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Background:Several large randomised controlled trials (RCTs) in primary Sjögren’s syndrome (pSS) failed to demonstrate drug efficacy.1-4 Many of these trials used ESSDAI as primary endpoint, showing large but similar response rates in active treatment and placebo groups.1,3,4 Given the heterogeneous nature of pSS, there is need for a composite endpoint including multiple clinically relevant parameters.Objectives:To develop and validate the Composite of Relevant Endpoints in Sjögren’s Syndrome (CRESS).Methods:A multidisciplinary team of pSS experts selected clinically relevant items and measurements to include in the CRESS. Definition of response of CRESS items was based on clinical relevance, previously defined minimal clinically important improvement (MCII) and data of the single-centre ASAP-III (abatacept) trial.1 CRESS was validated in three independent RCTs: TRACTISS (rituximab) trial2, multi-centre abatacept trial3 and ETAP (tocilizumab) trial4. CRESS response rates were assessed at the primary endpoint visit of all four trials.Results:Five complementary items were selected to form CRESS: systemic disease activity, patient-reported symptoms, tear gland, salivary gland and serological item. Definition of response per item is presented in Table 1. Total CRESS response was defined as response on ≥3 of 5 items. Since not all trials have ocular staining score or salivary gland ultrasonography (SGUS) available, the concise CRESS (cCRESS) was developed simultaneously, leaving Schirmer’s test and unstimulated whole saliva flow for the tear and salivary gland items, respectively. In the ASAP-III trial, CRESS response rates were 24/40 (60%) for abatacept vs. 7/39 (18%) for placebo at week 24 (pTable 1.CRESS items and definition of responseItemsMeasurementsDefinition of responseSystemic disease activityClinESSDAIScorePatient-reported symptomsESSPRIDecrease of ≥1 point or ≥15%Tear gland*Schirmer/OSS**-If abnormal Schirmer (≤5 mm) at baseline: increase of ≥5 mm in Schirmer-Or if abnormal OSS (≥3 points) at baseline: decrease ≥2 points in OSS-Or if both Schirmer/OSS normal scores at baseline: no change to abnormal in bothSalivary gland*UWS/SGUSIncrease of ≥25% in UWS (or if score is 0 at baseline, any increase)Or decrease of ≥25% in total Hocevar score (SGUS)SerologicalRF/IgGDecrease of ≥25% in RFOr decrease of ≥10% in IgGCRESS responderResponder on ≥3 of 5 itemsOcular Staining Score (OSS), Unstimulated whole salivary flow (UWS), Salivary gland ultrasonography (SGUS), Rheumatoid factor (RF), Immunoglobuline G (IgG)*Concise CRESS (cCRESS): CRESS without OSS and SGUS, leaving Schirmer and UWS for tear and salivary gland items, respectively**Mean of both eyesIn the external validation trials, cCRESS response rates for TRACTISS were: 33/67 (49%) rituximab vs. 20/66 (30%) placebo at week 48 (p=0.026). CRESS response rates (without SGUS) for the multi-centre abatacept trial were: 41/92 (45%) abatacept vs. 30/95 (32%) placebo at week 24 (p=0.067). cCRESS response rates (without rheumatoid factor) for ETAP were: 10/55 (18%) tocilizumab vs. 13/55 (24%) placebo at week 24 (p=0.482) (Figure 1A-D). Compared to ESSDAI MCII of ≥3 points decrease, CRESS was able to approximately halve placebo response rates in RCTs with high baseline ESSDAI scores (>5) (Figures 1E-H).Conclusion:CRESS shows lower placebo response rates compared to ESSDAI MCII, which is crucial for demonstrating treatment efficacy. With the CRESS, higher response rates in abatacept and rituximab treated patients compared to placebo were found in RCTs which previously showed negative primary endpoint results. CRESS confirmed that no differences were found for almost all outcome measures between tocilizumab and placebo,4 with low response rates. The CRESS is a well-balanced, feasible, composite endpoint for use in clinical trials in pSS patients.References:[1]Van Nimwegen 2020;9913(19):1–11[2]Bowman 2017;69(7):1440–50[3]Baer (doi:218599)[4]Felten (doi:21846)Acknowledgements:The authors would like to acknowledge all contributors of the included trials.Disclosure of Interests:Suzanne Arends: None declared, Liseth de Wolff: None declared, Jolien F. van Nimwegen Speakers bureau: Bristol Myers Squibb, Consultant of: Bristol Myers Squibb, Gwenny M. Verstappen: None declared, Jelle Vehof: None declared, Michele Bombardieri Consultant of: MedImmune, GlaxoSmithKline, Grant/research support from: MedImmune, Simon J. Bowman Consultant of: AstraZenecea/MedImmune, Bristol Myers Squibb, Celgene, Eli Lilly, Glenmark, GlaxoSmithKline, MTPharma, Novartis, Ono, Pfizer, Takeda, UCB, XTLBio, Elena Pontarini: None declared, Alan Baer Consultant of: Bristol Myers Squibb, Sanofi, VielaBio, Novartis, Marleen Nys Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Jacques-Eric Gottenberg Grant/research support from: Bristol Myers Squibb, Pfizer, Renaud FELTEN: None declared, Neelanjana Ray Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Arjan Vissink: None declared, Frans G.M. Kroese Speakers bureau: Bristol Myers Squibb, Roche and Janssen-Cilag, Consultant of: Bristol Myers Squibb, Grant/research support from: Unrestricted grants from Bristol Myers Squibb, Hendrika Bootsma Speakers bureau: Bristol Myers Squibb and Novartis, Consultant of: Bristol Myers Squibb, Roche, Novartis, Medimmune, Union Chimique Belge, Grant/research support from: Unrestricted grants from Bristol Myers Squibb and Roche

Introduction Les alleles HLA-DRB1 contenant l’epitope partage (EP), fortement associes a la PR, existent chez 70 a 80 % des patients (pts) ayant une PR et seropositifs aux anticorps anti-proteines citrullinees (ACPA+). Les reponses au traitement (tt) a 24 semaines ont ete numeriquement plus elevees avec abatacept (ABA) vs adalimumab (ADA) chez les pts PR immunopositifs, essentiellement chez les EP+. Le but de cette analyse est d’evaluer prospectivement la relation entre l’EP HLA-DRB1 et l’activite de la PR suite au passage de l’ADA vers l’ABA apres 24 semaines chez les pts naifs de biologiques et ayant une PR recente active. Patients et methodes L’etude ( NCT02557100 ) a inclus des pts ACPA+ ayant une PR recente (≤ 12 mois) moderee a severe (ACR/EULAR 2010). Les pts etaient randomises pour recevoir l’ABA SC 125 mg/semaine ou a l’ADA 40 mg toutes les 2 semaines (+ MTX oral stable une fois par semaine, dans les 2 bras) pendant 24 semaines en simple aveugle. A la semaine 28, les pts sous ADA sont passes a ABA en ouvert suite a un wash out de 6 semaines (bras de switch) ; les pts sous ABA ont continue leur tt en ouvert (bras sans switch). Les pts etaient groupes selon le statut EP HLA-DRB1 (−, sans allele EP ; + ≥ 1 allele EP). L’efficacite a ete evaluee a 48 semaines selon les taux de reponses ACR 20/50/70 et de remission DAS28 (CRP). La tolerance a ete evaluee pendant l’etude et jusqu’a 8 semaines apres la derniere dose. Resultats Quarante pts sous ABA et 36 sur 40 sous ADA sont rentres dans la periode de switch vers ABA en ouvert ; 3 pts (2 pour perte de vue ; 1 autre) et un pt (demande d’arret de tt) ont interrompu respectivement cette periode. Les caracteristiques a l’inclusion etaient comparables ; la duree moyenne (SD) de la PR etait 5,5 (2,6) mois. Les reponses les plus importantes atteintes avec ABA vs ADA a 24 semaines ont ete maintenues a 48 semaines dans le bras sans switch ; dans le bras de switch, les reponses ont augmente pendant le switch jusqu’en semaine 48. Plus precisement, dans la population generale ( Fig. 1 ) et dans la sous-population EP+ ( Fig. 2 ), les taux de reponse ACR 20/50 et de remission DAS28 (CRP) ont ete similaires entre les 2 bras a 48 semaines ; le taux de reponse ACR70 etait numeriquement plus eleve dans le bras sans switch. Dans la sous-population EP−, a 24 semaines, les taux de reponse ACR50 dans les bras sans et avec switch etaient respectivement 56 % et 44 % ; a 48 semaines, 56 % et 67 % des pts dans les bras sans et avec switch ont atteint respectivement une reponse ACR50. Cependant, les donnees de la sous-population EP− doivent etre interpretees avec precaution en raison du faible nombre de pts (n = 9/bras). Aucun nouvel evenement indesirable n’a ete signale. Conclusion Dans la population seropositive atteinte de PR recente, particulierement dans la sous-population EP+, des reponses d’efficacite elevees et soutenues ont ete observees avec ABA dans le bras sans switch therapeutique a la semaine 48 ; une tendance vers une amelioration etait observee dans le bras de switch de l’ADA vers l’ABA.

Background:Mechanistic differences between protein biologics are poorly understood.HLA-DRB1alleles containing the shared epitope (SE), which are strongly associated with RA, are present in 70–80% of anti-citrullinated protein antibody+ patients (pts) with RA.1Numerically higher efficacy responses with abatacept (ABA) vs adalimumab (ADA) were reported after 24 wks of treatment (Tx) in pts with early seropositive RA, specifically in SE+ pts.2Objectives:To prospectively explore the relationship betweenHLA-DRB1SE genotype and the effects on disease activity after switching from ADA to ABA after completing 24 wks of initial Tx in biologic-naïve pts with early active RA.Methods:This head-to-head exploratory trial (NCT02557100) enrolled seropositive (anti-cyclic citrullinated peptide 2+ and RF+) adults with early (≤12 mos of symptoms), moderate-to-severe RA (ACR/EULAR 2010 criteria). Pts were randomised 1:1 to SC ABA 125 mg/wk or SC ADA 40 mg every 2 wks (both with stable, oral MTX wkly) for 24 wks (single-blind period). At Wk 28, ADA-treated pts were switched to open-label (OL) ABA, following a 6-wk washout period (switch arm); ABA-treated pts continued treatment with ABA in an OL manner (non-switch arm). Pts were grouped by SE status based onHLA-DRB1genotype (−, no SE allele; +, ≥1 SE allele). Clinical efficacy was assessed to Wk 48 to determine the proportion of ACR20/50/70 responders and DAS28 (CRP) remitters in each arm. Safety was analysed throughout the trial and up to 8 wks post last dose.Results:All 40 ABA-treated and 36/40 ADA-treated pts entered the OL ABA period; 3 (lost to follow up n=2, other n=1) and 1 (pt request to discontinue) pts, respectively, discontinued during the OL period. Baseline characteristics were balanced2; mean (SD) RA duration was 5.5 (2.6) mos. The greater efficacy responses seen with ABA vs ADA to Wk 242were sustained at Wk 48 in the non-switch arm; in the switch arm, the efficacy responses generally increased over the OL period to Wk 48. Specifically, in both the overall population (Figure 1) and among SE+ pts (Figure 2), ACR20/50 response rates (RRs) and DAS28 (CRP) remission rates were similar between arms at Wk 48; ACR70 RR was still somewhat higher in the non-switch arm. Among SE− pts, ACR50 RRs were 56% in the non-switch arm vs 44% in the switch arm at Wk 24; at Wk 48, 56% of pts in the non-switch arm and 67% of pts in the switch arm achieved ACR50. However, data from the SE− subgroup must be interpreted with caution due to low pt numbers (n=9/arm). No new safety signals were identified.Conclusion:In this seropositive early RA population, particularly in the SE+ subgroup, a trend towards numerically higher and sustained efficacy responses by stringent definitions was seen in the abatacept non-switch arm at Wk 48; trends towards further improvement were observed in the adalimumab-to-abatacept switch arm.References:[1]Terao C, et al.Arthritis Rheumatol2015;67:1744–50.[2]Rigby W, et al.Ann Rheum Dis2019:78:abstract 263.Acknowledgments:Marianne Peluso (protocol manager); medical writing: Lola Parfitt (Caudex; funding: BMS)Disclosure of Interests:William Rigby Grant/research support from: Bristol-Myers Squibb, Consultant of: AbbVie, Bristol-Myers Squibb, Genentech, Pfizer, Jane Buckner Grant/research support from: Bristol-Myers Squibb, Janssen, S. Louis Bridges, Jr.: None declared, Marleen Nys Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, Sheng Gao Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, Martin Polinsky Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, Neelanjana Ray Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, Vivian Bykerk: None declared

Microcomputed tomography allows the true three-dimensional structure of bone to be assessed by a nondestructive analysis. This article describes how this technique has for the first time been applied to rat bone to determine the effects of aging, ovariectomy, and antiresorptive drugs on bone structure and how these results compare with those determined by histological and histomorphometric techniques. During the procedure, a micro X-ray source is directed toward the bone sample. Modifications in the X-ray beam induced by bone crystals are determined for a range of acquisitions before three-dimensional reconstruction of bone architecture is performed. Morphometric parameters determined were trabecular bone volume/tissue volume, trabecular number, and trabecular thickness. The results show that ovariectomy has a dramatic effect on rat bone structure. Following treatment with the bone resorption inhibitor tiludronate, the morphometric parameters were significantly improved. The results obtained with three-dimensional microcomputed tomography were in agreement with observations made using classical techniques. Microcomputed tomography should prove useful for evaluating the antiresorptive effects of bisphosphon-ates on bone architecture and in allowing between-drug comparisons.

The study aimed to examine the relationship between the subgingival flora around implants and their periodontal parameters. Plaque samples from 561 implants (297 patients) were analyzed by means of differential phase contrast microscopy and compared with the sample site's probing depth. bleeding tendency on probing, and plaque and gingivitis indices. If possible, one implant with deep and one with shallow pockets were selected within the same patient. The impact of the intraoral exposure time on the microbial composition around the implants was examined cross-sectionally, with the same group of patients. Only tendencies can be detected by the latter, and no concrete conclusions can be drawn. From the clinical parameters, increased probing depth was found to detrimentally increase the proportion of spirochetes and motile organisms, whereas the other parameters were found to be of minor importance. For partially edentulous patients only, there was a tendency for increased proportions of spirochetes and motile organisms the longer the intraoral exposure time. These observations emphasize the importance of the periodontal health of the remaining teeth (as a reservoir of pathogenic micro organisms) in partial edentulous patients rehabilitated by means of implants and indicate the importance of shallow pockets around imnlants (flan trimming when aesthetics and phonetics allow).

The Periotest device was used to evaluate the damping characteristics of different bone-to-implant interfaces of Branemark implants. Implant and abutment lengths were found to have a significant influence on Periotest value (PTV). There was no statistical difference between PTVs of implants located in the anterior and posterior areas of the same jaw at abutment connection. No differences were found between PTVs of standard and self-tapping implants. PTVs at abutment connection were highly influenced by the bone quality. The contact with two corticals, one at each extremity of the implant, was of a greater influence in the maxillary than in the mandibular jaw, indicating a firmer anchorage between the bi-cortical implants and the surrounding bone. A progressive decrease of PTVs over time was observed, significant up to 5 years of loading.

1. Selection for leanness by selecting for food conversion (FC‐line) or selection for rapid growth and, thus, a concomitant fat increase (GL line) has also resulted in a lower egg laying rate of the fat birds. In birds of both lines that were effectively laying, plasma progesterone (P4), but not oestradiol concentrations were significantly different, with the lower concentration found in the GL line. This difference could not be attributed to differences in follicle population because this was similar in both groups of selected birds. 2. The in vivo decreased P4 secretion was investigated in vitro using granulosa cells of Fl follicles in a primary cell culture system. Basal P4 secretion tended to be lower in the GL line, whereas LH stimulation resulted in a diminished difference between the two lines. This was mainly caused by a higher relative P4 increase in the GL‐line. 3. Pre‐incubation with FSH increased the LH stimulated P4 secretion equally in both lines, probably through an increase of LH ...

For a long time, it has been recognized that the effects of excessive production of reactive oxygen species leading to oxidative stress are damaging to cellular constituents with subsequent tissue necrosis. There is now evidence that reactive oxygen species can alter cell functions by acting as ‘second messengers’ [1] or by affecting proteins of the signal transduction pathway that leads to gene expression or to apoptosis [2–4]. But many questions remain about the role of reactive oxygen and nitrogen compounds: how and where do they act? Do they act by themselves or by way of secondary products like nitroso- or nitrated compounds, oxidized forms of thiol compounds such as GSSG (the oxidized form of gluthatione), α,β-unsaturated aldehydes or carbonylated proteins? Do they alter specific proteins of the signal transduction pathway or intervene in Ca2+ metabolism? Do they act at the level of the nucleus by oxidation of thiol proteins involved in the activation of gene expression? Do specific reactive oxygen species (ROS) such as nitric oxide (NO) or peroxynitrite, have specific activity on selected biomolecules? And, above all else, what can be transposed from in vitro studies or laboratory models to in vivo situations?

To compare the anti-hypertensive efficacy, safety, and tolerability of irbesartan with those of the full dose range of enalapril in patients with mild-to-moderate hypertension.A total of 200 patients were randomised to irbesartan 75 mg or enalapril 10 mg (once daily). Doses were doubled at Weeks 4 and/or 8 if seated diastolic blood pressure (DBP) wasor = 90 mm Hg. Trough blood pressure was measured after completion of a 4- to 5-week placebo lead-in period and again after 2, 4, 8, and 12 weeks of treatment.Efficacy was evaluated by determining the change from baseline in trough seated blood pressure and the proportion of patients normalised (seated DBP90 mm Hg) at Week 12. Safety and tolerability were assessed by adverse events reported by physicians, by patients in response to a specific-symptoms questionnaire, by open-ended questioning of patients by physicians, and by clinical laboratory evaluations.Both treatments significantly lowered blood pressure with no significant difference in efficacy between treatment groups. At Week 12, the percentage of patients titrated to either enalapril 40 mg or irbesartan 300 mg was 24% and 28%, respectively. The frequency of overall adverse events was similar in both groups. The incidence of cough in the enalapril and irbesartan groups was 17% and 10%, respectively. In contrast to other AII receptor antagonists, there was no change in uric acid concentrations with irbesartan.Irbesartan was as effective as the full dose range of enalapril. Irbesartan also demonstrated an excellent tolerability profile.

The study aimed to examine the relationship between the subgingival flora around implants and their periodontal parameters. Plaque samples from 561 implants (279 patients) were analyzed by means of differential phase contrast microscopy and compared with the sample site's probing depth, bleeding tendency on probing, and plaque and gingivitis indices. If possible, one implant with deep and one with shallow pockets were selected within the same patient. The impact of the intraoral exposure time on the microbial composition around the implants was examined cross-sectionally, with the same group of patients. Only tendencies can be detected by the latter, and no concrete conclusions can be drawn. From the clinical parameters, increased probing depth was found to detrimentally increase the proportion of spirochetes and motile organisms, whereas the other parameters were found to be of minor importance. For partially edentulous patients only, there was a tendency for increased proportions of spirochetes and motile organisms the longer the intraoral exposure time. These observations emphasize the importance of the periodontal health of the remaining teeth (as a reservoir of pathogenic microorganisms) in partial edentulous patients rehabilitated by means of implants and indicate the importance of shallow pockets around implants (flap trimming when aesthetics and phonetics allow).

The hospital records of all the patients who underwent cholecystectomy because of specific biliary symptoms, between October 1990 and March 1993, were prospectively analyzed. The series consisted of 192 patients (159 women and 33 men), the mean age was 56 years and the mean body mass index was 26. Indication for surgery was uncomplicated gallstones in 113, common bile duct stones in 28 and cholecystitis in 51 patients. In those groups, respectively 94 (83%), 16 (57%) and 23 (45%) patients had a laparoscopic cholecystectomy. In total, laparoscopic cholecystectomy was successfully performed in 127 (95%) of the 133 patients in whom it was attempted. When compared with laparotomy, laparoscopic cholecystectomy was associated with shorter operative time: 88 +/- 41 min. (Mean +/- SD) versus 132 +/- 64 min. (p0,001), shorter postoperative hospital stay: 5 +/- 3 days versus 13 +/- 7 days (p0.001) and reduced cost of hospitalization: 103.301 +/- 51.062 BF versus 186.931 +/- 113.651 BF (p0.001). We noted an equivalent perioperative morbidity incidence in the two groups. The advantages of laparoscopy compared to laparotomy were recorded whatever the indication for cholecystectomy was. Therefore, with the increasing experience of surgeons and the improving quality of laparoscopic instruments, we think that laparoscopy can be considered for all patients requiring cholecystectomy.

The Periotest device was used to evaluate the damping characteristics of different bone-to-implant interfaces of Brånemark implants. Implant and abutment lengths were found to have a significant influence on Periotest value (PTV). There was no statistical difference between PTVs of implants located in the anterior and posterior areas of the same jaw at abutment connection. No differences were found between PTVs of standard and self-tapping implants. PTVs at abutment connection were highly influenced by the bone quality. The contact with two corticals, one at each extremity of the implant, was of a greater influence in the maxillary than in the mandibular jaw, indicating a firmer anchorage between the bi-cortical implants and the surrounding bone. A progressive decrease of PTVs over time was observed, significant up to 5 years of loading.

For several years, implant-supported overdentures have been used with excellent results in rehabilitation of the edentulous mandible. The effect on the antagonistic jaw bone resorption however, has not yet been evaluated. The aim of this study was to examine on orthopantomograms the anterior and posterior maxillary ridge resorption in three groups of patients with different mandibular prosthetic reconstructions: (1) overdentures supported by two implants, (2) fixed prostheses supported by four to six implants, and (3) complete dentures. The results indicated a more pronounced annual bone resorption in complete denture wearers compared to patients with implant-supported overdentures. A limited but continuing bone resorption was observed for the patients with implant-supported overdentures, and a slightly higher annual bone resorption occurred in the implant-supported fixed prosthesis group.

Although current statistical packages are convenient and powerful tools for statistical analysis, their usefulness in the planning stage of the experiment is limited. In this paper we describe a system that assists the user in building up a design with many possibilities to examine its properties and change them.

The aim of the present study was to evaluate the capability of the Periotest device in detecting and monitoring functional changes in the periodontal as well as in the pari-implant damping characteristics. In the first part of this study, 107 teeth were splinted by means of 40 full acrylic fixed prostheses (AFP) and another 37 teeth were splinted by means of 14 ceramometallic fixed prostheses (C-MFP). The Periotest measurements of individual teeth were done the day the fixed prostheses were cemented temporary (PTV 1), and again after a mean observation period of 27.4 days (PTV 2). In the 2nd part, 78 osseointegrated two-stage implants were splinted by means of 23 full acrylic fixed prosthesis (AFP) and other 18 implants were left without it. Using the same abutment length, Periotest measurements were performed, at abutment connections and before installation of the final prosthesis. In a 3rd part, using both implants and teeth as abutments, 29 osseointegrated implants were connected with 25 abutment teeth by means of 7 AFP. The measurements were performed at the beginning of the prosthetic treatment and 2, 4 and 6 weeks later. After splinting teeth by means of AFP for the observation period, no statistically significant reduction in PTVs was found. When on the other hand, a C-MFP was used, PTV 2 showed a significant reduction. The PTVs at abutment connection went down after a period of time, during which some implants were interconnected by means of an AFP and others were not.(ABSTRACT TRUNCATED AT 250 WORDS)

Summary. The effect of post preparation on the apical seal of endodontically treated specimens was studied. The canals prepared in bovine bone were instrumented and obturated using five obturation techniques: the silver point technique, the lateral condensation of gutta-percha technique, the warm vertical condensation of gutta-percha technique, the Hygenic Ultrafil injection system and the Obtura technique. In addition to these five control groups, the five experimental groups were also subjected to post preparation. In the latter group, the gutta-percha was removed with an engine-driven root canal reamer 48 hours after obturation. Both the control and experimental groups were suspended in a 0.5 per cent crystal violet solution for 48 hours. After dye penetration, the specimens were immersed in liquid nitrogen and then split longitudinally. Linear measurements of the resultant apical dye leakage were determined by image processing. For each obturation technique, all specimens in both the control and experimental groups were recorded if they showed leakage. Using Fisher's exact probability test, it was shown that there was no significant difference between the obturation techniques used.