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In this case series, we present six cases with the initial complaint of pain and/or progressive unilateral pre-auricular swelling. All patients presented at our Department of Oral and Maxillofacial surgery from January 2000 to December 2018. CT and/or MRI revealed cystic lesions with a preferred diagnosis of synovial or ganglion cyst. In four patients, the cyst was surgically removed and anatomopathological findings confirmed the diagnosis of a synovial cyst in three patients and a ganglion cyst in one case. In one patient, the cyst disappeared after puncture biopsy. The last patient did not have significant complaints and was treated conservatively. Even though recurrence of ganglion cysts in the temporomandibular joint has not been described before, we observed a recurrent ganglion cyst after complete initial surgical removal in one of our cases. This occurred 3.5 years after the initial surgery.Due to the limited duration of follow-up in most case series, recurrence rates may be underestimated. This case series aims to raise awareness for the possible presence and recurrence of ganglion cysts and to thoroughly evaluate the symptoms before resection is considered. If a diagnosis of a synovial of ganglion cyst is suspected, a diagnostic workup should be performed. Surgical removal of the cyst is indicated in cases where the cyst is symptomatic and has an impact on daily life. Otherwise, a conservative treatment can be considered.

To address the question of whether translocation of bacterial lipopolysaccharide (LPS) into the blood could be involved in the process of exercise-induced polymorphonuclear neutrophil (PMN) activation, 12 healthy male subjects who took part in a sprint triathlon (1.5 km river swim, 40 km bicycle race, 10 km road race) were studied. While there was no detectable amount of endotoxin in the blood samples drawn at rest, exercise was followed by the appearance of circulating endotoxin molecules at the end of competition in four subjects, and after one and 24 h recovery in three and seven athletes, respectively. The concentrations of plasma granulocyte myeloperoxidase ([MPO]), were significantly higher immediately after exercise and one hour later than baseline values (P

Abstract Background Life-history theory predicts a trade-off between investment into immune defence and other fitness-related traits. Accordingly, individuals are expected to upregulate their immune response when subjected to immune challenge. However, this is predicted to come at the expense of investment into a range of other traits that are costly to maintain, such as growth, reproduction and survival. Currently, it remains unclear whether the magnitude of such costs, and trade-offs involving immune investment and other traits, manifests consistently across species and sexes. To address this, we conducted a meta-analysis to investigate how changes in sex, ontogenetic stage and environmental factors shape phenotypic trait expression following an immune challenge. Results We explored the effects of immune challenge on three types of traits across sexually reproducing metazoans: life-history, morphological and proximate immune traits (235 effect sizes, 53 studies, 37 species [21 invertebrates vs. 16 vertebrates]). We report a general negative effect of immune challenge on survival and reproduction, a positive effect on immune trait expression, but no effect on morphology or development time. The negative effects of immune challenge on reproductive traits and survival were larger in females than males. We also report a pronounced effect of the immune treatment agent used (e.g. whether the treatment involved a live pathogen or not) on the host response to immune challenge, and find an effect of mating status on the host response in invertebrates. Conclusion These results suggest that costs associated with immune deployment following an immune challenge are context-dependent and differ consistently in their magnitude across the sexes of diverse taxonomic lineages. We synthesise and discuss the outcomes in the context of evolutionary theory on sex differences in life-history and highlight the need for future studies to carefully consider the design of experiments aimed at disentangling the costs of immune deployment.

The present study aimed to identify the factors that affect immediate (within 24 h after farrowing onset) postnatal piglet mortality in litters with hyperprolific sows, and investigate their associations with behaviour of postpartum sows in two different farrowing housing systems. A total of 30 sows were housed in: (1) CRATE (n=15): the farrowing crate closed (0.80×2.20 m) within a pen (2.50×1.70 m), and (2) OPEN (n=15): the farrowing crate open (0.80×2.20×1.80 m) within a pen (2.50×2.40 m) with a provision of 20 ls of hay in a rack. A total of 518 live born piglets, produced from the 30 sows, were used for data analyses during the first 24 h after the onset of parturition (T24). Behavioural observations of the sows were assessed via video analyses during T24. Total and crushed piglet mortality rates were higher in OPEN compared with CRATE (P

Introduction Psychiatric comorbidities, including depressive and anxiety disorders, are common in individuals with autism spectrum disorder (ASD). Use of conventional therapies for treating depression and anxiety are of limited efficacy in individuals with ASD making treatment a challenging field. Repetitive Transcranial Magnetic Stimulation (rTMS) is a safe and efficacious technique in major depressive disorder, and a similar approach could yield therapeutic benefits in ASD. Objectives The aim of this case study is to present the effectiveness of rTMS in a 17 year old patient diagnosed with ASD and comorbid major depression disorder with anxiety symptoms. Methods This is a case study of a male adolescent aged 17, diagnosed with ASD and comorbid major depression disorder with anxiety symptoms, suicidal ideation and aggressive behavior. The protocol applied was 4 weeks of daily rTMS sessions. This involved rTMS to the left dorsomedial prefrontal cortex (10 Hz, 3.000 pulses/120% motor threshold) to treat depressive symptoms and to the right (50Hz, 600 pulses/ 120%motor threshold) to treat anxiety symptoms. Assessments were conducted using the BDI, PHQ-9 and GAD-7 scales at baseline and one month follow up. Suicidal ideation and aggressive behavior were assessed by a clinician at same intervals. Results Patient showed overall improvement in scores both in depression and anxiety scales. Suicidal Ideation and aggressive behavior showed significant reduction. No side effects were recorded during therapy. Conclusions Our findings suggest that the use of rTMS therapy in adolescents in the autistic spectrum and comorbid major depression disorder and anxiety symptoms is an efficacious and safe therapeutic treatment option.

A system was developed for automatic estimations of tree positions and stem diameters. The sensor trajectory was first estimated using a positioning system that consists of a low precision inertial measurement unit supported by image matching with data from a stereo-camera. The initial estimation of the sensor trajectory was then calibrated by adjustments of the sensor pose using the laser scanner data. Special features suitable for forest environments were used to solve the correspondence and matching problems. Tree stem diameters were estimated for stem sections using laser data from individual scanner rotations and were then used for calibration of the sensor pose. A segmentation algorithm was used to associate stem sections to individual tree stems. The stem diameter estimates of all stem sections associated to the same tree stem were then combined for estimation of stem diameter at breast height (DBH). The system was validated on four 20 m radius circular plots and manual measured trees were automatically linked to trees detected in laser data. The DBH could be estimated with a RMSE of 19 mm (6 %) and a bias of 8 mm (3 %). The calibrated sensor trajectory and the combined use of circle fits from individual scanner rotations made it possible to obtain reliable DBH estimates also with a low precision positioning system.

Formaldehyde (FA), the smallest aldehyde, is generated endogenously, and is widespread in the environment in foods, beverages and as a gas phase product of incomplete combustion. The main metabolite of FA, formate, was increased significantly in murine urine (∼3×) after overnight feeding. Because feeding increases mesenteric blood flow, we explored the direct effects of FA in isolated murine superior mesenteric artery (SMA). Over the concentration range of 30–1,200 μM, FA strongly and reversibly relaxed contractions of SMA induced by three different agonists: phenylephrine (PE), thromboxane A2 analog (U46,619) and high potassium (60K, 60 mM K+). Formate (to 1.5 mM) induced a modest relaxation. FA (>1,500 μM) irreversibly depressed vascular function in SMA indicating vasotoxicity. The sensitivity (EC50) but not the efficacy (% relaxation) of FA-induced relaxations was dependent on blood vessel type (SMA << aorta) and contractile agonist (PE, EC50= 52 ± 14 μM; U46,619, EC50= 514 ± 129 μM; 60K, EC50= 1,093 ± 87 μM). The most sensitive component of FA vasorelaxation was within physiological levels (30–150 μM) and was inhibited significantly by: (1) mechanically impaired endothelium; (2) Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME); (3) transient receptor potential ankyrin-1 (TRPA1) antagonist (A967079); (4) guanylyl cyclase (GC) inhibitor (ODQ); and, (5) K+ channel inhibitor (BaCl2). A similar mechanism of SMA vasorelaxation was stimulated by the TRPA1 agonist cinnamaldehyde. Positive TRPA1 immunofluorescent staining and gene-specific sequence were present in SMA but not in aorta. These data indicate FA, but not formate, robustly relaxes SMA via a sensitive TRPA1- and endothelium-dependent mechanism that is absent in aorta. Thus, as FA levels increase with feeding, FA likely contributes to the physiological reflex of post-prandial hyperemia via SMA vasodilatation.

Biopsy samples of head and neck carcinomas were investigated with regard to elafin, secretory leukocyte protease inhibitor (SLPI), interleukin 1-receptor antagonist [(IL)1-RA] and soluble tumour necrosis factor α receptor antagonist (STNFα RI). SLPI and elafin are serine protease inhibitors produced in the serous cells of the upper respiratory airways and in the keratinocytes, respectively. We have now found the presence of elafin and SLPI in squamous cell carcinomas of the upper respiratory tract (tonsillar, hypopharyngeal, tongue, mouth floor, gingival and laryngeal cancer). Significantly higher amounts of SLPI and elafin are present in well-differentiated and moderately differentiated tumours than in poorly differentiated tumours (p

Snakebite envenoming is a neglected tropical disease that causes over 100,000 deaths annually. Envenomings result in variable pathologies, but systemic neurotoxicity is among the most serious and is currently only treated with difficult to access and variably efficacious commercial antivenoms. Venom-induced neurotoxicity is often caused by α-neurotoxins antagonising the muscle-type nicotinic acetylcholine receptor (nAChR), a ligand-gated ion channel. Discovery of therapeutics targeting α-neurotoxins is hampered by relying on binding assays that do not reveal restoration of receptor activity or more costly and/or lower throughput electrophysiology-based approaches. Here, we report the validation of a screening assay for nAChR activation using immortalised TE671 cells expressing the γ-subunit containing muscle-type nAChR and a fluorescent dye that reports changes in cell membrane potential. Assay validation using traditional nAChR agonists and antagonists, which either activate or block ion fluxes, was consistent with previous studies. We then characterised antagonism of the nAChR by a variety of elapid snake venoms that cause muscle paralysis in snakebite victims, before defining the toxin-inhibiting activities of commercial antivenoms, and new types of snakebite therapeutic candidates, namely monoclonal antibodies, decoy receptors, and small molecules. Our findings show robust evidence of assay uniformity across 96-well plates and highlight the amenability of this approach for the future discovery of new snakebite therapeutics via screening campaigns. The described assay therefore represents a useful first-step approach for identifying α-neurotoxins and their inhibitors in the context of snakebite envenoming, and it should provide wider value for studying modulators of nAChR activity from other sources., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Our aim was to determine the accuracy of the three-dimensional (3D) virtual planning and stability of LeFort I osteotomy in cleft lip and/or palate patients (CLP) using a validated 3D method., Materials and Methods: Eight patients with a history of cleft lip/palate treated with LeFort I osteotomy for maxillary hypoplasia between January 2016 and April 2020 were included in this retrospective study. Three-dimensional virtual planning was performed using Proplan software then transferred to the operation theater via 3D printed occlusal wafers. The accuracy of the 3D planning and the 1-year stability of the maxilla were evaluated by means of a validated semiautomatic stepwise module in Amira software resulting into 3 linear measurements: anterior/posterior, medial/lateral, superior/inferior and 3 rotational measurements: pitch, roll, yaw., Results: The largest mean absolute difference (MAD) for accuracy assessment was found in the A/P direction (2.75mm±2.25 mm) and in pitch (3.23°±2.11°). For A/P translation, an error of >2 mm was observed in 5(62.5%), for S/I translation an error of >2 mm was observed in 4(50.0%) of the 8 patients, whereas for pitch 3 patients(37,5%) showed an error >4° At one year follow-up, the largest linear and rotational MAD was found in the A/P direction (1.20mm±0.92 mm) and in pitch (3.31°±2.31°)., Conclusions: Findings of this study show that 3D virtual computer-assisted orthognathic surgery enables an accurate repositioning of the hypoplastic maxilla in CLP patients. However, A/P translations and pitch rotations remain challenging to achieve during surgery. These movements were also found to be least stable at one year follow-up., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Introduction: One target of rheumatoid arthritis (RA) treatment is to achieve early sustained remission; over the long term, patients in sustained remission have less structural joint damage and physical disability. We evaluated Simplified Disease Activity Index (SDAI) remission with abatacept + methotrexate versus abatacept placebo + methotrexate and impact of de-escalation (DE) in anti-citrullinated protein antibody (ACPA)-positive patients with early RA., Methods: The phase IIIb, randomized, AVERT-2 two-stage study (NCT02504268) evaluated weekly abatacept + methotrexate versus abatacept placebo + methotrexate., Primary Endpoint: SDAI remission (≤ 3.3) at week 24. Pre-planned exploratory endpoint: maintenance of remission in patients with sustained remission (weeks 40 and 52) who, from week 56 for 48 weeks (DE period), (1) continued combination abatacept + methotrexate, (2) tapered abatacept to every other week (EOW) + methotrexate for 24 weeks with subsequent abatacept withdrawal (abatacept placebo + methotrexate), or (3) withdrew methotrexate (abatacept monotherapy)., Results: Primary study endpoint was not met: 21.3% (48/225) of patients in the combination and 16.0% (24/150) in the abatacept placebo + methotrexate arm achieved SDAI remission at week 24 (p = 0.2359). There were numerical differences favoring combination therapy in clinical assessments, patient-reported outcomes (PROs) and week 52 radiographic non-progression. After week 56, 147 patients in sustained remission with abatacept + methotrexate were randomized (combination, n = 50; DE/withdrawal, n = 50; abatacept monotherapy, n = 47) and entered DE. At DE week 48, SDAI remission (74%) and PRO improvements were mostly maintained with continued combination therapy; lower remission rates were observed with abatacept placebo + methotrexate (48.0%) and with abatacept monotherapy (57.4%). Before withdrawal, de-escalating to abatacept EOW + methotrexate preserved remission., Conclusions: The stringent primary endpoint was not met. However, in patients achieving sustained SDAI remission, numerically more maintained remission with continued abatacept + methotrexate versus abatacept monotherapy or withdrawal., Trial Registration: ClinicalTrials.gov identifier, NCT02504268. Video abstract (MP4 62241 KB)., (© 2023. The Author(s).)

Mutant KRAS is a major driver of oncogenesis in a multitude of cancers but remains a challenging target for classical small molecule drugs, motivating the exploration of alternative approaches. Here, we show that aggregation-prone regions (APRs) in the primary sequence of the oncoprotein constitute intrinsic vulnerabilities that can be exploited to misfold KRAS into protein aggregates. Conveniently, this propensity that is present in wild-type KRAS is increased in the common oncogenic mutations at positions 12 and 13. We show that synthetic peptides (Pept-ins™) derived from two distinct KRAS APRs could induce the misfolding and subsequent loss of function of oncogenic KRAS, both of recombinantly produced protein in solution, during cell-free translation and in cancer cells. The Pept-ins exerted antiproliferative activity against a range of mutant KRAS cell lines and abrogated tumor growth in a syngeneic lung adenocarcinoma mouse model driven by mutant KRAS G12V. These findings provide proof-of-concept that the intrinsic misfolding propensity of the KRAS oncoprotein can be exploited to cause its functional inactivation.

Study Design: Fractures of the mandibular condyle are a common injury in maxillofacial trauma. Both conservative treatment (i.e., analgesic therapy and soft diet) and intermaxillary fixation (IMF) or open reduction internal fixation (ORIF) have satisfactory and functional outcomes, though severe late-onset complications have been reported., Objective: We compared the long-term complications of patients with condylar fractures treated conservatively, with IMF, or with combined ORIF and IMF., Methods: We retrospectively analyzed all patients diagnosed with unilateral or bilateral condylar fracture, isolated or combined with a fracture of the mandibular body, admitted to the Department of Maxillofacial Surgery at UZ Leuven between January 2013 and January 2020. We collected data on age, gender, side of condylar fracture, presence of associated fracture of the mandibular body, referrals, initial treatment, long-term complications and secondary treatment. Long-term complications were defined as sequelae still present 6 weeks after initial treatment., Results: Among 192 patients, 68.8% had unilateral and 31.2% bilateral condylar fractures; an associated fracture of the mandibular body was seen in 45.8%, 31% received conservative treatment, 51% IMF only, and 18% combined ORIF and IMF. Forty-eight percent of all patients suffered from 1 or more long-term complications, most frequently malocclusion (24%), reduced mouth opening (15.1%), nerve disturbances (13.5%), pain (8.9%), and facial asymmetry (2.6%). Surgery as a secondary treatment was necessary in 25% of all cases., Conclusions: The presence of bilateral condylar fractures or associated fracture of the mandibular body is a risk factor for developing long-term complications. Most patients with long-term complications were initially treated with combined ORIF and IMF, but long-term complications after initial conservative or IMF treatment were treated with secondary surgery., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2021.)

Bites by elapid snakes (e.g. cobras) can result in life-threatening paralysis caused by venom neurotoxins blocking neuromuscular nicotinic acetylcholine receptors. Here, we determine the cryo-EM structure of the muscle-type Torpedo receptor in complex with ScNtx, a recombinant short-chain α-neurotoxin. ScNtx is pinched between loop C on the principal subunit and a unique hairpin in loop F on the complementary subunit, thereby blocking access to the neurotransmitter binding site. ScNtx adopts a binding mode that is tilted toward the complementary subunit, forming a wider network of interactions than those seen in the long-chain α-Bungarotoxin complex. Certain mutations in ScNtx at the toxin-receptor interface eliminate inhibition of neuronal α7 nAChRs, but not of human muscle-type receptors. These observations explain why ScNtx binds more tightly to muscle-type receptors than neuronal receptors. Together, these data offer a framework for understanding subtype-specific actions of short-chain α-neurotoxins and inspire strategies for design of new snake antivenoms., (© 2022. The Author(s).)

The present aim was to estimate direct health care costs of patients suffering from post-traumatic trigeminal neuropathy (PTTN) and to compare the use of health care services, medications, and costs between temporary and persistent (>3 months) PTTN cohorts. A pre-existing clinical dataset of PTTN patients visiting a tertiary orofacial pain clinic in Belgium was utilized, including symptoms and quality of life measurements. Cost and resource utilization data were obtained by Belgium's largest health insurance provider for a period of 5 years after onset. Data from 158 patients was analyzed. The average cost per patient in the first year after injury was €2353 (IQR 1426-4499) with an out-of-pocket expense of 25% of the total cost. Hospitalization and technical interventions were the main drivers of cumulative costs, followed by consultation costs. For each cost category, expenditure was significantly higher in patients with persistent PTTN than in those with temporary PTTN (median 5-year total costs in persistent PTTN patients yielded €8866 (IQR 4368-18191) versus €4432 (IQR 2156-9032) in temporary PTTN, p <0.001) PTTN patients received repeated and frequent head and neck imaging (mean number of imaging investigations per patient was 10 ± 12). Medication consumption was high, with an unwarranted higher use of opioids and antibiotics in persistent PTTN patients. Within the limitations of this study, it seems there is a need for informing patients in detail on the inherent risks of nerve damage during dental and oromaxillofacial procedures. Every surgery should be preceded by a risk-benefit assessment in order to avoid unnecessary nerve damage., Competing Interests: Declaration of competing interest None to declare., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Treatment of mandibular coronoid process hyperplasia (MCPH) has been described and explored in the literature. This systematic review aims to provide a comprehensive overview of the surgical and non-surgical treatment options for MCPH in pediatric and adult populations. Three databases were searched for treatment of MCPH patients (MEDLINE, Embase, and Web of Science). Two reviewers selected case reports and case series based on titles and abstracts. Finally, 55 studies reporting a total of 127 cases were included for qualitative synthesis and data extraction. The mean age at symptom onset was 15.6 years, while the mean age at diagnosis was 23.5 years. Of the included cases, 83.7% were male, and the condition was bilateral in more than 81% of the cases. Coronoidectomy was performed in 82.7% of the included cases, while coronoidotomy was performed in 3.9% of the cases. In 85.0% of the surgically treated cases, the approach was intraoral. The mean maximal intraoperative mouth opening was 38.1 mm compared with 16.5 mm at diagnosis. The mean maximal postoperative mouth opening was 35.3 mm, and the mean follow-up period was 16.3 months. Maximum mouth opening was achieved intraoperatively, and non-surgical treatment after surgery aims to reduce the risk of relapse. Additional research with a higher level of evidence is necessary to confirm these findings.

Background: Certain risk alleles associated with autoantibody-positive rheumatoid arthritis (RA) have been linked to poorer prognoses. In patients with autoantibody-positive RA, abatacept shows differential efficacy to tumor necrosis factor inhibitors. Our aim was to investigate the relationship between clinical response to abatacept and to adalimumab and presence of risk alleles encoding human leukocyte antigen (HLA)-DRB1 shared epitope (SE) in RA., Methods: In this head-to-head study, biologic-naïve adults with early (≤ 12 months), moderate-to-severe RA and inadequate response to methotrexate (MTX-IR), autoantibody-positive for both anti-cyclic citrullinated peptide 2 and rheumatoid factor, were randomized 1:1 to receive subcutaneous abatacept 125 mg weekly or subcutaneous adalimumab 40 mg every 2 weeks for 24 weeks with stable, weekly oral MTX. An open-label period to 48 weeks followed, during which adalimumab-treated patients were switched to abatacept. Patients were genotyped for HLA-DRB1 alleles and classified as SE-positive (≥ 1 SE allele) or SE-negative (no SE alleles). Efficacy was assessed at weeks 24 and 48., Results: Forty patients each received abatacept (9 SE-negative, 30 SE-positive, one unknown) or adalimumab (9 SE-negative, 31 SE-positive). Mean age and disease duration were 46.0 years and 5.5 months, respectively. At week 24, a greater percentage of abatacept patients achieved 50% improvement in ACR criteria (ACR50) compared with adalimumab patients (73% vs 45%, respectively) and estimate of difference (95% confidence interval [CI]), 28 (5, 48). In SE-positive patients, ACR50 estimate of difference (95% CI) was 32 (7, 55). During the open-label period, responses were sustained in the abatacept non-switch group and showed trends toward further improvement in the adalimumab-to-abatacept switch group at week 48, in both the overall and the SE-positive subpopulation. No new safety signals were identified., Conclusions: In MTX-IR patients with early, autoantibody-positive RA, abatacept resulted in numerically higher efficacy responses versus adalimumab after 24 weeks, with more pronounced treatment differences in SE-positive patients. After 48 weeks, responses were sustained in patients who continued abatacept while those who switched to abatacept showed further clinical improvement, overall, and in SE-positive patients. This supports co-stimulation blockade as an effective treatment strategy for patients with early, autoantibody-positive RA, particularly among SE-positive patients., Trial Registration: NIH US National Library of Medicine, NCT02557100 . Registered on September 23, 2015., (© 2021. The Author(s).)

Background: Recent randomised controlled trials (RCTs) in primary Sjögren's syndrome used the European League Against Rheumatism (EULAR) Sjögren's Syndrome Disease Activity Index (ESSDAI) as their primary endpoint. Given the heterogeneous and complex nature of primary Sjögren's syndrome, it might be more appropriate to also assess other clinically relevant disease features. We aimed to develop a novel composite endpoint for assessing treatment efficacy in patients with primary Sjögren's syndrome: the Composite of Relevant Endpoints for Sjögren's Syndrome (CRESS)., Methods: A multidisciplinary expert team selected clinically relevant items and candidate measurements for inclusion in the composite score. For each measurement, cutoff points for response to treatment were chosen based on expert opinion, previously published data on minimal clinically important improvements, and trial data, primarily the week-24 data of the single-centre ASAP-III trial of abatacept versus placebo. CRESS was validated using data from three independent RCTs: one trial of rituximab (TRACTISS), one of abatacept (multinational trial), and one of tocilizumab (ETAP). We calculated the number and percentage of patients who were responders in the separate CRESS items, and the percentage of responders based on the total CRESS at the primary endpoint visits (week 48 for TRACTISS, week 24 for the other two trials). Patients with fewer than three items available for evaluating CRESS response were imputed as non-responders., Findings: Based on expert opinion, five complementary items were selected to assess response: (1) systemic disease activity by Clinical ESSDAI (less than 5 points); (2) patient-reported symptoms by EULAR Sjögren's Syndrome Patient Reported Index, assessed by a decrease of at least 1 point or at least 15% from baseline; (3) tear gland item by Schirmer's test and ocular staining score, assessed by an increase of at least 5 mm or decrease of at least 2 points, respectively, in patients with abnormal Schirmer's test or ocular staining score findings at baseline, or, in patients with normal baseline values, assessed by no change to abnormal for both; (4) salivary gland item, assessed by unstimulated whole saliva secretion (increase of at least 25%) and salivary gland ultrasonography (decrease of at least 25%); and (5) serology, assessed by rheumatoid factor (decrease of at least 25%) and IgG (decrease of at least 10%). Total CRESS response is defined as response on at least three of five items. Post-hoc assessment of phase 3 trial data showed that CRESS response rates at the primary endpoint visits were 60% (24 of 40) for abatacept versus 18% (seven of 39) for placebo (p<0·0001) in ASAP-III, 49% (33 of 67) for rituximab versus 30% (20 of 66) for placebo (p=0·026) in the TRACTISS trial, 45% (41 of 92) for abatacept versus 32% (30 of 95) for placebo (p=0·067) in the multinational abatacept trial, and 18% (10 of 55) for tocilizumab versus 24% (13 of 55) for placebo (p=0·48) in the ETAP trial., Interpretation: The CRESS is a feasible, well-balanced, composite endpoint for use in trials of primary Sjögren's syndrome. As a next step, the CRESS will require validation in a prospective RCT., Funding: None., Translation: For the Dutch translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests ANB reports personal fees from Bristol-Myers Squibb and Sanofi-Aventis, outside the submitted work. MB reports grants and personal fees from Amgen/Medimmune, Janssen, and GSK, and personal fees from UCB, outside the submitted work. HB reports grants and personal fees from Bristol Myers Squibb and Roche, and personal fees from Novartis, Medimmune, personal fees and Union Chimique Belge, outside the submitted work. SJB reports consulting fees from Novartis, AstraZeneca, and Abbvie/Galapagos, outside the submitted work. J-EG reports grants and personal fees from Bristol Myers Squibb and Pfizer, and personal fees from CSL Behring, Lilly, Janssen, UCB, and Roche, outside the submitted work. FGMK reports grants and personal fees from Bristol Myers Squibb and Roche, and personal fees from Janssen-Cilag, outside the submitted work. MN and NR are employees and shareholders of Bristol-Myers Squibb. JFvN reports personal fees from Bristol Myers Squibb, outside the submitted work. JV reports personal fees from Santen and Tramedico, outside the submitted work. AV reports grants from Bristol Myers Squibb and Roche, during the conduct of the study. SA, LdW, GMPJV, EP, and RF declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: To assess the relationship between infection risk and abatacept (ABA) exposure levels in patients with polyarticular-course juvenile idiopathic arthritis (pJIA) following treatment with subcutaneous (SC) and intravenous (IV) ABA., Methods: Data from 2 published studies (ClinicalTrials.gov: NCT01844518, NCT00095173) of ABA treatment in pediatric patients were analyzed. One study treated patients aged 2-17 years with SC ABA and the other treated patients aged 6-17 years with IV ABA. Association between serum ABA exposure measures and infection was evaluated using Kaplan-Meier plots of probability of first infection vs time on treatment by ABA exposure quartiles and log-rank tests. Number of infections by ABA exposure quartiles was investigated., Results: Overall, 343 patients were included in this analysis: 219 patients received SC ABA and 124 patients received IV ABA. Overall, 237/343 (69.1%) patients had ≥ 1 infection over 24 months. No significant difference in time to first infection across 4 quartiles of ABA exposure levels was observed in the pooled ( P = 0.45), SC (2-5 yrs: P = 0.93; 6-17 yrs: P = 0.48), or IV ( P = 0.50) analyses. Concomitant use of methotrexate and glucocorticoids (at baseline and throughout) with ABA did not increase infection risk across the ABA exposure quartiles. There was no evidence of association between number of infections and ABA exposure quartiles. No opportunistic infections related to ABA were reported., Conclusion: In patients aged 2-17 years with pJIA, no evidence of association between higher levels of exposure to IV ABA or SC ABA and incidence of infection was observed., (Copyright © 2021 by the Journal of Rheumatology.)

Objectives: To evaluate efficacy and safety of abatacept in adults with active primary Sjögren's syndrome (pSS) in a phase III, randomised, double-blind, placebo-controlled trial., Methods: Eligible patients (moderate-to-severe pSS [2016 ACR/European League Against Rheumatism (EULAR) criteria], EULAR Sjögren's Syndrome Disease Activity Index [ESSDAI] ≥5, anti-SS-related antigen A/anti-Ro antibody positive) received weekly subcutaneous abatacept 125 mg or placebo for 169 days followed by an open-label extension to day 365. Primary endpoint was mean change from baseline in ESSDAI at day 169. Key secondary endpoints were mean change from baseline in EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) and stimulated whole salivary flow (SWSF) at day 169. Other secondary clinical endpoints included glandular functions and patient-reported outcomes. Selected biomarkers and immune cell phenotypes were examined. Safety was monitored., Results: Of 187 patients randomised, 168 completed double-blind period and 165 continued into open-label period. Mean (SD) baseline ESSDAI and ESSPRI total scores were 9.4 (4.3) and 6.5 (2.0), respectively. Statistical significance was not reached for primary (ESSDAI -3.2 abatacept vs -3.7 placebo, p=0.442) or key secondary endpoints (ESSPRI, p=0.337; SWSF, p=0.584). No clinical benefit of abatacept over placebo at day 169 was seen with other clinical and PRO endpoints. Relative to baseline, abatacept was associated with significant differences vs placebo in some disease-relevant biomarkers (including IgG, IgA, IgM-rheumatoid factor) and pathogenic cell subpopulations (post hoc analyses). No new safety signals were identified., Conclusions: Abatacept treatment did not result in significant clinical efficacy compared with placebo in patients with moderate-to-severe pSS, despite evidence of biological activity., Competing Interests: Competing interests: ANB: Consultant: Bristol Myers Squibb Company, Sanofi, VielaBio; Fees: UpToDate; Clinical trials: VielaBio, Novartis. J-EG: Grant/research support: Bristol Myers Squibb Company; Consultant: Bristol Myers Squibb Company, Lilly, UCB, Sanofi-Genzyme, Pfizer. EWSC: Consulting fees and grant/research support: Bristol Myers Squibb Company; Consulting fees: AbbVie, VielaBio. TS: Grant/research support and Speakers’ bureau: Bristol Myers Squibb Company. TT: Grant/Research: AbbVie, Asahi Kasei, Astellas, AYUMI, Chugai, Daiichi Sankyo, Eisai, Mitsubishi Tanabe, Nipponkayaku, Novartis, Pfizer Japan, Takeda; Consultant: AbbVie, Astellas, Astra Zeneca, Chugai, Eli Lilly Japan, GlaxoSmithKline, Janssen, Mitsubishi Tanabe, Nipponkayaku, Novartis, Taiho, Taisho Toyama, UCB Japan; Speakers’ bureau: AbbVie, Astellas, Bristol Myers Squibb Company, Chugai, Daiichi Sankyo, Eisai, Mitsubishi Tanabe, Novartis, Pfizer Japan, Sanofi, Takeda, Teijin. RS: Grant/research support: Pfizer; Consultant: Amgen, Bristol Myers Squibb Company, Celgene, GlaxoSmithKline, Lilly, Pfizer, Roche. GF: Consultant: Aldeyra, Allysta, Aurinia, Bristol Myers Squibb Company, Clemencia, Hovione, Kala, Lexitas PharmaServices, Nicox, Noveome, Sight Sciences, Tarsus, Tear Solutions; Stock: TearLab. MN: Employee: Bristol Myers Squibb Company; Shareholder: Bristol Myers Squibb Company. SM: Employee: Bristol Myers Squibb Company; Shareholder: Bristol Myers Squibb Company. RW: Employee: Bristol Myers Squibb Company; Shareholder: Bristol Myers Squibb Company. NR: Employee: Bristol Myers Squibb Company; Shareholder: Bristol Myers Squibb Company. HB: Unrestricted grant: Bristol Myers Squibb Company, Roche; Consultant: Speakers bureau: Bristol Myers Squibb Company, Novartis., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Advances in the literature of sex-related differences in autobiographical memory increasingly tend to highlight the importance of psychosocial factors such as gender identity, which may explain these differences better than sex as a biological factor. To date, however, none of these behavioral studies have investigated this hypothesis using neuroimaging. The purpose of this fMRI study is to examine for the first time sex and gender identity-related differences in episodic and semantic autobiographical memory in healthy participants (M=19, W=18). No sex-related differences were found; however, sex-related effects of masculine and feminine gender identity were identified in men and women independently. These results confirm the hypothesis that differences in episodic and semantic autobiographical memory are best explained by gender but are an interaction between biological sex and gender identity and extend these findings to the field of neuroimaging. We discuss the importance of hormonal factors to be taken into consideration in the future., (Copyright © 2020. Published by Elsevier Inc.)

Juvenile idiopathic arthritis (JIA) encompasses several forms of chronic inflammatory arthritis of unknown etiology presenting in children < 16 years of age, with a minimum symptom duration of 6 weeks. Approximately half of affected children have polyarticular-course JIA (pJIA), a functional concept related to several clinically and genetically heterogeneous JIA categories (systemic, extended oligoarthritis, polyarticular rheumatoid factor-positive or rheumatoid factor-negative, enthesitis-related arthritis, and psoriatic arthritis), which has as its defining feature the involvement of five or more joints during the disease course. Chronic inflammation and joint damage lead to the manifestations of JIA such as pain, limitation of motion, and loss of physical function, all of which negatively impact patients' quality of life. The American College of Rheumatology recommends initial treatment with a conventional synthetic disease-modifying antirheumatic drug (csDMARD), such as methotrexate (MTX) and, in patients with pJIA who have an inadequate response or intolerance to MTX, the use of a biologic DMARD (bDMARD) such as a tumor necrosis factor inhibitor, abatacept, or tocilizumab. Abatacept selectively modulates the CD80/CD86:CD28 co-stimulatory signal required for full T cell activation, and thus has a distinct mechanism of action upstream of that of other currently available bDMARD treatments for rheumatic diseases. To enable physicians to make informed treatment decisions, it is important to review available data for the existing therapeutic agents. Here, we summarize the current evidence from phase III pivotal trials of intravenous (IV) and subcutaneous (SC) abatacept and from an ongoing registry of patients with JIA treated with abatacept. In the pivotal trials for IV and SC abatacept, either with or without MTX, both formulations demonstrated clinical efficacy, with a high proportion of patients achieving stringent clinical responses, as well as improvements in patient-reported outcomes and a favorable safety profile, particularly with regard to infections.

TRPM3 channels play important roles in the detection of noxious heat and in inflammatory thermal hyperalgesia. The activity of these ion channels in somatosensory neurons is tightly regulated by µ-opioid receptors through the signaling of Gβγ proteins, thereby reducing TRPM3-mediated pain. We show here that Gβγ directly binds to a domain of 10 amino acids in TRPM3 and solve a cocrystal structure of this domain together with Gβγ. Using these data and mutational analysis of full-length proteins, we pinpoint three amino acids in TRPM3 and their interacting partners in Gβ 1 that are individually necessary for TRPM3 inhibition by Gβγ. The 10-amino-acid Gβγ-interacting domain in TRPM3 is subject to alternative splicing. Its inclusion in or exclusion from TRPM3 channel proteins therefore provides a mechanism for switching on or off the inhibitory action that Gβγ proteins exert on TRPM3 channels., Competing Interests: The authors declare no competing interest.

Background: Patients with polyarticular-course juvenile idiopathic arthritis (pJIA), receiving disease-modifying anti-rheumatic drugs with immunosuppressive effects, may be at increased risk of vaccine-preventable infections. This substudy assessed protective antibody responses to diphtheria and tetanus vaccination given prior to study enrolment in patients with pJIA., Findings: This was a substudy of a 24-month, single-arm, open-label, multicenter, Phase III trial (NCT01844518) of subcutaneous abatacept in children with active pJIA (N = 219). Patients aged 2-5 years, with ≥2 continuous months of weekly weight-tiered (10-< 25 kg [50 mg], 25-< 50 kg [87.5 mg]) subcutaneous abatacept treatment (with/without methotrexate and/or low-dose corticosteroids), who received diphtheria/tetanus vaccine prior to enrolment, were eligible. Protective antibody levels to diphtheria/tetanus (> 0.1 IU/mL), and safety, were assessed. Overall, 29 patients were analyzed: 19 (65.5%), 1 (3.4%) and 9 (31.0%) patients had > 12, 6-12 and 2-< 6 months of abatacept exposure, respectively. All patients had protective antibody levels to tetanus and 26 (89.7%) patients had protective antibody levels to diphtheria. Of the 3 patients without protective antibody levels to diphtheria, each had an antibody level of 0.1 IU/mL, bordering the lower threshold of protection. Concomitant use of methotrexate and/or low-dose corticosteroids had no evident effect on antibody levels. No unexpected adverse events, including cases of diphtheria or tetanus, were reported during the 24-month period., Conclusions: Patients aged 2-5 years with pJIA who received 2-24 months of weekly subcutaneous abatacept, with or without concomitant methotrexate and/or low-dose corticosteroids, maintained effective diphtheria and tetanus vaccination protection without new safety signals., Trial Registration: ClinicalTrials.gov (NCT01844518); registered May 1, 2013; https://clinicaltrials.gov/ct2/show/NCT01844518?term=NCT01844518&rank=1.

SDS22 is an ancient regulator of protein phosphatase-1 (PP1). Our crystal structure of SDS22 shows that its twelve leucine-rich repeats adopt a banana-shaped fold that is shielded from solvent by capping domains at its extremities. Subsequent modeling and biochemical studies revealed that the concave side of SDS22 likely interacts with PP1 helices α5 and α6, which are distal from the binding sites of many previously described PP1 interactors. Accordingly, we found that SDS22 acts as a "third" subunit of multiple PP1 holoenzymes. The crystal structure of SDS22 also revealed a large basic surface patch that enables binding of a phosphorylated form of splicing factor BCLAF1. Taken together, our data provide insights into the formation of PP1:SDS22 and the recruitment of additional interaction proteins, such as BCLAF1., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The aim of this study was to determine the long-term outcome of autotransplanted maxillary canines and to investigate the influencing parameters. Seventy-one patients (84 transplanted canines) volunteered to participate in this study. The mean follow-up time was 21 years. In case of tooth survival and when patients were found willing for recall, teeth were investigated clinically and radiographically. Transplanted teeth were compared to the contralateral canine and scored with an aesthetic and radiographic index. The survival rate was 67.9%, considering that 27 transplanted teeth were lost before examination. The mean survival time was 15.8 years. Maxillary canine autotransplantation may have a successful outcome up to 21 years after transplantation requiring minimal patient compliance and low financial costs. The survival rate can be considered favorable realizing that autotransplantation is a treatment option in a selected group of cases.