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ABSTRACT: Background: Low back pain (LBP) is a highly prevalent, disabling condition affecting millions of people. Patients with an identifiable anatomic pain generator and resulting neuropathic lower extremity symptoms often undergo spine surgery, but many patients lack identifiable and/or surgically corrective pathology. Nonoperative treatment options often fail to provide sustained relief. Spinal cord stimulation (SCS) is sometimes used to treat these patients, but the lack of level 1 evidence limits its widespread use and insurance coverage. The DISTINCT RCT study evaluates the efficacy of passive recharge burst SCS compared to conventional medical treatment (CMM) in alleviating chronic, refractory axial low back pain. Methods: This prospective, multicenter, randomized, study with an optional 6-month crossover involved patients who were not candidates for lumbar spine surgery. The primary and secondary endpoints evaluated improvements in low back pain intensity (NRS), back pain-related disability (ODI), pain catastrophizing (PCS), and healthcare utilization. Patients were randomized to SCS therapy or CMM at 30 US study sites. Results: The SCS arm reported an 85.3% NRS responder rate (≥ 50% reduction) compared to 6.2% (5/81) in the CMM arm. After the 6M primary endpoint, SCS patients elected to remain on assigned therapy and 66.2% (49/74) of CMM patients chose to trial SCS (crossover). At the 12M follow-up, SCS and crossover patients reported 78.6% and 71.4% NRS responder rates. Secondary outcomes indicated significant improvements in ODI, PCS, and reduced healthcare utilization. Six serious adverse events were reported and resolved without sequelae. Conclusion: DISTINCT chronic low back pain patients with no indication for corrective surgery experienced a significant and sustained response to burst SCS therapy for up to 12 months. CMM patients who crossed over to the SCS arm reported profound improvements after 6 months. This data advocates for a timely consideration of SCS therapy in patients unresponsive to conservative therapy.

Background: Postoperative cognitive decline (POCD) after cardiosurgical interventions are well described through objective psychometric tests. However, a patient’s subjective perception is essential to clinical assessment and quality of life. This study systematically evaluated patient-reported POCD between subjects undergoing coronary artery bypass grafting and heart valve replacement. Methods: This study was a multicentre, prospective questionnaire survey conducted at the cardiac surgery departments at the Kerckhoff Clinic in Bad Nauheim and the University Hospital in Giessen, Germany. We included patients undergoing elective coronary artery bypass grafting (CABG), aortic valve replacement (AVR), mitral valve replacement or reconstruction (MVR), and combined surgery (CABG + valve replacement [VR]) with extracorporeal circulation. The Hospital Anxiety and Depression Scale, the Cognitive Failures Questionnaire (CFQ) for Self-assessment (CFQ-S), and the external assessment (CFQ-foreign [F]) were completed preoperatively, as well as at 3 and 12 months postoperatively. Results: A total of 491 patients were available for analyses (CABG = 182, AVR = 134, MVR = 93, CABG + VR = 82). POCD and postoperative depression increase (PODI) were observed for each surgical procedure. (At the 3-month follow-up: CFQ-S [CABG = 7.1%, AVR = 3.7%, MVR = 9.7%, CABG + VR = 9.8%]; CFQ-F [CABG = 9.9%, AVR = 9.7%, MVR = 9.7%, CABG + VR = 15.9%]; PODI [CABG = 7.7%, AVR = 9.7%, MVR = 6.5%, CABG + VR = 8.5%]. At the 12-month follow-up: CFQ-S [CABG = 6.6%, AVR = 7.5%, MVR = 15.1%, CABG + VR = 7.3%]; CFQ-F [CABG = 7.1%, AVR = 14.9%, MVR = 10.8%, CABG + VR = 9.8%]; PODI [CABG = 10.4%, AVR = 11.2%, MVR = 6.5%, CABG + VR = 4.9%]). No significant between-group effects were observed for the CFQ-S, CFQ-F, or the Hospital Anxiety and Depression Scale. Conclusions: For clinicians, paying attention to patients' self-reported experiences of reduced cognitive function and symptoms of depression following cardiac surgery is important. Such reporting is an indication that interventions such as cognitive training or psychotherapy should be considered. Résumé: Contexte: Le déclin cognitif postopératoire (DCPO) à la suite d’interventions de chirurgie cardiaque est bien décrit par des évaluations psychométriques objectives. Cependant, la perception subjective du patient est essentielle à l’évaluation clinique et à la qualité de vie. Cette étude visait à évaluer de façon systématique le DCPO déclaré par le patient chez des sujets ayant subi un pontage aortocoronarien ou une chirurgie valvulaire. Méthodologie: Cette étude prospective multicentrique par questionnaire a été menée aux services de chirurgie cardiaque de la clinique Kerckhoff de Bad Nauheim et de l’hôpital universitaire de Giessen, en Allemagne. Elle a porté sur des patients ayant subi un pontage aortocoronarien (PAC), un remplacement valvulaire aortique (RVA), un remplacement ou une reconstruction de la valvule mitrale (RVM) ou une chirurgie combinée (PAC et remplacement valvulaire [RV]) avec circulation extracorporelle, en situation non urgente. L’échelle d’évaluation de l’anxiété et de la dépression à l’hôpital (HADS), le questionnaire d’auto-évaluation des déficits cognitifs (CFQ-S) et le questionnaire d’évaluation externe des déficits cognitifs (CFQ-F) ont été remplis avant l’intervention chirurgicale, ainsi que 3 et 12 mois après la chirurgie. Résultats: Au total, les résultats de 491 patients étaient disponibles aux fins d’analyses (PAC = 182, RVA = 134, RVM = 93, PAC et RV = 82). Des cas de DCPO et une augmentation postopératoire des symptômes de dépression (APOD) ont été observés après chacune des interventions chirurgicales. (Lors du suivi après 3 mois : DCPO selon le CFQ-S [PAC = 7,1 %, RVA = 3,7 %, RVM = 9,7 %, PAC + RV = 9,8 %]; DCPO selon le CFQ-F [PAC = 9,9 %, RVA = 9,7 %, RVM = 9,7 %, PAC + RV = 15,9 %]; APOD [PAC = 7,7 %, RVA = 9,7 %, RVM = 6,5 %, PAC + RV = 8,5 %]. Lors du suivi après 12 mois : DCPO selon le CFQ-S [PAC = 6,6 %, RVA = 7,5 %, RVM = 15,1 %, PAC + RV = 7,3 %]; DCPO selon le CFQ-F [PAC= 7,1 %, RVA = 14,9 %, RVM = 10,8 %, PAC+ RV = 9,8 %]; APOD [PAC = 10,4 %, RVA = 11,2 %, RVM = 6,5 %, PAC + RV = 4,9 %]). Aucun effet intergroupe significatif n’a été observé relativement aux questionnaires CFQ-S et CFQ-F ou à l’échelle HADS. Conclusions: Il est important que les cliniciens portent attention aux déclarations des patients en ce qui concerne la diminution des fonctions cognitives et les symptômes de dépression à la suite d’une chirurgie cardiaque. De telles déclarations sont une indication que des interventions comme l’entraînement cognitif ou la psychothérapie doivent être envisagées.

This is a report of successful treatment of an abdominal aortic aneurysm via standard endovascular aortic repair with an ultra-low dose (ULD) of 2.4 Gy∗cm2 using the latest imaging software in a hybrid operating room. To the best of our knowledge, no case has yet been reported achieving a successful outcome with such ULD values to date. The key factors to achieving an ULD regarding the dose area product comprise the right technology, procedural standardization, and team education and training. This case highlights the potential for reducing the radiation dose routinely for patients and staff alike, especially for operating room staff with daily radiation exposure.

OBJECTIVES:. Accurate classification of disorders of consciousness (DoC) is key in developing rehabilitation plans after brain injury. The Coma Recovery Scale—Revised (CRS-R) is a sensitive measure of consciousness validated in the rehabilitation phase of care. We tested the feasibility, safety, and impact of CRS-R-guided rehabilitation in the ICU for patients with DoC after acute hemorrhagic stroke. DESIGN:. Retrospective cohort study. SETTING:. This single-center study was conducted in the neurocritical care unit at the University of Maryland Medical Center. PATIENTS:. We analyzed records from consecutive patients with subarachnoid hemorrhage (SAH) or intracerebral hemorrhage (ICH), who underwent serial CRS-R assessments during ICU admission from April 1, 2018, to December 31, 2021, where CRS-R less than 8 is vegetative state/unresponsive wakefulness syndrome (VS/UWS); CRS-R greater than or equal to 8 is a minimally conscious state (MCS). INTERVENTIONS:. None. MEASUREMENTS AND MAIN RESULTS:. Outcomes included adverse events during CRS-R evaluations and associations between CRS-R and discharge disposition, therapy-based function, and mobility. We examined the utility of CRS-R compared with other therapist clinical assessment tools in predicting discharge disposition. Seventy-six patients (22 SAH, 54 ICH, median age = 59, 50% female) underwent 276 CRS-R sessions without adverse events. Discharge to acute rehabilitation occurred in 4.4% versus 41.9% of patients with a final CRS-R less than 8 and CRS-R greater than or equal to 8, respectively (odds ratio [OR] 13.4; 95% CI, 2.7–66.1; p < 0.001). Patients with MCS on final CRS-R completed more therapy sessions during hospitalization and had improved mobility and functional performance. Compared with other therapy assessment tools, the CRS-R had the best performance in predicting discharge disposition (area under the curve: 0.83; 95% CI, 0.72–0.94; p < 0.0001). CONCLUSIONS:. Early neurorehabilitation guided by CRS-R appears to be feasible and safe in the ICU following hemorrhagic stroke complicated by DoC and may enhance access to inpatient rehabilitation, with the potential for lasting benefit on recovery. Further research is needed to assess generalizability and understand the impact on long-term outcomes.

Introduction: Curative-intent treatment of superior sulcus tumors (SSTs) of the lung invading the spine presents considerable challenges. We retrospectively studied outcomes in a single center, uniformly staged patient cohort treated with induction concurrent chemoradiotherapy followed by surgical resection (trimodality therapy). Methods: An institutional surgical database from the period between 2002 and 2021 was accessed to identify SSTs in which the resection included removal of at least part of the vertebral body. All patients were staged using fluorodeoxyglucose positron emission tomography (/computed tomography), computed tomography scan of the chest/upper abdomen, and brain imaging. Surgical morbidity was assessed using the Clavien-Dindo classification. Overall and disease-free survival were calculated using the Kaplan-Meier method. Results: A total of 18 patients were included: 8 complete and 10 partial vertebrectomies were performed, with six of the eight complete vertebrectomies involving two vertebral levels, resulting in Complete surgical resection (R0) in 94%. Nine patients had a 1-day procedure, and nine were staged over 2 days. The median follow-up was 30 months (interquartile range 11–57). The 90-day postoperative morbidity was 44% (grade III/IV), with no 90-day surgery–related mortality. There were 83% who had a major pathologic response, associated with improved survival (p = 0.044). The 5-year overall and disease-free survival were 55% and 40%, respectively. Disease progression occurred in 10 patients, comprising locoregional recurrences in two and distant metastases in eight patients. Conclusions: Multimodality treatment in selected patients with a superior sulcus tumor invading the spine is safe and results in good survival. Such patients should be referred to expert centers. Future research should focus on improving distant control (e.g. [neo]adjuvant immunotherapy).

Background. Although steroid avoidance (SA) has been studied in deceased donor liver transplant, little is known about SA in living donor liver transplant (LDLT). We report the characteristics and outcomes, including the incidence of early acute rejection (AR) and complications of steroid use, in 2 cohorts of LDLT recipients. Methods. Routine steroid maintenance (SM) after LDLT was stopped in December 2017. Our single-center retrospective cohort study spans 2 eras. Two hundred forty-two adult recipients underwent LDLT with SM (January 2000–December 2017), and 83 adult recipients (December 2017–August 2021) underwent LDLT with SA. Early AR was defined as a biopsy showing pathologic characteristics within 6 mo after LDLT. Univariate and multivariate logistic regressions were performed to evaluate the effects of relevant recipient and donor characteristics on the incidence of early AR in our cohort. Results. Neither the difference in early AR rate between cohorts (SA 19/83 [22.9%] versus SM 41/242 [17%]; P = 0.46) nor a subset analysis of patients with autoimmune disease (SA 5/17 [29.4%] versus SM 19/58 [22.4%]; P = 0.71) reached statistical significance. Univariate and multivariate logistic regressions for early AR identified recipient age to be a statistically significant risk factor (P

Objective:. The study aimed to assess major adverse cardiovascular events (MACEs), complications requiring revision surgery, and bariatric conversion surgery 7 years after gastric bypass (GB) and sleeve gastrectomy (SG) using real-world data. Background:. GB and SG both result in weight loss and improved cardiometabolic health. Whether the long-term rate of MACE differs between the 2 bariatric procedures is unclear. Methods:. In this population-based retrospective cohort study, we used inhospital National Health Registry data from January 2012 to December 2018. Patients undergoing GB were 1:1 propensity score-matched with patients who had SG. The primary outcome was the incidence of MACE, defined as acute myocardial infarction, ischemic stroke, cardiac arrest, or hospitalization for heart failure. Secondary outcomes encompassed individual MACE components, postoperative complications, and the need for bariatric conversion surgery. Results:. Among 5240 propensity score-matched pairs, the incidence rate per 1000 person-years of MACE was 2.8 among patients undergoing GB and 3.2 among those undergoing SG (hazard ratio [HR], 0.92; 95% confidence interval [CI], 0.62–1.37). Single components of MACE were not different between both groups. Patients after GB had a higher risk of long-term postoperative complications requiring a revision surgery compared with those after SG (HR, 3.53 [95% CI, 2.78–4.49]). Bariatric conversion surgery was less frequently performed among patients undergoing GB compared with patients undergoing SG (HR, 0.09 [95% CI, 0.06–0.13]). Conclusions:. In this study, the performance of GB versus SG was associated with a similar risk of MACE. While postoperative complications were more frequent among patients undergoing GB, patients following SG had a higher probability of bariatric conversion surgery.

Introduction: Superior sulcus tumors (SSTs) are uncommon, and their anatomical location can make treatment challenging. We analyzed late outcomes of patients with SST treated with concurrent chemoradiotherapy followed by surgical resection (trimodality) in a single tertiary institution. Methods: Patients with non–small cell SSTs, who underwent trimodality therapy between 2002 and 2017, were selected from a prospective institutional surgical database. Patients were uniformly staged with 18F-fluorodeoxyglucose–positron emission tomography, computed tomography scan of the chest and upper abdomen, and brain imaging. Patients undergoing resection of the lung plus chest wall were grouped as limited SST and those needing extensive resections (e.g., including the vertebral body) as extended SST. Kaplan-Meier survival analysis was performed to determine difference in survival. Multivariate Cox regression was used to identify prognostic factors. Results: A total of 123 patients were identified with a median follow-up of 4.9 years (interquartile range: 1.6–8.9 y). The 90-day postoperative mortality and morbidity (Clavien-Dindo grades III–V) were 6.5% and 21.1%, respectively. Patients with a radical resection (R0: 92.7%) had better survival (p = 0.002), as did those who had major pathologic response (73%) (p = 0.001). Ten-year overall survival (OS) and disease-free survival were 48.1% and 42.6%, respectively. There were no differences in 90-day mortality (p = 0.31) and OS (p = 0.79) between extended SST and limited SST patients. Conclusions: In patients with SST, trimodality resulted in a 10-year estimated OS and disease-free survival of 48.1% and 42.6%, respectively, which were improved after radical resection (R0) and major pathologic response. Survival for limited and extended resections was comparable, and distant relapse was the main pattern of failure. Better systemic treatments are therefore needed.

Background: Unplanned visits for care following a surgical procedure can represent a lapse in quality of care. The purpose of this study was to define the proportion of patients undergoing thoracic surgery who return to the emergency department (ED) within 6 months after discharge and the reasons for the returns. In addition, the risk factors for ED visits after thoracic surgery were identified. Methods: All adult patients undergoing thoracic surgery at the Leiden University Medical Center between January 1, 2016, and December 31, 2017, were reviewed. To identify potential risk factors for ED return visits, a multivariate regression analysis was performed. A subgroup analysis of patients who reported pain during the ED visit was performed to identify the risk factors for pain-related return to the ED. Results: Of 277 patients who underwent thoracic surgery, 27.4% (n = 76) returned to the ED within 6 months after discharge. Among these patients, 41 (53.9%) presented with postoperative pain. Younger patients (odds ratio [OR], 0.98; P = .04), those who were operated on through a thoracotomy (OR, 2.92; P = .04), and those reporting a high pain score on the ward (OR, 1.98; P

Background. The development and progression of cardiac allograft vasculopathy documented by coronary angiography (CAVangio) after heart transplantation (HTx) has prognostic relevance. Yet there are limited data regarding the role of concomitant intracoronary imaging in the presence CAVangio. In particular, atherosclerotic plaques might represent a potential target for prevention, but their impact on stenosis is understudied. Methods. We used high-resolution intracoronary optical coherence tomography (OCT) to quantify and compare findings of intimal hyperplasia (IH) and plaque morphologies in HTx patients (fibrotic plaque, lipid plaque, and calcified plaque). OCT findings were related to the presence of CAVangio as well as to the severity of stenosis. Results. We included 65 consecutive patients into analysis (66% with CAVangio, posttransplant interval 9.9 ± 7.6 y). Fibrotic, lipid, and calcified plaques were present in 41 (63.1%), 39 (60%), and 18 (27.7%) patients, respectively. In addition to IH, the presence of fibrotic, lipid, and calcified plaques was found to be associated with CAVangio. The prevalence of lipid plaque and quantitative measurements of fibrotic plaque increased with stenosis severity (lipid plaque, P < 0.001, maximal and mean fibrotic arc, P = 0.05 and P = 0.001, respectively). Receiver operating characteristic analysis showed that area under the curve of the fibrotic plaque parameter mean fibrotic arc (0.87, 95% confidence interval [0.76-0.99]; P = 0.002) was superior to area under the curve of intima parameters regarding CAVangio. The effect of mean fibrotic arc (r = 0.52, P < 0.001) was relevant regarding stenosis severity. Conclusions. After a longer posttransplant interval, CAV findings in OCT included a combination of IH and atherosclerotic plaques. In addition to IH, the presence of fibrotic, lipid, and calcified plaques is associated with CAVangio. Further studies are warranted to evaluate if the in vivo screening for plaque progress, particularly of fibrotic plaque, could improve individual secondary prevention and outcome in HTx patients.

Background. Stopping immunosuppression in a transplant patient with donor-derived malignancy offers the theoretical benefit that reconstitution of the patient’s immune system will allow “rejection” of the malignancy, as the malignancy also originates from allogeneic tissue. However, this option exists with the caveat that the patient’s allograft(s) will likely be rejected too. In simultaneous pancreas-kidney (SPK) recipients, the normal continued functioning and possible absence of malignancy in either the unaffected kidney or pancreas further complicate this decision. Methods. The charts of 3 patients with donor-derived metastatic malignancies after SPK were retrospectively reviewed in detail. We provide treatment and management recommendations based on successful outcomes and a review of the existing literature. Results. Consistent with a broad review of the literature, in all 3 cases, complete immunosuppression cessation, removal of both grafts, and in 1 case treatment with an immune checkpoint inhibitor to augment the immune response was successful. One patient is doing well 1 year after successfully undergoing kidney retransplantation, while a second patient is active on the waitlist for SPK retransplantation after no evidence of metastatic disease for 2 years. Conclusion. The successful management of metastatic donor-derived malignancies requires allograft removal, immunosuppression cessation, and adjuvant therapy that includes occasional use of checkpoint inhibitors to augment the immune response.

Background. With the use of split liver grafts as well as living donor liver transplantation (LDLT) it is imperative to know the minimum graft volume to avoid complications. Most current formulas to predict standard liver volume (SLV) rely on weight-based measures that are likely inaccurate in the setting of cirrhosis. Therefore, we sought to create a formula for estimating SLV without weight-based covariates. Methods. LDLT donors underwent computed tomography scan volumetric evaluation of their livers. An optimal formula for calculating SLV using the anthropomorphic measure thoracoabdominal circumference (TAC) was determined using leave-one-out cross-validation. The ability of this formula to correctly predict liver volume was checked against other existing formulas by analysis of variance. The ability of the formula to predict small grafts in LDLT was evaluated by exact logistic regression. Results. The optimal formula using TAC was determined to be SLV = (TAC × 3.5816) − (Age × 3.9844) − (Sex × 109.7386) − 934.5949. When compared to historic formulas, the current formula was the only one which was not significantly different than computed tomography determined liver volumes when compared by analysis of variance with Dunnett posttest. When evaluating the ability of the formula to predict small for size syndrome, many (10/16) of the formulas tested had significant results by exact logistic regression, with our formula predicting small for size syndrome with an odds ratio of 7.94 (95% confidence interval, 1.23-91.36; P = 0.025). Conclusion. We report a formula for calculating SLV that does not rely on weight-based variables that has good ability to predict SLV and identify patients with potentially small grafts.

Objective: To compare the response to nonsteroidal antiinflammatory drugs (NSAIDs) in patients with longstanding axial spondyloarthritis (axSpA) and controls with back pain (nonspondyloarthritis [non-SpA])., Methods: Consecutive outpatients with chronic back pain (axSpA or non-SpA), were prospectively recruited. Any previous NSAIDs were withdrawn 2 days before study start (baseline). Back pain was assessed using a numerical rating scale (NRS; range 0-10) starting at 2 hours after baseline and several times thereafter up to 4 weeks. "Any response" to NSAIDs was defined as improvement of back pain on the NRS > 2 units, and "good response" as improvement > 50%, compared to baseline., Results: Among 233 patients included, 68 had axSpA (29.2%) and 165 had non-SpA back pain (70.8%). The mean age was 42.7 (SD 10.7) vs 49.3 (SD 11.1) years, symptom duration 15.1 (SD 11.1) years vs 14.6 (SD 11.9) years, and pain score 5.9 (SD 2.3) vs 6.3 (SD 2.0), respectively. Overall, of patients with axSpA or non-SpA back pain, 30.9% vs 29.1% of patients showed any response and 23.5% vs 16.4% of patients showed a good response after 4 weeks, respectively ( P value not significant). No differences were found in the rapidity of response or between subgroups of patients based on demographics, including different stages of axSpA., Conclusion: No major differences in the response to NSAIDs were found between patients with axSpA and those with non-SpA with longstanding chronic back pain. The item in the Assessment of SpondyloArthritis international Society classification criteria on "response to NSAIDs" needs more study., (Copyright © 2024 by the Journal of Rheumatology.)

Objective: Axial spondyloarthritis (axSpA) is associated with decreased function and mobility of patients as a result of inflammation and radiographic damage. The Epionics SPINE device (ES), an electronic device that objectively measures spinal mobility, including range of motion (RoM) and speed (ie, range of kinematics [RoK]) of movement, has been clinically validated in axSpA. We investigated the performance of the ES relative to radiographic damage in the axial skeleton of patients with axSpA., Methods: A total of 103 patients with axSpA, 31 with nonradiographic axSpA (nr-axSpA) and 72 with radiographic axSpA (r-axSpA), were consecutively examined. Conventional radiographs of the spine (including presence, number, and location of syndesmophytes) and the sacroiliac joints (SIJs; rated by the modified New York criteria) were analyzed with the ES. Function and mobility were assessed using analyses of covariance and Spearman correlation., Results: The number of syndesmophytes correlated positively with Bath Ankylosing Spondylitis Metrology Index scores ( r 0.38, P = 0.02) and correlated negatively with chest expansion ( r -0.39, P = 0.02) and ES measurements (-0.53 ≤ r ≤ -0.34, all P < 0.03), except for RoM and RoK regarding rotation and RoK for extension of the lumbar and thoracic spines. In the radiographic evaluation of the SIJs, the extent of damage correlated negatively with ES scores and metric measurements (-0.49 ≤ r ≤ -0.33, all P < 0.001). Patients with r-axSpA, as compared to those with nr-axSpA, showed significantly worse ES scores for RoM, RoK, and chest expansion., Conclusion: The ES scores, in accordance with mobility measurements, correlated well with the presence and extent of radiographic damage in the spine and the SIJs. As expected, patients with r-axSpA had more severe impairments than those with nr-axSpA., (Copyright © 2023 by the Journal of Rheumatology.)

Objective: To assess the prevalence of foot insufficiency fractures (IF) in patients with rheumatic musculoskeletal disease (RMD) with foot pain., Methods: In a retrospective design, 1752 magnetic resonance imaging (MRI) scans of consecutive patients presenting with foot pain in 2 time periods between 2016 and 2018 were evaluated. The group with IF was matched with controls with foot pain without IF. Bone mineral density (BMD) was assessed by dual-energy x-ray absorptiometry. Multivariate analyses were performed., Results: A total of 1145 MRI scans of patients (median age 59 yrs, 82.9% female) with an inflammatory (65.4%) and of 607 with no inflammatory (34.6%) RMD (median age 58 yrs, 80.8% female) were available. Most patients had rheumatoid arthritis (RA; 42.2%), and others had psoriatic arthritis (22.4%), axial spondyloarthritis (11.1%), or connective tissue disease (CTD; 7.6%). Foot IF were found in 129 MRI scans of patients (7.5%). There was no difference between time periods. The prevalence of IF was highest in CTD (23%) and RA (11.4%). More patients with an inflammatory than a noninflammatory RMD had IF (9.1% vs 4.1%, respectively; P < 0.001). Using conventional radiography, IF were only detected in 25%. Low BMD and a history of fractures were more frequent in patients with IF than without (42.6% vs 16.2% and 34.9% vs 8.6%, respectively; P < 0.001)., Conclusion: A high prevalence of foot fractures was found in MRI scans of patients with RMD, many without osteoporosis. MRI was more sensitive than radiographs to detect IF., (Copyright © 2023 by the Journal of Rheumatology.)

CACNA1C encodes the pore-forming α1C subunit of the L-type Ca 2+ channel, Cav1.2. Mutations and polymorphisms of the gene are associated with neuropsychiatric and cardiac disease. Haploinsufficient Cacna1c +/- rats represent a recently developed model with a behavioral phenotype, but its cardiac phenotype is unknown. Here, we unraveled the cardiac phenotype of Cacna1c +/- rats with a main focus on cellular Ca 2+ handling mechanisms. Under basal conditions, isolated ventricular Cacna1c +/- myocytes exhibited unaltered L-type Ca 2+ current, Ca 2+ transients (CaTs), sarcoplasmic reticulum (SR) Ca 2+ load, fractional release, and sarcomere shortenings. However, immunoblotting of left ventricular (LV) tissue revealed reduced expression of Cav1.2, increased expression of SERCA2a and NCX, and augmented phosphorylation of RyR2 (at S2808) in Cacna1c +/- rats. The β-adrenergic agonist isoprenaline increased amplitude and accelerated decay of CaTs and sarcomere shortenings in both Cacna1c +/- and WT myocytes. However, the isoprenaline effect on CaT amplitude and fractional shortening (but not CaT decay) was impaired in Cacna1c +/- myocytes exhibiting both reduced potency and efficacy. Moreover, sarcolemmal Ca 2+ influx and fractional SR Ca 2+ release after treatment with isoprenaline were smaller in Cacna1c +/- than in WT myocytes. In Langendorff-perfused hearts, the isoprenaline-induced increase in RyR2 phosphorylation at S2808 and S2814 was attenuated in Cacna1c +/- compared to WT hearts. Despite unaltered CaTs and sarcomere shortenings, Cacna1c +/- myocytes display remodeling of Ca 2+ handling proteins under basal conditions. Mimicking sympathetic stress with isoprenaline unmasks an impaired ability to stimulate Ca 2+ influx, SR Ca 2+ release, and CaTs caused, in part, by reduced phosphorylation reserve of RyR2 in Cacna1c +/- cardiomyocytes.

Objective: To assess test-retest reliability, construct validity, known groups discrimination, and responsiveness of the Assessment of the SpondyloArthritis international Society Health Index (ASAS HI) to evaluate functioning, disability, and health in patients with radiographic axial spondyloarthritis (r-axSpA)., Methods: Data were generated from 2 randomized, placebo-controlled, active-controlled phase III ixekizumab studies (COAST-V, N = 341; COAST-W, N = 316). Assessments included the following: test-retest reliability (ie, intraclass correlation coefficients [ICCs] between ASAS HI scores at screening and baseline), construct validity (ie, Spearman correlation with standard r-axSpA outcome measures), known groups discrimination (ie, 1-way ANOVA comparing the ASAS HI with different disease activity categories, measured by the Ankylosing Spondylitis Disease Activity Score [ASDAS]), and responsiveness (ie, Spearman correlation between changes in the ASAS HI and changes in the Bath Ankylosing Spondylitis Functional Index [BASFI], the Bath Ankylosing Spondylitis Disease Activity Index [BASDAI], the ASDAS, and the Patient Global Assessment [PtGA] as well as ANOVA comparing changes in the ASAS HI with various responder categories)., Results: The ICC for test-retest reliability was 0.78 for COAST-V and 0.76 for COAST-W, indicating adequate agreement. Moderate-to-large correlations ( r = 0.40-0.61) were observed between the ASAS HI and the BASDAI. Statistically significant differences (all P < 0.001) between mean ASAS HI scores were observed for subgroups based on ASDAS-defined disease activity categories at baseline and week 16. Moderate-to-large correlations existed between changes in the ASAS HI and the BASFI, BASDAI, ASDAS, and PtGA from baseline to week 16. The ASAS HI differentiated statistically ( P < 0.001) between ASAS, BASDAI, and ASDAS response groups., Conclusion: The ASAS HI demonstrated reliability, construct validity, known groups discrimination, and responsiveness in adults with r-axSpA in 2 clinical trials., (Copyright © 2023 by the Journal of Rheumatology.)

Objective: To assess the association between self-reported and performance-based physical functioning and to evaluate which performance tests are most frequently impaired in patients with axial spondyloarthritis (axSpA)., Methods: Consecutive patients with axSpA underwent standardized assessments including patient and disease characteristics; patient-reported outcomes for disease activity, functioning, depression, mobility, and physical activity; and performance tests. Patients were defined as being impaired if they were not able to perform ≥ 1 of the performance tests. Validated cut-offs were used to define impaired physical performance. Impairment of performance tests as well as discrimination between subgroups were analyzed., Results: A total of 200 patients (radiographic axSpA 66.5%, nonradiographic axSpA 33.5%) were included: 69% males, mean age 44.3 (SD 12.5) years, and mean symptom duration 17.9 (SD 12.6) years. The 2 most frequently impaired performance tests were the repeated chair stand test (n = 75, 37.5%) and putting on socks (n = 44, 22%). An impairment in ≥ 1 performance test was seen in 91 patients (45.5%). Patients with impairments were older (49.1 yrs vs 40.3 yrs); had a higher BMI (28.9 kg/m 2 vs 25.8 kg/m 2 ); a more active disease (Ankylosing Spondylitis Disease Activity Score, 3.0 vs 2.1); higher Bath Ankylosing Spondylitis Functional Index (BASFI; 5.8 vs 2.7), Bath Ankylosing Spondylitis Metrology Index (BASMI; 4.4 vs 2.7), and Assessment of Spondyloarthritis international Society Health Index scores (9.5 vs 4.9); and higher depression screen values (9-item Patient Health Questionnaire, 11.6 vs 6.5; all P < 0.01)., Conclusion: Many patients with axSpA had impairments in physical performance tests. Importantly, this was frequently seen in tasks requiring coordination and muscle power of the lower extremity. Performance tests provide qualitatively different information than BASFI and BASMI assessments in patients with axSpA., (Copyright © 2023 by the Journal of Rheumatology.)

Objective: The Assessment of Spondyloarthritis international Society Health Index (ASAS HI) measures global functioning and health in patients with axial spondyloarthritis (axSpA) covering domains of physical, emotional, and social functioning. The main aim of this study was to investigate the sensitivity to change of ASAS HI in comparison with established variables of disease activity, function, and mental health., Methods: Patients with axSpA from the disease register RABBIT-SpA with follow-up time of at least 12 months and available ASAS HI questionnaires were included. Patients received questionnaires addressing disease activity (Bath Ankylosing Spondylitis Disease Activity Index [BASDAI], Ankylosing Spondylitis Disease Activity Score [ASDAS]), physical function (Bath Ankylosing Spondylitis Functional Index [BASFI]), mental health (5-item World Health Organization Well-Being Index [WHO-5]), and global functioning (ASAS HI). Standardized response means (SRMs) were calculated to compare the sensitivity to change of different variables., Results: Six hundred and sixty-seven patients were included, 552 treated with biologic disease-modifying antirheumatic drugs (bDMARDs) and 115 with conventional synthetic DMARDs and/or nonsteroidal antiinflammatory drugs (control group). Between baseline and month 12, the mean ASAS HI declined from 6.9 to 5.1 in the bDMARD group and from 5.9 to 5.6 in the conventionally treated group. In the bDMARD group, the SRM of ASAS HI was 0.52, compared to 0.59 for BASFI, 0.65 for WHO-5, 0.73 for BASDAI, and 0.90 for ASDAS. The following ASAS HI domains were most frequently affected: pain (78% agreed), maintaining body position (75%), and energy/drive (73%). In the patients receiving bDMARDs, there was an improvement in all items. In the control group, the largest improvement was seen in pain., Conclusion: As expected, ASDAS and BASDAI as disease activity scores showed high sensitivity to change, whereas changes in physical function (BASFI), mental health (WHO-5), and the broader concept of functioning and health (ASAS HI) were moderate., (Copyright © 2023 by the Journal of Rheumatology.)

Bipolar disorder (BD) is a chronic mood disorder characterized by manic and depressive episodes. Dysregulation of neuroplasticity and calcium homeostasis are frequently observed in BD patients, but the underlying molecular mechanisms are largely unknown. Here, we show that miR-499-5p regulates dendritogenesis and cognitive function by downregulating the BD risk gene CACNB2. miR-499-5p expression is increased in peripheral blood of BD patients, as well as in the hippocampus of rats which underwent juvenile social isolation. In rat hippocampal neurons, miR-499-5p impairs dendritogenesis and reduces surface expression and activity of the L-type calcium channel Cav1.2. We further identified CACNB2, which encodes a regulatory β-subunit of Cav1.2, as a direct functional target of miR-499-5p in neurons. miR-499-5p overexpression in the hippocampus in vivo induces short-term memory impairments selectively in rats haploinsufficient for the Cav1.2 pore forming subunit Cacna1c. In humans, miR-499-5p expression is negatively associated with gray matter volumes of the left superior temporal gyrus, a region implicated in auditory and emotional processing. We propose that stress-induced miR-499-5p overexpression contributes to dendritic impairments, deregulated calcium homeostasis, and neurocognitive dysfunction in BD., (© 2022 The Authors. Published under the terms of the CC BY 4.0 license.)

Objective: To investigate the performance of a health app with respect to usability, adherence, and equivalence of data in daily care of patients with axial spondyloarthritis (axSpA)., Methods: Consecutive patients with axSpA were asked to export patient-reported outcomes (PRO) electronically with the AxSpA Live App regularly every 2 weeks over a period of 6 months. The first clinical visit was followed by 2 further personal visits after 3 and 6 months. Patients completed paper-based PRO at every visit; they also completed the Mobile App Rating Scale and the System Usability Scale after 3 and 6 months., Results: Of 103 patients with axSpA, 69 agreed to participate (67.0%): age 41.5 (11.3) years, 58.0% male, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) 4.3 (2.0), and 76.8% treated with biologic disease-modifying antirheumatic drugs. Patients' adherence to regular app exports was 29.0% and 28.4% after 3 and 6 months, respectively. Significant predictors for good adherence were high disease activity ( P = 0.02) and older age ( P = 0.04). No systematic differences between digital and paper-based BASDAI scores were found (intraclass correlation coefficients 0.99 [95% CI 0.98-0.99]). Performance of the app was rated as good., Conclusion: Collection of digital PROs by AxSpA Live App may be successfully used in patients with axSpA with high disease activity. Our study showed equivalence of digital data, but adherence to the app after 6 months was poor. Higher disease activity and older age resulted in increased adherence to the app. This suggests that the use of health apps like this should concentrate on more severely affected patients., (Copyright © 2022 by the Journal of Rheumatology.)

Objective: Epionics SPINE (ES), a novel device that measures spinal movements using electronic sensors including range of motion (RoM) and speed (range of kinematics [RoK]), has already been validated in patients with mechanical back pain and healthy individuals. This study aimed to evaluate ES for quantification of spinal mobility in patients with axial spondyloarthritis (axSpA)., Methods: A total of 153 individuals, 39 female and 114 male, were examined including 134 patients with axSpA, of whom 40 had nonradiographic (nr)-axSpA, 94 had radiographic (r)-axSpA; 19 were healthy controls (HCs). The results were compared using mean ES scores and modeling was performed using multivariable logistic regression models resulting in good validity and high discriminative power., Results: ES measurements showed meaningful differences between patients with axSpA and HCs (all P < 0.001), as well as between r- and nr-axSpA ( P < 0.01). In patients with axSpA, a negative correlation between ES and Bath Ankylosing Spondylitis Metrology Index values was found: -0.76 ≤ r ≤ -0.52 ( P < 0.05). Bath Ankylosing Spondylitis Functional Index scores showed a similar trend ( r > -0.39). Patients with r-axSpA had a more limited and slower spinal mobility than those with nr-axSpA. Other patient-reported outcomes almost did not correlate., Conclusion: This study shows that the ES is an objective performance measure and a valid tool to assess spinal mobility in axSpA, also based on the Outcomes Measures in Rheumatology (OMERACT) criteria. RoK and RoM scores provide additional information on physical function of patients with axSpA., (© 2022 The Journal of Rheumatology.)

Objective: This study evaluated the effect of ixekizumab (IXE) on self-reported functioning and health in patients with radiographic axial spondyloarthritis (r-axSpA) who were either biological disease-modifying antirheumatic drug (bDMARD)-naïve or failed at least 1 tumor necrosis factor inhibitor (TNFi)., Methods: In 2 multicenter, randomized, double-blind, placebo-controlled, and active-controlled (bDMARD-naïve only) trials, patients with r-axSpA were randomly assigned to receive 80 mg of IXE [every 2 weeks (Q2W) or every 4 weeks (Q4W)], placebo (PBO), or adalimumab (ADA; bDMARD-naïve only). After 16 weeks, patients who received PBO or ADA were rerandomized to receive IXE (Q2W or Q4W) up to Week 52. Functioning and health were measured by the generic 36-item Short Form Health Survey (SF-36) and the disease-specific Assessment of Spondyloarthritis international Society Health Index (ASAS HI). Societal health utility was assessed by the 5-level EuroQol-5 Dimension (EQ-5D-5L)., Results: At Week 16, both doses of IXE in bDMARD-naïve and TNFi-experienced patients resulted in larger improvement in SF-36, ASAS HI, and EQ-5D-5L versus placebo. For SF-36, the largest improvements were seen for the domains of bodily pain, physical function, and role physical. A larger proportion of patients reaching improvement in ASAS HI ≥ 3 as well as an achievement of ASAS HI good health status was reported in patients treated with IXE. Improvements were maintained through Week 52., Conclusion: IXE significantly improved functioning and health as assessed by both generic and disease-specific measures, as well as societal health utility values in patients with r-axSpA, as measured by SF-36, ASAS HI, and EQ-5D-5L at Week 16, and improvements were sustained through 52 weeks., (Copyright © 2021 by the Journal of Rheumatology.)

Introduction: This retrospective analysis assessed geographic atrophy (GA) progression in fellow eyes from the Proxima B trial intermediate age-related macular degeneration (iAMD) subcohort using high-resolution multimodal imaging anchored on optical coherence tomography (OCT)., Methods: Thirty-two patients from the Proxima B iAMD subcohort were assessed; all had GA with no macular neovascularization (MNV) in the contralateral eye. Imaging data, including color fundus photography, fluorescein angiography, near-infrared reflectance, fundus autofluorescence (FAF), and spectral-domain OCT, were obtained. Features preceding progression/conversion to advanced AMD (drusen, reticular pseudodrusen [RPD], MNV, incomplete/complete retinal pigment epithelium and outer retinal atrophy [iRORA/cRORA]) were assessed., Results: Of 30 fellow eyes with available follow-up images, 12 converted to GA (FAF), 2 converted to MNV, and 16 were nonconverters during the review period (median: 17.8 months). iRORA/cRORA features (present in all converters at baseline) were identified on OCT in eyes that progressed to GA. Median time interval from iRORA to cRORA and from cRORA to GA was 7 months each. GA development/progression was either drusen- or RPD-associated (n = 6 each). Eyes with baseline RPD showed faster GA progression versus eyes with drusen (1.49 vs. 0.38 mm2/year)., Conclusions: RPD presence was associated with rapid GA lesion enlargement and may provide an early indication of faster GA progression., (© 2021 The Author(s) Published by S. Karger AG, Basel.)

As cross-disorder risk gene, CACNA1C is implicated in the etiology of all major neuropsychiatric disorders characterized by deficits in social behavior and communication and there is evidence for sex-dependent influences of single-nucleotide polymorphisms within CACNA1C on diagnosis, course, and recovery in humans. In this study, we aimed, therefore, at further exploring the role of Cacna1c in regulating behavioral phenotypes, focusing on sex-specific differences in social behavior and communication during the critical developmental period of adolescence in rats. Specifically, we compared rough-and-tumble play, concomitant emission of pro-social 50-kHz ultrasonic vocalizations, and social approach behavior in response to playback of 50-kHz ultrasonic vocalizations between constitutive heterozygous Cacna1c +/- females and wildtype Cacna1c +/+ littermate controls, and contrasted present female findings to data previously reported in males. Our results show for the first time that partial depletion of Cacna1c leads to sex-dependent alterations in social behavior and communication in rats. In females, Cacna1c haploinsufficiency led to hypermasculinization, with rough-and-tumble play behavior, in general, and pinning behavior, in particular, being even higher than in males without affecting concomitant 50-kHz ultrasonic vocalizations. In males, in contrast, rough-and-tumble play behavior was not altered, yet emission of 50-kHz ultrasonic vocalizations was diminished following partial Cacna1c depletion. The behavioral responses elicited by playback of 50-kHz ultrasonic vocalizations were reduced upon partial Cacna1c depletion in both sexes. It thus can be concluded that Cacna1c plays a prominent sex-dependent role in regulating juvenile rat social play behavior and pro-social 50-kHz ultrasonic communication with relevance to sex-specific effects seen in neuropsychiatric disorders., (© 2018 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.)

Objective: International recommendations for the management of axial spondyloarthritis including ankylosing spondylitis (AS) recommend a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) level of disease activity of ≥ 4 to initiate treatment with biologics. We aimed to evaluate the level of disease activity used to initiate tumor necrosis factor inhibitor (TNFi) treatment and the level of responses to treatment based on different BASDAI cutoffs., Methods: This is a posthoc analysis of the noninterventional, prospective, GO-NICE study in the subgroup of biologic-naive AS treated with golimumab (GOL) 50 mg subcutaneously once monthly., Results: Of the 244 biologic-naive AS patients at baseline, 70.5% had a BASDAI ≥ 4 (Group 1), 14.3% had 2.8 to < 4 (Group 2), and 15.2% had even < 2.8 (Group 3). A total of 134 patients (54.9%) completed the 24-month observational period. The mean BASDAI in Groups 1, 2, and 3 was initially 5.9 ± 1.3, 3.4 ± 0.4, and 2.0 ± 0.8, decreased to 2.2 ± 2.0, 1.9 ± 1.2, and 1.0 ± 1.2 within 3 months (all p < 0.0001 vs baseline), and decreased significantly to 2.2 ± 1.7, 1.9 ± 1.7, and 1.4 ± 1.0 at Month 24 (all p < 0.005), respectively. BASDAI 50% improvement was noted in 68.8%, 44.8%, and 45.2% of patients at Month 3, and in 84.9%, 61.9%, and 55.0% at Month 24., Conclusion: TNFi treatment was initiated in almost a third of AS patients with lower disease activity states as assessed by BASDAI cutoff of ≥ 4. Patients with a BASDAI between 2.8 and < 4 appeared to benefit significantly from GOL treatment, while patients with BASDAI < 2.8 did not. This finding should lead to a reevaluation of the established BASDAI cutoff of ≥ 4.

Genetic and environmental influences are thought to interact in their contribution to the etiology of major neuropsychiatric disorders. One of the best replicated findings obtained in genome-wide association studies are genetic variants in the CACNA1C gene. Here, we used our constitutive heterozygous Cacna1c rat model in combination with a 4-week exposure to either post-weaning social isolation, standard housing or social and physical environmental enrichment during the critical juvenile developmental period to observe their long-term interactive effects with Cacna1c haploinsufficiency. Our study provides evidence for a gene × environment interaction, i.e. an interplay between Cacna1c haploinsufficiency and environment during juvenile development, on object recognition, spatial memory and reversal learning capabilities. Social and physical enrichment had a positive influence on Cacna1c+/- rats and Cacna1c+/+ littermate controls on spatial and reversal learning, while post-weaning social isolation negatively affected novel object recognition in both genotypes. Despite intact spatial learning and re-learning abilities in all groups, slight but consistent deficits were evident in Cacna1c+/- rats previously housed under standard conditions particularly during reversal learning but not Cacna1c+/- rats previously exposed to social and physical enrichment. Together, this supports the notion that Cacna1c interacts with the environment to shape disease vulnerability and associated alterations in cognitive functioning., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: The volumetric interpolated breath-hold examination (VIBE) magnetic resonance imaging (MRI) technique can visualize erosive cartilage defects in peripheral joints. We evaluated the ability of VIBE to detect erosions in sacroiliac joints (SIJ) of patients with axial spondyloarthritis (axSpA) compared to the established T1-weighted MRI sequence and computed tomography (CT)., Methods: MRI (T1-weighted and VIBE) and CT scans of SIJ of 109 patients with axSpA were evaluated by 2 blinded readers based on SIJ quadrants (SQ). Erosions were defined according to Assessment of Spondyloarthritis international Society (ASAS) definitions. Scores were recorded if readers were in agreement., Results: Erosions were less frequently detected by CT (153 SQ) than by T1-weighted MRI (182 SQ; p = 0.008) and VIBE-MRI (199 SQ; p < 0.001 vs CT and p = 0.031 vs T1-weighted MRI). Taking CT as the gold standard, the sensitivity of VIBE-MRI (71.2%) was higher than that for T1-weighted MRI (63.4%), with similar specificity (87.3% vs 88%, respectively). In linear regression analysis, younger age was significantly associated with occurrence of erosions independently in VIBE-MRI (β = 0.384, p < 0.001) and T1-weighted MRI (β = 0.369, p < 0.001) compared to CT., Conclusion: The VIBE-MRI sequence was more sensitive than T1-weighted MRI in identifying erosive damage in the SIJ, especially in younger patients. This might be due to the ability of VIBE-MRI to identify structural changes in the cartilage that have not yet extended to the underlying bone, where CT seems to be superior.

The pathophysiology of neuropsychiatric disorders involves complex interactions between genetic and environmental risk factors. Confirmed by several genome-wide association studies, Cacna1c represents one of the most robustly replicated psychiatric risk genes. Besides genetic predispositions, environmental stress such as childhood maltreatment also contributes to enhanced disease vulnerability. Both, Cacna1c gene variants and stressful life events are associated with morphological alterations in the prefrontal cortex and the hippocampus. Emerging evidence suggests impaired mitochondrial bioenergetics as a possible underlying mechanism of these regional brain abnormalities. In the present study, we simulated the interaction of psychiatric disease-relevant genetic and environmental factors in rodents to investigate their potential effect on brain mitochondrial function using a constitutive heterozygous Cacna1c rat model in combination with a four-week exposure to either post-weaning social isolation, standard housing, or social and physical environmental enrichment. Mitochondria were isolated from the prefrontal cortex and the hippocampus to evaluate their bioenergetics, membrane potential, reactive oxygen species production, and respiratory chain complex protein levels. None of these parameters were considerably affected in this particular gene-environment setting. These negative results were very robust in all tested conditions demonstrating that Cacna1c depletion did not significantly translate into altered bioenergetic characteristics. Thus, further investigations are required to determine the disease-related effects on brain mitochondria., (Copyright © 2019 Michels, Dolga, Braun, Kisko, Sungur, Witt, Rietschel, Dempfle, Wöhr, Schwarting and Culmsee.)

The CACNA1C gene is strongly implicated in the etiology of multiple major neuropsychiatric disorders, such as bipolar disorder, major depression, and schizophrenia, with cognitive deficits being a common feature. It is unclear, however, by which mechanisms CACNA1C variants advance the risk of developing neuropsychiatric disorders. This study set out to investigate cognitive functioning in a newly developed genetic Cacna1c rat model. Specifically, spatial and reversal learning, as well as object recognition memory were assessed in heterozygous Cacna1c +/- rats and compared to wildtype Cacna1c +/+ littermate controls in both sexes. Our results show that both Cacna1c +/+ and Cacna1c +/- animals were able to learn the rewarded arm configuration of a radial maze over the course of seven days. Both groups also showed reversal learning patterns indicative of intact abilities. In females, genotype differences were evident in the initial spatial learning phase, with Cacna1c +/- females showing hypo-activity and fewer mixed errors. In males, a difference was found during probe trials for both learning phases, with Cacna1c +/- rats displaying better distinction between previously baited and non-baited arms; and regarding cognitive flexibility in favor of the Cacna1c +/+ animals. All experimental groups proved to be sensitive to reward magnitude and fully able to distinguish between novel and familiar objects in the novel object recognition task. Taken together, these results indicate that Cacna1c haploinsufficiency has a minor, but positive impact on (spatial) memory functions in rats., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The cross-disorder risk gene CACNA1C is strongly implicated in multiple neuropsychiatric disorders, including autism spectrum disorder (ASD), bipolar disorder (BPD) and schizophrenia (SCZ), with deficits in social functioning being common for all major neuropsychiatric disorders. In the present study, we explored the role of Cacna1c in regulating disorder-relevant behavioral phenotypes, focusing on socio-affective communication after weaning during the critical developmental period of adolescence in rats. To this aim, we used a newly developed genetic Cacna1c rat model and applied a truly reciprocal approach for studying communication through ultrasonic vocalizations, including both sender and receiver. Our results show that a deletion of Cacna1c leads to deficits in social behavior and pro-social 50-kHz ultrasonic communication in rats. Reduced levels of 50-kHz ultrasonic vocalizations emitted during rough-and-tumble play may suggest that Cacna1c haploinsufficient rats derive less reward from playful social interactions. Besides the emission of fewer 50-kHz ultrasonic vocalizations in the sender, Cacna1c deletion reduced social approach behavior elicited by playback of 50-kHz ultrasonic vocalizations. This indicates that Cacna1c haploinsufficiency has detrimental effects on 50-kHz ultrasonic communication in both sender and receiver. Together, these data suggest that Cacna1c plays a prominent role in regulating socio-affective communication in rats with relevance for ASD, BPD and SCZ.This article has an associated First Person interview with the first author of the paper., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2018. Published by The Company of Biologists Ltd.)