bluuebunny/crossref_metadata_2025_split huggingface dataset:
Polygenic risk scores validated in patient-derived cells stratify for mitochondrial subtypes of Parkinson’s disease
Authors: Arena Giuseppe , Landoulsi Zied , Grossmann Dajana , Vitali Armelle , Delcambre Sylvie , Baron Alexandre , Antony Paul , Boussaad Ibrahim , Bobbili Dheeraj Reddy , Sreelatha Ashwin Ashok Kumar , Pavelka Lukas , Klein Christine , Seibler Philip , Glaab Enrico , Sharma Manu , Krüger Rejko , May Patrick , Grünewald Anne 
Published: May 2023

AbstractBackgroundParkinson’s disease (PD) is the fastest growing neurodegenerative disorder, with affected individuals expected to double during the next 20 years. This raises the urgent need to better understand the genetic architecture and downstream cellular alterations underlying PD pathogenesis, in order to identify more focused therapeutic targets. While only ∼10% of PD cases can be clearly attributed to monogenic causes, there is mounting evidence that additional genetic factors could play a role in idiopathic PD (iPD). In particular, common variants with low to moderate effect size in multiple genes regulating key neuroprotective activities may act as risk factors for PD. In light of the well-established involvement of mitochondrial dysfunction in PD, we hypothesized that a fraction of iPD cases may harbour a pathogenic combination of common variants in nuclear-encoded mitochondrial genes, ultimately resulting in neurodegeneration.Methodsto capture this mitochondria-related “missing heritability”, we leveraged on existing data from previous genome-wide association studies (GWAS) – i.e., the large PD GWAS from Nalls and colleagues. We then used computational approaches based on mitochondria-specific polygenic risk scores (mitoPRSs) for imputing the genotype data obtained from different iPD case-control datasets worldwide, including the Luxembourg Parkinson’s Study (412 iPD patients and 576 healthy controls) and the COURAGE-PD cohorts (7270 iPD cases and 6819 healthy controls).Resultsapplying this approach to gene sets controlling mitochondrial pathways potentially relevant for neurodegeneration in PD, we demonstrated that common variants in genes regulatingOxidative Phosphorylation (OXPHOS-PRS)were significantly associated with a higher PD risk both in the Luxembourg Parkinson’s Study (odds ratio, OR=1.31[1.14-1.50],p=5.4e-04) and in COURAGE-PD (OR=1.23[1.18-1.27],p=1.5e-29). Functional analyses in primary skin fibroblasts and in the corresponding induced pluripotent stem cells-derived neuronal progenitor cells from Luxembourg Parkinson’s Study iPD patients stratified according to theOXPHOS-PRS, revealed significant differences in mitochondrial respiration between high and low risk groups (p< 0.05). Finally, we also demonstrated that iPD patients with highOXPHOS-PRS have a significantly earlier age at disease onset compared to low-risk patients.Conclusionsour findings suggest that OXPHOS-PRS may represent a promising strategy to stratify iPD patients into pathogenic subgroups – in which the underlying neurodegeneration is due to a genetically defined mitochondrial burden – potentially eligible for future, more tailored mitochondrially targeted treatments.
Dissection of medical AI reasoning processes via physician and generative-AI collaboration
Authors: DeGrave Alex J. , Cai Zhuo Ran , Janizek Joseph D. , Daneshjou Roxana , Lee Su-In 
Published: May 2023

AbstractDespite the proliferation and clinical deployment of artificial intelligence (AI)-based medical software devices, most remain black boxes that are uninterpretable to key stakeholders including patients, physicians, and even the developers of the devices. Here, we present a general model auditing framework that combines insights from medical experts with a highly expressive form of explainable AI that leverages generative models, to understand the reasoning processes of AI devices. We then apply this framework to generate the first thorough, medically interpretable picture of the reasoning processes of machine-learning–based medical image AI. In our synergistic framework, a generative model first renders “counterfactual” medical images, which in essence visually represent the reasoning process of a medical AI device, and then physicians translate these counterfactual images to medically meaningful features. As our use case, we audit five high-profile AI devices in dermatology, an area of particular interest since dermatology AI devices are beginning to achieve deployment globally. We reveal how dermatology AI devices rely both on features used by human dermatologists, such as lesional pigmentation patterns, as well as multiple, previously unreported, potentially undesirable features, such as background skin texture and image color balance. Our study also sets a precedent for the rigorous application of explainable AI to understand AI in any specialized domain and provides a means for practitioners, clinicians, and regulators to uncloak AI’s powerful but previously enigmatic reasoning processes in a medically understandable way.
Disrupted seasonality and association of COVID-19 with medically attended respiratory syncytial virus infections among young children in the US: January 2010–January 2023
Authors: Wang Lindsey , Davis Pamela B. , Berger Nathan A. , Kaelber David C. , Volkow Nora D. , Xu Rong 
Published: May 2023

AbstractRespiratory syncytial virus (RSV) infections and hospitalizations surged sharply in 2022 among young children. To assess whether COVID-19 contributed to this surge, we leveraged a real-time nation-wide US database of electronic health records (EHRs) using time series analysis from January 1, 2010 through January 31, 2023, and propensity-score matched cohort comparisons for children aged 0–5 years with or without prior COVID-19 infection. Seasonal patterns of medically attended RSV infections were significantly disrupted during the COVID-19 pandemic. The monthly incidence rate for first-time medically attended cases, most of which were severe RSV-associated diseases, reached a historical high rate of 2,182 cases per 1,0000,000 person-days in November 2022, corresponding to a related increase of 143% compared to expected peak rate (rate ratio: 2.43, 95% CI: 2.25–2.63). Among 228,940 children aged 0–5 years, the risk for first-time medically attended RSV during 10/2022–12/2022 was 6.40% for children with prior COVID-19 infection, higher than 4.30% for the matched children without COVID-19 (risk ratio or RR: 1.40, 95% CI: 1.27–1.55); and among 99,105 children aged 0–1 year, the overall risk was 7.90% for those with prior COVID-19 infection, higher than 5.64% for matched children without (RR: 1.40, 95% CI: 1.21–1.62). These data provide evidence that COVID-19 contributed to the 2022 surge of severe pediatric RSV cases.
Spirituality, quality of life, and general health: a cross-sectional study
Authors: Yoshizawa Takeshi , Makram Abdelrahman M , Nakamura Sadako , Elsheikh Randa , Makram Engy Mohamed , Huy Nguyen Tien , Moji Kazuhiko 
Published: May 2023

AbstractBackgroundSome researchers have highlighted the need to integrate spirituality into the definition of health, as they have found a positive relationship between spirituality and quality of life (QoL). Hence, we aim to ascertain the effect of spirituality on mental health and QoL in older people residing in Kumejima Town in Japan.MethodsWe conducted an interview-based survey between September 2010 and 2011 on people residing in Kumejima Town aged 65 years or older. The scale used was The Spirituality Health Scale for the Elderly. The survey includes items on basic attributes (e.g., age, sex); physical, mental, and social health; spirituality; and quality of life. The analysis was conducted on a causal structure model in which spirituality is a distinct item influencing QoL (Model 1) and a causal structure model in which spirituality poses direct and indirect effects on QoL (Model 2). For each model, we reported the goodness-of-fit in terms of the goodness-of-fit index (GFI), adjusted goodness-of-fit index (AGFI), comparative fit index (CFI), and root mean square error of approximation (RMSEA). To compare the models, we used the Akaike information criterion (AIC).ResultsThe total number of participants was 338, of whom 72.5% were female. The average age and its standard deviation were 77.2 ± 6.4 years. We presented a comparison of the results of the analysis of Model 1 and Model 2, with the results favoring Model 2. Also, Model 2 was superior to Model 1 in terms of the AIC, where the value of the AIC is 313.67 for Model 2 compared to 330.48 for Model 1.ConclusionThis study was able to show the possibility of preventing a decline in QoL until death by building up spiritual health. However, further studies are required to further investigate these outcomes in the wider population (Japanese and other nationalities) and with some focus on male participants.
Patterns of Failure for Recurrent Head and Neck Squamous Cell Carcinoma Treated with Salvage Surgery and Postoperative IMRT Reirradiation
Authors: Mohamed Abdallah S. R. , Martin Geoffrey V. , Ng Sweet Ping , Takiar Vinita , Beadle Beth M. , Zafereo Mark , Garden Adam S. , Frank Steven J. , Fuller C. David , Gunn G. Brandon , Morrison William H. , Rosenthal David I. , Reddy Jay , Moreno Amy , Lee Anna , Phan Jack 
Published: May 2023

AbstractPurpose/ObjectivesDetermining the optimal postoperative reirradiation volume following salvage surgery for recurrent head and neck squamous cell cancer (HNSCC) is critical given the significant risk of severe reirradiation toxicity and need to provide durable local control. The purpose of this study was to evaluate patterns of locoregional recurrence (LRR) after surgical salvage and adjuvant reirradiation with IMRT.Materials/MethodsPatterns of LRR for 61 patients treated consecutively between 2003-2014 who received post-operative IMRT reirradiation to ≥60 Gy for recurrent HNSCC were determined by 2 methods: 1) physician classification via visual comparison of post-radiotherapy imaging to reirradiation plans; and 2) using deformable image registration (DIR). Those without evaluable CT planning image data were excluded. All recurrences were verified by biopsy or radiological progression. Failures were defined as in-field, marginal, or out-of-field. Logistic regression analyses were performed to identify predictors for LRR.ResultsA total of 55 patients were eligible for analysis and 23 (42%) had documented LRR after reirradiation. Location of recurrent disease prior to salvage surgery (lymphatic vs. mucosal) was the only significant predictor of LRR after post-operative reirradiation (p = 0.037). Physician classification of LRR yielded 14 (61%) in-field failures, 3 (13%) marginal failures, and 6 (26%) out-of-field failures, while DIR yielded 10 (44%) in-field failures, 4 (17%) marginal failures, and 9 (39%) out-of-field failures. Most failures (57%) occurred within the original site of recurrence or first echelon lymphatic drainage. Of patients who had a free flap placed during salvage surgery, 56% of failures occurred within 1 cm of the surgical flap.ConclusionThe majority of locoregional recurrences after surgical salvage and adjuvant reirradiation for recurrent HNSCC occurred marginally or in-field, often in or near the anastomotic site.
Significant Production of Ozone from Germicidal UV Lights at 222 nm
Authors: Peng Zhe , Day Douglas A. , Symonds Guy , Jenks Olivia , Stark Harald , Handschy Anne V. , de Gouw Joost , Jimenez Jose L. 
Published: May 2023

AbstractLamps emitting at 222 nm have attracted recent interest for germicidal ultraviolet disinfection (“GUV222”). Their impact on indoor air quality is considered negligible. In this study, ozone formation is observed for eight different lamps from five manufacturers, in amounts an order-of-magnitude larger than previous reports. Most lamps produce O3in amounts close to the first-principles calculation, with e.g. a generation rate of 22 ppb h-1for Ushio B1 modules in a 21 m3chamber. Much more O3is produced by lamps when optical filters were removed for tests, and by an undesired internal electrical discharge. A test in an office shows an increase of ∼6.5 ppb during lamp-on periods, consistent with a simple model with the O3generation rate, ventilation and O3losses. We demonstrate the use of a photolytic tracer to quantify the averaged GUV222 fluence rate in a room. Low-cost electrochemical O3sensors were not useful below 100 ppb. Formation of O3increases indoor particulate matter (PM), which is ∼10-30 times more deadly than O3per unit mass, and which is ignored when only considering O3threshold limit values. To limit GUV222-created indoor pollution, lower fluence rates should be used if possible, especially under low-ventilation conditions.TOC graphic
Improvement in Expanded Disability Status Scale (EDSS) and anti-inflammatory parameters in patients with multiple sclerosis following oral consumption of N-163 strain ofAureobasidium pullulansproduced beta glucan in a pilot clinical study
Authors: Dedeepiya Vidyasagar Devaprasad , Vetrievel Chockanathan , Ikewaki Nobunao , Ichiyama Koji , Yamamoto Naoki , Kawashima Hiroto , Bharatidasan Sudhakar S , Srinivasan Subramaniam , Senthilkumar Rajappa , Preethy Senthilkumar , Abraham Samuel JK 
Published: May 2023

AbstractIntroductionMultiple Sclerosis (MS) is a debilitating neurodegenerative disease in which demyelination due to auto-inflammation is considered to be the underlying pathogenesis, though the exact etiology is not known. Most of the management strategies involve medications that are anti-inflammatory or immune-suppressive, which do have associated side effects. In this study we have evaluated in MS patients, the clinical effects of a novel beta-glucan which has a track record of anti-inflammatory, immune-modulating potentials in earlier clinical and pre-clinical studies.MethodThe study involved 12 MS patients who consumed two sachets of N-163 strain ofAureobasidium pullulansproduced B-Glucan, daily for 60 days along with routine medication.ResultsThe Expanded Disability Status Scale (EDSS) improved by 0.5 in two patients and by 1 in one patient post-intervention, worsened in 1 patient, remaining stable in the rest. Decrease in IL-6, improvement in CD4+ve, CD19+ve, CD3+ve, and CD8+ ve cell count, increase in Lymphocyte to C-reactive protein ratio (LCR), Leukocyte to CRP ratio (LeCR) and a decrease in Neutrophil to Lymphocyte ratio (NLR) were observed.ConclusionThis study having proven the safety of N-163 strain ofA.pullulansproduced B-Glucan food supplement and the efficacy by improvement in the EDSS score, besides beneficial modulation of inflammation and immune parameters of relevance in MS patients in a short duration of 60 days, has significant potential as a disease modifying adjuvant in MS. Immunological parameters like NLR, LCR, LeCR correlating with clinical improvement, in line with earlier reports using the same beta-glucans, gain further significance for their potentials as biomarkers in MS.
Neoadjuvant chemotherapy and adjuvant chemotherapy are similarly beneficial for five-year overall survival in locally advanced gastric cancer patients
Authors: Birendra Kumar Sah , Zhenjia Yu , Sheng Lu , Yanan Zheng , Zhenglun Zhu , Jian Li , Chen Li , Min Yan , Zhenggang Zhu 
Published: May 2023

AbstractBackgroundDifferent types of neoadjuvant chemotherapy regimens have been compared for gastric cancer, mostly in terms of radiological downgrading or pathological tumor regression; however, no large-scale multicenter RCT study has conducted a head-to-head comparison of the overall survival rate between perioperative or neoadjuvant chemotherapy(NAC) and postoperative or adjuvant chemotherapy(AC). We explored whether the five-year overall survival rate was greater in patients who received perioperative chemotherapy plus surgery than in those who underwent surgery first and then had postoperative chemotherapy.MethodsAltogether, 77 patients with a clinical diagnosis of cTNM stage III were included. Five-year overall survival rates (OS) were compared between patients who underwent neoadjuvant chemotherapy plus surgery (NAC) and patients who underwent surgery first plus adjuvant chemotherapy (AC). Propensity score matching was applied to adjust for the disparity between the two groups. A Kaplan‒Meier plot was created for survival analysis, and the log rank method was used to compare the difference in OS.ResultsA total of 34 patients were in the NAC group, and 43 patients were in the AC group. There was no significant difference in age (median 64 vs. 66 years), cTNM staging, or extent of gastrectomy between the two groups (p<0.05).The median follow-up time was 58 months (range of 53-65 months). The five-year overall survival (OS) rates for the patients in the NAC group and AC group were 61.8% and 73.5%, respectively. There was no significant difference between the two groups in the five-year overall survival rates (p>0.05). There was no significant difference in the severity grading of postoperative complications between the two groups (p>0.05).ConclusionsThere was no significant difference in the five-year overall survival rate between the patients who underwent perioperative chemotherapy plus surgery and those who underwent surgery first plus postoperative chemotherapy. A well-controlled prospective study is necessary to reconfirm whether perioperative chemotherapy is superior to postoperative chemotherapy for gastric cancer patients.
A Genome-Informed Functional Modeling Approach to Evaluate the Responses of Breast Cancer Patients to CDK4/6 Inhibitors-Based Therapies and Simulate Real-World Clinical Trials
Authors: Yang Mei , Liu Yuhan , Zhang Chunming , Hsueh Yi-Ching , Zhang Qiangzu , Fan Yanhui , Xu Juntao , Huang Min , Li Xu , Yang Jianfei , Tan Guangming , Niu Gang 
Published: May 2023

AbstractPURPOSEVaried therapeutic responses were observed among cancer patients receiving the same treatment regimen, highlighting the challenge of identifying patients most likely to benefit from a given therapy. Here, we present an artificial intelligence-based approach, called CDK4/6 inhibitor Response Model (CRM), to address the complexity of predicting patient responses to treatment by a certain clinical scene on CDK4/6 inhibitors (CDK4/6i).PATIENTS AND METHODSTo train the CRM, we transformed the genomic data of 980 breast cancer patients from the TCGA database into activity profiles of signaling pathways (APSP) by utilizing the modified Damage Assessment of Genomic Mutations (DAGM) algorithm. A scoring model was then established by random forest algorithm to classify the HR+/HER2− and HR−/HER2− breast cancer molecular subtypes by the differential APSP features between the two, which reasonably reflected the potential role played by CDK4/6 molecules in HR+/HER2− breast cancer cells. The effectiveness of CRM was then tested in a separate local patient cohort (n = 343) in Guangdong, China. Twin in-silico clinical trials (ICT) of previously disclosed clinical trials (NCT02246621,NCT02079636,NCT03155997,NCT02513394,NCT02675231) were performed to demonstrate the potential of CRM in generating concerted results as the real-world clinical outcomes.RESULTSThe CRM displayed high precision in classifying HR+/HER2− and HR−/HER2− breast cancer patients in both TCGA (AUC=0.9956) and local patient cohorts (AUC=0.9795). Significantly, the scores were distinct (p = 0.025) between CDK4/6i-treated patients with different responses. Breast cancer patients from different subtypes were grouped into five distinct populations based on the scores assigned by the CRM. From twin ICT, the CRM scores reflected the differential responses of patient groups to CDK4/6i-based therapies.CONCLUSIONThe CRM score showed not only a robust association to clinically observed CDK4/6i responses but also heterogenetic responses across subtypes. More than half of HR+/HER2+ patients may be benefited from CDK4/6i-based treatment. The CRM empowered us to conduct ICT on different types of cancer patients responding to CDK4/6i-based therapies. These findings showed the potential of CRM as the companioned ICT to guide CDK4/6i application in the clinical end. CRM-guided ICT could be a universal method to demonstrate drug sensitivity to various patients.
Cross-sectional associations between 24-hour time-use composition, grey matter volume and cognitive function in healthy older adults
Authors: Mellow Maddison L , Dumuid Dorothea , Olds Timothy , Stanford Ty , Dorrian Jillian , Wade Alexandra T , Fripp Jurgen , Xia Ying , Goldsworthy Mitchell R , Karayanidis Frini , Breakspear Michael J , Smith Ashleigh E 
Published: May 2023

BackgroundIncreasing physical activity (PA) is an effective strategy to slow reductions in cortical volume and maintain cognitive function in older adulthood. However, PA does not exist in isolation, but coexists with sleep and sedentary behaviour to make up the 24-hour day. We investigated how the balance of all three behaviours (24-hour time-use composition) is associated with grey matter volume in healthy older adults, and whether grey matter volume influences the relationship between 24-hour time-use composition and cognitive function.MethodsThis cross-sectional study included 378 older adults (65.6 ± 3.0 years old, 123 male) from the ACTIVate study across two Australian sites (Adelaide and Newcastle). Time-use composition was captured using 7-day accelerometry, and T1-weighted magnetic resonance imaging was used to measure grey matter volume both globally and across regions of interest (ROI: frontal lobe, temporal lobe, hippocampi, and lateral ventricles). Pairwise correlations were used to explore univariate associations between time-use variables, grey matter volumes and cognitive outcomes. Compositional data analysis linear regression models were used to quantify associations between ROI volumes and time-use composition, and explore potential associations between the interaction between ROI volumes and time-use composition with cognitive outcomes.ResultsAfter adjusting for covariates (age, sex, education), there were no significant associations between time-use composition and any volumetric outcomes. There were significant interactions between time-use composition and frontal lobe volume for long-term memory (p=0.018) and executive function (p=0.018), and between time-use composition and total grey matter volume for executive function (p=0.028). Spending more time in moderate-vigorous PA was associated with better long-term memory scores, but only for those with smaller frontal lobe volume (below the sample mean). Conversely, spending more time in sleep and less time in sedentary behaviour was associated with better executive function in those with smaller total grey matter volume.ConclusionsAlthough 24-hour time use was not associated with total or regional grey matter independently, total grey matter and frontal lobe grey matter volume mediated the relationship between time-use composition and several cognitive outcomes. Future studies should investigate these relationships longitudinally to assess whether changes in time-use composition correspond to changes in grey matter volume and cognition.