Hepatotoxicity of antipsychotics: an exploratory pharmacoepidemiologic and pharmacodynamic study integrating FAERS data and in vitro receptor-binding affinities.

Introduction: Antipsychotic psychopharmacotherapy is associated with the risk of drug-induced liver injury (DILI). However, understanding specific risk factors remains challenging due to limited data. This study investigates the relationship between receptor binding affinities and occupancies of antipsychotics and their associated hepatotoxic risks. Methods: A disproportionality analysis with calculation of the Reporting Odds Ratio (ROR) and the Information Component (IC) was conducted using data from the FDA Adverse Event Reporting System (FAERS) to identify signals related to the Standardised MedDRA Query "drug-related hepatic disorders", which served as a proxy for drug-induced hepatotoxicity. This was followed by a pharmacoepidemiologic-pharmacodynamic approach to investigate the relationship between the ROR and substance-related receptor binding affinities and occupancy, which was estimated based on in vitro receptor-binding profiles. Results: Significant signals were identified for several antipsychotics, including chlorpromazine, loxapine, olanzapine, and quetiapine, with chlorpromazine and loxapine showing the highest RORs for DILI. Gender-specific analysis revealed a higher frequency of signals in female patients. Statistically significant negative correlations were identified between the ROR for drug-related hepatic disorders and the affinity for serotonin receptor 5-HT1A (r (17) = -0.68, p = 0.0012), while a positive correlation was observed for cholinergic receptors (r (17) = 0.46, p = 0.048). No significant correlations were found related to other receptors or drug properties. Conclusion: Our findings suggest that the serotonin and probably the cholinergic system may play a role in the development of DILI related to antipsychotic medications. The identification of antipsychotics with a higher association with DILI, such as chlorpromazine, underscores the need for careful monitoring in clinical practice. However, our findings need further longitudinal studies to confirm causality. A better understanding of the associations may inform clinical decision-making, particularly in patients with an increased susceptibility to liver damage.

Dark-Sector Search via Pion-Produced η and η

We present the first results from a proof-of-concept search for dark sectors via invisible decays of pseudoscalar η and η^{'} mesons in the NA64h experiment at the CERN SPS. Our novel technique uses the charge-exchange reaction of 50 GeV π^{-} on nuclei of an active target as the source of neutral mesons. The η,η^{'}→invisible events would exhibit themselves via a striking signature-the complete disappearance of the incoming beam energy in the detector. No evidence for such events has been found with 2.9×10^{9} pions on target accumulated during one day of data taking. This allows us to set a stringent limit on the branching ratio Br(η^{'}→invisible)<2.1×10^{-4} improving the current bound by a factor of ≃3. We also set a limit on Br(η→invisible)<1.1×10^{-4} comparable with the existing one. These results demonstrate the great potential of our approach and provide clear guidance on how to enhance and extend the sensitivity for dark sector physics from future searches for invisible neutral meson decays.

Prevalence, risk factors, microbiological results and clinical outcome in unexpected positive intraoperative cultures in unclear and presumed aseptic hip and knee revision arthroplasties - A ten-year retrospective analysis with a minimum follow up of 2 years.

Background: The aim of this study was to assess the prevalence, microbiological spectrum, risk factors, and clinical outcomes of unexpected-positive-intraoperative-cultures (UPIC) in presumed aseptic and unclear revision-total-hip-/knee-arthroplasties (rTHA and rTKA) compared to culture-negative (CN) revisions. Methods: This study reviewed all International-consensus-meeting-2018 (ICM 2018) negative or inconclusive rTHA (n = 751) and rTKA (n = 679) performed at our institution from 2011 to 2020 with a minimum follow-up of two years. A Kaplan-Meier-analysis was performed to determine the septic and aseptic-free implant survival in cases with UPIC's and matched culture-negative cases. Patient demographics, risk factors, microbiological spectrum and clinical outcomes were evaluated. Results: There were significantly more UPIC cases in rTHA 196/751 (26.1 %) compared to rTKA 113/679 (16.6 %); (p < 0.001). UPICs in rTKA and rTHA have a lower septic and aseptic implant-free-survival compared to CN revisions. Patients with a history of nickel allergy have a higher risk of an UPIC in rTHA and rTKA (p < 0.001). Septic re-revisions after UPIC had a significantly (H: p = 0.004; K: p = 0.030) shorter time period to the primary/previous surgery (H: 84 (IQR:41-797); K: 115 (IQR:55-446)) compared to patients with aseptic re-revisions after UPIC (H:1248 (IQR:178-3534); K: 827 (IQR:361-1183)). Conclusion: UPICs have a higher rate of septic and aseptic failure than CN outcomes. UPICs are twice as common in rTHA compared to rTKA. Preoperative PJI workup reduces the UPIC rate. Nickel allergy is a risk factor for UPIC. Early revisions with UPICs after primary THA or TKA have a higher risk of septic failure. The translational potential of this article: This article provides new information on revision rates for UPIC and potential risk factors for UPIC and its treatment failure.

[Outpatient treatment for hernia surgery in Germany]. / Ambulantisierung in der Hernienchirurgie in Deutschland.

Outpatient surgery in the treatment of hernia is currently a major challenge for patients and treating physicians in Germany due to the new legal regulations (key term hybrid diagnosis-related groups, DRG). Despite large economic challenges and empty funds, the principle of medical treatment is still the patient-oriented scientifically founded medicine. Although outpatient treatment would be very desirable, clear medical knowledge should the basis for the justification of surgical strategies: outpatient short hospitalization (24h) or fully inpatient hospitalization (>24h). A completely outpatient treatment of hernias is not meaningful and the demarcation of outpatient, short inpatient and inpatient treatment should be demonstrated in a risk-adjusted manner. A classification is essential, particularly against the background of an intersectoral hybrid DRG.

High-Statistics Measurement of Collins and Sivers Asymmetries for Transversely Polarized Deuterons.

New results are presented on a high-statistics measurement of Collins and Sivers asymmetries of charged hadrons produced in deep inelastic scattering of muons on a transversely polarized ^{6}LiD target. The data were taken in 2022 with the COMPASS spectrometer using the 160 GeV muon beam at CERN, statistically balancing the existing data on transversely polarized proton targets. The first results from about two-thirds of the new data have total uncertainties smaller by up to a factor of three compared to the previous deuteron measurements. Using all the COMPASS proton and deuteron results, both the transversity and the Sivers distribution functions of the u and d quark, as well as the tensor charge in the measured x range are extracted. In particular, the accuracy of the d quark results is significantly improved.

Perioperative Durvalumab with Neoadjuvant Chemotherapy in Operable Bladder Cancer.

BACKGROUND: Neoadjuvant chemotherapy followed by radical cystectomy is the standard treatment for cisplatin-eligible patients with muscle-invasive bladder cancer. Adding perioperative immunotherapy may improve outcomes. METHODS: In this phase 3, open-label, randomized trial, we assigned, in a 1:1 ratio, cisplatin-eligible patients with muscle-invasive bladder cancer to receive neoadjuvant durvalumab plus gemcitabine-cisplatin every 3 weeks for four cycles, followed by radical cystectomy and adjuvant durvalumab every 4 weeks for eight cycles (durvalumab group), or to receive neoadjuvant gemcitabine-cisplatin followed by radical cystectomy alone (comparison group). Event-free survival was one of two primary end points. Overall survival was the key secondary end point. RESULTS: In total, 533 patients were assigned to the durvalumab group and 530 to the comparison group. The estimated event-free survival at 24 months was 67.8% (95% confidence interval [CI], 63.6 to 71.7) in the durvalumab group and 59.8% (95% CI, 55.4 to 64.0) in the comparison group (hazard ratio for progression, recurrence, not undergoing radical cystectomy, or death from any cause, 0.68; 95% CI, 0.56 to 0.82; P<0.001 by stratified log-rank test). The estimated overall survival at 24 months was 82.2% (95% CI, 78.7 to 85.2) in the durvalumab group and 75.2% (95% CI, 71.3 to 78.8) in the comparison group (hazard ratio for death, 0.75; 95% CI, 0.59 to 0.93; P = 0.01 by stratified log-rank test). Treatment-related adverse events of grade 3 or 4 in severity occurred in 40.6% of the patients in the durvalumab group and in 40.9% of those in the comparison group; treatment-related adverse events leading to death occurred in 0.6% in each group. Radical cystectomy was performed in 88.0% of the patients in the durvalumab group and in 83.2% of those in the comparison group. CONCLUSIONS: Perioperative durvalumab plus neoadjuvant chemotherapy led to significant improvements in event-free survival and overall survival as compared with neoadjuvant chemotherapy alone. (Funded by AstraZeneca; NIAGARA ClinicalTrials.gov number, NCT03732677; EudraCT number, 2018-001811-59.).

Prosthetic Joint Infections due to Candida Species: A Multicenter International Study.

BACKGROUND: Prosthetic joint infection (PJI) caused by Candida spp is a severe complication of arthroplasty. We investigated the outcomes of Candida PJI. METHODS: This was a retrospective observational multinational study including patients diagnosed with Candida-related PJI between 2010 and 2021. Treatment outcome was assessed at 2-year follow-up. RESULTS: A total of 269 patients were analyzed. Median age was 73.0 (interquartile range [IQR], 64.0-79.0) years; 46.5% of patients were male and 10.8% were immunosuppressed. Main infection sites were hip (53.0%) and knee (43.1%), and 33.8% patients had fistulas. Surgical procedures included debridement, antibiotics, and implant retention (DAIR) (35.7%), 1-stage exchange (28.3%), and 2-stage exchange (29.0%). Candida spp identified were Candida albicans (55.8%), Candida parapsilosis (29.4%), Candida glabrata (7.8%), and Candida tropicalis (5.6%). Coinfection with bacteria was found in 51.3% of cases. The primary antifungal agents prescribed were azoles (75.8%) and echinocandins (30.9%), administered for a median of 92.0 (IQR, 54.5-181.3) days. Cure was observed in 156 of 269 (58.0%) cases. Treatment failure was associated with age >70 years (OR, 1.811 [95% confidence interval {CI}: 1.079-3.072]), and the use of DAIR (OR, 1.946 [95% CI: 1.157-3.285]). Candida parapsilosis infection was associated with better outcome (OR, 0.546 [95% CI: .305-.958]). Cure rates were significantly different between DAIR versus 1-stage exchange (46.9% vs 67.1%, P = .008) and DAIR versus 2-stage exchange (46.9% vs 69.2%, P = .003), but there was no difference comparing 1- to 2-stage exchanges (P = .777). CONCLUSIONS: Candida PJI prognosis seems poor, with high rate of failure, which does not appear to be linked to immunosuppression, use of azoles, or treatment duration.

Final COMPASS Results on the Transverse-Spin-Dependent Azimuthal Asymmetries in the Pion-Induced Drell-Yan Process.

The COMPASS Collaboration performed measurements of the Drell-Yan process in 2015 and 2018 using a 190 GeV/c π^{-} beam impinging on a transversely polarized ammonia target. Combining the data of both years, we present final results on the amplitudes of five azimuthal modulations, which correspond to transverse-spin-dependent azimuthal asymmetries (TSAs) in the dimuon production cross section. Three of them probe the nucleon leading-twist Sivers, transversity, and pretzelosity transverse-momentum dependent (TMD) parton distribution functions (PDFs). The other two are induced by subleading effects. These TSAs provide unique new inputs for the study of the nucleon TMD PDFs and their universality properties. In particular, the Sivers TSA observed in this measurement is consistent with the fundamental QCD prediction of a sign change of naive time-reversal-odd TMD PDFs when comparing the Drell-Yan process with deep inelastic scattering. Also, within the context of model predictions, the observed transversity TSA is consistent with the expectation of a sign change for the Boer-Mulders function.

High Demand for Psychological Support in Patients Who Have Periprosthetic Hip and Knee Joint Infections: An Analysis of 13,976 Patients.

BACKGROUND: There is only sparse knowledge on the psychological burden of patients who have periprosthetic joint infections. The aim of our study was to assess the need for psychological support following total joint arthroplasty of the hip and knee. A special focus was set on patients who had aseptic and septic complications. METHODS: A total of 13,976 patients who underwent total hip (n = 6,926) or total knee arthroplasty (n = 7,050) between January 1, 2012 and December 31, 2019 at a single institution were retrospectively evaluated for the postoperative need for a psychological consultation. Data were collected on age, sex, type of surgery, and indications for revision procedures. The need for a psychological consultation was assessed during the daily postoperative visits, which were further coordinated by 2 institutional psychologists. RESULTS: The average age was 68 years (range, 12 to 100), and there were 63.5% women. The overall rate of psychological consultations was 1.7%. Patients who had a septic indication for revision surgery had an 18.7-fold higher rate of postoperative psychological consultations compared to patients following primary surgery and a 5.4-fold higher rate compared to patients who had an aseptic indication. In detail, this rate was 1.0% in the primary subgroup, compared to 7.7% following revision arthroplasty (P < .001). In the revision subgroup, the rate was 17.9% for septic and 3.3% for aseptic revision arthroplasty cases (P < .001). Postoperative psychological consultations were twice as frequent in women (2.1%) compared to men (1.0%), P < .001. CONCLUSIONS: The present study raises awareness of the markedly high psychological burden in revision arthroplasty cases, in the view of the high estimated number of unknown cases. There is a significant correlation between periprosthetic joint infectionsand the postoperative need for a psychological consultation, with women being at an even higher risk. Health care providers should aim at offering psychological support for patients who have a septic complication, with affected patients being at risk for psychological stress. LEVEL OF EVIDENCE: IV.

The role of BioFire Joint Infection Panel in diagnosing periprosthetic hip and knee joint infections in patients with unclear conventional microbiological results.

Aims: This study aimed to evaluate the BioFire Joint Infection (JI) Panel in cases of hip and knee periprosthetic joint infection (PJI) where conventional microbiology is unclear, and to assess its role as a complementary intraoperative diagnostic tool. Methods: Five groups representing common microbiological scenarios in hip and knee revision arthroplasty were selected from our arthroplasty registry, prospectively maintained PJI databases, and biobank: 1) unexpected-negative cultures (UNCs), 2) unexpected-positive cultures (UPCs), 3) single-positive intraoperative cultures (SPCs), and 4) clearly septic and 5) aseptic cases. In total, 268 archived synovial fluid samples from 195 patients who underwent acute/chronic revision total hip or knee arthroplasty were included. Cases were classified according to the International Consensus Meeting 2018 criteria. JI panel evaluation of synovial fluid was performed, and the results were compared with cultures. Results: The JI panel detected microorganisms in 7/48 (14.5%) and 15/67 (22.4%) cases related to UNCs and SPCs, respectively, but not in cases of UPCs. The correlation between JI panel detection and infection classification criteria for early/late acute and chronic PJI was 46.6%, 73%, and 40%, respectively. Overall, the JI panel identified 12.6% additional microorganisms and three new species. The JI panel pathogen identification showed a sensitivity and specificity of 41.4% (95% confidence interval (CI) 33.7 to 49.5) and 91.1% (95% CI 84.7 to 94.9), respectively. In total, 19/195 (9.7%) could have been managed differently and more accurately upon JI panel evaluation. Conclusion: Despite its microbial limitation, JI panel demonstrated clinical usefulness by complementing the traditional methods based on multiple cultures, particularly in PJI with unclear microbiological results.

Targeted mapping and utilization of the perihepatic surface for therapeutic beta cell replacement and retrieval in diabetic non-human primates.

Introduction: Successful diabetes reversal using pancreatic islet transplantation by various groups illustrates the significant achievements made in cell-based diabetes therapy. While clinically, intraportal islet delivery is almost exclusively used, it is not without obstacles, including instant blood-mediated inflammatory reaction (IBMIR), relative hypoxia, and loss of function over time, therefore hindering long-term success. Here we demonstrate the perihepatic surface of non-human primates (NHPs) as a potential islet delivery site maximizing favorable characteristics, including proximity to a dense vascular network for adequate oxygenation while avoiding IBMIR exposure, maintenance of portal insulin delivery, and relative ease of accessibility through minimally invasive surgery or percutaneous means. In addition, we demonstrate a targeted mapping technique of the perihepatic surface, allowing for the testing of multiple experimental conditions, including a semi-synthetic hydrogel as a possible three-dimensional framework to improve islet viability. Methods: Perihepatic allo-islet cell transplants were performed in immunosuppressed cynomolgus macaques using a targeted mapping technique to test multiple conditions for biocompatibility. Transplant conditions included islets or carriers (including hydrogel, autologous plasma, and media) alone or in various combinations. Necropsy was performed at day 30, and histopathology was performed to assess biocompatibility, immune response, and islet viability. Subsequently, single-injection perihepatic allo-islet transplant was performed in immunosuppressed diabetic cynomolgus macaques. Metabolic assessments were measured frequently (i.e., blood glucose, insulin, C-peptide) until final graft retrieval for histopathology. Results: Targeted mapping biocompatibility studies demonstrated mild inflammatory changes with islet-plasma constructs; however, significant inflammatory cell infiltration and fibrosis were seen surrounding sites with the hydrogel carrier affecting islet viability. In diabetic NHPs, perihepatic islet transplant using an autologous plasma carrier demonstrated prolonged function up to 6 months with improvements in blood glucose, exogenous insulin requirements, and HbA1c. Histopathology of these islets was associated with mild peri-islet mononuclear cell infiltration without evidence of rejection. Discussion: The perihepatic surface serves as a viable site for islet cell transplantation demonstrating sustained islet function through 6 months. The targeted mapping approach allows for the testing of multiple conditions simultaneously to evaluate immune response to biomaterials at this site. Compared to traditional intraportal injection, the perihepatic site is a minimally invasive approach that allows the possibility for graft recovery and avoids IBMIR.

Silicone rubber membrane devices permit islet culture at high density without adverse effects.

Introduction: Conventional culture conditions, such as in T-flasks, require that oxygen diffuse through the medium to reach the islets; in turn, islet surface area density is limited by oxygen availability. To culture a typical clinical islet preparation may require more than 20 T-175 flasks at the standard surface area density of 200 IE/cm2. To circumvent this logistical constraint, we tested islets cultured on top of silicon gas-permeable (GP) membranes which place islets in close proximity to ambient oxygen. Methods: Oxygenation of individual islets under three culture conditions, standard low-density, non-GP high density, and GP high density, were first modeled with finite element simulations. Porcine islets from 30 preparations were cultured for 2 days in devices with GP membrane bottoms or in paired cultures under conventional conditions. Islets were seeded at high density (HD, ∼4000 IE/cm2, as measured by DNA) in both GP and non-GP devices. Results: In simulations, individual islets under standard culture conditions and high density cultures on GP membranes were both well oxygenated whereas non-GP high density cultured islets were anoxic. Similarly, compared to the non-GP paired controls, islet viability and recovery were significantly increased in HD GP cultures. The diabetes reversal rate in nude diabetic mice was similar for HD GP devices and standard cultures but was minimal with non-GP HD cultures. Discussion: Culturing islets in GP devices allows for a 20-fold increase of islet surface area density, greatly simplifying the culture process while maintaining islet viability and metabolism.

Corynebacterium glutamicum pyruvate:quinone oxidoreductase: an enigmatic metabolic enzyme with unusual structural features.

Pyruvate:quinone oxidoreductase (PQO) is a flavin-containing peripheral membrane enzyme catalyzing the decarboxylation of pyruvate to acetate and CO2 with quinone as an electron acceptor. Here, we investigate PQO activity in Corynebacterium glutamicum, examine purified PQO, and describe the crystal structure of the native enzyme and a truncated version. The specific PQO activity was highest in stationary phase cells grown in complex medium, lower in cells grown in complex medium containing glucose or acetate, and lowest in cells grown in minimal acetate-medium. A similar pattern with about 30-fold higher specific PQO activities was observed in C. glutamicum with plasmid-bound pqo expression under the control of the tac promoter, indicating that the differences in PQO activity are likely due to post-transcriptional control. Continuous cultivation of C. glutamicum at dilution rates between 0.05 and 0.4 h-1 revealed a negative correlation between PQO activity and growth rate. Kinetic analysis of PQO enzymes purified from cells grown in complex or in minimal acetate-medium revealed substantial differences in specific activity (72.3 vs. 11.9 U·mg protein-1) and turnover number (kcat: 440 vs. 78 s-1, respectively), suggesting post-translational modifications affecting PQO activity. Structural analysis of PQO revealed a homotetrameric arrangement very similar to the Escherichia coli pyruvate oxidase PoxB except for the C-terminal membrane binding domain, which exhibited a conformation markedly different from its PoxB counterpart. A truncated PQO variant lacking 17 C-terminal amino acids showed higher affinity to pyruvate and was independent of detergent activation, highlighting the importance of the C-terminus for enzyme activation and lipid binding.

α- or ß-Adrenergic blockade does not affect transplanted islet cell responses to hypoglycemia in type 1 diabetes.

Type 1 diabetes recipients of intrahepatic islet transplantation exhibit glucose-dependent suppression of insulin and activation of glucagon secretion in response to insulin-induced hypoglycemia associated with clinical protection from hypoglycemia. Whether sympathetic activation of adrenergic receptors on transplanted islets is required for these responses in defense against hypoglycemia is not known. To evaluate the adrenergic contribution to posttransplant glucose counterregulation, we performed a randomized, double-blind crossover study of responses during a hyperinsulinemic euglycemic-hypoglycemic clamp under phentolamine (α-adrenergic blockage), propranolol (ß-adrenergic blockage), or placebo infusion. Characteristics of participants (5 females/4 males) were as follows: median (range) age 53 (34-63) yr, diabetes duration 29 (18-56) yr, posttransplant 7.0 (1.9-8.4) yr, HbA1c 5.8 (4.5-6.8)%, insulin in-/dependent 5/4, all on tacrolimus-based immunosuppression. During the clamp, blood pressure was lower with phentolamine and heart rate was lower with propranolol versus placebo (P < 0.05). There was no difference in the suppression of endogenous insulin secretion (derived from C-peptide measurements) during the euglycemic or hypoglycemic phases, and although levels of glucagon were similar with phentolamine or propranolol vs. placebo, the increase in glucagon from eu- to hypoglycemia was greater with propranolol vs. placebo (P < 0.05). Pancreatic polypeptide was greater with phentolamine versus placebo during the euglycemic phase (P < 0.05), and free fatty acids were lower and the glucose infusion rate was higher with propranolol versus placebo during the hypoglycemic phase (P < 0.05 for both). These results indicate that neither physiological α- nor ß-adrenergic blockade attenuates transplanted islet responses to hypoglycemia, suggesting sympathetic reinnervation of the islet graft is not necessary for posttransplant glucose counterregulation.NEW & NOTEWORTHY Whether adrenergic input to islets is necessary for glucose homeostasis in humans is debated. Here, the adrenergic contribution to intrahepatically transplanted islet cell responses to hypoglycemia in individuals with type 1 diabetes was investigated through α- or ß-adrenergic receptor blockade during hyperinsulinemic euglycemic-hypoglycemic clamps. Neither α- nor ß-adrenergic blockage affected the suppression of endogenous insulin or activation of glucagon secretion, suggesting that sympathetic reinnervation of islet grafts is not required for posttransplant defense against hypoglycemia.

Brivaracetam effectiveness and tolerability in older and younger adults with epilepsy: EXPERIENCE, a pooled analysis of international data from retrospective studies.

This analysis assessed the effectiveness and tolerability of brivaracetam (BRV) in older (≥65 years of age) and younger (≥16 to <65 years of age) adults with epilepsy. This was a subgroup analysis from EXPERIENCE/EPD332, a pooled analysis of individual patient records from multiple independent, non-interventional studies of patients with epilepsy starting BRV in Australia, Europe, and the United States. Included patients had ≥6 months of follow-up data. Outcomes included responders (≥50 % reduction from baseline in seizure frequency), seizure freedom (no seizures within 3 months before the time point), and continuous seizure freedom (no seizures from baseline) at 12 months; BRV discontinuation during the whole study follow-up; and treatment-emergent adverse events (TEAEs) at 3, 6, and 12 months. Patients with missing data after BRV discontinuation were deemed non-responders/not seizure-free. Analysis populations included the Full Analysis Set (FAS; patients who received ≥1 BRV dose and had seizure type and age documented at baseline) and the modified FAS (FAS patients who had ≥1 seizure recorded during baseline). The FAS was used for all outcomes except seizure reduction. The FAS included 147 (8.9 %) patients aged ≥65 years and 1497 (91.1 %) aged ≥16 to <65 years. Compared with the younger subgroup, patients aged ≥65 years had a longer median epilepsy duration (33.0 years [n = 144] vs 17.0 years [n = 1460]) and lower median seizure frequency at index (2.0 seizures/28 days [n = 129] vs 4.0 seizures/28 days [n = 1256]), and less commonly had >1 prior antiseizure medication (106/141 [75.2 %] vs 1265/1479 [85.5 %]). At 12 months, a numerically higher percentage of patients aged ≥65 years versus the younger subgroup achieved ≥50 % seizure reduction (46.5 % [n = 71] vs 36.0 % [n = 751]), seizure freedom (26.0 % [n = 100] vs 13.9 % [n = 1011]), and continuous seizure freedom (22.0 % [n = 100] vs 10.7 % [n = 1011]). During the whole study follow-up, 43/147 (29.3 %) patients aged ≥65 years and 508/1492 (34.0 %) aged ≥16 to <65 years discontinued BRV. The incidence of TEAEs since the prior visit was similar in both subgroups at 3 months (≥65 years vs ≥16 to <65 years: 38/138 [27.5 %] vs 356/1404 [25.4 %]), 6 months (19/119 [16.0 %] vs 176/1257 [14.0 %]), and 12 months (8/104 [7.7 %] vs 107/1128 [9.5 %]). This real-world analysis suggests BRV was effective in patients aged ≥65 years and ≥16 to <65 years, with numerically higher effectiveness in the older subgroup. BRV was well tolerated in both subgroups.

Therapeutic strategies during cenobamate treatment initiation: Delphi panel recommendations.

The goal of epilepsy treatment is seizure freedom, typically with antiseizure medication (ASM). If patients fail to attain seizure control despite two trials of appropriately chosen ASMs at adequate doses, they are classified as having drug-resistant epilepsy (DRE). Adverse events (AEs) commonly occur in people with DRE because they are typically on ⩾2 ASMs, increasing the potential for drug-drug interactions. Early emerging AEs may impact adherence, decrease quality of life, and delay achieving optimal treatment dosages. Cenobamate is an oral ASM with a long half-life which has proven to be highly effective in clinical trials. An international Delphi panel of expert epileptologists experienced in the clinical use of cenobamate and other ASMs was convened to develop consensus best practices for managing patients during and after cenobamate titration, with consideration for its known pharmacokinetic and pharmacodynamic interactions, to allow patients to reach the most appropriate cenobamate dose while limiting tolerability issues. The modified Delphi process included one open-ended questionnaire and one virtual face-to-face meeting. Participants agreed that cenobamate can be prescribed for most patients experiencing focal-onset seizures. Patients initiating cenobamate therapy should have access to healthcare professionals as needed and their treatment response should be evaluated at the 100-mg dose. Patients with intellectual disabilities may need additional support to navigate the titration period. Proactive down-titration or withdrawal of sodium channel blockers (SCBs) is recommended when concomitant ASM regimens include ⩾2 SCBs. When applicable, maintaining a concomitant clobazam dose at ~5-10 mg may be beneficial. Patients taking oral contraceptives, newer oral anticoagulants, or HIV antiretroviral medications should be monitored for potential interactions. Because clinical evidence informing treatment decisions is limited, guidance regarding dose adjustments of non-ASM drugs was not developed beyond specific recommendations presented in the Summary of Product Characteristics.

First Results in the Search for Dark Sectors at NA64 with the CERN SPS High Energy Muon Beam.

We report the first search for dark sectors performed at the NA64 experiment employing a high energy muon beam and a missing energy-momentum technique. Muons from the M2 beamline at the CERN Super Proton Synchrotron with a momentum of 160 GeV/c are directed to an active target. The signal signature consists of a single scattered muon with momentum <80 GeV/c in the final state, accompanied by missing energy, i.e., no detectable activity in the downstream calorimeters. For a total dataset of (1.98±0.02)×10^{10} muons on target, no event is observed in the expected signal region. This allows us to set new limits on the remaining (m_{Z^{'}},g_{Z^{'}}) parameter space of a new Z^{'} (L_{µ}-L_{τ}) vector boson which could explain the muon (g-2)_{µ} anomaly. Additionally, our study excludes part of the parameter space suggested by the thermal dark matter relic abundance. Our results pave the way to explore dark sectors and light dark matter with muon beams in a unique and complementary way to other experiments.

The cenobamate KORK study-A prospective monocenter observational study investigating cenobamate as an adjunctive therapy in refractory epilepsy, with comparisons to historical cohorts treated with add-on lacosamide, perampanel, and brivaracetam.

OBJECTIVE: In Europe, cenobamate has been approved for use as an adjunctive therapy in adult patients with epilepsy (PWE) with focal-onset seizures (FOS) who have not responded satisfactorily to treatment with at least two antiseizure medications (ASMs). Pivotal trials and real-world observational studies have demonstrated a high efficacy of cenobamate, even in very difficult-to-treat epilepsies. Our aim was to investigate the efficacy of add-on cenobamate in adult PWE who were prospectively monitored. We compared these results with those previously obtained for add-on lacosamide, perampanel, and brivaracetam therapy. METHODS: Patients were enrolled from the CENKORK study, which is a prospective, non-interventional, open-label, monocenter cohort study of adult PWE experiencing FOS. The titration of cenobamate was performed according to the guidelines outlined in the summary of product characteristics. The primary outcome measure was the retention rate at 6 months and 1 year. In addition, we assessed seizure-free rates, the proportion of patients achieving at least a 50% seizure reduction, adverse events, and the reasons for treatment discontinuation. These outcome measures were compared with historical controls treated with adjunctive lacosamide, perampanel, or brivaracetam at our center. RESULTS: Between June 2021 and 2022, 172 PWE with ongoing FOS were included. 22 cases were lost to follow-up, leaving 150 cases for the 1-year assessment. The retention rates at 6 months and 1 year were 88.7% and 80%, respectively. Seizure freedom was achieved in 14% of patients at both the 6-month and 1-year marks, while the ≥50% responder rates were 50% and 61%, respectively. The 6-month retention rate was significantly higher in cenobamate than in other ASMs (p < 0.001 for each comparator). Adverse events were significantly more common with perampanel (p < 0.001). SIGNIFICANCE: Add-on cenobamate proved to be particularly efficacious compared to our experience with other recently introduced ASMs. PLAIN LANGUAGE SUMMARY: This observational study was carried out in 172 adult patients with difficult-to-treat epilepsy who were treated with adjunctive cenobamate. After 1 year, the data of 150 patients could be analyzed. Seizure freedom, in the preceding 3 months, was achieved in 14%. The rate of PWE continuing cenobamate was 80%. In our hands, cenobamate showed promising efficacy and tolerability even when compared to other recently introduced antiseizure medications.

Cenobamate Plasma Levels in Patients with Epilepsy: Correlation with Efficacy and Tolerability?

Objective: Cenobamate is approved by the European Medicine Agency for the treatment of adult patients with epilepsy (PWEs) with ongoing focal-onset seizures despite appropriate treatment with at least two established antiseizure medications. Pivotal trials and post-marketing real-world observational studies suggest high efficacy with unusually high seizure-free rates. The authors sought to investigate the plasma levels of cenobamate under steady-state conditions in seizure-free versus non-responding PWEs, and in PWEs who experienced adverse events versus those who did not. Methods: Blood samples were collected from adult PWEs who were treated with adjunct cenobamate under steady-state conditions. Daily doses, concomitant medications, efficacy, and tolerability were assessed. The plasma cenobamate levels of seizure-free versus non-responding PWEs and between PWEs with and those without clinical adverse events were compared. Results: Samples from 101 PWEs were included. Thirty-six PWEs were seizure-free and 65 were non-responders. In 31 PWEs, adverse events were apparent, whereas in the remaining 70, no tolerability issues were reported. A linear correlation was found between the daily doses (range: 100 mg-400 mg) and the plasma levels (3.8 mg/L-54.6 mg/L). Neither the daily doses nor the plasma levels differed significantly between the investigated subgroups. The main reason for this result was that the individual therapeutic ranges varied widely: seizure freedom and adverse effects were observed alongside low doses and plasma levels in some PWEs. Conversely, there were examples of PWEs who did not respond or who reported no tolerability issues at high doses or plasma levels. Conclusions: To evaluate the individual therapeutic range and to better understand the influence of other drugs in cases where concomitant medications are used, the therapeutic drug monitoring of cenobamate may be useful. A general therapeutic range cannot be defined.

Evaluating the Inheritance Risk: Epilepsy Prevalence among Offspring of Adults with Epilepsy in a Tertiary Referral Epilepsy Center.

While significant strides have been made in comprehending the pathophysiology and treatment of epilepsy, further investigation is warranted to elucidate the factors impacting its development and transmission, particularly within familial contexts. This study sought to explore the prevalence and risk factors associated with epilepsy in the offspring of patients with epilepsy who were treated at a tertiary epilepsy center. Adult patients with confirmed epilepsy (PWE) receiving outpatient care were consecutively enrolled, starting from January 2021 to January 2023. Data were recorded for various variables, including age, gender, epilepsy pathophysiology, cognitive impairment, and family history of epilepsy. Descriptive statistics, various statistical tests, and multivariate logistic regression analyses were employed to analyze the data. A total of 1456 PWE were included. Among them, 463 patients (31.8%) had children. Twenty-five patients had offspring diagnosed with epilepsy, representing a prevalence of 5.4%. Analysis of the offspring with epilepsy revealed older ages, a higher proportion of parents with idiopathic epilepsy, and a greater prevalence of a positive family history of epilepsy. Multivariate logistic regression analysis demonstrated a significant association between a family history of epilepsy and increased epilepsy risk in offspring. Genetic syndrome-immanent predisposition, advanced age, and a family history of epilepsy were identified as significant risk factors for epilepsy in offspring by means of this mono-center study.