bluuebunny/crossref_metadata_2025_split huggingface dataset:
Unwarranted claims of drug efficacy in pharmaceutical sales visits: are drugs approved on the basis of surrogate outcomes promoted appropriately?
Authors: Habibi Roojin , Lexchin Joel , Mintzes Barbara , Holbrook Anne 
Published: June 2017

AimsThis study compares physicians' recall of the claims of benefits on cardiovascular disease and diabetes made by pharmaceutical sales representatives for drugs approved on the basis of a surrogate outcome, i.e., an off‐label claim, compared with those approved on the basis of a serious morbidity or mortality (clinical) outcome.MethodsPhysicians in primary care practices in Montreal, Vancouver, Sacramento and Toulouse, who saw sales representatives as part of their usual practice and served a non‐referral population, were contacted in blocks of 25 from a randomized list of all physicians practising in the relevant metropolitan area. We compared how frequently physicians reported that sales reps made claims of serious morbidity or mortality (clinically meaningful) benefits for drugs approved on the basis of surrogate outcomes vs. drugs approved on the basis of clinical outcomes.ResultsThere were 448 promotions for 58 unique brand name cardiovascular and diabetes drugs. Claims of clinically meaningful benefit were reported in 156 (45%) of the 347 promotions for surrogate outcome drugs, constituting unwarranted efficacy claims, i.e., off‐label promotion. Claims of clinical benefit were reported in 72 of the 101 promotions (71%) for drugs approved on the basis of clinical outcomes, adjusted OR = 0.3 (95% CI 0.2, 0.6), P < 0.001.ConclusionsClaims of efficacy made in sales visit promotions for drugs approved only on the basis of surrogate outcomes extended beyond the regulator‐approved efficacy information for the product in almost half of promotions. Unapproved claims of drug efficacy constitute a form of off‐label promotion and merit greater attention from regulators.
Cross‐sectional association of coffee and caffeine consumption with sex hormone‐binding globulin in healthy nondiabetic women
Authors: Pihan‐Le Bars Florence , Gusto Gaëlle , Boutron‐Ruault Marie‐Christine , Fagherazzi Guy , Bonnet Fabrice 
Published: June 2017

SummaryObjectiveLow sex hormone‐binding globulin (SHBG) is a consistent risk factor for type 2 diabetes, particularly in women. Coffee consumption has been associated with a lower risk of type 2 diabetes, but its effects on SHBG are less known.Design and methodsThis was a cross‐sectional study of 2377 nondiabetic pre‐ and postmenopausal women from the E3N cohort study whose baseline SHBG was measured. Information on diet (including coffee and caffeine consumption), lifestyle and medical conditions was collected through questionnaires. The relationship between coffee and caffeine consumption and SHBG was modelled, with adjustment for covariates and stratification by body mass index (BMI) categories (< or ≥25 kg/m2) and menopausal status.ResultsThe mean age was 57.2±6.4 years and 61% of the 2377 women were postmenopausal. High coffee (≥3 cups/day) and caffeine (≥265 mg/day) intakes were associated with a reduced risk of being in the 1st quartile of the SHBG level distribution (<46.3 nmol/L) in a multivariate adjusted model (OR: 0.72 [95% CI: 0.52‐1.01] and OR: 0.71 [95% CI: 0.53–0.95], respectively). No association was found between tea consumption and SHBG levels. In multivariate models stratified on BMI categories and menopausal status, associations were restricted to women with a BMI ≥25 kg/m2 or being postmenopausal. The association with SHBG was consistently noted with consumption of both caffeinated coffee and caffeine, but not decaffeinated coffee.ConclusionsConsumption of high coffee and caffeine is associated with a reduced risk of low SHBG, an established risk marker for T2DM, which might contribute to the protective effects of coffee for type 2 diabetes.
Effect of fatigue loading on the fracture strength and failure mode of lithium disilicate and zirconia implant abutments
Authors: Elsayed Adham , Wille Sebastian , Al‐Akhali Majed , Kern Matthias 
Published: June 2017

AbstractObjectiveThe aim of this study was to test five types of implant restorations using titanium, zirconia and lithium disilicate abutments after being subjected to long‐term fatigue loading.Materials and methodsForty single‐tooth implant restorations were assembled on titanium implants (FairTwo; FairImplant). The restorations differed only in the type of abutment used and were divided into five groups [Ti: titanium; Zr: zirconia with no metal base; ZrT: zirconia with titanium base; LaT: lithium disilicate abutment with titanium base; and LcT: lithium disilicate hybrid‐abutment–crown with titanium base]. Specimens were subjected to dynamic load of 49 N up to 1,200,000 cycles using a dual‐axis chewing simulator (Kausimulator; Willytech). The surviving specimens were subjected to quasi‐static loading using a universal testing machine (Z010; Zwick) until the implant–abutment connection failed. The values of force (N) at which fracture or plastic deformation of the restoration occurred were calculated and the rate of deformation was analyzed. The data was then analyzed using Mann–Whitney tests.ResultsGroups Ti, ZrT, LaT and LcT withstood 1,200,000 fatigue load cycles and higher forces than physiological occlusal forces without fracture or debonding of the ceramic suprastructure. In group Zr, some specimen did not survive the chewing simulation and this group showed the lowest resistance to failure with a median of 198 N.ConclusionsWithin the limitations of this study, it could be concluded that lithium disilicate abutments and hybrid‐abutment–crowns show promising durability and strength after long‐term dynamic loading. The use of titanium base enhances the strength of the zirconia abutments.
Rapid screening for malignancy in organ donors: 15‐year experience with the Verona “Alert” protocol and review of the literature
Authors: Eccher Albino , Cima Luca , Ciangherotti Andrea , Montin Umberto , Violi Paola , Carraro Amedeo , Tedeschi Umberto , Nacchia Francesco , Fior Francesca , Rostand Momo , Boschiero Luigino , D'Errico Antonietta , Scarpa Aldo , Casartelli‐Liviero Marilena , Ferrari Giuseppe , Rodini Viviana , Tomaselli Elisabetta , Zampicinini Laura , Vanzo Francesca , Bovo Chiara , Feltrin Giuseppe , Neil Desley , Brunelli Matteo 
Published: June 2017

AbstractBackgroundPrevention of transmission of malignancy from donors to recipients is an aim of donor assessment. We report the most stringent interpretation of the Italian National Guidelines.MethodsA two‐step ALERT process was used: ALERT1 consisting of clinical, radiological, and laboratory tests; ALERT2, consisting of intraoperative assessment in suspicious lesions.ResultsFour hundred of 506 potential deceased donors entered the ALERT system. Forty‐one of 400 (10%) donors were excluded due to unacceptable risk of transmission. Of the remaining 359 193 required histopathology, which excluded malignancy or determined acceptable risk in 161/193 (83%). Thirty‐five malignancies were identified: 19 (54%) at ALERT1, four (11%) at ALERT2, nine (26%) picked up at ALERT1 and confirmed by ALERT2. Three (9%) were missed by ALERT and diagnosed at postmortem examination. Prostate (n=12%, 34%) and renal cell (n=7%, 20%) were the most frequent carcinomas. The majority (92%) of prostate adenocarcinomas were of low risk and donation proceeded compared to 43% of renal carcinomas. Four renal carcinomas, two breast carcinomas, and a single case of nine different malignancies excluded donation.Positive ALERT donors had statistically more malignant reports than negative ALERT donors (P=<.05).ConclusionHistopathology is an essential component of the multidisciplinary assessment of donors.
Chemogenetic inhibition reveals midline thalamic nuclei and thalamo‐accumbens projections mediate cocaine‐seeking in rats
Authors: Wunsch Amanda M. , Yager Lindsay M. , Donckels Elizabeth A. , Le Calvin T. , Neumaier John F. , Ferguson Susan M. 
Published: June 2017

AbstractDrug addiction is a chronic disease that is shaped by alterations in neuronal function within the cortical–basal ganglia‐thalamic circuit. However, our understanding of how this circuit regulates drug‐seeking remains incomplete, and relapse rates remain high. The midline thalamic nuclei are an integral component of the cortical–basal ganglia‐thalamic circuit and are poised to mediate addiction behaviors, including relapse. It is surprising that little research has examined the contribution of midline thalamic nuclei and their efferent projections in relapse. To address this, we expressed inhibitory, Gi/o‐coupled DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) in a subset of the midline thalamic nuclei or in midline thalamic nuclei neurons projecting to either the nucleus accumbens or the amygdala. We examined the effect of transiently decreasing activity of these neuronal populations on cue‐induced and cocaine‐primed reinstatement of cocaine‐seeking. Reducing activity of midline thalamic nuclei neurons attenuated both cue‐induced and cocaine‐primed reinstatement, but had no effect on cue‐induced reinstatement of sucrose‐seeking or locomotor activity. Interestingly, attenuating activity of efferent projections from the anterior portion of midline thalamic nuclei to the nucleus accumbens blocked cocaine‐primed reinstatement but enhanced cue‐induced reinstatement. Decreasing activity of efferent projections from either the posterior midline thalamic nuclei to the nucleus accumbens or the midline thalamic nuclei to amygdala had no effect. These results reveal a novel contribution of subsets of midline thalamic nuclei neurons in drug‐seeking behaviors and suggest that modulation of midline thalamic nuclei activity may be a promising therapeutic target for preventing relapse.
Human papillomavirus‐related carcinoma with adenoid cystic‐like features: a series of five cases expanding the pathological spectrum
Authors: Hang Jen‐Fan , Hsieh Min‐Shu , Li Wing‐Yin , Chen Jo‐Yu , Lin Shih‐Yao , Liu Shih‐Hao , Pan Chin‐Chen , Kuo Ying‐Ju 
Published: June 2017

AimsHuman papillomavirus (HPV)‐related carcinoma with adenoid cystic‐like features is a newly described entity of the sinonasal tract. In this study, we evaluated histomorphology, immunophenotype and molecular testing to identify potentially helpful features in distinguishing it from classic adenoid cystic carcinoma (AdCC).Methods and resultsWe retrospectively collected five HPV‐related carcinomas with adenoid cystic‐like features and 14 AdCCs of the sinonasal tract. All histological slides were retrieved for morphological evaluation. As comparing with AdCC, HPV‐related carcinomas with adenoid cystic‐like features were associated with squamous dysplasia of surface epithelium (80% versus 0%, P < 0.01) and the presence of a solid growth pattern (100% versus 29%, P = 0.01), but less densely hyalinized tumour stroma (20% versus 86%, P = 0.02). Squamous differentiation in the invasive tumour was seen in three HPV‐related carcinomas with adenoid cystic‐like features, two of them showing abrupt keratinization and one with scattered non‐keratinizing squamous nests. Diffuse p16 staining in ≥75% of tumour cells was noted in all HPV‐related carcinomas with adenoid cystic‐like features but in only one AdCC (100% versus 7%, P < 0.01). High‐risk HPV testing gave positive results in all HPV‐related carcinomas with adenoid cystic‐like features (four associated with type 33 and one associated with type 16) but not in AdCCs. MYB rearrangement was tested in four HPV‐related carcinomas with adenoid cystic‐like features, and all were negative.ConclusionsThis study has further clarified the histological spectrum of this tumour type, and reports the first HPV type 16‐related case. Diffuse p16 staining followed by HPV molecular testing is useful in distinguishing HPV‐related carcinomas with adenoid cystic features from classic AdCCs.
Microguided Endodontics: a method to achieve minimally invasive access cavity preparation and root canal location in mandibular incisors using a novel computer‐guided technique
Authors: Connert T. , Zehnder M. S. , Amato M. , Weiger R. , Kühl S. , Krastl G. 
Published: June 2017

AbstractAimTo present a novel miniaturized and minimally invasive treatment approach for root canal localization in mandibular incisors with pulp canal calcification and apical periodontitis.SummaryA 51‐year‐old male patient presented with pain from his mandibular incisors. The patient had a history of severe dental trauma over 30 years ago. Both mandibular central incisors (teeth 31, 41) were tender to percussion and had a yellowish discoloration. They did not respond to thermal and electrical sensitivity tests. Two periapical radiographs from different projections revealed severe pulp canal calcifications and signs of periapical periodontitis. To facilitate the ‘Microguided Endodontics’ technique, a CBCT and an intra‐oral surface scan were aligned using special software. This allowed the virtual planning of optimal access cavities up to the apical third of the root. In this technique, a 3D‐printed template guides a customized drill to the orifice of the root canal. After negotiation of the root canals, conventional root canal treatment was performed. This case report demonstrates that minimally invasive and apically extended access cavities are feasible in mandibular incisors with this technique.Key learning points

The ‘Microguided Endodontics’ technique is a safe and minimally invasive method for root canal location and prevention of technical failures in anterior teeth with pulp canal calcification.
Video instruction with explanation to another person for intellectually disabled students
Authors: Blik H. , Harskamp E.G. , van Leeuwen S. , Hoekstra R. 
Published: June 2017

AbstractIntellectually disabled (ID) students in secondary education are often taught in an individual setting where video instruction is used. Especially, when the instruction is about complex assignments, many students may forget parts of it. In this study, we tried to find out if prompting ID students to explain video instruction would help them to improve their performance. Research with regular students indicated that explaining instructional materials can be effective (Roy & Chi, 2005).In a first experiment with 41 ID students in Dutch secondary education, we varied the complexity of assignments and compared students who first watched and then explained video instruction of assignments (n=21) with students who watched twice but were not required to explain (n=20). It turned out that only for complex assignments, explaining to another person was more effective for students' task performance than just watch video instruction.In the second experiment with 58 ID students, we repeated the study with complex assignments. The students in the experimental group (n=29) improved more after explaining video instructions than the students who only watched videos (n=29). The experimental group also had a more complete mental representation of an assignment and could better assess how well they had performed it.
Vitamin D3 ameliorates podocyte injury through the nephrin signalling pathway
Authors: Trohatou Ourania , Tsilibary Effie‐Fotini , Charonis Aristidis , Iatrou Christos , Drossopoulou Garyfalia 
Published: June 2017

AbstractRenal podocytes form the main filtration barrier possessing unique phenotype maintained by proteins including podocalyxin and nephrin, which are modulated in pathological conditions. In diabetic nephropathy (DN), podocytes become structurally and functionally compromised. Nephrin, a structural backbone protein of the slit diaphragm, acts as regulator of podocyte intracellular signalling with renoprotective role. Vitamin D3 through its receptor, VDR, provides renal protection in DN but limited data exist about its effect on podocytes. In this study, we used isolated rat glomeruli to assess podocalyxin and nephrin expression after treatment with the 1,25‐dihydroxyvitamin D3 analogue paricalcitol in the presence of normal and diabetic glucose levels. The role of 1,25‐dihydroxyvitamin D3 (calcitriol) and its analogue, paricalcitol, on podocyte morphology and survival was also investigated in the streptozotocin (STZ)‐diabetic animal model. In our ex vivo model, glomeruli exhibited high glucose‐mediated down‐regulation of podocalyxin, and nephrin, while paricalcitol reversed the high glucose‐induced decrease of nephrin and podocalyxin expression. Paricalcitol treatment enhanced VDR expression and promoted VDR and RXR co‐localization in the nucleus. Our data also indicated that hyperglycaemia impaired survival of cultured glomeruli and suggested that the implemented nephrin down‐regulation was reversed by paricalcitol treatment, initiating Akt signal transduction which may be involved in glomerular survival. Our findings were further verified in vivo, as in the STZ‐diabetic animal model, calcitriol and paricalcitol treatment resulted in significant amelioration of hyperglycaemia and restoration of nephrin signalling, suggesting that calcitriol and paricalcitol may provide molecular bases for protection against loss of the permselective renal barrier in DN.
Social isolation stress and chronic glutathione deficiency have a common effect on the glutamine‐to‐glutamate ratio and myo‐inositol concentration in the mouse frontal cortex
Authors: Corcoba Alberto , Gruetter Rolf , Do Kim Q. , Duarte João M.N. 
Published: June 2017

AbstractEnvironmental stress can interact with genetic predisposition to increase the risk of developing psychopathology. In this work, we tested the hypothesis that social isolation stress interacts with impaired glutathione synthesis and have cumulative effects on the neurochemical profile of the frontal cortex. A mouse model with chronic glutathione deficit induced by knockout (−/−) of the glutamate‐cysteine ligase modulatory subunit (Gclm) was exposed to social isolation stress from weaning to post‐natal day 65. Using magnetic resonance methods at high‐field (14.1 T), we analysed the neurochemical profile in the frontal cortex, brain size and ventricular volume of adult animals. Glutathione deficit was accompanied by elevated concentrations of N‐acetylaspartate, alanine, and glutamine, as well as the ratio of glutamine‐to‐glutamate (Gln/Glu), and by a reduction in levels of myo‐inositol and choline‐containing compounds in the frontal cortex of −/− animals with respect to wild‐type littermates. Although there was no significant interaction between social isolation stress and glutathione deficiency, mice reared in isolation displayed lower myo‐inositol concentration (−8.4%, p < 0.05) and larger Gln/Glu (+7.6%, p < 0.05), relative to those in group housing. Furthermore, glutathione deficiency caused a reduction in whole brain volume and enlargement of ventricles, but social isolation had no effect on these parameters. We conclude that social isolation caused neurochemical alterations that may add to those associated to impaired glutathione synthesis.
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Temperature variation, bacterial diversity and fungal infection dynamics in the amphibian skin
Authors: Longo Ana V. , Zamudio Kelly R. 
Published: June 2017

AbstractHost‐associated bacterial communities on the skin act as the first line of defence against invading pathogens. Yet, for most natural systems, we lack a clear understanding of how temperature variability affects structure and composition of skin bacterial communities and, in turn, promotes or limits the colonization of opportunistic pathogens. Here, we examine how natural temperature fluctuations might be related to changes in skin bacterial diversity over time in three amphibian populations infected by the pathogenic fungus Batrachochytrium dendrobatidis (Bd). Our focal host species (Eleutherodactylus coqui) is a direct‐developing frog that has suffered declines at some populations in the last 20 years, while others have not experienced any changes. We quantified skin bacterial alpha‐ and beta‐diversity at four sampling time points, a period encompassing two seasons and ample variation in natural infections and environmental conditions. Despite the different patterns of infection across populations, we detected an overall increase in bacterial diversity through time, characterized by the replacement of bacterial operational taxonomic units (OTUs). Increased frog body temperatures possibly allowed the colonization of bacteria as well as the recruitment of a subset of indicator OTUs, which could have promoted the observed changes in diversity patterns. Our results suggest that natural environmental fluctuations might be involved in creating opportunities for bacterial replacement, potentially attenuating pathogen transmission and thus contributing to host persistence in E. coqui populations.
Cis‐regulatory evolution in a wild primate: Infection‐associated genetic variation drives differential expression of MHC‐DQA1 in vitro
Authors: Simons Noah D. , Eick Geeta N. , Ruiz‐Lopez Maria J. , Omeja Patrick A. , Chapman Colin A. , Goldberg Tony L. , Ting Nelson , Sterner Kirstin N. 
Published: June 2017

AbstractFew studies have combined genetic association analyses with functional characterization of infection‐associated SNPs in natural populations of nonhuman primates. Here, we investigate the relationship between host genetic variation, parasitism and natural selection in a population of red colobus (Procolobus rufomitratus tephrosceles) in Kibale National Park, Uganda. We collected parasitological, cellular and genomic data to test the following hypotheses: (i) MHC‐DQA1 regulatory genetic variation is associated with control of whipworm (Trichuris) infection in a natural population of red colobus; (ii) infection‐associated SNPs are functional in driving differential gene expression in vitro; and (iii) balancing selection has shaped patterns of variation in the MHC‐DQA1 promoter. We identified two SNPs in the MHC‐DQA1 promoter, both in transcription factor binding sites, and both of which are associated with decreased control of Trichuris infection. We characterized the function of both SNPs by testing differences in gene expression between the two alleles of each SNP in two mammalian cell lines. Alleles of one of the SNPs drove differential gene expression in both cell lines, while the other SNP drove differences in expression in one of the cell lines. Additionally, we found evidence of balancing selection acting on the MHC‐DQA1 promoter, including extensive trans‐species polymorphisms between red colobus and other primates, and an excess of intermediate‐frequency alleles relative to genome‐wide, coding and noncoding RADseq data. Our data suggest that balancing selection provides adaptive regulatory flexibility that outweighs the consequences of increased parasite infection intensity in heterozygotes.