bluuebunny/crossref_metadata_2025_split huggingface dataset:
A novel direct method to determine adherence to atorvastatin therapy in patients with coronary heart disease
Authors: Kristiansen Oscar , Vethe Nils T. , Fagerland Morten W. , Bergan Stein , Munkhaugen John , Husebye Einar 
Published: September 2019

AimsObjective methods to monitor statin adherence are needed. We have established a liquid chromatography–tandem mass spectrometry assay for quantification of atorvastatin and its metabolites in blood. This study aimed to develop an objective drug exposure variable with cut‐off values to discriminate among adherence, partial adherence and nonadherence to atorvastatin therapy in patients with coronary heart disease.MethodsTwenty‐five patients treated with atorvastatin 10 mg (n = 5), 20 mg (n = 6), 40 mg (n = 7) and 80 mg (n = 7) participated in a directly observed atorvastatin therapy study to confirm baseline adherence. After the directly observed therapy, half of the patients (test group) were instructed to stop taking atorvastatin and return for blood sample collection the subsequent 3 days. Levels of atorvastatin and metabolites were compared between the test group and the adherent control group.ResultsThe sum of parent drug and all measured primary metabolites correlated well with the atorvastatin dose administered (Spearman's rho = 0.71, 95% CI 0.44–0.87). The dose‐normalized atorvastatin plus metabolites concentrations completely separated the partially adherent test group from the controls at 0.18 nM/mg after 3 days without atorvastatin. To reduce the risk of misinterpreting adherent patients as partially adherent, a corresponding cut‐off at 0.10 nM/mg is proposed. A metabolite level of 2‐OH atorvastatin acid <0.014 nmol/L provided the optimal cut‐off for nonadherence.ConclusionA direct method to discriminate among adherence, partial adherence and nonadherence to atorvastatin therapy in patients with coronary heart disease has been developed. This tool may be important for novel studies on adherence and potentially useful in clinical practice.
Hearing screening outcome in neonatal intensive care unit graduates from a tertiary care centre in Singapore
Authors: Jayagobi Pooja Agarwal , Yeoh Annie , Hee Karen Y.M. , Sok Bee Lim Lim , Choo Khoo Poh , Kun Kiaang Henry Tan , Lazaroo Derek , Daniel Lourdes Mary 
Published: September 2019

AbstractBackgroundWe aimed to analyse the outcome of universal newborn hearing screening (UNHS) and high‐risk hearing screening in neonatal intensive care unit (NICU) graduates in a tertiary care unit.MethodsThe hearing screen programme comprises a 2‐stage automated auditory brainstem response protocol followed by a high‐risk hearing screen at 3–6 months. This study is a retrospective study of NICU graduates born between April 2002 and December 2009. Data on hearing screening, audiological assessment, and management were extracted from a computerized data management system (HITRACK).ResultsOf 100,225 newborn infants, 2.9% were admitted to the NICU during the study period. The overall incidence of hearing loss (HL) of any type/severity was 35/1,000 infants. Of infants with HL, 92.4% had their first automated auditory brainstem response at/before 1 month of corrected age. The incidence of congenital permanent HL identified by the UNHS was 15.4/1,000. The corrected median age of diagnosis was 4.5 months (1–23.5 months). Of 2,552 NICU graduates who passed the UNHS, 75.5% were retested at 3–6 months of life. Twelve infants with permanent late‐onset HL were identified, raising the overall incidence of permanent HL to 19.9/1,000; 1.1/1,000 had auditory neuropathy. Of the 92 infants with HL, 89 (96.7%) had multiple risk factors.ConclusionsThere is a high incidence of HL in NICU graduates; 22.6% were late in onset. An early rescreen in those who pass the UNHS is a beneficial step for this high risk population.
Mechanisms of Dupilumab
Authors: Harb Hani , Chatila Talal A. 
Published: September 2019

AbstractThe Th2 cytokines interleukin 4 (IL‐4) and IL‐13 and the heterodimeric IL‐4 receptor (IL‐4R) complexes that they interact with play a key role in the pathogenesis of allergic disorders. Dupilumab is a humanized IgG4 monoclonal antibody that targets the IL‐4 receptor alpha chain (IL‐4Rα), common to both IL‐4R complexes: type 1 (IL‐4Rα/γc; IL‐4 specific) and type 2 (IL‐4Rα/IL‐13Rα1; IL‐4 and IL‐13 specific). In this review, we detail the current state of knowledge of the different signalling pathways coupled to the IL‐4R complexes and examine the possible mechanisms of Dupilumab action and survey its clinical efficacy in different allergic disorders. The development of Dupilumab and the widening spectrum of its clinical applications is relevant to the current emphasis on precision medicine approaches to the blockade of pathways involved in allergic diseases.
What is the appropriate management of nonfunctioning pancreatic neuroendocrine tumours disclosed on screening in adult patients with multiple endocrine neoplasia type 1?
Authors: Challis Benjamin G. , Casey Ruth T. , Grossman Ashley , Newell‐Price John , Newey Paul , Thakker Rajesh V. 
Published: September 2019

AbstractMultiple endocrine neoplasia type 1 (MEN1) is an inherited tumour syndrome characterised by a predisposition to the development of endocrine tumours of the parathyroid glands, pituitary and pancreas: 30%‐80% of patients with MEN1 develop pancreatic neuroendocrine tumours (pNETs), with metastatic tumours and/or their sequelae contributing to increased morbidity and early mortality. The optimal management of nonfunctioning (NF) pNETs in MEN1 remains controversial. Whilst pancreatic resection is widely recommended for tumours >2 cm, for smaller tumours (≤2 cm) a well‐established consensus guiding the indications for surgical intervention does not exist. Although total pancreatectomy may be curative for some patients, both short‐ and long‐term complications make this an unsatisfactory option for many patients. For small (<2 cm) MEN1 NF‐pNETs, some clinicians advocate surveillance based largely on retrospective data that suggest 50%‐80% of these lesions are stable over time and infrequently exhibit accelerated growth rates. It is increasingly recognised, however, that NF‐pNETs exhibit unpredictable malignant behaviour that is not determined by tumour size alone, thereby prompting other clinicians to advocate surgery for all MEN1 NF‐pNETs, irrespective of size. Such uncertainty poses clinical management challenges with regards to the timing and extent of surgery, which is further hindered by the inability to stratify patients based on predicted tumour behaviour. It is therefore critical that future MEN1 research initiatives include: (a) the discovery of biomarkers that better predict tumour behaviour; (b) the evaluation of medical therapies that may delay, or even prevent, the need for pancreatic surgery; and, ultimately, (c) improvement in the quality of life for individuals with MEN1. Here, based on the published literature, we address the Clinical Question, ‘What is the management of NF‐pNETs disclosed on screening in adult patients with MEN1?’.
Trabecular micro‐bypass stent implantation with cataract extraction in pigmentary glaucoma
Authors: Ferguson Tanner J. , Ibach Mitch , Schweitzer Justin , Karpuk Kayla L. , Stephens John D. , Berdahl John P. 
Published: September 2019

AbstractImportanceUse of the trabecular micro‐bypass stent with cataract surgery is well established to be safe and effective in primary open‐angle glaucoma. This is the first study to exclusively evaluate use of the device in pigmentary glaucoma.BackgroundThis study aimed to investigate the safety and efficacy of a trabecular micro‐bypass stent in combination with cataract surgery in pigmentary glaucoma.DesignRetrospective, consecutive case series.ParticipantsTwenty‐four eyes of 12 patients with pigmentary glaucoma implanted with one trabecular micro‐bypass stent with concomitant cataract surgery.MethodsBaseline data was collected and compared to the following postoperative time points: 1 day, 1 week, 1 month out to 36 months (M36) after the procedure.Main Outcome MeasuresThese included intraocular pressure (IOP), number of glaucoma medications and need for additional surgery.ResultsAt M36 there was a 25% reduction in IOP to 14.68 ± 3.0 (P < .01) from 19.50 ± 6.7 mmHg at baseline. The mean number of glaucoma medications was 0.75 ± 1.0 prior to the surgery and 0.59 ± 0.6 (P > .05) at 36 M. At the 36 M time‐point, 95% of eyes had IOP ≤ 18 mmHg and 68% of eyes were ≤ 15 mmHg. No eyes underwent a secondary glaucoma procedure.Conclusions and RelevanceThe insertion of a single trabecular micro‐bypass stent in combination with cataract surgery effectively provides a sustained reduction in IOP up to 3 years after surgery in patients with pigmentary glaucoma. The safety profile is favourable with low rate of IOP spikes and no patients requiring additional surgery.
In vitro diagnostic accuracy of low‐dose CBCT for evaluation of peri‐implant bone lesions
Authors: Schwindling Franz Sebastian , Hilgenfeld Tim , Weber Dorothea , Kosinski Matthias Adalbert , Rammelsberg Peter , Tasaka Akinori 
Published: September 2019

AbstractObjectivesTo investigate the in vitro diagnostic accuracy of low‐dose cone‐beam computed tomography (LD‐CBCT) for the detection, classification, and measurement of peri‐implant bone lesions.Material and methodsTitanium dental implants with all‐ceramic single crowns (n = 24) were inserted into bovine bone. At twelve implants, four types of peri‐implant bone lesions were created. Radiographic imaging was performed using three techniques: LD‐CBCT, high‐definition CBCT (HD‐CBCT), and intraoral radiography (IR). The datasets were presented twice to four observers in a random order. Diagnostic accuracy was measured by calculating sensitivity and specificity, and analyzed using the McNemar's test at a significance level of 0.05. Absolute agreement between the defect sizes was assessed by means of intraclass correlation coefficients (ICC).ResultsFor all three techniques, diagnostic accuracy and reliability for the detection of defects were almost perfect. The following order was found for classification of the different defect types (sensitivity/specificity): HD‐CBCT (0.96/0.99) > LD‐CBCT (0.93/0.98) > IR (0.71/0.95). No significant difference was found between the two CBCT techniques. Their performance was superior to that of IR. With regard to absolute agreement of defect size, LD‐CBCT agreement with HD‐CBCT (ICC, 95% confidence interval) was slight for defect depth (0.342, 0.181–0.625) and substantial for defect width (0.911, 0.775–0.963).ConclusionIntraoral radiography is useful for detecting peri‐implant bone lesions. LD‐CBCT provides additional information regarding the geometry of defects. The even higher diagnostic accuracy of the HD‐CBCT protocol tested needs to be carefully weighed against its radiation dose, which is 14 times higher than that of LD‐CBCT.
Exploring the bi‐directional relationship between autophagy and Alzheimer’s disease
Authors: Kuang Huang , Tan Cheng‐Yong , Tian Hui‐Zhen , Liu Li‐Hua , Yang Mei‐Wen , Hong Fen‐Fang , Yang Shu‐Long 
Published: September 2019

AbstractAlzheimer's disease (AD) is characterized by β‐amyloid (Aβ) deposition and Tau phosphorylation, in which its pathogenesis has not been cleared so far. The metabolism of Aβ and Tau is critically affected by the autophagy. Abnormal autophagy is thought to be involved in the pathogenesis of AD, regulating autophagy may become a new strategy for AD treatment. In the early stage of AD, the presence of Aβ and Tau can induce autophagy to promote their clearance by means of mTOR‐dependent and independent manners. As AD progress, the autophagy goes aberrant. As a result, Aβ and Tau generate continually, which aggravates both autophagy dysfunction and AD. Besides, several related genes and proteins of AD can also adapt autophagy to make an effect on the AD development. There seems to be a bi‐directional relationship between AD pathology and autophagy. At present, this article reviews this relationship from these aspects: (a) the signaling pathways of regulating autophagy; (b) the relationships between the autophagy and the processing of Aβ; (c) Aβ and Tau cause autophagy dysfunction; (d) normal autophagy promotes the clearance of Aβ and Tau; (e) the relationships between the autophagy and both genes and proteins related to AD: TFEB, miRNAs, Beclin‐1, Presenilin, and Nrf2; and (f) the small molecules regulating autophagy on AD therapy. All of the above may help to further elucidate the pathogenesis of AD and provide a theoretical basis for clinical treatment of AD.
GIT1 regulates angiogenic factor secretion in bone marrow mesenchymal stem cells via NF‐κB/Notch signalling to promote angiogenesis
Authors: Li Linwei , Tang Pengyu , Zhou Zheng , Wang Qian , Xu Tao , Zhao Shujie , Huang Yifan , Kong Fanqi , Liu Wei , Cheng Lin , Zhou Zhimin , Zhao Xuan , Gu Changjiang , Luo Yongjun , Tao Gaojian , Qian Dingfei , Chen Jian , Fan Jin , Yin Guoyong 
Published: September 2019

AbstractObjectivesOsteogenesis is coupled with angiogenesis during bone remodelling. G‐protein‐coupled receptor (GPCR) kinase 2‐interacting protein‐1 (GIT1) is an important protein that participates in fracture healing by regulating angiogenesis. This study investigated whether GIT1 could affect bone mesenchymal stem cells (BMSCs) to secrete angiogenic factors to enhance fracture healing by promoting angiogenesis and its possible mechanism.Materials and methodsThe angiogenesis of mice post‐fracture was detected by micro‐CT and immunofluorescence. Subsequently, vascular endothelial growth factor (VEGF) level in mouse and human BMSCs (hBMSCs) under TNF‐α stimulation was detected. The hBMSCs were transfected with GIT1 shRNAs to further explore the relationship between GIT1 and VEGF and angiogenesis in vitro. Furthermore, based on previous research on GIT1, possible signal pathways were investigated.ResultsGIT1 knockout mice exhibited impaired angiogenesis and delayed fracture healing. And GIT1 deficiency remarkably reduced the expression of VEGF mRNA in BMSCs, which affected the proliferation and migration of human umbilical vein endothelial cells. GIT1 knockdown inhibited the activation of Notch and NF‐κB signals by decreasing nuclear transportation of NICD and P65/P50, respectively. Overexpression of the canonical NF‐κB subunits P65 and P50 markedly increased NICD‐dependent activation of recombination signal‐binding protein‐jκ reporter. Finally, GIT1 enhanced the affinity of NF‐κB essential modulator (NEMO) for K63‐linked ubiquitin chains via interaction with NEMO coiled‐coil 2 domains.ConclusionThese data revealed a positive role for GIT1 by modulating the Notch/NF‐κB signals which promoting paracrine of BMSCs to enhance angiogenesis and fracture healing.
Ant–hemipteran association decreases parasitism of Phenacoccus solenopsis by endoparasitoid Aenasius bambawalei
Authors: Xu Chong , Li Qiuling , Qu Xiaobin , Chen Jian , Zhou Aiming 
Published: September 2019

1. Mutualism between ants and honeydew‐excreting hemipterans is ubiquitous in the ecosystem. It is widely accepted that ant tending facilitates the colony growth of hemipterans by protecting them from predators and parasitoids. However, few studies have explored how ant tending helps defend against natural enemies.2. Ghost ant Tapinoma melanocephalum and the invasive mealybug Phenacoccus solenopsis have a close mutual relationship. Previous studies have shown that ghost ant tending can definitely reduce parasitism and visit frequency of Aenasius bambawalei, the dominant endoparasitoid of P. solenopsis. However, the ghost ant workers seldom attack the parasitoids. It is still unclear how the ghost ant adversely affects parasitoids. This study explored the mechanism underlying the impacts of ants on natural enemies of the mealybugs.3. Honeydew produced by P. solenopsis was an attractant to A. bambawalei. Parasitoids exhibited less searching activity, shorter longevity and lower parasitism when supplied with less honeydew. Aenasius bambawalei showed significant avoidance of pygidial gland secretions and visual cues of ghost ants. Parasitism in plants treated with 6‐methyl‐5‐hepten‐2‐one, actinidine, and gland extracts was significantly lower than that in plants treated only with solvents (paraffin oil or double‐distilled water).4. It is concluded that honeydew consumption by ghost ants could negatively influence the performance of parasitoids. The pygidial gland secretions and visual cues of ghost ants also significantly inhibit the parasitism. These results may contribute to a better understanding of the regulation mechanism in ant–hemipteran–enemy interactions.
Determinants of pathways to care among young adults with early psychosis entering a coordinated specialty care program
Authors: Marino Leslie , Scodes Jennifer , Ngo Hong , Nossel Ilana , Bello Iruma , Wall Melanie , Dixon Lisa 
Published: September 2019

AbstractAimTo describe the characteristics of the pathway to coordinated specialty care for young adults with early psychosis in the United States, to examine how various factors correlate with the duration of untreated psychosis (DUP), and to explore factors associated with time from onset of symptoms to first mental health service contact (help‐seeking DUP).MethodsThe sample included 779 individuals ages 16 to 30 with recent‐onset non‐affective psychosis enrolled in OnTrackNY. Domains assessed included demographics, clinical characteristics, mental health service utilization and characteristics of the pathway to care. Primary outcomes included the time from onset of psychotic symptoms to admission to OnTrackNY (DUP) and time from onset of psychotic symptoms to first mental health service contact (help‐seeking DUP).ResultsThe mean DUP was 231.2 days (SD = 87.7, median = 169) and mean help‐seeking DUP was 73.7 days (SD = 110.8, median = 27). Being in school, better social functioning, and greater number of ER visits or hospitalizations were associated with shorter DUP. Violent ideation or behaviour and having an outpatient mental health visit as the first service contact or hallucinations as the reason for first service contact were significantly associated with longer DUP. Only the type of first service contact (outpatient mental health treatment or other non‐mental health service provider) and having hallucinations as the clinical reason for the first service contact were associated with help‐seeking DUP.ConclusionsReferral delays were longer than help‐seeking delays. Strategies to reduce treatment referral delays through systems‐level interventions may be most likely to reduce the overall DUP in this population.
Successful closed reduction and conservative management with traumatic elbow luxation and medial collateral ligament rupture in an equid
Authors: Collar E. M. , Watson L. J. , Whitmer C. , Hansen S. 
Published: September 2019

SummaryA 9‐year‐old donkey jenny (212 kg) presented with an acute, nonweight‐bearing left forelimb lameness of 24‐ to 36‐h duration. The limb was held in flexion and abduction, with the toe above the ground, and was unable to be manually straightened. There was significant palpable swelling along the medial aspect of the elbow joint. Radiographic evaluation revealed a medial luxation of the elbow joint with rupture of the medial collateral ligament. Closed reduction was accomplished under injectable anaesthesia without complication. The patient was weight‐bearing and comfortable on the limb immediately upon recovery from anaesthesia. The jenny was tied and kept standing for 60 days. Full limb bandages, splints (extending proximal to the scapula), hobbles,NSAIDs and cold laser therapy were utilised, decreased and discontinued. At 74 days, a rehab programme was initiated. At 8 months post‐injury, the patient was not lame and was back to her previous level of exercise. Although elbow luxation has been described as having a guarded prognosis, there has now been success in 4/5 (80%) reported cases when treatment has been attempted. Closed reduction without surgical intervention in adult animals with elbow luxation can be successful, likely dependent on the level of associated injury.
Increased expression of GAB1 promotes inflammation and fibrosis in systemic sclerosis
Authors: Shi Xiangguang , Liu Qingmei , Zhao Han , Lu Jiaying , Huang Yan , Ma Yanyun , Xia Jingjing , Liu Mengguo , Tu Wenzhen , Jin Li , Wang Jiucun , Zhao Yinhuan , Wu Wenyu 
Published: September 2019

AbstractSystemic sclerosis (SSc) is an autoimmune disease mainly characterized by persistent inflammation and fibrosis. The receptor tyrosine kinase (RTK) signal pathway plays an important role in the process of SSc, and Grb2‐associated binding protein (GAB) is crucial in activating RTK signalling. A previous study found elevated levels of GAB1 in bleomycin (BLM)‐induced fibrotic lungs, but the effects of GAB1 in SSc remain unclear. Our aim was to investigate whether GAB1 was dysregulated and its potential role in SSc. Compared with healthy donors, we found GAB1 expression was 1.6‐fold higher in peripheral blood mononuclear cells (PBMC), 2.5‐fold higher in CD4 + T cells, and 2‐fold higher in skin from of SSc patients (P < .01). At the same time, the levels of type one collagen (COLI) were also significantly increased (1.8‐fold higher) in SSc skin. Additionally, BLM‐induced SSc mice showed mRNA levels of Gab1 2‐fold higher than saline‐treated controls, and Gab1 expression correlated positively with collagen content. A further in vitro study showed silencing of GAB1 suppressed inflammatory gene expression in TNF‐α induced fibroblasts. Additionally, GAB1 deficiency prominently inhibited cell proliferation and reduced COLI protein levels in TGF‐β induced fibroblasts. Taken together, these data suggest that GAB1 has a relatively high expression rate in SSc, and knockdown of GAB1 may attenuate SSc by stimulating inflammatory and fibrotic processes.
Interleukin‐4 and interleukin‐13 evoke scratching behaviour in mice
Authors: Campion Michelle , Smith Leila , Gatault Solène , Métais Charles , Buddenkotte Jörg , Steinhoff Martin 
Published: September 2019

AbstractPersistent and relapsing itch commonly manifests in inflammatory skin disorders such as atopic dermatitis (AD). AD pathogenesis is driven by interleukin‐4 (IL‐4) and interleukin‐13 (IL‐13). Dupilumab, a monoclonal antibody blocking the action of IL‐4 and IL‐13 effectively reduces the symptoms of AD and itch. Little is known whether IL‐4 and IL‐13 directly contribute to itch transduction. A recently published study (Oetjen et al, Cell, 2017, 171, 217) found IL‐4 and IL‐13 to directly activate itch‐sensory neurons in vitro. Surprisingly, they found no significant increase in scratching after intradermally injecting high doses (2.5 ug/ml) of IL‐4 and IL‐13 into mice. Similar experiments in our lab, however, suggested that both IL‐4 and IL‐13 contribute to acute itch in vivo. We intradermally injected lower doses (1 ug/ml) of IL‐4 and IL‐13 into mice and found a significant increase of scratching bouts compared to vehicle. Interestingly, the combined treatment of IL‐4 and IL‐13 produced additive increase of scratching and acute pruritus at an earlier time point compared to each cytokine administered alone. In summary, our study shows a rapid and significant increase of scratching after intradermal injection of IL‐4, IL‐13 or combined IL‐4/ IL‐13 compared to vehicle in mice 5‐10 minutes after injection. Our data suggest that IL‐4 and IL‐13 alone and combined directly act as potent acute pruritogens on sensory nerves. This finding expands our understanding of cytokines as pruritogens, how targeted anticytokine medications act in AD, and about neuroimmune communication in the skin.