Procalcitonin and C-reactive protein as early markers of anastomotic leakage in intestinal resections for advanced ovarian cancer (EDMOCS).

INTRODUCTION: Serum levels of procalcitonin and C-reactive protein (CRP) have been used to predict anastomotic leakage after colorectal surgery, but information is scarce in advanced ovarian cancer (AOC) surgery with bowel resection. This study aimed to assess the predictive value of procalcitonin and CRP in detecting anastomotic leakage after AOC surgery with bowel resection. The study also aimed to determine the optimal postoperative reference values and the best day for evaluating these markers. MATERIAL AND METHODS: This prospective, observational and multicentric trial included 92 patients with AOC undergoing debulking surgery with bowel resection between 2017 and 2020 in 10 reference hospitals in Spain. Procalcitonin and CRP levels were measured at baseline and on postoperative days 1-6. Receiver operating characteristic analysis was performed to evaluate the predictive value of procalcitonin and CRP at each postoperative day. Sensitivity, specificity, positive and negative predictive values were calculated. RESULTS: Anastomotic leakage was detected in six patients (6.5%). Procalcitonin and CRP values were consistently higher in patients with anastomotic leakage at all postoperative days. The maximum area under the curve (AUC) for procalcitonin was observed at postoperative day 1 (AUC = 0.823) with a cutoff value of 3.8 ng/mL (83.3% sensitivity, 81.3% specificity). For CRP, the maximum AUC was found at postoperative day 3 (AUC = 0.833) with a cutoff level of 30.5 mg/dL (100% sensitivity, 80.4% specificity). CONCLUSIONS: Procalcitonin and C-reactive protein are potential biomarkers for early detection of anastomotic leakage after ovarian cancer surgery with bowel resection. Further prospective studies with a larger sample size are needed to confirm these findings.

Influence of the pilates method on postural balance parameters in older women: An exploratory single-arm trial.

BACKGROUND: Human aging is a natural, biological, progressive, dynamic and complex process that involves morphological, physiological and social changes. Alterations such as decreased postural balance increase the risk of falls and exercise has shown benefits. One of the possible exercise modalities for this population is Pilates. OBJECTIVES: To investigate the effects of Pilates on parameters of static and dynamic postural balance in older women. METHODS: Women aged 60 years or over were evaluated at three time points (pre-training, mid-training, and post-training). Postural balance was assessed using the Short Physical Performance Battery (SPPB), the Timed Up and Go test (TUG), and a force platform. The Pilates exercise protocol consisted of 16 sessions, twice a week, lasting 50 min each. Normality of the data was determined by the Shapiro-Wilk test. Repeated measures ANOVA followed by the Bonferroni post hoc test was used for comparison between assessments. Statistical significance was set at p ≤ 0.05. RESULTS: Fourteen older women were included. Assessment on the force platform revealed no significant differences for most of the variables evaluated. There was a significant difference in SPPB scores and TUG times pre- and post-treatment (p < 0.001). CONCLUSION: Pilates training significantly improved dynamic postural balance evaluated by the TUG and SPPB but did not significantly improve static balance evaluated by the force platform, although the values have decreased in most assessments.

Oncological outcomes of intraperitoneal chemotherapy in advanced ovarian cancer: BRCA mutation role.

INTRODUCTION: The knowledge of BRCA status offers a chance to evaluate the role of the intraperitoneal route in patients selected by biomolecular profiles after primary cytoreduction surgery in advanced ovarian cancer. MATERIALS AND METHODS: We performed a retrospective, multicenter study to assess oncological outcomes depending on adjuvant treatment (intraperitoneal [IP] vs intravenous [IV]) and BRCA status (BRCA1/2 mutated vs. BRCA wild type [WT]). The primary endpoint was to determine progression-free survival. The secondary objectives were overall survival and toxicity. RESULTS: A total of 288 women from eight centers were included: 177 in the IP arm and 111 in the IV arm, grouped into four arms according to BRCA1/2 status. Significantly better PFS was observed in BRCA1/2-mutated patients with IP chemotherapy (HR: 0.35; 95% CI, 0.16-0.75, p = 0.007), which was not present in BRCA1/2-mutated patients with IV chemotherapy (HR: 0.65; 95% CI, 0.37-1.12, p = 0.14). Significantly better OS was also observed in IP chemotherapy (HR: 0.17; 95% CI, 0.06-043, p < 0.0001), but was not present in IV chemotherapy in relation with BRCA mutation (HR: 0.52; 95% CI, 0.22-1.27, p = 0.15). For BRCA WT patients, worse survival was observed regardless of the adjuvant route used. The IP route was more toxic compared to the IV route, but toxicity was equivalent at the long-term follow-up. CONCLUSION: This retrospective study suggests that BRCA status can help to offer an individualized, systematic treatment after optimal primary surgery for advanced ovarian cancer, but is limited by the small sample size. Prospective trials are essential to confirm these results.

IgLON5 deficiency produces behavioral alterations in a knockout mouse model.

Background: Anti-IgLON5 disease is a neurological disorder characterized by autoantibodies against IgLON5 and pathological evidence of neurodegeneration. IgLON5 is a cell adhesion molecule of unknown function that is highly expressed in the brain. Our aim was to investigate the impact of IgLON5 loss-of-function in evaluating brain morphology, social behavior, and the development of symptoms observed in an IgLON5 knockout (IgLON5-KO) mouse model. Methods: The IgLON5-KO mice were generated using CRISPR-Cas9 technology. Immunohistochemistry on fixed sagittal brain sections and Western blotting brain lysates were used to confirm IgLON5 silencing and to evaluate the presence of other cell surface proteins. Two- month-old IgLON5-KO and wild-type (WT) mice underwent a comprehensive battery of behavioral tests to assess 1) locomotion, 2) memory, 3) anxiety, 4) social interaction, and 5) depressive-like behavior. Brain sections were examined for the presence of anatomical abnormalities and deposits of hyperphosphorylated tau in young adult (2-month-old) and aged (22-month-old) mice. Results: Mice did not develop neurological symptoms reminiscent of those seen in patients with anti-IgLON5 disease. Behavioral testing revealed that 2-month-old IgLON5-KO mice showed subtle alterations in motor coordination and balance. IgLON5-KO females exhibited hyperactivity during night and day. Males were observed to have depressive-like behavior and excessive nest-building behavior. Neuropathological studies did not reveal brain morphological alterations or hyperphosphorylated tau deposits. Conclusion: IgLON5-KO mice showed subtle alterations in behavior and deficits in fine motor coordination but did not develop the clinical phenotype of anti-IgLON5 disease.

Correction: "Acute kidney injury in critically ill patients with COVID-19: The AKICOV multicenter study in Catalonia".

[This corrects the article DOI: 10.1371/journal.pone.0284248.].

Should We Abandon Intraperitoneal Chemotherapy in the Treatment of Advanced Ovarian Cancer? A Meta-Analysis.

BACKGROUND: Ovarian cancer is the gynaecological malignancy with the highest mortality and diagnosis often occurs in its advanced stages. Standard treatment in these cases is based on complete cytoreductive surgery with adjuvant intravenous chemotherapy. Other types of treatment are being evaluated to improve the prognosis of these patients, including intraperitoneal chemotherapy and antiangiogenic therapy. These may improve survival or time to relapse in addition to intravenous chemotherapy. OBJECTIVE: The aim of this meta-analysis is to determine whether treatment with intravenous chemotherapy remains the gold standard, or whether the addition of intraperitoneal chemotherapy has a benefit in overall survival (OS) and disease-free interval (DFS). MATERIALS AND METHODS: A literature search was carried out in Pubmed and Cochrane, selecting clinical studies and systematic reviews published in the last 10 years. Statistical analysis was performed using the hazard ratio measure in the RevMan tool. RESULTS: Intraperitoneal chemotherapy shows a benefit in OS and DFS compared with standard intravenous chemotherapy. The significant differences in OS (HR: 0.81 CI 95% 0.74-0.88) and in DFS (HR: 0.81 CI 95% 0.75-0.87) are statistically significant (p < 0.00001). There were no clinical differences in toxicity and side-effects. CONCLUSION: Intraperitoneal chemotherapy is an option that improves OS and DFS without significant toxicity regarding the use of intravenous chemotherapy alone. However, prospective studies are needed to determine the optimal dose and treatment regimen that will maintain the benefits while minimising side effects and toxicity and the profile of patients who will benefit most from this treatment.

Analysis of Intraoperative Variables Responsible for the Increase in Lactic Acid in Patients Undergoing Debulking Surgery.

Background: Cytoreductive surgery (CRS) is a complex procedure with a high incidence of perioperative complications. Elevated lactacidaemia levels have been associated with complications and perioperative morbidity and mortality. This study aims to analyse the intraoperative variables of patients undergoing CRS and their relationship with lactacidaemia levels. Methods: This retrospective, observational study included 51 patients with peritoneal carcinomatosis who underwent CRS between 2014 and 2016 at the Abdomino-Pelvic Oncological Surgery Reference Unit (URCOAP) of the General University Hospital of Castellón (HGUCS). The main variable of interest was the level of lactic acid at the end of surgery. Intraoperative variables, including preoperative haemoglobin, duration of surgery, intraoperative bleeding, fluid therapy administered, administration of blood products, and intraoperative peritoneal cancer index (PCI), were analysed. Results: Positive correlations were found between lactic acid levels and PCI, duration of intervention, fluid therapy, intraoperative bleeding, and transfusion of blood products. Additionally, a negative correlation was observed between haemoglobin levels and lactic acid levels. Notably, the strongest correlations were found with operative PCI (ρ = 0.532; p-value < 0.001) and duration of surgery (ρ = 0.518; p-value < 0.001). Conclusions: PCI and duration of surgery are decisive variables in determining the prognosis of patients undergoing debulking surgery. This study suggests that, for each minute of surgery, lactic acid levels increase by 0.005 mmol/L, and for each unit increase in PCI, lactic acid levels increase by 0.060 mmol/L.

Neoadjuvant Chemotherapy plus Interval Cytoreductive Surgery with or without Hyperthermic Intraperitoneal Chemotherapy (NIHIPEC) in the Treatment of Advanced Ovarian Cancer: A Multicentric Propensity Score Study.

INTRODUCTION: Epithelial ovarian cancer (EOC) is primarily confined to the peritoneal cavity. When primary complete surgery is not possible, neoadjuvant chemotherapy (NACT) is provided; however, the peritoneum-plasma barrier hinders the drug effect. The intraperitoneal administration of chemotherapy could eliminate residual microscopic peritoneal tumor cells and increase this effect by hyperthermia. Intraperitoneal hyperthermic chemotherapy (HIPEC) after interval cytoreductive surgery could improve outcomes in terms of disease-free survival (DFS) and overall survival (OS). MATERIALS AND METHODS: A multicenter, retrospective observational study of advanced EOC patients who underwent interval cytoreductive surgery alone (CRSnoH) or interval cytoreductive surgery plus HIPEC (CRSH) was carried out in Spain between 07/2012 and 12/2021. A total of 515 patients were selected. Progression-free survival (PFS) and OS analyses were performed. The series of patients who underwent CRSH or CRSnoH was balanced regarding the risk factors using a statistical analysis technique called propensity score matching. RESULTS: A total of 170 patients were included in each subgroup. The complete surgery rate was similar in both groups (79.4% vs. 84.7%). The median PFS times were 16 and 13 months in the CRSH and CRSnoH groups, respectively (Hazard ratio (HR) 0.74; 95% CI, 0.58-0.94; p = 0.031). The median OS times were 56 and 50 months in the CRSH and CRSnoH groups, respectively (HR, 0.88; 95% CI, 0.64-1.20; p = 0.44). There was no increase in complications in the CRSH group. CONCLUSION: The addition of HIPEC after interval cytoreductive surgery is safe and increases DFS in advanced EOC patients.

[The Research Network on Preventive Activities and Health Promotion (redIAPP): a reference network and promoter of primary care research]. / La Red de Investigación en Actividades Preventivas y Promoción de la Salud (redIAPP): una red de referencia e impulsora de la investigación en atención primaria.

The Research Network on Preventive Activities and Health Promotion (redIAPP), a reference network and promoter of primary care research was created in 2003 thanks to the program Thematic Networks for Cooperative Research in Health (RETICS) of the Instituto de Salud Carlos III (ISCIII). Its creation has meant a radical change in the situation of research in primary care. Throughout its 19 years (2003-2021), different research groups and autonomous communities have participated, and different lines of research have been developed with numerous projects and publications. Despite the difficulties suffered, it has created a collaborative research experience between different autonomous communities with great vitality and with important results for primary care. The redIAPP, therefore, has been a great reference for research in primary care and for the deepening of its area of knowledge. Several lines of improvement are suggested for the future of primary care research.

Surgery in Recurrent Ovarian Cancer: A Meta-Analysis.

Background: The second cytoreductive surgery performed for a patient who has recurrent ovarian cancer remains controversial. Our study analyzes overall survival (OS) and disease-free survival (DFS) for cytoreductive surgery in addition to chemotherapy in recurrent ovarian cancer instead of chemotherapy alone. Methods: A meta-analysis was conducted using PubMed and the Cochrane database of systematic reviews to select randomized controlled studies. In total, three randomized studies were used, employing a total of 1249 patients. Results: The results of our meta-analysis of these randomized controlled trials identified significant differences in OS (HR = 0.83, IC 95% 0.70-0.99, p < 0.04) and DFS (HR = 0.63, IC 95% 0.55-0.72, p < 0.000001). A subgroup analysis comparing complete cytoreductive surgery and surgery with residual tumor achieved better results for both OS (HR = 0.65, IC 95% 0.49-0.86, p = 0.002) and DFS (HR = 0.67, IC 95% 0.53-0.82, p = 0.0008), with statistical significance. Conclusions: A complete secondary cytoreductive surgery (SCS) in recurrent ovarian cancer (ROC) demonstrates an improvement in the OS and DFS, and this benefit is most evident in cases where complete cytoreductive surgery is achieved. The challenge is the correct patient selection for secondary cytoreductive surgery to improve the results of this approach.

Primary health care research in COVID-19: analysis of the protocols reviewed by the ethics committee of IDIAPJGol, Catalonia.

BACKGROUND: Since March of 2020, the scientific community has been engaged a marathon to answer the different questions that COVID-19 pandemic has brought. During this time, Ethics Committees played an important role in reviewing the research protocols, COVID-19 or not, ensuring that the quality of scientific research is not relaxed by the hasty need for answers. METHODS: Descriptive study from January 2019 to December 2021, comparing COVID-19 protocols to those not COVID-19 related protocols and comparing the work overload. Variables related to the characteristics of the research protocols (i.e. study design, funding…), the principal investigators (gender, PhD degree, professional role…) and outcomes of the Ethics Committee process (requirements of modifications and time until approval) were analyze. RESULTS: The number of sessions increased during COVID-19 pandemics (12 in 2019, 25 in 2020 and 18 in 2021). In total 751 protocols were evaluated during the study period; 513 (68.3%) had an observational design and 434 (57.8%) had no funding. The principal investigator was a woman in 491 (65.4%) studies and a General Practitioner in 330 (43.9%). The mean of the days until the protocol approval was 42.09 days (SD 60.2) with a decrease of 20.1 days from 2019 to 2021. A total of 614 (81.7%) protocols were approved, 336 (54.7%) within the first month after their initial evaluation. Less than half of the protocols were COVID-19 related (208, 44.3%). The COVID-19 protocols main topics were impact on the population (71, 34.1%); and COVID-19 pharmacological treatments (including vaccines) showed a higher increase in 2021 (37, 30.3%). CONCLUSIONS: Despite the work overload during the pandemic due to the increase in the number of meetings and protocols, the IDIAPJGol EC reviewed all of them (COVID-19 or not) adapting to the new situation but according to its criteria of good practices to provide a quick response in the EC opinion. In Primary Health Care the most study designs have been observational studies, many of them with no funding and led by GPs. In 2021 there was an increase in the number of protocols focused on drugs, most likely related to COVID-19 vaccines studies.

"Acute kidney injury in critically ill patients with COVID-19: The AKICOV multicenter study in Catalonia".

This study describes the incidence, evolution and prognosis of acute kidney injury (AKI) in critical COVID-19 during the first pandemic wave. We performed a prospective, observational, multicenter study of confirmed COVID-19 patients admitted to 19 intensive care units (ICUs) in Catalonia (Spain). Data regarding demographics, comorbidities, drug and medical treatment, physiological and laboratory results, AKI development, need for renal replacement therapy (RRT) and clinical outcomes were collected. Descriptive statistics and logistic regression analysis for AKI development and mortality were used. A total of 1,642 patients were enrolled (mean age 63 (15.95) years, 67.5% male). Mechanical ventilation (MV) was required for 80.8% and 64.4% of these patients, who were in prone position, while 67.7% received vasopressors. AKI at ICU admission was 28.4% and increased to 40.1% during ICU stay. A total of 172 (10.9%) patients required RRT, which represents 27.8% of the patients who developed AKI. AKI was more frequent in severe acute respiratory distress syndrome (ARDS) ARDS patients (68% vs 53.6%, p<0.001) and in MV patients (91.9% vs 77.7%, p<0.001), who required the prone position more frequently (74.8 vs 61%, p<0.001) and developed more infections. ICU and hospital mortality were increased in AKI patients (48.2% vs 17.7% and 51.1% vs 19%, p <0.001) respectively). AKI was an independent factor associated with mortality (IC 1.587-3.190). Mortality was higher in AKI patients who required RRT (55.8% vs 48.2%, p <0.04). Conclusions There is a high incidence of AKI in critically ill patients with COVID-19 disease and it is associated with higher mortality, increased organ failure, nosocomial infections and prolonged ICU stay.

Effectiveness of Hyperthermic Intraperitoneal Chemotherapy Associated with Cytoreductive Surgery in the Treatment of Advanced Ovarian Cancer: Systematic Review and Meta-Analysis.

OBJECTIVE: The use of hyperthermic intraperitoneal chemotherapy (HIPEC) as a treatment for epithelial ovarian cancer remains controversial. Our study aims to analyze the overall survival and disease-free survival for the use of HIPEC as a treatment for advanced epithelial ovarian cancer after neoadjuvant chemotherapy. METHODS: A systematic review and meta-analysis was carried out using PubMed, Cochrane, Web of Science, and ClinicalTrials.gov. A total of six studies were used, comprising a total of 674 patients. RESULTS: The results of our meta-analysis of all studies analyzed together (observational and randomized controlled trials (RCT)) did not achieve significant results. Contrary to the OS (HR = 0.56, 95% IC = 0.33-0.95, p = 0.03) and DFS (HR = 0.61, 95% IC = 0.43-0.86, p < 0.01) of the RCT analyzed separately, a clear impact on survival was suggested. The subgroup analysis showed that studies making use of higher temperatures (≥42 °C) for a shorter period of time (≤60 min) achieved better results for both OS and DFS, as well as the use of cisplatin as the form of chemotherapy in HIPEC. Moreover, the use of HIPEC did not increase high-grade complications. CONCLUSIONS: The addition of HIPEC to cytoreductive surgery demonstrates an improvement in OS and DFS for patients with epithelial ovarian cancer in advanced stages, without an increase in the number of complications. The use of cisplatin as chemotherapy in HIPEC obtained better results.

Influence of initial clinical suspicion on the diagnostic yield of laboratory enzymatic testing in lysosomal storage disorders. Experience from a multispecialty hospital.

Lysosomal storage disorders (LSD) are a group of inherited metabolic diseases mainly caused by a deficiency of lysosomal hydrolases, resulting in a gradual accumulation of non-degraded substrates in different tissues causing the characteristic clinical manifestations of such disorders. Confirmatory tests of suspected LSD individuals include enzymatic and genetic testing. A well-oriented clinical suspicion can improve the cost-effectiveness of confirmatory tests and reduce the time expended to achieve the diagnosis. Thus, this work aims to retrospectively study the influence of clinical orientation on the diagnostic yield of enzymatic tests in LSD by retrieving clinical, biochemical, and genetic data obtained from subjects with suspicion of LSD. Our results suggest that the clinical manifestations at the time of diagnosis and the initial clinical suspicion can have a great impact on the diagnostic yield of enzymatic tests, and that clinical orientation performed in specialized clinical departments can contribute to improve it. In addition, the analysis of enzymatic tests as the first step in the diagnostic algorithm can correctly guide subsequent confirmatory genetic tests, in turn increasing their diagnostic yield. In summary, our results suggest that initial clinical suspicion plays a crucial role on the diagnostic yield of confirmatory enzymatic tests in LSD.

Structural and Electrical Response of Emerging Memories Exposed to Heavy Ion Radiation.

Hafnium oxide- and GeSbTe-based functional layers are promising candidates in material systems for emerging memory technologies. They are also discussed as contenders for radiation-harsh environment applications. Testing the resilience against ion radiation is of high importance to identify materials that are feasible for future applications of emerging memory technologies like oxide-based, ferroelectric, and phase-change random-access memory. Induced changes of the crystalline and microscopic structure have to be considered as they are directly related to the memory states and failure mechanisms of the emerging memory technologies. Therefore, we present heavy ion irradiation-induced effects in emerging memories based on different memory materials, in particular, HfO2-, HfZrO2-, as well as GeSbTe-based thin films. This study reveals that the initial crystallinity, composition, and microstructure of the memory materials have a fundamental influence on their interaction with Au swift heavy ions. With this, we provide a test protocol for irradiation experiments of hafnium oxide- and GeSbTe-based emerging memories, combining structural investigations by X-ray diffraction on a macroscopic, scanning transmission electron microscopy on a microscopic scale, and electrical characterization of real devices. Such fundamental studies can be also of importance for future applications, considering the transition of digital to analog memories with a multitude of resistance states.

Donor-derived acute myeloid leukemia in solid organ transplantation.

We report the transmission of acute myeloid leukemia (AML) undetected at donation from a deceased organ donor to two kidneys and one liver recipients. We reviewed the medical records, and performed molecular analyses and whole exome sequencing (WES) to ascertain AML donor origin and its molecular evolution. The liver recipient was diagnosed 11 months after transplantation and died from complications 2 months later. The two kidney recipients (R1 and R2) were diagnosed 19 and 20 months after transplantation and both received treatment for leukemia. R1 died of complications 11 months after diagnosis, while R2 went into complete remission for 44 months, before relapsing. R2 died 10 months later of complications from allogenic bone marrow transplantation. Microsatellite analysis demonstrated donor chimerism in circulating cells from both kidney recipients. Targeted molecular analyses and medical records revealed NPM1 mutation present in the donor and recipients, while FLT3 was mutated only in R1. These findings were confirmed by WES, which revealed additional founder and clonal mutations, and HLA genomic loss in R2. In conclusion, we report the first in-depth genomic analysis of AML transmission following solid organ transplantation, revealing distinct clonal evolution, and providing a potential molecular explanation for tumor escape.

Fertility-Sparing Surgery versus Radical Hysterectomy in Early Cervical Cancer: A Propensity Score Matching Analysis and Noninferiority Study.

OBJECTIVE: Fertility-sparing surgery (FSS) is the treatment of choice for patients with early cervical cancer (ECC) and fertility desire, but survival rates compared to radical hysterectomy (RH) have been scarcely reported. The aim of this study was to analyse the oncological outcomes of FSS compared to a balanced group of standard RH. METHODS: A retrospective multicentre study of ECC patients who underwent FSS or RH was carried out in 12 tertiary hospitals in Spain between January 2005 and January 2019. The experimental group included patients who underwent a simple and radical trachelectomy, and the control group included patients who underwent RH. Optimal 1:1 propensity score (PS) matching analysis was performed to balance the series. RESULTS: The study included 222 patients with ECC; 111 (50%) were treated with FSS, and 111 (50%) were treated with RH. After PS matching, a total of 38 patients in the FSS group and 38 patients in the RH group were analysed. In both groups, the overall survival (HR 2.5; CI 0.89, 7.41) and recurrence rates (28.9% in the FSS group vs. 13.2% in RH group) were similar. The rate of disease-free survival at 5 years was 68.99% in the FSS group and 88.01% in the RH group (difference of -19.02 percentage points; 95% CI -32.08 to -5.96 for noninferiority). In the univariate analysis, only tumour size reached statistical significance. CONCLUSION: FSS offers excellent disease-free and overall survival in women with ECC with fertility desire and is not inferior compared to RH.

Human Metabotropic Glutamate Receptor 5 Antibodies Alter Receptor Levels and Behavior in Mice.

Ophelia syndrome or encephalitis with antibodies against the metabotropic glutamate receptor 5 (mGluR5) manifests with behavioral changes, memory deficits, and anxiety. To study the antibody pathogenicity, mice received continuous cerebroventricular infusion of patients' or controls' immunoglobulin G (IgG) for 14 days, followed by a 15-day washout. The effects on hippocampal mGluR5 clusters were determined by confocal microscopy. Animals infused with patients' IgG, but not controls' IgG, showed memory impairment, increased anxiety, and decreased neuronal surface mGluR5 clusters. After antibody clearance, both behavioral and molecular changes reversed to baseline conditions. These findings support the pathogenicity of these antibodies in anti-mGluR5 encephalitis. ANN NEUROL 2022;92:81-86.

Human CASPR2 Antibodies Reversibly Alter Memory and the CASPR2 Protein Complex.

OBJECTIVE: The encephalitis associated with antibodies against contactin-associated proteinlike 2 (CASPR2) is presumably antibody-mediated, but the antibody effects and whether they cause behavioral alterations are not well known. Here, we used a mouse model of patients' immunoglobulin G (IgG) transfer and super-resolution microscopy to demonstrate the antibody pathogenicity. METHODS: IgG from patients with anti-CASPR2 encephalitis or healthy controls was infused into the cerebroventricular system of mice. The levels and colocalization of CASPR2 with transient axonal glycoprotein 1 (TAG1) were determined with stimulated emission depletion microscopy (40-70µm lateral resolution). Hippocampal clusters of Kv1.1 voltage-gated potassium channels (VGKCs) and GluA1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) were quantified with confocal microscopy. Behavioral alterations were assessed with standard behavioral paradigms. Cultured neurons were used to determine the levels of intracellular CASPR2 and TAG1 after exposure to patients' IgG. RESULTS: Infusion of patients' IgG, but not controls' IgG, caused memory impairment along with hippocampal reduction of surface CASPR2 clusters and decreased CASPR2/TAG1 colocalization. In cultured neurons, patients' IgG led to an increase of intracellular CASPR2 without affecting TAG1, suggesting selective CASPR2 internalization. Additionally, mice infused with patients' IgG showed decreased levels of Kv1.1 and GluA1 (two CASPR2-regulated proteins). All these alterations and the memory deficit reverted to normal after removing patients' IgG. INTERPRETATION: IgG from patients with anti-CASPR2 encephalitis causes reversible memory impairment, inhibits the interaction of CASPR2/TAG1, and decreases the levels of CASPR2 and related proteins (VGKC, AMPAR). These findings fulfill the postulates of antibody-mediated disease and provide a biological basis for antibody-removing treatment approaches. ANN NEUROL 2022;91:801-813.