bluuebunny/crossref_metadata_2025_split huggingface dataset:
Population pharmacokinetic and exposure‐response analyses from ALTA‐1L: Model‐based analyses supporting the brigatinib dose in ALK‐positive NSCLC
Authors: Gupta Neeraj , Reckamp Karen L. , Camidge David R. , Kleijn Huub J. , Ouerdani Aziz , Bellanti Francesco , Maringwa John , Hanley Michael J. , Wang Shining , Zhang Pingkuan , Venkatakrishnan Karthik 
Published: January 2022

AbstractThe ALK in Lung Cancer Trial of brigAtinib in First Line (ALTA‐1L) compared brigatinib versus crizotinib in anaplastic lymphoma kinase (ALK) inhibitor‐naive patients with ALK+ non‐small cell lung cancer (NSCLC). A population pharmacokinetic (PK) model was used to estimate brigatinib exposures for exposure‐efficacy and exposure‐safety analyses in ALTA‐1L. A previously developed population PK model for brigatinib was applied to estimate brigatinib PK parameters. Relationships between static (time‐independent) and dynamic (time‐varying) exposure metrics and efficacy (progression‐free survival [PFS], objective response rate [ORR], and intracranial ORR [iORR]) and safety outcomes (selected grade ≥2 and grade ≥3 adverse events [AEs]) were evaluated using logistic regression and time‐to‐event analyses. There were no meaningful differences in brigatinib PK in the first‐line and second‐line settings, supporting use of the previous population PK model for the first‐line population. Exposure‐response analyses showed no significant effect of time‐varying brigatinib exposure on PFS. Brigatinib exposure was not significantly related to ORR, but higher exposure was associated with higher iORR (odds ratio: 1.13, 95% confidence interval: 1.01–1.28, p = 0.049). Across the observed median exposure (5th–95th percentile) at steady state for 180 mg once daily, the predicted probability of iORR was 0.83 (0.58–0.99). AEs significantly associated with higher exposure were elevated lipase (grade ≥3) and amylase (grade ≥2). Time to first brigatinib dose reduction was not related to exposure. These results support the benefit‐risk profile of first‐line brigatinib 180 mg once daily (7‐day lead‐in dose at 90 mg once daily) in patients with ALK+ NSCLC.
Haemoperitoneum associated with bilateral granulosa cell tumours in a pregnant mare treated by standing ovariectomy
Authors: Sinovich M. , Archer D. C. , Kane‐Smyth J. , Scarabelli S. , Ritchie A. , Kelly P. G. 
Published: January 2022

SummaryThis report describes the likely development and growth of bilateral granulosa cell tumours (GCTs) in a Warmblood pony mare, during the first trimester of pregnancy after artificial insemination. The GCTs were initially suspected to be ovarian haematomas and were managed conservatively. However, they ultimately led to life‐threatening haemoperitoneum (HP) and were later diagnosed as GCTs with histopathology. The case was successfully managed with emergency standing laparoscopic‐assisted bilateral ovariectomy after haemodynamic supportive therapy. The mare made a full recovery and delivered a live filly foal at term. GCTs can be a rare cause of life‐threatening HP and can be successfully managed with haemodynamic support and standing laparoscopic‐assisted removal. Bilateral ovariectomy in a pregnant mare after 70 days of gestation can result in successful delivery of a live foal.
Patient‐reported outcomes in autosomal inherited bleeding disorders: A systematic literature review
Authors: van Hoorn Evelien S. , Houwing Maite E. , Al Arashi Wala , Leebeek Frank W. G. , Hazelzet Jan A. , Gouw Samantha C. , Schutgens Roger E. G. , Schols Saskia E. M. , Lingsma Hester F. , Cnossen Marjon H. ,   the SYMPHONY consortium
Published: January 2022

AbstractAimCurrently, it is unknown which patient‐reported outcomes are important for patients with autosomal inherited bleeding disorders. Therefore, the purpose of this study is to systematically review the available literature assessing patient‐reported outcomes and their measurement methods in autosomal inherited bleeding disorders.MethodsThe Embase, Medline ALL, Web of Science Core Collection, Cochrane Central Register of Controlled Trails and Google Scholar databases were searched from inception until 14 August 2020. Studies on patient‐reported outcomes in patients with von Willebrand disease, inherited platelet function disorders and coagulation factor deficiencies were included.ResultsTwenty‐one articles met the inclusion criteria. Three studies were assessed as having poor quality, and therefore a high risk of bias. Nineteen studies had fair quality rating. Different measurements methods were used, ranging from predefined to self‐developed questionnaires. The majority of included studies focused on von Willebrand disease. Patients with von Willebrand disease reported lower health‐related quality of life compared to the general population. Overall, this trend was especially visible in the following domains: vitality, physical and social functioning and pain. Women with inherited bleeding disorders scored lower on health‐related quality of life compared to men, especially women with heavy menstrual bleeding. Patients with joint bleeds or heavy menstrual bleeding reported an increased level of pain.ConclusionPatients with autosomal inherited bleeding disorders report lower health related quality of life, especially those with joint bleeds or heavy menstrual bleeding. Numerous measurement methods are used in patients with autosomal inherited bleeding disorders, highlighting the need for studies using established, standardized measurement methods.
Upregulation of the novel lncRNA U731166 is associated with migration, invasion and vemurafenib resistance in melanoma
Authors: Siena Ádamo Davi Diógenes , Barros Isabela Ichihara de , Storti Camila Baldin , de Biagi Júnior Carlos Alberto Oliveira , da Costa Carvalho Larissa Anastacio , Maria‐Engler Silvya Stuchi , Sousa Josane de Freitas , Silva Wilson Araújo 
Published: January 2022

AbstractOur previous work using a melanoma progression model composed of melanocytic cells (melanocytes, primary and metastatic melanoma samples) demonstrated various deregulated genes, including a few known lncRNAs. Further analysis was conducted to discover novel lncRNAs associated with melanoma, and candidates were prioritized for their potential association with invasiveness or other metastasis‐related processes. In this sense, we found the intergenic lncRNA U73166 (ENSG00000230454) and decided to explore its effects in melanoma. For that, we silenced the lncRNA U73166 expression using shRNAs in a melanoma cell line. Next, we experimentally investigated its functions and found that migration and invasion had significantly decreased in knockdown cells, indicating an essential association of lncRNA U73166 for cancer processes. Additionally, using naïve and vemurafenib‐resistant cell lines and data from a patient before and after resistance, we found that vemurafenib‐resistant samples had a higher expression of lncRNA U73166. Also, we retrieved data from the literature that indicates lncRNA U73166 may act as a mediator of RNA processing and cell invasion, probably inducing a more aggressive phenotype. Therefore, our results suggest a relevant role of lncRNA U73166 in metastasis development. We also pointed herein the lncRNA U73166 as a new possible biomarker or target to help overcome clinical vemurafenib resistance.
Application of 3D‐printed colored 3D‐models for the fabrication of full ceramic restorations: A technical report
Authors: Schweiger Josef , Güth Jan‐Frederik , Edelhoff Daniel , Seidel Kathrin , Graf Tobias 
Published: January 2022

AbstractObjectiveThis paper presents a novel digital workflow that expedites and facilitates the manufacturing of high‐end full‐ceramic restorations based on “Print and Press”‐Technology combined with 3D‐printed colored 3D‐models.Clinical considerationsDespite ongoing innovations and developments in the digital workflow, the precision, and the final esthetic outcome is still limited compared with conventional press ceramics. The proposed method combines the advantages of digital scan‐ and design technologies with the proven conventional press‐technology to accomplish high‐end full‐ceramic restorations. The restoration is digitally designed, the data set is 3D‐printed in resin that can be burned out, subsequently conventionally embedded and pressed. Final esthetic finishing of the partial restorations is done on a 3D‐printed physical colored 3D‐model.ConclusionThe report describes synergetic effects of digital and analog procedures. 3D‐printed colored 3D‐models can positively support the manufacturing of full ceramic restorations regarding their optical integration. Therefore, the use of 3D‐printed colored 3D‐models signifies a new innovative technique with many promising application areas.Clinical significanceThe combination of excellent clinical long‐term data for pressed ceramic restorations and proven digital processes, like intraoral scanning, design, and additive manufacturing, in the dental field promise an individual workflow for predictability and excellent esthetics.
Effects of antipsychotics on intravenous sedation with midazolam and propofol during dental treatment for patients with intellectual disabilities
Authors: Oda Y. , Yoshida K. , Kawano R. , Yoshinaka T. , Oda A. , Takahashi T. , Oue K. , Mukai A. , Irifune M. , Okada Y. 
Published: January 2022

AbstractBackgroundSome patients with intellectual disabilities (ID) are prescribed antipsychotic drugs for symptomatic treatment of behavioural disorders. Nevertheless, it can still prove difficult to perform dental treatments safely for some patients with ID. In such cases, treatment under intravenous sedation (IVS) is one option. Sedative, hypnotic and α‐blocking effects of antipsychotic drugs may cause adverse events, such as severe hypotension, among patients who take antipsychotic drugs regularly. This study aimed to investigate the effects of oral antipsychotic medication on cardiovascular function during IVS. Accordingly, we compared mean blood pressure (MBP) and heart rate (HR) between patients who regularly take antipsychotic drugs and patients who do not.MethodsThirty‐seven patients with ID were enrolled in this study. All participants were outpatients of Special Care Dentistry of general hospital and received dental treatment under IVS performed with a combination of midazolam and propofol. Eighteen patients regularly took antipsychotics (medication group), and 19 patients were not currently taking antipsychotics (non‐medication group). MBP, HR, dose, and effect‐site concentration of intravenous sedative medications were measured at three points: ‘before IVS’, ‘at optimal sedation’, and ‘during dental treatment’.ResultsThe magnitude of reduction of MBP was significantly smaller in the medication group than in the non‐medication group (P < 0.023). However, there were no differences in MBP, HR, dose, and effect‐site concentration of midazolam and propofol between groups at any point.ConclusionThese results suggest that antipsychotic medication may not have clinically significant adverse effects on cardiovascular fluctuations during dental treatment under IVS for persons with ID.
Role of miRNAs in melanin metabolism: Implications in melanin‐related diseases
Authors: Zhang Zhigang , Shen Wanlu , Liu Weimin , Lyu Lechun 
Published: January 2022

AbstractBackgroundMicroRNAs (miRNAs) are short single‐stranded non‐coding RNAs that regulate degradation and expression of messenger RNA (mRNA) and play a wide range of key roles in different biological processes. They mediate different stages of melanocyte differentiation, growth, and apoptosis through a variety of pathways and can mediate melanin production by targeting key enzymes.AimsThis article was aimed to review the role of miRNAs in melanin metabolism and to introduce the role and significance of miRNAs in melanin‐related diseases.Materials & MethodsSystematic search and retrospective review were performed on the published data.ResultsThis paper reviews the process of melanin synthesis and the regulatory mechanism, explores the miRNA expression profiles in different model organisms, and introduces the mechanisms of several key miRNAs participating in melanin metabolism through target genes. We also explore the potential role of miRNA as a new target for the treatment of melanin metabolism disease, including vitiligo, melanoma, and chloasma.ConclusionmiRNAs play a key role in melanin‐related diseases, and the miRNAs involved may be potential therapeutic targets.
An ethylene‐responsive transcription factor and a flowering locus KH domain homologue jointly modulate photoperiodic flowering in chrysanthemum
Authors: Huang Yaoyao , Xing Xiaojuan , Tang Yun , Jin Jinyu , Ding Lian , Song Aiping , Chen Sumei , Chen Fadi , Jiang Jiafu , Fang Weimin 
Published: January 2022

AbstractThe timely transition from vegetative to reproductive development is coordinated through the quantitative regulation of floral pathway genes in response to physiological and environmental cues. The function of ethylene‐responsive element‐binding protein (ERF) transcription factors in the regulation of flowering in chrysanthemum (Chrysanthemum morifolium Ramat.) is not well understood. Here, chrysanthemum overexpressing CmERF110 flowered earlier than the wild‐type plants, while those in which CmERF110 was suppressed flowered later. RNA‐seq results revealed that several genes involved in the circadian rhythm were transcribed differently in CmERF110 transgenic plants from that of the wild‐type plants. The rhythm peak of the circadian clock genes in transgenic plants was delayed. Yeast two‐hybrid screening of CmERF110 interactors identified a chrysanthemum FLOWERING LOCUS KH DOMAIN (FLK) homologue CmFLK, which was further confirmed with both in vitro and in vivo assays. KEGG pathway enrichment also revealed that CmFLK is involved in the regulation of circadian rhythm‐related genes. CmFLK transgenic plants showed a change in flowering time and delayed rhythm peak of the circadian rhythm genes. Taken together, the present data not only suggest that CmERF110 interacts with CmFLK to promote floral transition by tuning the circadian clock, but also provides evidence for the evolutionary conservation of the components in the autonomous pathway in chrysanthemum.
NovelADAMTSL4gene mutations in Chinese patients with isolated ectopia lentis
Authors: Guo Dongwei , Yang Fengmei , Zhou Yijing , Zhang Xinyu , Cao Qianzhong , Jin Guangming , Zheng Danying 
Published: January 2022

BackgroundTo characterise the phenotype and genetic defects of isolated ectopia lentis (IEL) and to determine theADAMTSL4gene mutation frequencies in a Chinese congenital ectopia lentis (CEL) cohort.MethodsIn total, 127 Chinese probands with a clinical CEL diagnosis were recruited for this study and underwent ocular and systemic examinations. Whole-exome sequencing was used to detect variants, and Sanger sequencing and bioinformatics analysis verified the pathogenic mutations.ResultsOverall, biallelic mutations inADAMTSL4,involving 8 novelADAMTSL4mutations (c.21–2A>G, c.1174G>C, c.2169C>A, c.2236C>T, c.2263delG, c.2397C>A, c.2488dupC and c.2935T>C) were identified in 5 probands (5/127, 3.94%) with IEL. Additionally, four patients had combined congenital cataracts, and two patients had ectopia lentis et pupillae (ELP). One of eight mutations was a homozygous missense mutation, and the other seven mutations were compound heterozygous. These eight consisted of three missense (37.5%), three frameshift (37.5%), one stop-gain (12.5%) and one spicing mutation (12.5%). These mutations co-segregated with the IEL, and the substitution of amino acids greatly affected conserved residues. Most of the novel mutations were located in the thrombospondin type 1 (TSP1) domain, which ultimately alters the structure of the ADAMTSL4 protein.ConclusionsThis study reported five IEL probands with eight novel mutations in theADAMTSL4gene. The clinical IEL phenotypes caused by these mutations were variable and complex. This study thus establishes theADAMTSL4gene mutation frequency and expands the gene’s mutation spectrum to help recogniseADAMTSL4-related IEL clinical manifestations.
Prevalence of common mental health disorders in military veterans: using primary healthcare data
Authors: Finnegan Alan , Randles R 
Published: January 2022

IntroductionServing military personnel and military veterans have been identified as having a high prevalence of mental disorders. Since 1985, UK patients’ primary healthcare (PHC) medical records contain Read Codes (now being replaced by Systematized Nomenclature of Medicine - Clinical Terms (SNOMED CT) codes) that mark characteristics such as diagnosis, ethnicity and therapeutic interventions. This English study accesses a cohort profile of British Armed Forces veterans to examine the diagnosed common mental disorders by using PHC records.MethodsThis analysis has been drawn from initiatives with PHC practices in the Northwest of England to increase veteran registration in general practice. Demographic data were collected including gender, age and marital status. Data were also collected on common mental health disorders associated with the Armed Forces.Result2449 veteran PHC records were analysed. 38% (N=938) of veterans in this cohort had a code on their medical record for common mental health disorders. The highest disorder prevalence was depression (17.8%, N=437), followed by alcohol misuse (17.3%, N=423) and anxiety (15.0%, N=367). Lower disorder prevalence was seen across post-traumatic stress disorder (PTSD) (3.4%, N=83), dementia (1.8%, N=45) and substance misuse (0.8%, N=19). Female veterans had a higher prevalence of mental disorders than their male counterparts, while men a higher prevalence of PTSD; however, the gender difference in the latter was not significant (p>0.05).ConclusionThe SNOMED searches do not detail why certain groups had higher recordings of certain disorders. A future study that accesses the PHC written medical notes would prove enlightening to specifically identify what situational factors are having the most impact on the veteran population. The results from a sizeable English veteran population provide information that should be considered in developing veteran-specific clinical provision, educational syllabus and policy.
Use of the kidney failure risk equation to inform clinical care of patients with chronic kidney disease: a mixed-methods systematic review
Authors: Bhachu Harjeet Kaur , Fenton Anthony , Cockwell Paul , Aiyegbusi Olalekan , Kyte Derek , Calvert Melanie 
Published: January 2022

Rationale and objectiveThe Kidney Failure Risk Equation (KFRE) predicts the risk of end-stage kidney disease in patients with chronic kidney disease (CKD). This study aimed to evaluate the impact of the utility of KFRE in clinical practice.Study designSystematic review.Setting and study populationsAdult patients with CKD but not receiving renal replacement therapy enrolled in studies where KFRE was used in clinical care pathways.Selection criteria for studiesAll studies published from April 2011 to October 2021 identified from Medline, Cumulative Index to Nursing and Allied Health Literature, Embase and reference and citation searches of included studies.Data extractionRelevant data were extracted, and two reviewers independently assessed study quality using appropriate appraisal tools.Analytical approachFindings reported as a narrative synthesis due to heterogeneity of the included studies.ResultsOf 1635 studies identified, 440 duplicates were removed. The remaining 1195 titles and abstracts were screened. All five studies for full-text review were included in the analysis. Three uses of KFRE were assessed: (1) primary to specialty care interface; (2) general nephrology to multidisciplinary care transition; and (3) treatment planning. Evidence of impact on number of patient referrals into nephrology care was conflicting. However, wait times improved in one study. Although KFRE identified high-risk patients for increased multidisciplinary support, there was concern patients stepped down, no longer meeting eligibility criteria, may lack access to services.ConclusionsThis is the first systematic review of studies that have assessed the actual impact of KFRE in clinical practice with five studies of varying quality reported to date. Trials are in progress assessing the impact on clinical outcomes of using KFRE in clinical practice, and KFRE is being incorporated into guidelines for CKD management. Further studies are needed to assess the impact of KFRE on clinical care.Trial registration numberProtocol registered on PROSPERO before initiation of the study (Ref: CRD42020219926).
Integration of rapid PCR testing as an adjunct to NGS in diagnostic pathology services within the UK: evidence from a case series of non-squamous, non-small cell lung cancer (NSCLC) patients with follow-up
Authors: Finall Alison , Davies Gareth , Jones Trevor , Emlyn Gwion , Huey Pearl , Mullard Anna 
Published: January 2022

AimsSomatic genetic testing in non-squamous, non-small cell lung carcinoma (NSCLC) patients is required to highlight subgroups eligible for a number of novel oncological therapies. This study aims to determine whether turnaround times for reporting epidermal growth factor receptors (EGFR) by next-generation sequencing (NGS) alone is sufficient to meet the needs of lung cancer patients.MethodsWe performed a retrospective case series with follow-up. Outcomes of EGFR testing (102 tests) in 96 patients by NGS were compared with a rapid, fully automated PCR-based platform (Idylla) in local histopathology laboratories.ResultsTurnaround time for reporting NGS was 17 calendar days. Reporting using the Idylla EGFR Mutation Test, by contrast, gave a potential turnaround time of 3.8 days from request to authorisation. Three-quarters of patients presenting with stage IV disease had a performance status of 0, 1, or 2 but 18% experienced rapid clinical deterioration (p<0.05). A third of these patients were deceased by the time NGS reports were available.ConclusionsWe discuss issues around integrating rapid PCR testing alongside NGS in multidisciplinary care pathways and strategies for mitigating against foreseeable difficulties. Dual testing for stage IV non-squamous, NSCLC patients has the potential to improve care and survival outcomes by providing access to the right test at the right time.
Evaluation of long-term TNFi effectiveness after a first switch in early axial spondyloarthritis considering time-varying prescription bias: an inverse-probability weighting analysis of the DESIR cohort
Authors: Pons Marion , Chevret Sylvie , Briot Karine , d’Agostino Maria-Antonietta , Roux Christian , Dougados Maxime , Molto Anna 
Published: January 2022

ObjectiveTo evaluate long-term effectiveness of tumour necrosis factor inhibitor (TNFi) after a first switch, and their associated factors in an early axial spondyloarthritis (axSpA) population, considering time-varying prescription bias.MethodsObservational prospective cohort (DEvenir des Spondylarthropathies Indifférenciées Récentes) with 5 years of follow-up, including 708 TNFi-naïve patients with early axSpA. Long-term effectiveness of TNFi after a first switch (ASAS40 response after at least 2 visits under treatment) were estimated using marginal structural models (implementing inverse-probability weighting and iterative propensity scores). Factors associated with the outcome were explored by multivariate Cox regression models.ResultsThe hazard to present an ASAS40 response after a first TNFi switch was increased (HR=2.4 (95% CI 1.9 to 3.0)); this response ratio was slightly lower compared with the response in TNFi naïve patients after a first TNFi (HR=3.3 (95% CI 2.9 to 3.8)). HLA-B27 positive was the only factor independently associated with ASAS40 response after a first TNFi switch.ConclusionAfter application of innovative methods to overcome time-varying prescription bias, the magnitude of the TNFi response after a first switch was found to be numerically lower but clinically relevant from the response in TNFi-naïve patients.