bluuebunny/crossref_metadata_2025_split huggingface dataset:
The risk of major osteoporotic fractures with GLP-1 receptor agonists when compared to DPP-4 inhibitors: A Danish nationwide cohort study
Authors: Al-Mashhadi Zheer Kejlberg , Viggers Rikke , Fuglsang-Nielsen Rasmus , Vestergaard Peter , Gregersen Søren , Starup-Linde Jakob 
Published: October 2022

BackgroundType 2 diabetes mellitus (T2D) is associated with an increased fracture risk. There is little evidence for the effects of glucagon-like peptide 1 receptor agonists (GLP-1RA) on fracture risk in T2D. We aimed to investigate the risk of major osteoporotic fractures (MOF) for treatment with GLP-1RA compared to dipeptidyl peptidase 4 inhibitors (DPP-4i) as add-on therapies to metformin.MethodsWe conducted a population-based cohort study using Danish national health registries. Diagnoses were obtained from discharge diagnosis codes (ICD-10 and ICD-8-system) from the Danish National Patient Registry, and all redeemed drug prescriptions were obtained from the Danish National Prescription Registry (ATC classification system). Subjects treated with metformin in combination with either GLP-1RA or DPP-4i were enrolled from 2007 to 2018. Subjects were propensity-score matched 1:1 based on age, sex, and index date. MOF were defined as hip, vertebral, humerus, or forearm fractures. A Cox proportional hazards model was utilized to estimate hazard rate ratios (HR) for MOF, and survival curves were plotted using the Kaplan-Meier estimator. In addition, Aalen’s Additive Hazards model was applied to examine additive rather than relative hazard effects while allowing time-varying effects.ResultsIn total, 42,816 individuals treated with either combination were identified and included. After matching, 32,266 individuals were included in the main analysis (16,133 in each group). Median follow-up times were 642 days and 529 days in the GLP-1RA and DPP-4i group, respectively. We found a crude HR of 0.89 [0.76–1.05] for MOF with GLP-1RA compared to DPP-4i. In the fully adjusted model, we obtained an unaltered HR of 0.86 [0.73–1.03]. For the case of hip fracture, we found a crude HR of 0.68 [0.49–0.96] and a similar adjusted HR. Fracture risk was lower in the GLP-1RA group when examining higher daily doses of the medications, when allowing follow-up to continue after medication change, and when examining hip fractures, specifically. Additional subgroup- and sensitivity analyses yielded results similar to the main analysis.ConclusionIn our primary analysis, we did not observe a significantly different risk of MOF between treatment with GLP-1RA and DPP-4i. We conclude that GLP-1RA are safe in terms of fracture.
Identification of a novel founder variant in DNAI2 cause primary ciliary dyskinesia in five consanguineous families derived from a single tribe descendant of Arabian Peninsula
Authors: Al-Mutairi Dalal A. , Alsabah Basel H. , Alkhaledi Bashar A. , Pennekamp Petra , Omran Heymut 
Published: October 2022

Introduction: Primary ciliary dyskinesia (PCD) is caused by dysfunction of motile cilia resulting in insufficient mucociliary clearance of the lungs. The overall aim of this study is to identify disease causing genetic variants for PCD patients in the Kuwaiti population.Methods: A cohort of multiple consanguineous PCD families was identified from Kuwaiti patients and genomic DNA from the family members was analysed for variant screening. Transmission electron microscopy (TEM) and immunofluorescent (IF) analyses were performed on nasal brushings to detect specific structural abnormalities within ciliated cells.Results: All the patients inherited the same founder variant in DNAI2 and exhibited PCD symptoms. TEM analysis demonstrated lack of outer dynein arms (ODA) in all analysed samples. IF analysis confirmed absence of DNAI1, DNAI2, and DNAH5 from the ciliary axoneme. Whole exome sequencing, autozygosity mapping and segregation analysis confirmed that seven patients carry the same homozygous missense variant (DNAI2:c.740G&gt;A; p.Arg247Gln; rs755060592).Conclusion:DNAI2:c.740G&gt;A is the founder variant causing PCD in patients belonging to a particular Arabian tribe which practices consanguineous marriages.
Long-term efficacy of enucleation combined with primary orbital implantation in children with retinoblastoma histopathological invasion of optic nerve
Authors: Wang Nan , Liu Rui , Li Jing , Wang Jinjin , Xu Liangyuan , Guo Qihan , Zhang Xuan , Ma Jianmin 
Published: October 2022

ObjectiveThis study aimed to observe the long-term effect of enucleation combined with primary orbital implantation in children with histopathologic optic nerve invasive retinoblastoma (RB).MethodsWe retrospectively analyzed the clinical data and outcomes of children with RB optic nerve invasion confirmed by histopathology who underwent enucleation combined with primary orbital implantation between March 2010 and April 2014 in Beijing Tongren Hospital. The follow-up time ranged from 81 to 129 months, with a mean follow-up of 96 ± 14 months.ResultsA total of 59 children were included in this study. There were 32 males and 27 females; 52 children were affected in one eye and seven children in both eyes. The time from onset of symptoms to visit was between 3 days and 16 months, with a mean of 2.2 ± 2.8 months. The age at the of surgery was between 2 and 65 months, with an average of 24 ± 13 months. Patients were classified based on the degree of optic nerve invasion into four grades: grade 1 (invasion of prelaminar) in 28 cases, grade 2 (invasion of laminar) in 14 cases, grade 3 (invasion of retrolaminar but not reaching the optic nerve transection) in 16 cases, and grade 4 (invasion of the optic nerve transection) in 1 case. Post-operatively, all children were treated with 0–9 cycles of intravenous chemotherapy based on histopathology results from the removed eye. Of the 59 children, 13 had postoperative complications, and one died from recurrence. The survival rate was 98% (58/59). There was one case of orbital implant exposure, one of orbital cellulitis, six of enophthalmos and superior sulcus deformity, two of blepharoptosis, one of granuloma complicated with blepharoptosis, and one with a subconjunctival cyst.ConclusionFor children with RB histopathologic invasion of the optic nerve, enucleation combined with primary orbital implantation reveals future potential treatment options when combined with a full course of intravenous chemotherapy.
Design and implementation of a Stroke Rehabilitation Registry for the systematic assessment of processes and outcomes and the development of data-driven prediction models: The STRATEGY study protocol
Authors: Chiavilli Marco , Campagnini Silvia , Baretta Teresa , Castagnoli Chiara , Paperini Anita , Politi Angela Maria , Pellicciari Leonardo , Baccini Marco , Basagni Benedetta , Marignani Sara , Bardi Donata , Sodero Alessandro , Lombardi Gemma , Guolo Erika , Navarro Jorge Solano , Galeri Silvia , Montesano Angelo , Falco Lucia , Rovaris Marco Giuseppe , Carrozza Maria Chiara , Macchi Claudio , Mannini Andrea , Cecchi Francesca 
Published: October 2022

BackgroundStroke represents the second preventable cause of death after cardiovascular disease and the third global cause of disability. In countries where national registries of the clinical quality of stroke care have been established, the publication and sharing of the collected data have led to an improvement in the quality of care and survival of patients. However, information on rehabilitation processes and outcomes is often lacking, and predictors of functional outcomes remain poorly explored. This paper describes a multicenter study protocol to implement a Stroke rehabilitation Registry, mainly based on a multidimensional assessment proposed by the Italian Society of Physical and Rehabilitation Medicine (PMIC2020), in a pilot Italian cohort of stroke survivors undergoing post-acute inpatient rehabilitation, to provide a systematic assessment of processes and outcomes and develop data-driven prediction models of functional outcomes.MethodsAll patients with a diagnosis of ischemic or haemorrhagic stroke confirmed by clinical assessment, admitted to intensive rehabilitation units within 30 days from the acute event, aged 18+, and providing informed consent will be enrolled. Measures will be taken at admission (T0), at discharge (T1), and at follow-up, 3 months (T2) and 6 months (T3) after the stroke. Assessment variables include anamnestic data, clinical and nursing complexity information and measures of body structures and function, activity and participation (PMIC2020), rehabilitation interventions, adverse events and discharge data. The modified Barthel Index will be our primary outcome. In addition to classical biostatistical analysis, learning algorithms will be cross-validated to achieve data-driven prognosis prediction models.ConclusionsThis study will test the feasibility of a stroke rehabilitation registry in the Italian health context and provide a systematic assessment of processes and outcomes for quality assessment and benchmarking. By the development of data-driven prediction models in stroke rehabilitation, this study will pave the way for the development of decision support tools for patient-oriented therapy planning and rehabilitation outcomes maximization.Clinical tial registrationThe registration on ClinicalTrials.gov is ongoing and under review. The identification number will be provided when the review process will be completed.
Altered regional homogeneity and functional connectivity of brain activity in young HIV-infected patients with asymptomatic neurocognitive impairment
Authors: Han Shuai , Aili Xire , Ma Juming , Liu Jiaojiao , Wang Wei , Yang Xue , Wang Xi , Sun Lijun , Li Hongjun 
Published: October 2022

ObjectiveAsymptomatic neurocognitive impairment (ANI) is a predominant form of cognitive impairment in young HIV-infected patients. However, the neurophysiological mechanisms underlying this disorder have not been clarified. We aimed to evaluate the altered patterns of functional brain activity in young HIV-infected patients with ANI by quantifying regional homogeneity (ReHo) and region of interest (ROI)-based functional connectivity (FC).MethodsThe experiment involved 44 young HIV-infected patients with ANI and 47 well-matched healthy controls (HCs) undergoing resting-state functional magnetic resonance imaging (rs-fMRI) and neurocognitive tests. Reho alterations were first explored between the ANI group and HC groups. Subsequently, regions showing differences in ReHo were defined as ROIs for FC analysis. Finally, the correlation of ReHo and FC with cognitive function and clinical variables was assessed.ResultsCompared with HCs, ANI patients had a significant ReHo decrease in the right lingual gyrus (LING. R), right superior occipital gyrus (SOG. R), left superior occipital gyrus (SOG. L), left middle occipital gyrus (MOG. L), right middle frontal gyrus (MFG. R), cerebellar vermis, ReHo enhancement in the left middle frontal gyrus (MFG. L), and left insula (INS L). The ANI patients showed increased FC between the LING. R and MOG. L compared to HC. For ANI patients, verbal and language scores were negatively correlated with increased mean ReHo values in the MFG.L. Increased mean ReHo values in the INS. L was positively correlated with disease duration—the mean ReHo values in the LING. R was positively correlated with the abstraction and executive function scores. Increased FC between the LING. R and MOG. L was positively correlated with verbal and language performance.ConclusionThe results suggest that the visual network might be the most vulnerable area of brain function in young HIV-infected patients with ANI. The middle frontal gyrus, cerebellar vermis, and insula also play an important role in asymptomatic neurocognitive impairment. The regional homogeneity and functional connectivity of these regions have compound alterations, which may be related to the course of the disease and neurocognitive function. These neuroimaging findings will help us understand the characteristics of brain network modifications in young HIV-infected patients with ANI.
Incorporating neck circumference or neck-to-height ratio into the GOAL questionnaire to better detect and describe obstructive sleep apnea with application to clinical decisions
Authors: Zhao Ying , Yan Xiangru , Liang Chunguang , Wang Liying , Zhang Hui , Yu Haitao 
Published: October 2022

ObjectiveAlthough neck circumference (NC) and neck-to-height ratio (NHR) have been recognized as effective predictors of the clinical diagnosis of adult obstructive sleep apnea (OSA), they have not been included in the widely used GOAL questionnaire. Not coincidentally, the NHR has not been adequately considered in the development and validation of the STOP-Bang questionnaire, No-Apnea score and the NoSAS score. The motivation for the study was (1) to combine the GOAL questionnaire with the NC and NHR, respectively, to evaluate its predictive performance and (2) to compare it with the STOP-Bang questionnaire, the No-Apnea score, the NOSAS score, and the GOAL questionnaire.Materials and methodsThis retrospectively allocated cross-sectional study was conducted from November 2017 to March 2022 in adults who underwent nocturnal polysomnography (PSG) or home sleep apnea testing (HSAT). In this paper, the GOAL questionnaire was combined with the NC and NHR, respectively, using logistic regression. The performance of the six screening tools was assessed by discriminatory ability [area under the curve (AUC) obtained from receiver operating characteristic (ROC) curves] and a 2 × 2 league table [including sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (LR+), and negative likelihood ratio (LR−)] and compared under AHI ≥5/h, AHI ≥15/h, and AHI ≥30/h conditions.ResultsA total of 288 patients were enrolled in the study. For all severity OSA levels, the sensitivity of GOAL+NC ranged from 70.12 to 70.80%, and specificity ranged from 86.49 to 76.16%. The sensitivity of GOAL+NHR ranged from 73.31 to 81.75%, while specificity ranged from 83.78 to 70.86%. As for area under the curve (AUC) value under ROC curve, when AHI ≥5/h, compared with GOAL (0.806), No-Apnea (0.823), NoSAS (0.817), and GOAL+NC (0.815), GOAL+NHR (0.831) obtained the highest AUC value, but lower than STOP-Bang (0.837).ConclusionThe predictive power of incorporating NC or NHR into the GOAL questionnaire was significantly better than that of the GOAL itself. Furthermore, GOAL+NHR was superior to GOAL+NC in predicting OSA severity and better than the No-Apnea score and the NoSAS score.
Effect of flavonoids on skeletal muscle mass, strength and physical performance in middle-aged and older adults with or without Sarcopenia: A meta-analysis of randomized controlled trials
Authors: Li Yuzhuo , Liu Yun , Tan Rongshao , Liu Yan 
Published: October 2022

The role of flavonoids in regulating the synthesis and function of skeletal muscles is increasingly recognized. However, randomized controlled trials have yielded inconsistent results on the influence of flavonoids on human muscular parameters. Therefore, we performed a meta-analysis to evaluate the possible effects of flavonoids on sarcopenia-related parameters in middle-aged and elderly people. Eligible literature and randomized controlled trials reports have been extensively searched from PubMed, Cochrane Library, Web of Science, and EMBASE databases until April 2022. A total of 20 articles involving 796 participants were available for the meta-analysis. There were significant benefits for participants in appendicular muscle mass gain (SMD = 0.29; 95% CI: 0.07, 0.52; P = 0.01) and 6-min walk distance (SMD = 0.37; 95% CI: 0.01, 0.73; P = 0.05). A subgroup analysis indicated that flavonoid significantly improves appendicular muscle mass (SMD = 0.50; 95% CI: 0.21, 0.80; P &lt; 0.01) and Timed-Up and Go test (SMD = −0.47; 95% CI: −0.85, −0.09; P = 0.02) in Sarcopenia population. Our results provide insight into the effects of flavonoids on skeletal muscle mass and gait speed for those without exercise. However, there was no significant improvement in the subjects' muscle strength.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?RecordID=334383, identifier: CRD42022334383.
Mendelian randomization in blood metabolites identifies triglycerides and fatty acids saturation level as associated traits linked to pancreatitis risk
Authors: Mi Jiarui , Liu Zhengye , Jiang Lingjuan , Li Meizi , Wu Xia , Zhao Nan , Wan Ziqi , Bai Xiaoyin , Feng Yunlu 
Published: October 2022

BackgroundThere is very limited evidence on the causal effects of blood metabolites on pancreatitis risks. To reveal the causal associations between plasma metabolites and pancreatitis risks, we performed two-sample Mendelian randomization (MR) and Bayesian model averaging (MR-BMA) analyses in European ancestry.MethodsThe summary-level statistics from two genome-wide association studies with 249 and 123 metabolic traits derived from two separate cohorts involving ~115,000 (UK Biobank) and ~25,000 individuals from European ancestry were used for the analyses. The summary statistics of four pancreatitis datasets from FinnGen R5 and two pancreatitis datasets from UK Biobank were exploited as the outcome. We first performed univariable MR analysis with different metabolic GWAS data on multiple pancreatitis datasets to demonstrate the association pattern among different metabolites categories. Next, we exploited the MR-BMA method to pinpoint the dominating factors on the increased risk of pancreatitis.ResultsIn the primary analysis with 249 traits, we found that plasma triglycerides were positively associated with pancreatitis risk. Intriguingly, a large number of traits associated with saturation or unsaturation of fatty acids also demonstrated causal associations. The replication study analyzing 123 metabolic traits suggested that bisallylic groups levels and omega-3 fatty acids were inversely correlated with pancreatitis risk. MR-BMA analyses indicated that the ratio of triglycerides to total lipid in various HDL particles played leading roles in pancreatitis susceptibility. In addition, the degree of unsaturation, the ratio of polyunsaturated fatty acids to monounsaturated fatty acids and the level of monounsaturated fatty acids showed causal associations with either decreased or increased pancreatitis susceptibility.ConclusionsOur MR study provided an atlas of causal associations of genetically predicted blood metabolites on pancreatitis, and offered genetic insights showing intervention in triglycerides and the supplementation of unsaturated fatty acids are potential strategies in the primary prevention of pancreatitis.
MBTPS1 regulates proliferation of colorectal cancer primarily through its action on sterol regulatory element-binding proteins
Authors: Hartal-Benishay Liat H. , Saadi Esraa , Toubiana Shir , Shaked Lior , Lalzar Maya , Abu Hatoum Ossama , Tal Sharon , Selig Sara , Barki-Harrington Liza 
Published: October 2022

Among the main metabolic pathways implicated in cancer cell proliferation are those of cholesterol and fatty acid synthesis, both of which are tightly regulated by sterol regulatory element-binding proteins (SREBPs). SREBPs are activated through specific cleavage by membrane-bound transcription factor protease 1 (MBTPS1), a serine protease that cleaves additional substrates (ATF6, BDNF, CREBs and somatostatin), some of which are also implicated in cell proliferation. The goal of this study was to determine whether MBTPS1 may serve as a master regulator in proliferation of colorectal cancer (CRC). Tumors from CRC patients showed variable levels of MBTPS1 mRNA, which were in positive correlation with the levels of SREBPs and ATF6, and in reverse correlation with BDNF levels. Chemical inhibition of MBTPS1 activity in two CRC-derived cell lines resulted in a marked decrease in the levels of SREBPs, but not of its other substrates and a marked decrease in cell proliferation, which suggested that MBTPS1 activity is critical for proliferation of these cells. In accordance, CRISPR/Cas9 targeted knockout (KO) of the MBTPS1 gene resulted in the survival of only a single clone that presented a phenotype of severely attenuated proliferation and marked downregulation of several energy metabolism pathways. We further showed that survival of the MBTPS1 KO clone was dependent upon significant upregulation of the type-1 interferon pathway, the inhibition of which halted proliferation entirely. Finally, rescue of the MBTPS1 KO cells, resulted in partial restoration of MBTPS1 levels, which was in accordance with partial recovery in proliferation and in SREBP levels. These finding suggest that MBTPS1 plays a critical role in regulating colon cancer proliferation primarily through SREBP-associated lipid metabolism, and as such may serve as a possible therapeutic target in CRC.
An external validation of the nocera nomogram: Predicting non-organ confined stage of ≥pT3 in cT1 clear cell renal cell carcinoma
Authors: Wenzel Mike , Hoeh Benedikt , Rührup Jessica , Gambetta Hanna , Nocera Luigi , Würnschimmel Christoph , Tian Zhe , Karakiewicz Pierre I. , Briganti Alberto , Chun Felix K.H. , Roos Frederik C. , Becker Andreas , Krimphove Marieke J. 
Published: October 2022

BackgroundOnly one previously published study by Nocera et al. addressed the risk of upstaging to ≥pT3 in cT1 clear cell renal cell carcinoma (ccRCC) by using characteristics of the R.E.N.A.L and PADUA score (age, tumor size, rim location, exophytic rate, polar involvement) developing an accurate nomogram. However, this nomogram has never been externally validated yet.Material and methodsThe study cohort consisted of 288 patients with cT1a-b ccRCC, diagnosed between 2008-2021 at the University Hospital Frankfurt, Germany. Analyses addressed clinical, tumor and radiographic characteristics. The external validation of the nomogram relied on accuracy calculations derived from the area under the curve of the receiver operator characteristic analysis.ResultsOverall, 11.8% (n=34) patients harbored ≥pT3 ccRCC. Median radiographic tumor size (3.6 vs. 5.3cm), R.E.N.A.L. (8 vs. 9 points) and PADUA score (9 vs. 11 points), as well as proportions of renal sinus involvement (82.4% vs. 51.6%), renal hilus involvement (44.1 vs. 13.0%), and medial rim location significantly differed between the pT1-2 and ≥pT3 group (all p ≤ 0.01). In subgroup analyses of small renal mass ccRCC patients (&lt;4cm, cT1a), only 3.8% (n=6) patients had ≥pT3 pathology. Upstaged patients were significantly older and more frequently had endophytic tumor than pT1-2 counterparts (p&lt;0.05). The external validation of the Nocera nomogram showed a good accuracy of 76.6%. Using the suggested cut-off of 21%, 26.5% of patients exhibited ≥pT3 ccRCC. Conversely, within patients below cut-off, 5.9% patients exhibited ≥pT3 ccRCC.ConclusionWe reported the first external validation of the nomogram addressing the risk of ≥pT3 in cT1 ccRCC patients, demonstrating a good accuracy, with a low false-negative rate. Therefore, the nomogram can accurately be used for patients’ counselling and treatment decision making.