CI 1.01-3.82, p=0.048).
Conclusions: Serum sST2 level with a cut-off value of 36 ng/ml or more can be used as a predictor of AF recurrence in the long-term period after primary RFA.
AMESobreRuedas: early power mobility for increasing participation in children with Spinal Muscular Atrophy type I. Protocol of a randomized controlled trial
Authors: Palomo-Carrión Rocío , López-Muñoz Purificación , Longo Egmar , Romay-Barrero Helena , Ródenas-Martínez Maribel , Plasencia-Robledo María , de-Andrés-Beltrán Beatriz , Coello-Villalón María , Díaz-López Cristina , Pacheco-da-Costa Soraya
Published: April 2024

Background
Young children with spinal muscular atrophy type I have severe mobility and participation limitations, which can lead to delays in learning and cognitive development. Early powered mobility interventions may help young children with mobility limitations to move, play, and participate in their environment. The aim of this study is to evaluate whether an early power mobility intervention is effective for increasing participation, functional ability, independence, and quality of life of young children diagnosed with SMA type I.
Methods
AMESobreRuedas is a single-blinded randomized waiting list - controlled clinical trial. The sample (24 children − 10 months-5 years old diagnosed with SMA type I) will be randomly allocated into 2 groups. Experimental group will receive a powered mobility structured intervention 3 times a week for 12 weeks, and 4 weeks of follow-up where the child will be free to use the powered mobility device. Control group (waiting list) will continue with their daily routine and will receive the same intervention once experimental group finishes. The intervention will be family-centered and carried out in the natural environment of the children (home, school and community). Five assessments will be performed: at baseline, weeks 4, 8, 12 and 16. The primary outcomes are participation (YC-PEM); functional ability and independence (PEDI-CAT); and quality of life (PedsQL-Neuromuscular module).
Discussion
As far as the authors know, this is the first study on early power mobility for children with SMA type I. Therefore, it will provide valuable information about the impact of this type of intervention on improving participation, functional capacity, and quality of life. Besides, families will be involved in the intervention participating, together with the researchers, in the establishment of functional goals and the implementation of the intervention. Finally, early powered mobility could increase the opportunities for children with SMA type I to learn to move independently and participate in their natural context.
Trial Registration:
The study was registered on ClinicalTrials.gov with ID: NCT05589987 on October 18, 2022.
Gut microbiota and risk of ovarian diseases: a two-sample Mendelian randomization study
Authors: Liu Xueying , Zhu Kejing , He Renke , Jiang Zhaoying , Wu Haiyan , Yu Jiaen , Luo Qinyu , Sheng Jianzhong , Pan Jiexue , Huang Hefeng , Lin Zhongliang
Published: April 2024

Background Previous studies have reported an association between gut microbial dysbiosis and ovarian diseases, however, it is not clear whether a causal association exists. Methods Two-sample Mendelian randomization (MR) analysis was performed to genetically predict the causal effects of the gut microbiota on polycystic ovary syndrome (PCOS), premature ovarian failure (POF), ovarian endometriosis, and malignant and benign ovarian neoplasms. The inverse variance weighted (IVW) method was used as the primary statistical method. A series of sensitivity analyses, including weighted median, MR-Egger, simple mode, weighted mode methods, MR pleiotropy residual sum and outlier (MR-PRESSO) and leave-one-out analysis, were also conducted to assess the robustness of the MR analysis results. Reverse MR analysis was implemented to explore whether ovarian diseases have any causal impact on the bacterial genera. Additionally, the Cochran’s Q test was used to evaluate heterogeneity among instrumental variables. Results IVW analysis revealed that several bacteria were associated with decreased risk of PCOS, POF, ovarian endometriosis, and benign and malignant ovarian neoplasm. Moreover, several bacteria were the causes of increased risks for POF, ovarian endometriosis, and benign and malignant ovarian neoplasm, respectively. Reverse MR analysis did not reveal a significant causal effect of these ovarian diseases on the gut microbiota. These findings were robust according to extensive sensitivity analyses. Conclusion Our results provide genetic evidence to support the causal relationship between specific gut microbiota taxa and ovarian diseases; thus, the gut microbiota should be considered a preventative strategy for ovarian diseases.
Subclinical Association of Aortic Stiffness with Cardiac Structure and Function in African- Americans: the Jackson Heart Study
Authors: Jha Mawra , Musani Solomon , Mccarthy Inbar , Hundley W. Gregory , Carr J. Jeffrey , Terry James G. , Oshunbade Adebamike , Vasan Ramachandran S. , Butler Javed , Hall Michael , Mitchell Gary F. , Fox Ervin , Tsao Connie W.
Published: April 2024

Background
Cardiovascular disease (CVD) morbidity and mortality are high among black adults. We aimed to study the granular subclinical relations of aortic stiffness and left ventricular (LV) function and remodeling in blacks, in whom limited data are available.
Methods
In the Jackson Heart Study, 1,050 U.S. community-dwelling black adults without CVD (mean age 59±10 years, 62% women) underwent 1.5T cardiovascular magnetic resonance. We assessed regional and global aortic stiffness and LV structure and function, including LV mass indexed to body surface area (LVMI), end-diastolic volume (LVEDV), ejection fraction (EF), and global and regional circumferential strain (Ecc).
Results
Phase contrast images of the cross-sectional aorta at the pulmonary artery bifurcation and abdominal aorta bifurcation were acquired to measure pulse wave velocity of the aortic arch (AA-PWV) and thoracic aorta (T-PWV). Results of multivariable-adjusted analyses are presented as SD unit change in LV variables per SD change in PWV variables. Higher AA-PWV and T-PWV were associated with greater LVMI: for T-PWV, β=0.10, 95% CI=0.03-0.16, p=0.002. Higher AA-PWV and T-PWV were associated with worse (more positive) Ecc at the LV base (for AA-PWV, β=0.13, 95% CI=0.05-0.20, p=0.0007), but not mid-LV or apex. AA-PWV and T-PWV were not associated with LV mass/LVEDV or EF.
Conclusions
In this cross-sectional study of blacks without CVD in the U.S., aortic stiffness is associated with subclinical adverse LV function in basal segments. Future studies may elucidate the temporal relationships of aortic stiffness on the pattern and progression of LV remodeling, dysfunction, and associated prognosis in blacks.