Background: Myasthenia gravis (MG) is a rare autoimmune disease characterized by fatigable weakness of the voluntary muscles and can exacerbate to life-threatening myasthenic crisis (MC), requiring intensive care treatment. Routine laboratory parameters are a cost-effective and widely available method for estimating the clinical outcomes of several diseases, but so far, such parameters have not been established to detect disease progression in MG.

Methods: We conducted a retrospective analysis of selected laboratory parameters related to inflammation and hemogram for MG patients with MC compared to MG patients without MC. To identify potential risk factors for MC, we applied time-varying Cox regression for time to MC and, as a sensitivity analysis, generalized estimating equations logistic regression for the occurrence of MC at the next patient visit.

Results: 15 of the 58 examined MG patients suffered at least one MC. There was no notable difference in the occurrence of MC by antibody status or sex. Both regression models showed that higher counts of basophils (per 0.01 unit increase: HR = 1.32, 95% CI = 1.02–1.70), neutrophils (per 1 unit increase: HR = 1.40, 95% CI = 1.14–1.72), potentially leukocytes (per 1 unit increase: HR = 1.15, 95% CI = 0.99–1.34), and platelets (per 100 units increase: HR = 1.54, 95% CI = 0.99–2.38) may indicate increased risk for a myasthenic crisis.

Conclusion: This pilot study provides proof of the concept that increased counts of basophils, neutrophils, leukocytes, and platelets may be associated with a higher risk of developing MC in patients with MG.

Patients with mutations in Cldn16 suffer from familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC) which can lead to renal insufficiency. Mice lacking claudin-16 show hypomagnesemia and hypercalciuria, but no nephrocalcinosis. Calcium oxalate and calcium phosphate are the most common insoluble calcium salts that accumulate in the kidney in the case of nephrocalcinosis, however, the formation of these salts is less favored in acidic conditions. Therefore, urine acidification has been suggested to limit the formation of calcium deposits in the kidney. Assuming that urine acidification is causative for the absence of nephrocalcinosis in the claudin-16-deficient mouse model, we aimed to alkalinize the urine of these mice by the ablation of the subunit B1 of the vesicular ATPase in addition to claudin-16. In spite of an increased urinary pH in mice lacking claudin-16 and the B1 subunit, nephrocalcinosis did not develop. Thus, urinary acidification is not the only factor preventing nephrocalcinosis in claudin-16 deficient mice.

Functional avidity is supposed to critically shape the quality of immune responses, thereby influencing host protection against infectious agents including SARS-CoV-2. Here we show that after human SARS-CoV-2 vaccination, a large portion of high -avidity spike -specific CD4+ T cells lost CD3 expression after in vitro activation. The CD3- subset was enriched for cytokine-positive cells, including elevated per -cell expression levels, and showed increased polyfunctionality. Assessment of key metabolic pathways by flow cytometry revealed that superior functionality was accompanied by a shift toward fatty acid synthesis at the expense of their oxidation, whereas glucose transport and glycolysis were similarly regulated in SARS-CoV-2-specific CD3- and CD3+ subsets. As opposed to their CD3+ counterparts, frequencies of vaccine -specific CD3- T cells positively correlated with both the size of the naive CD4+ T cell pool and vaccine -specific IgG levels. Moreover, their frequencies negatively correlated with advancing age and were impaired in patients under immunosuppressive therapy. Typical recall antigen-reactive T cells showed a comparable segregation into functionally and metabolically distinct CD3+ and CD3- subsets but were quantitatively maintained upon aging, likely due to earlier recruitment in life. In summary, our data identify CD3- T helper cells as correlates of high -quality immune responses that are impaired in at -risk populations.

Background: Although commercially developed automated insulin delivery (AID) systems have recently been approved and become available in a limited number of countries, they are not universally available, accessible, or affordable. Therefore, open-source AID systems, cocreated by an online community of people with diabetes and their families behind the hashtag #WeAreNotWaiting, have become increasingly popular.

Objective: This study focused on examining the lived experiences, physical and emotional health implications of people with diabetes following the initiation of open-source AID systems, their perceived challenges, and their sources of support, which have not been explored in the existing literature.

Methods: We collected data from 383 participants across 29 countries through 2 sets of open-ended questions in a web-based survey on their experience of building and using open-source AID systems. Narratives were thematically analyzed, and a coding framework was identified through iterative alignment.

Results: Participants consistently reported improvements in glycemia, physical health, sleep quality, emotional impact on everyday life, and quality of life. Knowledge of open-source AID systems was largely obtained through the #WeAreNotWaiting community, which was also the primary source of practical and emotional support. The acquisition of the components to build an open-source AID system and the technical setup were sometimes problematic.

Conclusions: The #WeAreNotWaiting movement represents a primary example of how informed and connected patients proactively address their unmet needs, provide peer support to each other, and obtain results through impactful, user-driven solutions. Alongside providing evidence on the safety and efficacy of open-source AID systems, this qualitative analysis helps in understanding how patients’ experiences and benefits range from psychosocial improvements to a reduction in the burden of managing diabetes.

Background: The optimal fixation technique in periacetabular osteotomy (PAO) remains controversial. Modified fixation with Kirschner wires (K-wires) was described as a feasible and safe alternative. However, clinical follow-up of patients treated with this technique is lacking. Aims: To assess patient-reported outcomes (PROMs) in patients treated with PAO with the K-wire fixation technique and to compare it with the screw fixation technique. Methods: We conducted an analysis of 202 consecutive PAOs at a single university center between January 2015 and June 2017. A total of 120 cases with complete datasets were included in the final analysis. PAOs with K-wire fixation (n = 63) were compared with screw fixation (n = 57). Mean follow-up was 63 ± 10 months. PROMs assessed included the International Hip Outcome Tool (iHOT 12), Subjective Hip Value (SHV), and UCLA activity score (UCLA). Pain and patient satisfaction (NRS) were evaluated. Joint preservation was defined as non-conversion to total hip arthroplasty (THA). Results: Preoperative baseline PROMs in both fixation groups were similar. In both groups, PROMs (p = <0.001) and pain (p = <0.001) improved significantly. Postoperative functional outcome was similar in both groups: iHOT 12 (71.8 ± 25.1 vs. 73 ± 21.1; p = 0.789), SHV (77.9 ± 21.2 vs. 82.4 ± 13.1; p = 0.192), UCLA (6.9 ± 1.6 vs. 6.9 ± 1.9; p = 0.909), and pain (2.4 ± 2.1 vs. 2.0 ± 2.1; p = 0.302). Patient satisfaction did not differ significantly (7.6 ± 2.6 vs. 8.2 ± 2.2; p = 0.170). Conversion to THA was low in both groups (two vs. none; p = 0.497). Conclusion: Periacetabular osteotomy with K-wire fixation provided good clinical results at mid-term follow-up, comparable to those of screw fixation. The technique can therefore be considered a viable option when deciding on the fixation technique in PAO.

The liver-derived selenium (Se) transporter selenoprotein P (SELENOP) declines in critical illness as a negative acute phase reactant and has recently been identified as an autoantigen. Hepatic selenoprotein biosynthesis and cotranslational selenocysteine insertion are sensitive to inflammation, therapeutic drugs, Se deficiency, and other modifiers. As severe burn injury induces a heavy inflammatory burden with concomitant Se depletion, we hypothesized an impairment of selenoprotein biosynthesis in the acute post-burn phase, potentially triggering the development of autoantibodies to SELENOP (SELENOP-aAb). To test this hypothesis, longitudinal serum samples from severely burned patients were analyzed over a period of six months. Newly occurring SELENOP-aAb were detected in 8.4% (7/83) of the burn patients, with onset not earlier than two weeks after injury. Prevalence of SELENOP-aAb was associated with injury severity, as aAb-positive patients have suffered more severe burns than their aAb-negative counterparts (median [IQR] ABSI: 11 [7-12] vs. 7 [5.8-8], p = 0.023). Autoimmunity to SELENOP was not associated with differences in total serum Se or SELENOP concentrations. A positive correlation of kidney-derived glutathione peroxidase (GPx3) with serum SELENOP was not present in the patients with SELENOP-aAb, who showed delayed normalization of GPx3 activity post-burn. Overall, the data suggest that SELENOP-aAb emerge after severe injury in a subset of patients and have antagonistic effects on Se transport. The nature of burn injury as a sudden event allowed a time-resolved analysis of a direct trigger for new-onset SELENOP-aAb, which may be relevant for severely affected patients requiring intensified acute and long-term care.

Applying advanced molecular profiling together with highly specific targeted therapies offers the possibility to better dissect the mechanisms underlying immune-mediated inflammatory diseases such as systemic lupus erythematosus (SLE) in humans. Here we apply a combination of single-cell RNA-Seq and T/B cell repertoire analysis to perform an in-depth characterization of molecular changes in the immune-signature upon CD19 CAR T cell–mediated depletion of B cells in patients with SLE. The resulting data sets not only confirm a selective CAR T cell–mediated reset of the B cell response but simultaneously reveal consequent changes in the transcriptional signature of monocyte and T cell subsets that respond with a profound reduction in type I IFN signaling. Our current data, thus, provide evidence for a causal relationship between the B cell response and the increased IFN signature observed in SLE and additionally demonstrate the usefulness of combining targeted therapies and analytic approaches to decipher molecular mechanisms of immune-mediated inflammatory diseases in humans.

Memory B cells (mBCs) are characterized by their long-term stability, fast reactivation, and capability to rapidly differentiate into antibody-secreting cells (ASCs). However, the role of T cells in the differentiation of mBCs, in contrast to naive B cells, remains to be delineated. We study the role of T cells in mBC responses, using CD40L stimulation and autologous T-B co-cultures. Our results showed that increased CD40L levels led to a selective increased proliferation of IgM+ mBC, which did not class-switched, resulting in higher frequencies of IgM+ ASCs and a lower frequency of IgG+ ASCs. The IgG+/IgA+ mBCs were unaffected. We further compared the transcription of immune-related genes in IgM+ and IgG+ pre-plasmablasts cultured at high (500 ng/mL) and low (50 ng/mL) CD40L levels. In response to increased CD40L levels, both populations exhibited a core response to genes related to activation (TRAF1, AKT3, CD69, and CD80). However, they differed in genes related to cytokine/chemokine/homing interactions (CCL3/4/17, LTA, NKX2-3, BCL2 and IL21R) and cell-cell interactions (HLADR, CD40, and ICOSL), which were largely confined to IgG+ cells. Our findings revealed that in co-cultures with a high T-ratio, the response was similar to that found in cultures with high CD40L levels. These results suggest that IgG+ mBCs have a greater capacity for proliferation and T cell interaction, and weaker migration capabilities, leading to a preference for an IgG response over IgM in the short term. This adaptable response could fine-tune the memory repertoire with different functions of IgG versus IgM mBCs.

Background: Over the last three decades, the number of randomized controlled trials (RCTs) using stimulation of auricular vagal sensory nerves by means of electrical stimulation, auricular acupuncture, or acupressure to support weight loss has increased markedly. This systematic review focuses on the effects of auricular stimulation (AS) on anthropometric parameters and obesity-related blood chemistry.

Methods and analysis: The following databases were searched until November 2021: MEDLINE (PubMed), EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), ISI Web of Science, and Scopus Database. Data collection and analysis were conducted by two reviewers independently. Quality and risk assessment of included studies was performed using the risk of bias tool of the Cochrane Handbook, and the meta-analysis of the effect of the most frequently assessed biomarkers was conducted using the statistical software RevMan.

Results: The full texts of 1,274 studies were screened; 22 contained data on obesity-related outcomes, and 15 trials with 1,333 patients were included in the meta-analysis. The overall quality of the included trials was moderate. AS significantly reduced body mass index (BMI) (mean difference (MD) = −0.38 BMI points, 95% CI (−0.55 to −0.22), p < 0.0001), weight (MD = −0.66 kg, 95% CI (−1.12 to −0.20), p = 0.005), waist circumference (MD = −1.44 cm, 95% CI (−2.69 to −0.20), p = 0.02), leptin, insulin, and HOMA insulin resistance compared to controls. No significant reduction was found in body fat, hip circumference, ratio of waist/hip circumference, cholesterol, LDL, triglycerides, adiponectin, ghrelin, and glucose levels. The AS was safe throughout the trials, with only minor adverse reactions.

Conclusion: The study results suggest that a reduction of weight and BMI can be achieved by AS in obese patients; however, the size of the effect does not appear to be of clinical relevance. The effects might be underestimated due to active sham trials.

Introduction: Antimicrobial resistance is closely linked with the health and stability of environmental systems and therefore a challenge for the health of the planet. General Practitioners, owing to their trusted positions and close patient relationships, can play a crucial role in addressing antimicrobial resistance within the framework of Planetary Health. The goal of our study was to examine General Practitioners’ knowledge, attitude, and practice regarding the linkage of antimicrobial resistance with Planetary Health to understand their potential as agents of change in this domain.

Materials and methods: We conducted 19 guided interviews with General Practitioners from four different German federal states (August–September 2022). Participants were selected from the intervention group of the RedAres randomized controlled trial, a study designed to optimize therapy and prescribing practices for uncomplicated urinary tract infections in general practice. Data were analyzed using Mayring’s structured qualitative content analysis and the typology approach by Kelle and Kluge.

Results: General Practitioners generally demonstrated the ability to identify the interlinkages between antimicrobial resistance and Planetary Health. However, they exhibited varying levels of knowledge, problem awareness, and accountability for the associated challenges and partially outsourced the responsibility for Planetary Health. Some General Practitioners were capable of integrating Planetary Health arguments into patient counseling. They recognized rational prescribing practice, self-reflection on antimicrobial resistance and Planetary Health, interprofessional exchange, and raising awareness among patients as potential avenues for engagement in promoting Planetary Health.

Discussion: As antimicrobial resistance is increasingly recognized as a Planetary Health challenge, empowering General Practitioners as change agents requires tailored measures based on their level of previous knowledge and their attitude toward Planetary Health. General Practitioners express a need for concrete advice on how to integrate antimicrobial resistance as a Planetary Health topic into their daily activities. Developing and evaluating adaptable training materials is essential. Additionally, the integration of Planetary Health outcomes into clinical guidelines could accelerate the adoption of this dimension in antibiotic prescribing practices within primary care settings.

(1) Background: Dyslipidemia represents a major risk factor for atherosclerosis-driven cardiovascular disease. Emerging evidence suggests a close relationship between cholesterol metabolism and gut microbiota. Recently, we demonstrated that the short-chain fatty acid (SCFA) propionate (PA) reduces serum cholesterol levels through an immunomodulatory mechanism. Here, we investigated the effects of oral PA supplementation on the human serum metabolome and analyzed changes in the serum metabolome in relation to the cholesterol-lowering properties of PA. (2) Methods: The serum metabolome of patients supplemented with either placebo or propionate orally for 8 weeks was assessed using a combination of flow injection analysis-tandem (FIA-MS/MS) as well as liquid chromatography (LC-MS/MS) and mass spectrometry using a targeted metabolomics kit (MxP (R) Quant 500 kit: BIOCRATES Life Sciences AG, Innsbruck, Austria). A total of 431 metabolites were employed for further investigation in this study. (3) Results: We observed a significant increase in distinct bile acids (GCDCA: fold change = 1.41, DCA: fold change = 1.39, GUDCA: fold change = 1.51) following PA supplementation over the study period, with the secondary bile acid DCA displaying a significant negative correlation with the serum cholesterol levels. (4) Conclusions: Oral supplementation with PA modulates the serum metabolome with a particular impact on the circulatory bile acid profile. Since cholesterol and bile acid metabolism are interconnected, the elevation of the secondary bile acid DCA may contribute to the cholesterol-lowering effect of PA.

(1) Heart transplantation (HTX) improves the overall survival and functional status of end-stage heart failure patients with cardiomyopathies (CMPs). The majority of CMPs have genetic causes, and the overlap between CMPs and inherited myopathies is well documented. However, the long-term outcome in skeletal muscle function and possibility of an undiagnosed underlying genetic cause of both a cardiac and skeletal pathology remain unknown. (2) Thirty-nine patients were assessed using open and standardized interviews on muscle function, a quality-of-life (EuroQol EQ-5D-3L) questionnaire, and a physical examination (Medical Research Council Muscle scale). Whole-exome sequencing was completed in three stages for those with skeletal muscle weakness. (3) Seven patients (17.9%) reported new-onset muscle weakness and motor limitations. Objective muscle weakness in the upper and lower extremities was seen in four patients. In three of them, exome sequencing revealed pathogenic/likely pathogenic variants in the genes encoding nexilin, myosin heavy chain, titin, and SPG7. (4) Our findings support a positive long-term outcome of skeletal muscle function in HTX patients. However, 10% of patients showed clinical signs of myopathy due to a possible genetic cause. The integration of genetic testing and standardized neurological assessment of motor function during the peri-HTX period should be considered.

Gamma delta (γδ) T cells represent a minor fraction of human T cell repertoire but play an important role in mediating anti-infectious and anti-tumorous effects in the context of allogeneic hematopoietic stem cell transplantation (allo-HSCT). We performed a prospective study to analyze the effect of different transplant modalities on immune reconstitution of γδ T cells and subsets. CD3, CD4 and CD8 T cells were analyzed in parallel. Secondly, we examined the impact of γδ T cell reconstitution on clinical outcomes including acute Graft-versus-Host-Disease (aGvHD) and viral infections. Our cohort includes 49 pediatric patients who received unmanipulated bone marrow grafts from matched unrelated (MUD) or matched related (MRD) donors. The cohort includes patients with malignant as well as non-malignant diseases. Cell counts were measured using flow cytometry at 15, 30, 60, 100, 180 and 240 days after transplantation. Cells were stained for CD3, CD4, CD8, CD45, TCRαβ, TCRγδ, TCRVδ1, TCRVδ2, HLA-DR and combinations. Patients with a MRD showed significantly higher Vδ2+ T cells than those with MUD at timepoints +30, +60, +100 (p<0.001, respectively) and +180 (p<0.01) in univariate analysis. These results remained significant in multivariate analysis. Patients recovering with a high relative abundance of total γδ T cells and Vδ2+ T cells had a significantly lower cumulative incidence of grade II-IV aGvHD after transplantation (p=0.03 and p=0.04, respectively). A high relative abundance of Vδ2+ T cells was also associated with a lower incidence of EBV infection (p=0.02). Patients with EBV infection on the other hand showed higher absolute Vδ1+ T cell counts at days +100 and +180 after transplantation (p=0.046 and 0.038, respectively) than those without EBV infection. This result remained significant in a multivariate time-averaged analysis (q<0.1). Our results suggest a protective role of γδ T cells and especially Vδ2+ T cell subset against the development of aGvHD and EBV infection after pediatric HSCT. Vδ1+ T cells might be involved in the immune response after EBV infection. Our results encourage further research on γδ T cells as prognostic markers after HSCT and as possible targets of adoptive T cell transfer strategies.

Background: The holistic health and wellness Kneipp concept, has a long tradition in Europe with demonstrated health benefits. Based on the five elements of the Kneipp concept, kindergartens in and around Germany are used to certify “Kneipp Kindergartens” that practice regular Kneipp applications and activities: cold water applications, exercise, nutrition, herbs and mind-body interventions. Little is known about the potential health benefits for children, however. This study protocol describes our study design and intervention of the Kita Kneipp Study to investigate the effect of the Kneipp concept on kindergarten children aged 2–6 years.

Methods and design: The Kita Kneipp Study, registered with the German Clinical Trial Register (DRKS-ID: DRKS00029275), is a confirmatory, mixed-method, two-armed, waitlist, clinical, cluster randomized controlled trial (RCT). Kindergartens in Berlin, Germany that would like to implement the Kneipp concept into their facility will be recruited and randomized to the intervention or control group. Changes in the number of kindergarten sick days will be the primary outcome measure. Kindergarten attendance and reason for absence including illness will be collected on a weekly basis at two time points for 6 weeks from the parents and kindergarten directors: baseline and 1 year after baseline. Secondary outcomes will measure cold symptoms through the Common Cold Questionnaire (CCQ) and National Cancer Institute – Common Terminology Criteria for Adverse Events (NCI-CTCAE) Scales describing gastroenterological-based symptoms Kindergarten educator sick days will be aggregately reported for the same time period. Kneipp concept activities will be recorded on a weekly basis over the one-year intervention period. To understand the experience of Kneipp concept implementation and possible changes in the kindergarten, expert interviews will be conducted with intervention kindergarten educators and focused ethnographies will be planned to observe and analyze the intervention activities.

Discussion: This mixed method study design has potential to help identify if the Kneipp concept can be used for salutogenic purposes among young children and provide insights and experience of the implementation and practicing a holistic health and wellness concept in a kindergarten setting.

The melanocortin-4 receptor (MC4R) is a key player in the hypothalamic leptin-melanocortin pathway that regulates satiety and hunger. MC4R belongs to the G protein-coupled receptors (GPCRs), which are known to form heterodimers with other membrane proteins, potentially modulating receptor function or characteristics. Like MC4R, thyroid hormones (TH) are also essential for energy homeostasis control. TH transport across membranes is facilitated by the monocarboxylate transporter 8 (MCT8), which is also known to form heterodimers with GPCRs. Based on the finding in single-cell RNA-sequencing data that both proteins are simultaneously expressed in hypothalamic neurons, we investigated a putative interplay between MC4R and MCT8. We developed a novel staining protocol utilizing a fluorophore-labeled MC4R ligand and demonstrated a co-localization of MC4R and MCT8 in human brain tissue. Using in vitro assays such as BRET, IP1, and cAMP determination, we found that MCT8 modulates MC4R-mediated phospholipase C activation but not cAMP formation via a direct interaction, an effect that does not require a functional MCT8 as it was not altered by a specific MCT8 inhibitor. This suggests an extended functional spectrum of MCT8 as a GPCR signaling modulator and argues for the investigation of further GPCR-protein interactions with hitherto underrepresented physiological functions.

Objectives: Despite the growing evidence regarding the influence of social factors on frailty in older adults, the effect of social support remains unclear. This study aims to assess the association between social support and frailty progression (transition and incidence) in a sample of community-dwelling older adults.

Methods: Using a cohort study design, 1,059 older adults from the Berlin Initiative Study were followed up for 2.1 years. Multinomial and logistic regression analyses were performed to assess the association of social support using Oslo Social Support Scale-3 with frailty transition and incidence, respectively. Gender differences were explored using stratified analyses.

Results: At baseline, frailty prevalence in the study population [mean (SD) age 84.3 (5.6) years; 55.8% women] reached 33.1% with 47.0, 29.4 and 23.6% of the participants reporting moderate, strong and poor social support, respectively. Over the follow-up period, social support was not significantly associated with the frailty transition categories in the adjusted model. Conversely, the adjusted logistic regression analysis showed that participants with poor social support had twice the odds of becoming frail compared to those with strong social support (OR 2.07; 95% CI 1.08–3.95). Gender-stratified analyses showed comparable estimates to the main analysis but were statistically non-significant.

Discussion: Our study results underpin the role of social factors in frailty incidence and highlight social support as a potential target for frailty-preventing interventions in older adults. Therefore, it is important to adopt a biopsychosocial model rather than a purely biomedical model to understand and holistically improve the health of community-dwelling older adults.

Epilepsy is characterized by recurrent, unprovoked seizures. Accurate prediction of seizure occurrence has long been a clinical goal since this would allow to optimize patient treatment, prevent injuries due to seizures, and alleviate the patient burden of unpredictability. Advances in implantable electroencephalographic (EEG) devices, allowing for long-term interictal EEG recordings, have facilitated major progress in this field. Recently, it has been discovered that interictal brain activity demonstrates circadian and multi-dien cycles that are strongly aligned, or phase locked, with seizure risk. Thus, cyclical brain activity patterns have been used to forecast seizures. However, in the effort to develop a clinically useful EEG based seizure forecasting system, challenges remain. Firstly, multiple EEG features demonstrate cyclical patterns, but it remains unclear which feature is best suited for predicting seizures. Secondly, the technology for long-term EEG recording is currently limited in both spatial and temporal sampling resolution. In this study, we compare five established EEG metrics:synchrony, spatial correlation, temporal correlation, signal variance which have been motivated from critical dynamics theory, and interictal epileptiform discharge (IED) which are a traditional marker of seizure propensity. We assess their effectiveness in detecting 24-h and seizure cycles as well as their robustness under spatial and temporal subsampling. Analyzing intracranial EEG data from 23 patients, we report that all examined features exhibit 24-h cycles. Spatial correlation, signal variance, and synchrony showed the highest phase locking with seizures, while IED rates were the lowest. Notably, spatial and temporal correlation were also found to be highly correlated to each other, as were signal variance and IED-suggesting some features may reflect similar aspects of cortical dynamics, whereas others provide complementary information. All features proved robust under subsampling, indicating that the dynamic properties of interictal activity evolve slowly and are not confined to specific brain regions. Our results may aid future translational research by assisting in design and testing of EEG based seizure forecasting systems.

N-methyl-D-aspartate (NMDA) receptor antagonists are widely used to pharmacologically model schizophrenia and have been recently established in the treatment of treatment-resistant major depression demonstrating that the pharmacology of this substance class is complex. Cortical gamma oscillations, a rhythmic neuronal activity associated with cognitive processes, are increased in schizophrenia and deteriorated in depressive disorders and are increasingly used as biomarker in these neuropsychiatric diseases. The opposite use of NMDA receptor antagonists in schizophrenia and depression raises the question how their effects are in accordance with the observed disease pathophysiology and if these effects show a consequent sex-specificity. In this study in rats, we investigated the effects of subchronic (14 days) intraperitoneal injections of the NMDA receptor antagonist MK-801 at a subanesthetic daily dose of 0.2 mg/kg on the behavioral phenotype of adult female and male rats and on pharmacologically induced gamma oscillations measured ex vivo from the hippocampus. We found that MK-801 treatment leads to impaired recognition memory in the novel object recognition test, increased stereotypic behavior and reduced grooming, predominantly in female rats. MK-801 also increased the peak power of hippocampal gamma oscillations induced by kainate or acetylcholine only in female rats, without affecting the peak frequency of the oscillations. The findings indicate that blockade of NMDA receptors enhances gamma oscillations predominantly in female rats and this effect is associated with behavioral changes in females. The results are in accordance with clinical electrophysiological findings and highlight the importance of hippocampal gamma oscillations as a biomarker in schizophrenia and depression.

Introduction: There is a lack of real-world data directly comparing different valve prostheses for transaortic valve replacement (TAVR). We aimed to compare early clinical outcomes at 30-days between the self-expandable Portico valve (Abbott) with the balloon-expandable Edwards Sapien 3 valve (Edwards Lifesciences) (ES3).

Methods: Out of 1,901 patients undergoing TAVR between January 2018 and December 2021, all patients who received either Portico valve or ES3 valve via transfemoral TAVR were matched using nearest-neighbor (1:1) propensity scoring. Primary endpoints were single safety endpoints and early safety composite endpoints defined by Valve Academic Research Consortium-2 (VARC-2) criteria. The secondary endpoint was to analyze risk predictors for new permanent pacemaker (PPM) implantation in TAVR.

Results: Out of 661 complete cases, a total of 434 patients were successfully matched based on age, sex, Euro Score II and STS-score. In the matched cohort, 217 received either a Portico or valve and 217 received an ES3 valve. The VARC-2 early safety composite scores indicated a significantly greater overall 30-day safety risk in the Portico group at 9.2% (n = 20) compared to 3.7% (n = 8) in the ES3 group (p = 0.032). The requirement for new permanent pacemaker (PPM) implantation was also higher in the Portico group, at 21.2% (n = 46) vs. 13.4% (n = 29) in the ES3 group (p = 0.042). 30-day mortality was higher was 3.7% (n = 8) in Portico group compared to 0.9% in ES3 group (p = 0.11). Furthermore, implantation of the Portico valve was identified as a significant risk predictor for new PPM implantation, alongside higher age, preprocedural atrioventricular block (AVB) and longer total procedure duration.

Conclusion: This study shows significantly higher rates of early clinical complications for Portico valve prostheses compared to ES3. These findings should be especially taken into consideration when selecting valve prosthesis for high-risk patients.

Purpose: Passive tibiofemoral anterior-posterior (AP) laxity has been extensively investigated after posterior cruciate ligament (PCL) single-bundle reconstruction. However, the PCL also plays an important role in providing rotational stability in the knee. Little is known in relation to the effects of PCL single-bundle reconstruction on passive tibiofemoral rotational laxity. Gait biomechanics after PCL reconstruction are even less understood. The aim of this study was a comprehensive prospective biomechanical in vivo analysis of the effect of PCL single-bundle reconstruction on passive tibiofemoral rotational laxity, passive anterior-posterior laxity, and gait pattern.

Methods: Eight patients undergoing PCL single-bundle reconstruction (seven male, one female, mean age 35.6 ± 6.6 years, BMI 28.0 ± 3.6 kg/m2) were analyzed preoperatively and 6 months postoperatively. Three of the eight patients received additional posterolateral corner (PLC) reconstruction. Conventional stress radiography was used to evaluate passive translational tibiofemoral laxity. A previously established rotometer device with a C-arm fluoroscope was used to assess passive tibiofemoral rotational laxity. Functional gait analysis was used to examine knee kinematics during level walking.

Results: The mean side-to-side difference (SSD) in passive posterior translation was significantly reduced postoperatively (12.1 ± 4.4 mm vs. 4.3 ± 1.8 mm; p < 0.01). A significant reduction in passive tibiofemoral rotational laxity at 90° knee flexion was observed postoperatively (27.8° ± 7.0° vs. 19.9° ± 7.5°; p = 0.02). The range of AP tibiofemoral motion during level walking was significantly reduced in the reconstructed knees when compared to the contralateral knees at 6-month follow-up (16.6 ± 2.4 mm vs. 13.5 ± 1.6 mm; p < 0.01).

Conclusion: PCL single-bundle reconstruction with optional PLC reconstruction reduces increased passive tibiofemoral translational and rotational laxity in PCL insufficient knees. However, increased passive tibiofemoral translational laxity could not be fully restored and patients showed altered knee kinematics with a significantly reduced range of tibiofemoral AP translation during level walking at 6-month follow-up. The findings of this study indicate a remaining lack of restoration of biomechanics after PCL single-bundle reconstruction in the active and passive state, which could be a possible cause for joint degeneration after PCL single-bundle reconstruction.