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Gäbler, M, Prieske, O, Elferink-Gemser, MT, Hortobágyi, T, Warnke, T, and Granacher, U. Measures of physical fitness improve prediction of kayak and canoe sprint performance in young kayakers and canoeists. J Strength Cond Res XX(X): 000-000, 2021-Markers of talent selection and predictors of performance in canoe and kayak sprint are not yet well defined. We aimed to determine the combination of variables (i.e., demographic, anthropometric, and physical fitness) that most accurately predicts sprint performance (i.e., 500- and 2000-m race time) in semielite, young kayakers and canoeists (n = 39, age 13 year, 10F). The level of significance was set at p < 0.05. Linear regression analyses identified boat type (i.e., kayak or canoe), skeletal muscle mass, and average power during a 2-minute bench pull test, normalized to body mass, as predictors of 2000-m race time (R22000 m = 0.69, Akaike information criterion [AIC] = 425) and together with vertical jump height, as predictors of 500-m race time (R2500 m = 0.87, AIC = 255). This was an improvement over models containing solely demographic variables (R2500 m = 0.66, AIC = 293; R22000 m = 0.44, AIC = 446) and over models containing demographic and anthropometric variables (R2500m = 0.79, AIC = 277; R22000 m = 0.56, AIC = 437). Race time showed the strongest semipartial correlations with the 2-minute bench pull test (0.7 ≤ r ≤ 0.9). Adding physical fitness data (i.e., 2-minute bench pull test) to demographic and anthropometric data improves the prediction accuracy of race times in young kayak and canoe athletes. The characteristics of physical fitness tests should resemble as much as possible the biomechanical (e.g., prime movers) and metabolic (e.g., duration) demands of the sport.

Objective To assess if SARS-CoV-2 causes a persistent central nervous system infection. Methods SARS-CoV-2 specific antibody index and SARS-CoV-2 RNA studied in cerebrospinal fluid following COVID-19. Results Cerebrospinal fluid was assessed between day 1-30 (n=12), between day 31-90 (n=8), or later than 90 days (post-COVID-19, n=20) of COVID-19 diagnosis. SARS-CoV-2 RNA was absent in all patients, and in none of the 20 patients with post-COVID-19 syndrome intrathecally produced anti-SARS-CoV-2 antibodies were detected. Interpretation The absence of evidence of SARS-CoV-2 in cerebrospinal fluid argues against a persistent central nervous system infection as a cause of neurological or neuropsychiatric post-COVID-19 syndrome. This article is protected by copyright. All rights reserved.

Summary Background & aims Sarcopenia is characterized by the progressive loss of skeletal muscle mass and function, which reduces mobility and quality of life. Risk factors for sarcopenia include advanced age, physical inactivity, obesity, and chronic diseases such as cancer or rheumatoid arthritis. Omega-3 long chain polyunsaturated fatty acids (LC PUFAs) might be associated with a reduction in risk of sarcopenia due to their anti-inflammatory effects. Methods We conducted a systematic review and meta-analysis to quantify the effects of omega-3 LC PUFAs on muscle mass, volume and function parameters. The National Library of Medicine's MEDLINE/PubMed database was searched on 9th October 2020 for randomized controlled trials that used omega-3 LC PUFAs as an intervention with muscle-related endpoints. A snowballing search to identify additional studies was completed on 23rd April 2021. The meta-analysis was conducted using meta-essentials worksheet 3. Bias was assessed using the Jadad scale. Results 123 studies were identified with the systematic searches. Most studies were performed in disease populations, such as cancer or chronic obstructive pulmonary disease (COPD), or in healthy individuals after a fatiguing exercise bout. The endpoints lean body mass, skeletal muscle mass, mid-arm muscle circumference, handgrip strength, quadriceps maximal voluntary capacity (MVC), and 1-repetition maximum chest press were selected for meta-analysis based on the number of available studies; thus 66 studies were included in the quantitative synthesis. Using a random effects model and 2-tailed p-value, there was a significant relationship in favor of omega-3 LC PUFA supplementation for lean body mass (effect size 0.27, 95%CI 0.04 to 0.51), skeletal muscle mass (effect size 0.31, 95%CI 0.01 to 0.60) and quadriceps MVC (effect size 0.47, 95%CI 0.02 to 0.93). Conclusion The results indicate that there is a positive effect of omega-3 LC PUFA supplementation on overall body muscle mass and strength. Small study size and heterogeneity limit the applicability of these findings for sarcopenia prevention. Larger trials in populations at risk of sarcopenia would strengthen the evidence base.

OBJECTIVE The authors aimed to examine the relationship between mesial temporal subregion ablation volume and seizure outcome in a diverse cohort of patients who underwent stereotactic laser amygdalohippocampotomy (SLAH) for mesial temporal lobe epilepsy (MTLE). METHODS Seizure outcomes and pre- and postoperative images were retrospectively reviewed in patients with MTLE who underwent SLAH at a single institution. Mesial temporal subregions and the contrast-enhancing ablation volume were manually segmented. Pre- and postoperative MR images were coregistered to assess anatomical ablation. Postoperative MRI and ablation volumes were also spatially normalized, enabling the assessment of seizure outcome with heat maps. RESULTS Twenty-eight patients with MTLE underwent SLAH, 15 of whom had mesial temporal sclerosis (MTS). The rate of Engel class I outcome at 1 year after SLAH was 39% overall: 47% in patients with MTS and 31% in patients without MTS. The percentage of parahippocampal gyrus (PHG) ablated was higher in patients with an Engel class I outcome (40% vs 25%, p = 0.04). Subregion analysis revealed that extent of ablation in the parahippocampal cortex (35% vs 19%, p = 0.03) and angular bundle (64% vs 43%, p = 0.02) was positively associated with Engel class I outcome. The degree of amygdalohippocampal complex (AHC) ablated was not associated with seizure outcome (p = 0.30). CONCLUSIONS Although the AHC was the described target of SLAH, seizure outcome in this cohort was associated with degree of ablation for the PHG, not the AHC. Complete coverage of both the AHC and PHG is technically challenging, and more work is needed to optimize seizure outcome after SLAH.

BACKGROUND Since 2007, the National Living Donor Assistance Center has provided the most financial support to US living donors meeting specific income criteria by reimbursing travel, meal, and lodging expenses. In 2019, the National Kidney Registry started providing lost wages, travel, and lodging reimbursement via their Donor Shield program. Donor Shield is automatically provided to donors who participate in kidney paired donation through the National Kidney Registry or who donate at a Donor Shield Direct center, without any income restrictions. METHODS The support donors across the United States received from the Donor Shield program between January 2019 and February 2020 was studied. RESULTS During the study period, 326 (25.9%) of the 1260 donors covered by Donor Shield, from 46 programs received reimbursements amounting to a total of $647 384.45, with $472 389.97 (73.0%) covering lost wages. Median reimbursement per donor was $1813.80 (range, $44.0-$165.63). Eighty-one percent of 108 reimbursed donors who were surveyed reported that the lack of these reimbursements would have posed a financial hardship, and 4% said they would have been unable to donate without this support. CONCLUSIONS Expansion of lost wages reimbursement programs to all donors in the United States would be an important step toward achieving financial neutrality for this unique population and could also help meet the growing demand for transplantable organs by increasing living donation rates.

BackgroundAnterior capsulotomy is a well-established treatment for refractory obsessive–compulsive disorder (OCD). MRI-guided laser interstitial thermal therapy (LITT) allows creation of large, sharply demarcated lesions with the safeguard of real-time imaging.ObjectiveTo characterise the outcomes of laser anterior capsulotomy, including radiographical predictors of improvement.MethodsPatients with severe OCD refractory to pharmacotherapy and cognitive–behavioural therapy underwent bilateral anterior capsulotomy via LITT. The primary outcome was per cent reduction in Yale-Brown Obsessive–Compulsive Scale (Y-BOCS) score over time. Lesion size was measured on postablation MRI. Disconnection of the anterior limb of the internal capsule (ALIC) was assessed via individual and normative tractography.ResultsEighteen patients underwent laser anterior capsulotomy. Median follow-up was 6 months (range 3–51 months). Time occupied by obsessions improved immediately (median Y-BOCS item 1 score 4–1, p=0.002). Mean (±SD) decrease in Y-BOCS score at last follow-up was 46%±32% (16±11 points, pConclusionsLaser anterior capsulotomy resulted in immediate, marked improvement in OCD symptom severity. Larger lesions permit greater disconnection of prefrontal–subcortical pathways involved in OCD. The importance of greater disconnection is presumably related to variation in ALIC structure and the complex role of the PFC in OCD.

Aims Cardiac involvement in COVID-19 is associated with adverse outcome. However, it is unclear whether cell-specific consequences are associated with cardiac SARS-CoV-2 infection. Therefore, we investigated heart tissue utilizing in situ hybridization, immunohistochemistry, and RNA-sequencing in consecutive autopsy cases to quantify virus load and characterize cardiac involvement in COVID-19. Methods and results In this study, 95 SARS-CoV-2-positive autopsy cases were included. A relevant SARS-CoV-2 virus load in the cardiac tissue was detected in 41/95 deceased (43%). Massive analysis of cDNA ends (MACE)-RNA-sequencing was performed to identify molecular pathomechanisms caused by the infection of the heart. A signature matrix was generated based on the single-cell dataset ‘Heart Cell Atlas’ and used for digital cytometry on the MACE-RNA-sequencing data. Thus, immune cell fractions were estimated and revealed no difference in immune cell numbers in cases with and without cardiac infection. This result was confirmed by quantitative immunohistological diagnosis. MACE-RNA-sequencing revealed 19 differentially expressed genes (DEGs) with a q-value, Graphical Abstract

The ChAdOx1 nCoV-19 adenoviral vector vaccine to prevent contracting Covid-19 caused by infection with SARS-CoV-2 has been associated with vaccine-induced immune thrombotic thrombocytopenia (VITT) primarily leading to venous thromboses. Here, we report two cases of major arterial occlusions after ChAdOx1 nCov-19 vaccination, comprising a 42-year-old woman with thrombotic occlusion of the left carotid artery, and a 62-year-old man with occlusion of distal aorta and iliac arteries. Both were successfully treated with intravenous immunoglobulins and non-heparin anticoagulant agents leading to a beneficial short-term outcome of 6 weeks in case 1 and four months in case 2.

Coronavirus disease 2019 (COVID-19) radically modified the organization of healthcare systems with shutdown of routine activities and outpatient clinics. Herein, we report our institutional experience with a Telemonitoring and Care Program (TC-Program) to monitor and support left ventricular assist device (LVAD) patients during COVID-19 outbreak. This single-arm cohort study analyzed 156 patients who entered the TC-Program at our institution between April and August 2020. The TC-Program was based on routine phone calls to patients and a 24/7 emergency line. In November 2020, patients were asked for feedback on the TC-Program and checked for survival, transplant, or explant. The primary endpoint was the rate of TC-Program-driven interventions. Patients (males: 82.8%) were 61 years old (interquartile range [IQR]: 53.0-67.5) and on LVAD support for 1,266 days (IQR: 475-2,211). Patients were included in the TC-Program for a median time of 99 days (min:15, max:120) and received a median number of six phone calls (min:1, max:14). Twenty-three patients (14.7%) were referred for clinical evaluation after phone contact. Two patients (1.27%) were diagnosed with COVID-19: one of them died after intensive care, and one remained paucisymptomatic and recovered. Three patients asked to exit the program considering it not useful while the others gave high rates in terms of usefulness (median: 9, IQR: 8-10), information (median: 9, IQR: 8-10), good medical care (median: 9, IQR: 8-10), and psychologic support (median: 8, IQR: 7-10). A TC-Program based on the four ICSA principles (Inform, Care, Support, and Adapt) is feasible in LVAD patients and can be rapidly implemented during the COVID-19 pandemic.

Objectives To test if the early kinetics of neurofilament light (NFL) in blood adds to the absolute values of NFL in the prediction of outcome, and to evaluate if NFL can discriminate individuals with severe hypoxic–ischemic brain injury (sHIBI) from those with other causes of poor outcome after out-of-hospital cardiac arrest (OHCA). Design and setting Monocentric retrospective study involving individuals following non-traumatic OHCA between April 2014 and April 2016. NFL concentrations were determined on a SiMoA HD-1 device using NF-Light Advantage Kits. Participants Of 73 patients screened, 53 had serum samples available for NFL measurement at three timepoints (after 3, 24, and 48 h of admission). Of these 53 individuals, 43.4% had poor neurologic outcome at discharge as assessed by Glasgow–Pittsburgh cerebral performance categories, and, according to a current prognostication algorithm, poor outcome due to sHIBI in 20.7%. Main outcome measure Blood NFL and its early kinetics for prognostication of outcome and prediction of sHIBI after OHCA. Results An absolute NFL > 508.6 pg/ml 48 h after admission, or a change in NFL > 494 pg/ml compared with an early baseline value predicted outcome, and discriminated severe sHIBI from other causes of unfavorable outcome after OHCA with high sensitivity (100%, 95%CI 70.0–100%) and specificity (91.7%, 95%CI 62.5–100%). Conclusions Not only absolute values of NFL, but also early changes in NFL predict the outcome following OHCA, and may differentiate sHIBI from other causes of poor outcome after OHCA with high sensitivity and specificity. Our study adds to published data, overall corroborating that NFL measured in blood should be implemented in prognostication algorithms used in clinical routine.

Purpose Epileptiform activity limited to deep sources such as the hippocampus currently lacks reliable scalp correlates. Recent studies, however, have found that a subset of hippocampal interictal discharges may be associated with visible scalp signals, suggesting that some types of hippocampal activity may be monitored noninvasively. The purpose of this study is to characterize the relationship between these scalp waveforms and the underlying intracranial activity. Methods Paired intracranial and scalp EEG recordings obtained from 16 patients were used to identify hippocampal interictal discharges. Discharges were grouped by waveform shape, and spike-triggered averages of the intracranial and scalp signals were calculated for each group. Cross-correlation of intracranial and scalp spike-triggered averages was used to determine their temporal relationship, and topographic maps of the scalp were generated for each group. Results Cross-correlation of intracranial and scalp correlates resulted in two classes of scalp waveforms-those with and without time delays from the associated hippocampal discharges. Scalp signals with no delay showed topographies with a broad field with higher amplitudes on the side ipsilateral to the discharges and a left-right flip in polarity-observations consistent with the volume conduction of a single unilateral deep source. In contrast, scalp correlates with time lags showed rotational dynamics, suggesting synaptic propagation mechanisms. Conclusions The temporal relationship between the intracranial and scalp signals suggests that both volume conduction and synaptic propagation contribute to these scalp manifestations. Furthermore, the topographic evolution of these scalp waveforms may be used to distinguish spikes that are limited to the hippocampus from those that travel to or engage other brain areas.

Objectives To establish the relative bioavailability and to assess bioequivalence of oral, immediate-release tablets containing pridinol and to determine the pharmacokinetic properties of the compound. Methods and materials In this single-center, open-label, randomized, crossover trial, healthy male and female adult subjects received single doses of the test and reference product containing 4 mg pridinol mesylate (equivalent to 3 mg pridinol) each under fasting conditions. For pharmacokinetic evaluation, blood samples were withdrawn until 72 hours post dose. Pridinol in plasma was quantified by validated liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS). Adverse events (AEs) were analyzed descriptively. Results Of 34 randomized subjects, 33 completed all treatments. The determined pharmacokinetic parameters were quite similar for both products, with geometric means for maximum exposure (Cmax) of 29.27 ng/mL (test) and 27.44 ng/mL (reference), reached after 1.00 and 0.90 hours (mean tmax), respectively. The extents of bioavailability (geometric mean AUC0-tlast) were 187.93 h×ng/mL (test) and 183.51 h×ng/mL (reference). Elimination half-lives (T1/2) ranged from 8.97 to 34.85 hours with comparable mean T1/2 of 19.14 hours (test) and 18.85 hours (reference). The point estimates of the test/reference-adjusted geometric mean ratios of AUC0-tlast, Cmax (primary), and AUC0-∞ (secondary) were 102.54% (90% confidence interval: 96.19 - 109.32%), 106.79% (99.00 - 115.20%), and 102.60% (96.20 - 109.43%), respectively. Overall, 23 subjects experienced 50 AEs; headache and dizziness (15 cases each) were most frequently reported. Conclusion Bioequivalence of both pridinol products was demonstrated in terms of rate and extent of absorption. Safety and tolerability were in accordance with the known AE profile of the drug substance.

Here we describe the case of a 63-year old woman with a sacral perineural cysts presenting with different symptoms such as headache, dizziness, and lower back pain with radiation and neurological claudication. The patient was treated by endoscopic assisted cyst resection and sacrum reconstruction. Histopathological examination of the cyst material revealed a cystic lesion with degenerative changes and hemorrhages. Postoperative course was uneventful, and the patients is free of symptoms three years after surgery. This case illustrates that symptomatic Tarlov cysts with extensive degenerative tissue changes can successfully managed by cyst resection.

Die Transfusion von Chimaren-Antigenrezeptor(CAR)-T-Zellen hat sich als neue Therapieform in der Onkologie etabliert, geht jedoch regelhaft mit immunvermittelten Nebenwirkungen einher, die auch schwer verlaufen konnen sowie eine spezifische und intensivmedizinische Behandlung erfordern. Literaturrecherche zu CAR-T-Zell-Therapie, Toxizitaten und Nebenwirkungsmanagement. Das „cytokine release syndrome“ (CRS) und das „immune effector cell-associated neurotoxicity syndrome“ (ICANS) treten regelhaft kurz nach einer Therapie mit CAR-T-Zellen auf. Das CRS kann von einer milden grippeahnlichen Symptomatik bis zum Multiorganversagen fuhren. Beim ICANS kann es neben milden Symptomen wie Verwirrtheit und Aphasie auch zu Krampfanfallen und Hirnodem kommen. Das Management von CRS und ICANS orientiert sich am Schweregrad nach dem Grading der American Society for Transplantation and Cellular Therapy (ASTCT). Beim CRS werden Tocilizumab und Kortikosteroide empfohlen; beim ICANS werden Kortikosteroide eingesetzt. Im weiteren Verlauf sind eine persistierende Hypogammaglobulinamie und Zytopenien auch Monate nach der Therapie haufig; diese begunstigen Infektionen auch Monate nach CAR-T-Zell-Therapie. Nach CAR-T-Zell-Therapie kommt es regelhaft zu potenziell schweren Komplikationen. Eine interdisziplinare Zusammenarbeit zwischen Intensivmediziner*innen, Hamatolog*innen, Neurolog*innen und Arzt*innen anderer Fachabteilungen ist fur die optimale Versorgung von CAR-T-Zell-Patient*innen von entscheidender Bedeutung.

IntroductionSurrogate endpoints are widely used in clinical trials, especially in situations where the endpoint of interest is not directly observable or to avoid long trial periods. A typical example for this case is frequently found in clinical trials in oncology, where overall survival (OS) as endpoint of interest and progression free survival (PFS) as surrogate endpoint are discriminated.MethodsBased on the perspective of case definitions on surrogate endpoints, we provide a formal definition of such endpoints followed by a description of the structure of surrogate endpoints.ResultsSurrogate endpoints can be considered as case definitions for the endpoint of interest. Therefore, the performance of surrogate endpoints can be described using the classical terminology of diagnostic tests including sensitivity and specificity. Since such endpoints always focus on sensitivity with necessarily reduced specificity, efficacy estimates based on such endpoints are in general biased.ConclusionThe abovementioned has to be taken into account while interpreting the results of clinical trials and should not be ignored while planning or conducting a study.

Zusammenfassung Hintergrund In Deutschland sind schätzungsweise 240.000 Menschen an Multipler Sklerose (MS) erkrankt. Neben sensiblen, motorischen, vegetativen und neuropsychologischen Funktionsstörungen ist die Dysphagie ein sicherlich hochrelevantes, stark beeinträchtigendes und zugleich bislang nicht gut untersuchtes Symptom der Erkrankung. Ziel der Arbeit Dieser Artikel soll eine Übersicht über die aktuelle Studienlage zur Dysphagie bei MS geben und es dem Leser ermöglichen, die Wahrnehmung für das Symptom Schluckstörung zu schärfen. Techniken zur weiterführenden Diagnostik und Therapie werden vorgestellt mit dem langfristigen Ziel, betroffenen Patienten mit MS zukünftig verbesserte Hilfe zu bieten und ihre Lebensqualität zu verbessern. Methode Zur Entstehung, Manifestation, Diagnostik- und Therapiemöglichkeiten bei MS-bedingter Dysphagie wurde eine strukturierte Literaturrecherche zur aktuellen Studienlage in pubmed durchgeführt. Aufgrund fehlender Klasse-1-Evidenz aus prospektiven Studien, insbesondere zur Diagnostik und zu den Therapiemöglichkeiten, wurden auch Studien mit kleineren Fallzahlen oder Pilotprojekte mit berücksichtigt. Ergebnisse und Diskussion In bildgebenden Methoden, wie der Fiberoptischen Endoskopischen Evaluation des Schluckens und der Videofluroskopie, lassen sich Schluckstörungen objektivieren. Je nach gewählter Methode zur Erfassung der Schluckstörung wird die Häufigkeit der Dysphagie bei MS-Erkrankten sehr unterschiedlich angegeben (von 38 % bis 81 %). Es ist jedoch davon auszugehen, dass die Dysphagie als bewusstes Symptom sowohl vonseiten der betroffenen Personen mit Multipler Sklerose als auch ihren Behandlern stark unterschätzt wird. Spezifische Behandlungen werden laut aktueller Daten aus dem deutschen MS-Register nur bei 30 % der betroffenen Patienten durchgeführt.

Objectives To establish dose proportionality for trazodone and gabapentin at fixed ratios of trazodone/gabapentin 2.5/25, 10/100, and 30/300 and investigation of potential drug-drug interaction at a dose of 10/100. Materials and methods 29 out of 30 healthy subjects completed this single-center, open-label, randomized, 5-period cross-over trial with single-dose fasted administrations. Administrations were separated by a washout period of at least 6 days. Blood samples were drawn until 48 hours post dose. A validated liquid chromatography-tandem mass spectrometry method (LC-MS/MS) was applied for determination of trazodone and gabapentin in plasma. The lower limits of quantitation (LLOQ) were 1.00 ng/mL and 5.00 ng/mL for trazodone and gabapentin, respectively. Adverse events (AEs) were analyzed in the study population descriptively. Results Plasma concentrations were characterized thoroughly. For trazodone, assessment of proportionality (power model/pairwise-comparison by ANOVA) showed proportionality for AUC over all doses and for Cmax between the middle and high dose. For gabapentin, a less than proportional increase in both metrices was present with a likely proportional increase from 25 to 100 mg only. Considering common bioequivalence criteria, absence of pharmacokinetic interaction was confirmed comparing the combination and individual agents. 23 subjects experienced 53 AEs during the trial, the most frequent being fatigue (20 cases/15 subjects) and dizziness (14 cases/11 subjects). No serious AEs were reported. Conclusion To our knowledge, for the first time, proportionality for trazodone at doses of 2.5 to 30 mg and for gabapentin at doses of 25 to 300 mg was investigated. Absence of a pharmacokinetic interaction was shown.

ZusammenfassungEs wird von einem 13 Jahre alt gewordenen weiblichen Orang-Utan berichtet, der 4 Tage vor dem Tod an einer akuten Enterokolitis erkrankte. Die tierärztliche Ultraschalluntersuchung einen Tag vor dem Tod erbrachte den Nachweis von vermehrter Flüssigkeit im Zäkum und einer abschnittsweise verdickten Kolonwand. Nach dem für die Veterinärmediziner und die Zoomitarbeiter unerwarteten Todeseintritt erfolgte eine Obduktion durch Rechtsmediziner der Universitätsmedizin Rostock mit Unterstützung von Ärzten weiterer Fachrichtungen. Dabei wurde als Todesursache eine akute Escherichia-coli-Enterokolitis mit massiver Blutung in den Darm festgestellt. Begünstigend oder ursächlich für die letale Enterokolitis dürften wahrscheinlich zahlreiche rezidivierende Durchfallerkrankungen in der Anamnese des Orang-Utans als Folge eines Verweigerns des Stillens durch die Mutter nach der Geburt gewesen sein.

Purpose Weaning from mechanical ventilation is a key component of intensive care treatment; however, this process may be prolonged as some patients require care at specialised centres. Current data indicate that weaning from invasive mechanical ventilation is successful in approximately 65% of patients; however, data on long-term survival after discharge from a weaning centre are limited. Materials and methods We analysed predictors of survival among 597 patients (392 men, mean age 68 ± 11) post-discharge from a specialised German weaning centre. Results Complete weaning from mechanical ventilation was achieved in 407 (57.8%) patients, and 106 patients (15.1%) were discharged with non-invasive ventilation; thus, prolonged weaning was successful in 72.9% of the patients. The one-year and five-year survival rates post-discharge were 66.5% and 37.1%, respectively. Age, duration of mechanical ventilation, certain clusters of comorbidities, and discharged with mechanical ventilation significantly influenced survival (p Conclusions The identified predictors of survival after prolonged weaning could support therapeutic strategies during patients' intensive care unit stay. Patients should be closely monitored after discharge from a weaning centre.

Background 5-HTTLPR/rs25531 is suspected to be involved in the pathogenesis of both coronary heart disease (CHD)1 and depression. We aimed to investigate the role of 5-HTTLPR/rs25531 in the development of depressive symptoms among CHD patients in a longitudinal design. Methods N = 265 participants with CHD diagnosis were included while hospitalized in a department of cardiology and genotyped for the 5-HTTLPR/rs25531. Depressive symptoms were measured using the Patient Health Questionnaire (PHQ-9)7 at baseline and after 6 and 12 months. Binary logistic regression models were used to analyze the association of 5-HTTLPR/rs25531 with the prevalence of depressive symptoms at each time point as well as with the incidence and persistence of depressive symptoms at follow-up. Results “LALA” genotype was associated with a higher prevalence of depressive symptoms 12 months after study inclusion. “LALA” genotype was associated with a higher incidence of depressive symptoms 6 and 12 months after study inclusion. There was no association of 5-HTTLPR/rs25531 with the persistence of depressive symptoms. Limitations Inclusion criteria did not demand a particular cardiac event at baseline, which aggravated the interpretation of the time-specific results. The majority of the participants was of male gender which could cause bias. The present study only vaguely differentiated between ethnical groups which might cause bias regarding nationality-dependent allele distributions. Conclusion The present study suggests a time-dependent association of the “LALA” genotype with depressive symptoms in CHD patients. 5-HTTLPR/rs25531 might be an important marker to detect risk groups for later onset depressive symptoms among CHD patients.

An increasing number of highly effective disease-modifying therapies for people with multiple sclerosis (MS) have recently gained marketing approval. While the beneficial effects of these drugs in terms of clinical and imaging outcome measures is welcomed, these therapeutics are associated with substance-specific or group-specific adverse events that include severe and fatal complications. These adverse events comprise both infectious and non-infectious complications that can occur within, or outside of the central nervous system (CNS). Awareness and risk assessment strategies thus require interdisciplinary management, and robust clinical and paraclinical surveillance strategies. In this review, we discuss the current role of MRI in safety monitoring during pharmacovigilance of patients treated with (selective) immune suppressive therapies for MS. MRI, particularly brain MRI, has a pivotal role in the early diagnosis of CNS complications that potentially are severely debilitating and may even be lethal. Early recognition of such CNS complications may improve functional outcome and survival, and thus knowledge on MRI features of treatment-associated complications is of paramount importance to MS clinicians, but also of relevance to general neurologists and radiologists.

The Defense POW/MIA Accounting Agency (DPAA) continues to diligently locate, recover, and identify over 81,000 missing US service members from past conflicts. To fulfill this important mission, massive amounts of information must be integrated from historical records, genealogy records, anthropological data, archaeological data, odontology data, and DNA. Previously a machine learning record-linkage application was developed to integrate DNA Family Reference Samples (FRS) data systems with the DPAA’s master data. This application was shown to link large record systems with a high level of accuracy and precision. Here this work is extended to further optimize the blocking strategy used during record linkage as well as the record match alpha-level threshold for the Bayesian Classifier. Optimization of the blocking strategy was able to improve application run-time per record by 20%. After record-match alpha-level optimization, the application was found to link 89.6% of the record out-group to DPAA master data at an accuracy of 99.6%. The improved run-time efficiency and match rate of the record-linkage pipeline will greatly benefit not only the DPAA’s FRS import process but also the linking of other big data sources supporting the DPAA mission.

We report a case of a chronic mesotympanic otitis media with a smelly purulent secretion from both ears and recurrent otalgia over the last five years in a six-year-old girl after swimming in the German Baltic Sea. Besides Staphylococcus aureus a non-O1/non-O139 Vibrio cholerae strain could be isolated from patient samples. An antibiotic therapy with ciprofloxacin and ceftriaxone was administered followed by atticotomy combined with tympanoplasty. We conclude that V. cholerae should not be overlooked as a differential diagnosis to otitis infections, especially when patients present with extra-intestinal infections after contact with brackish- or saltwater aquatic environments.

Background Progressive multifocal leukoencephalopathy (PML) is caused by an opportunistic infection with JC polyoma virus (JCPyV) and mainly affects immunocompromised patients. It leads to pronounced demyelination of the central nervous system (CNS) resulting in severe disability or even death. Detection of JCPyV DNA in the cerebrospinal fluid (CSF) is usually accepted as proof for the diagnosis of PML. Routine CSF parameters, like CSF cell count, protein concentration, Qalbumin, or intrathecal immunoglobulin synthesis are mostly considered normal. However, this has not been investigated systematically. Methods We analyzed routine CSF parameters in a cohort of 108 PML patients that were treated at four different neurological centers in Germany. The patients exhibited different underlying conditions with natalizumab-treated multiple sclerosis (n = 54) and human immunodeficiency virus (HIV)-infection (n = 25) being the most frequent. The data were collected at the respective centers in accordance with local requirements and then jointly analyzed. The total PML cohort was compared with a control group of patients with normal pressure hydrocephalus (NPH) and idiopathic intracranial hypertension (IIH). Multiple sclerosis and HIV patients were additionally compared with their own non-PML control groups. Results The PML group showed an elevated cell count (p Conclusions This comprehensive, retrospective study on CSF diagnostic analysis in PML patients provides insight into the CSF of those patients. It demonstrates that CSF composition in PML patients may be specific for the underlying condition that predisposes for the development of PML and thus data have to be interpreted in this context.

Depression and coronary heart disease (CHD) are prevalent and often co-occurring disorders. Both have been associated with a dysregulated stress system. As a central element of the stress system, the FKBP5 gene has been shown to be associated with depression. In a prospective design, this study aims to investigate the association of FKBP5 with depressive symptoms in CHD patients. N = 268 hospitalized CHD patients were included. Depressive symptoms were measured using the Hospital Anxiety and Depression Scale (HADS-D) at four time points (baseline, and after 1 month, 6 months, and 12 months). The functional FKBP5 single-nucleotide polymorphism (SNP) rs1360780 was selected for genotyping. Linear regression models showed that a higher number of FKBP5 C alleles was associated with more depressive symptoms in CHD patients both at baseline (p = 0.015) and at 12-months follow-up (p = 0.025) after adjustment for confounders. Further analyses revealed that this effect was driven by an interaction of FKBP5 genotype with patients’ prior CHD course. Specifically, only in patients with a prior myocardial infarction or coronary revascularization, more depressive symptoms were associated with a higher number of C alleles (baseline: p = 0.046; 1-month: p = 0.026; 6-months: p = 0.028). Moreover, a higher number of C alleles was significantly related to a greater risk for dyslipidemia (p = .016). Our results point to a relevance of FKBP5 in the association of the two stress-related diseases depression and CHD.

Background Endoscopic third ventriculostomy (ETV) is a widely accepted treatment for obstructive hydrocephalus. For most practitioners, this procedure will be performed without navigation guidance. Without such guidance, the complications associated with the procedure have ranged from 1% to 8%. We hypothesized that the discrepancy between the surface bony anatomy and internal cranial anatomy contributes to the morbidities associated with ETV. We tested this hypothesis by comparing the position of the entry point defined by the classic Kocher's point relative to the ideal entry point that would result in no manipulation of the endoscope defined by frame-based stereotaxis. Methods The cranial computed tomography scan of 58 patients who had undergone frame-based stereotactic ETV was reformatted into 3-dimensional renderings. The location of this entry point was compared with the Kocher point, as determined by the external bony anatomy. Results Overall, >70% of the burr holes that provided an ideal trajectory to the third ventricle were ≥0.5 cm from the Kocher point in both the sagittal and the coronal planes. Median deviations of 0.74 and 0.81 cm in the coronal (P Conclusion The use of stereotactic endoscopic techniques increase the safety of third ventriculostomy by adding precision and reducing otherwise unnecessary surgical maneuvering.

Introduction Various orthopedic surgical procedures cause mechanical stress for gloves. In some cases, sharp-edged objects impact on the glove surfaces. The systematic description of lesions is still missing. Methods 2289 gloves from 409 surgeries [primary hip and knee arthroplasties (PA), revisions arthroplasties (RA) and arthroscopic shoulder, hip and knee surgery (AY)] from 3 clinics were examined for lesions using water tightening test according to the European norm EN 455-1. Results Arthroscopies showed the lowest rate of operations with damaged gloves (6.9%). Depending on clinic, 32.7% and 59.2% of PA surgeries generated damaged gloves, while in RA, these numbers rose to 76.0% and 72.8%, respectively. In PA and RA, the most affected finger was the index finger, whereas in arthroscopies, more damage occurred on the middle finger and the thumb. The size of the lesions was rather small with the vast majority being 1 mm or 2 mm in size. Conclusion All investigated interventions led to glove lesions. With increasing mechanical stress, the number of glove defects increased. EN 455 does not account for the intraoperative tear risk. Stricter requirements for gloves should be introduced. Glove change intervals should be defined and implemented, and new materials should be developed.

Objective To study the frequency of neurological symptoms and complications in COVID-19 patients in a systematic review of the literature. Methods Relevant studies were identified through electronic explorations of PubMed, medRxiv, and bioRxiv. Besides, three Chinese databases were searched. A snowballing method searching the bibliographies of the retrieved references was applied to identify potentially relevant articles. Articles published within 1 year prior to April 20th, 2020, were screened with no language restriction imposed. Databases were searched for terms related to SARS-CoV-2/COVID-19 and neurological manifestations, using a pre-established protocol registered on the International Prospective Register of Systematic Reviews database (ID: CRD42020187994). Results A total of 2441 articles were screened for relevant content, of which 92 full-text publications were included in the analyses of neurological manifestations of COVID-19. Headache, dizziness, taste and smell dysfunctions, and impaired consciousness were the most frequently described neurological symptoms, the latter more often among patients with a severe or critical disease course. To date, only smaller cohort studies or single cases have reported cerebrovascular events, seizures, meningoencephalitis, and immune-mediated neurological diseases, not suitable for quantitative analysis. Conclusion The most frequent neurological symptoms reported in association with COVID-19 are non-specific for the infection with SARS-CoV-2. Although SARS-CoV-2 may have the potential to gain direct access to the nervous system, so far, SARS-CoV-2 was detected in the cerebrospinal fluid in two cases only. Standardized international registries are needed to clarify the clinical relevance of the neuropathogenicity of SARS-CoV-2 and to elucidate a possible impact of SARS-CoV-2 infection on common neurological disease, such as Alzheimer’s, Parkinson’s disease or multiple sclerosis.

In children, the infection with SARS-CoV-2, the cause of COVID-19, tends to be clinically inapparent more often or less severe than in adults. The spread of this infection from children poses a danger to vulnerable adults. Therefore, child care institutions and schools currently are widely closed.Since the status of infection tends to be congruent in mothers and their children, we tested 401 mothers of children between 1 and 10 years in the city of Rostock (State of Mecklenburg-Westpomerania, northeast of Germany), for the presence of RNA of SARS-CoV-2 in throat swabs, and of antibodies against SARS-CoV-2 in serum.In none of the mothers tested, RNA of this virus was detected in the throat swab. In the ELISA test, IgG antibodies were positive in one serum sample, IgA antibodies were positive in 11, and borderline in 3 serum samples. All 401 sera were negative in the indirect immunofluorescence test (IIFT) with FITC-labeled IgG, IgA, und IgM antibodies.At the time of this study, neither SARS-CoV-2 RNA, nor specific antibodies against SARS-CoV-2 were detectable in the mothers tested in Rostock.Bei Kindern verläuft die Infektion mit SARS-CoV-2, dem Erreger von COVID-19, in der Regel weniger schwer und häufiger symptomlos als bei Erwachsenen. Kinder können aber diese Infektion u. a. auf vulnerable Erwachsene übertragen. Daher sind zur Zeit Einrichtungen der Kinderbetreuung und Schulen teilweise geschlossen.Da sich der Infektionsstatus bei Kindern unter 13 Jahren und deren Müttern meist ähnlich darstellt, untersuchten wir bei 401 Rostocker Müttern von Kindern zwischen 1 und 10 Jahren Rachenabstriche auf SARS-CoV-2 und Serumproben auf Antikörper gegen diesen Erreger.Wir fanden bei keiner der untersuchten Mütter RNA von SARS-CoV-2 im Rachenabstrich. Im ELISA waren IgG-Antikörper in einem Serum positiv, IgA-Antikörper waren in 11 Seren positiv und in 3 Seren grenzwertig. Alle 401 Seren waren im Fluoreszenz-Bestätigungstest (IIFT) mit FITC-markierten IgG-, IgA- und IgM-Antikörpern negativ.Im Untersuchungszeitraum waren bei den getesteten Rostocker Müttern weder RNA von SARS-CoV-2 noch spezifische Antikörper nachweisbar.

Background In the 2011 US hospital prevalence survey of healthcare-associated infections and antimicrobial use 50% of patients received antimicrobial medications on the survey date or day before. More hospitals have since established antimicrobial stewardship programs. We repeated the survey in 2015 to determine antimicrobial use prevalence and describe changes since 2011. Methods The Centers for Disease Control and Prevention’s Emerging Infections Program sites in 10 states each recruited ≤25 general and women’s and children’s hospitals. Hospitals selected a survey date from May–September 2015. Medical records for a random patient sample on the survey date were reviewed to collect data on antimicrobial medications administered on the survey date or day before. Percentages of patients on antimicrobial medications were compared; multivariable log-binomial regression modeling was used to evaluate factors associated with antimicrobial use. Results Of 12 299 patients in 199 hospitals, 6084 (49.5%; 95% CI, 48.6–50.4%) received antimicrobials. Among 148 hospitals in both surveys, overall antimicrobial use prevalence was similar in 2011 and 2015, although the percentage of neonatal critical care patients on antimicrobials was lower in 2015 (22.8% vs 32.0% [2011]; P = .006). Fluoroquinolone use was lower in 2015 (10.1% of patients vs 11.9% [2011]; P < .001). Third- or fourth-generation cephalosporin use was higher (12.2% vs 10.7% [2011]; P = .002), as was carbapenem use (3.7% vs 2.7% [2011]; P < .001). Conclusions Overall hospital antimicrobial use prevalence was not different in 2011 and 2015; however, differences observed in selected patient or antimicrobial groups may provide evidence of stewardship impact.

Valid models are central for credible simulation studies. If those models do not exist, they need to be developed. In fact, entire simulation studies are often aimed at developing valid models. Thereby, successive model refinement and execution of diverse simulation experiments are closely intertwined. Whereas software-based support for individual simulation experiments exists, the intricate interdependencies and the diversity of tasks that govern simulation studies have prevented a more comprehensive support. To achieve the required flexibility while adhering to the constraints that apply between individual tasks, we adopt a declarative, artifact-based workflow approach. Therefore, central products of these simulation studies are identified and specified as artifacts: the conceptual model (with a focus on formally defined requirements), the simulation model, and the experiment. Each artifact is characterized by stages the artifact moves through to reach certain milestones and which are guarded by conditions. Thereby, the relations and constraints between artifacts become explicit. This is instrumental to check and ensure the consistency between conceptual model and simulation model, to automatically execute simulation experiments to probe the specified requirements, and to develop plans to provide goal-directed guidance to the user. We demonstrate the approach by using it to repeat an existing simulation study.

Objective Corpus callosotomy is an effective palliative treatment for drug-resistant Lennox-Gastaut syndrome (LGS). Laser interstitial thermal therapy has been increasingly used in the treatment of epilepsy. Here, we assess the safety and effectiveness of minimally invasive stereotactic laser anterior corpus callosotomy (SLACC) for drop attacks in LGS. Methods We reviewed sequential cases of patients with medically intractable LGS who underwent SLACC using a two-cannula technique between November 2014 and July 2019. Pre- and postoperative magnetic resonance imaging was used to measure the anteroposterior length of callosal ablation (contrast-enhancing lesion) and estimated disconnection (gap in tract projections on diffusion tensor imaging). Patients were followed longitudinally to assess clinical outcomes. Results Ten patients were included in this study. The median age was 33 (range = 11-52) years, median duration of epilepsy was 26 (range = 10-49) years, and median duration of postoperative follow-up was 19 (range = 6-40) months. In the anteroposterior direction, 53 ± 7% (mean ± SD) of the corpus callosum was ablated and 62 ± 19% of the corpus callosum was estimated to be disconnected. Six (60%) of 10 patients achieved >80% seizure reduction, two (20%) of whom became seizure-free. Eight (80%) patients had >80% reduction in drop attacks, five (50%) of whom became free of drop attacks. Three patients subsequently underwent laser posterior callosotomy with further improvement in drop attacks and/or overall seizure frequency. One patient had an asymptomatic intracerebral hemorrhage along the cannula tract. One patient developed significant aggression after becoming seizure-free. Significance Seizure outcomes following SLACC were comparable to previously reported outcomes of open callosotomy, with reasonable safety profile. SLACC appears to be an effective alternative to open anterior corpus callosotomy with minimal postoperative discomfort and a short recovery period.

Efforts to improve epilepsy surgery outcomes have led to increased interest in the study of electroencephalographic oscillations outside the conventional EEG bands. These include fast activity above the gamma band, known as high frequency oscillations (HFOs), and infraslow activity (ISA) below the delta band, sometimes referred to as direct current (DC) or ictal baseline shifts (IBS). HFOs in particular have been extensively studied as potential biomarkers for epileptogenic tissue in light of evidence showing that resection of brain tissue containing HFOs is associated with good surgical outcomes. Not all HFOs are conclusively pathological, however, as they can be recorded in nonepileptic tissue and induced by cognitive, visual, or motor tasks. Consequently, efforts to distinguish between pathological and physiological HFOs have identified several traits specific to pathological HFOs, such as coupling with interictal spikes, association with delta waves, and stereotypical morphologies. On the opposite end of the EEG spectrum, sub-delta oscillations have been shown to co-localize with the seizure onset zones (SOZ) and appear in a narrower spatial distribution than activity in the conventional EEG frequency bands. In this report, we review studies that implicate HFOs and ISA in ictogenesis and discuss current limitations such as inter-observer variability and poor standardization of recording techniques. Furthermore, we propose that HFOs and ISA should be analyzed in addition to activity in the conventional EEG band during intracranial presurgical EEG monitoring to identify the best possible surgical margin.

Modern disease-modifying therapies (DMTs) in multiple sclerosis (MS) have variable modes of action and selectively suppress or modulate the immune system. In this review, we summarize the predicted and intended as well as unwanted adverse effects on leukocytes in peripheral blood as a result of treatment with DMTs for MS. We link changes in laboratory tests to the possible therapeutic risks that include secondary autoimmunity, infections, and impaired response to vaccinations. Profound knowledge of the intended effects on leukocyte counts, in particular lymphocytes, explained by the mode of action, and adverse effects which may require additional laboratory and clinical vigilance or even drug discontinuation, is needed when prescribing DMTs to treat patients with MS.

Aims In a randomized, parallel, blinded study, we investigate the impact of clopidogrel, prasugrel, or ticagrelor on peripheral endothelial function in patients undergoing stenting for an acute coronary syndrome. Methods and results The primary endpoint of the study was the change in endothelium-dependent flow-mediated dilation (FMD) following stenting. A total of 90 patients (age 62 ± 9 years, 81 males, 22 diabetics, 49 non-ST elevation myocardial infarctions) were enrolled. There were no significant differences among groups in any clinical parameter. Acutely before stenting, all three drugs improved FMD without differences between groups (P = 0.73). Stenting blunted FMD in the clopidogrel and ticagrelor group (both P Conclusion As compared to ticagrelor and clopidogrel, therapy with prasugrel in patients undergoing stenting for an acute coronary syndrome is associated with improved endothelial function, stronger platelet inhibition, and reduced IL-6 levels, all of which may have prognostic implications. This effect was lost in patients who received the study medication immediately after stenting. EUDRACT-No 2011-005305-73

ADHD often affects multiple generations in a family. Previous studies suggested that children with ADHD benefit less from therapy if parents are also affected, since ADHD symptoms interfere with treatment implementation. This two-group randomised controlled trial examined whether targeting maternal ADHD boosts the efficacy of parent–child training (PCT) for the child’s ADHD. Here, we report follow-up results 2 years from baseline. Mothers of 144 mother–child dyads (ADHD according to DSM-IV) were examined for eligibility (T1) and randomised to 12 weeks of intensive multimodal treatment comprising pharmacotherapy and DBT-based cognitive behavioural group psychotherapy (TG, n = 77) or clinical management comprising non-specific counselling (CG, n = 67) for Step 1 (concluded by T2). Subsequently, all dyads participated in 12 weekly PCT sessions for Step 2 (concluded by T3). In Step 3, participants received maintenance treatments for 6 months (concluded by T4). At 24 months after baseline (T5), we performed follow-up assessments. The primary endpoint was child ADHD/ODD score (observer blind rating). Outcomes at T5 were evaluated using ANCOVA. Assessments from 101 children and 95 mothers were available at T5. Adjusted means (m) of ADHD/ODD symptoms (range 0–26) in children did not differ between TG and CG (mean difference = 1.0; 95% CI 1.2–3.1). The maternal advantage of TG over CG on the CAARS-O:L ADHD index (range 0–36) disappeared at T5 (mean difference = 0.2; 95% CI − 2.3 to 2.6). Sensitivity analyses controlling for medication and significant predictors of follow-up participation showed unchanged outcomes. Within-group outcomes remained improved from baseline. At the 24-month follow-up, TG and CG converged. The superiority of intensive treatment regarding maternal symptoms disappeared. In general, cross-generational treatment seems to be effective in the long term. (BMBF grant 01GV0605; registration ISRCTN73911400).

The article presents the cognitive radar architecture of Fraunhofer FHR based on a three-layer model of human cognitive performance. The approach is illustrated using examples for non-cooperative target identification and classification. On the skill based layer, a target-matched waveform design is presented and experimental results are shown. For the transition to the rule-based layer, convolutional neural networks are explained for the identification of air-targets and a novel auto-encoder for change detection is introduced. For rule-based behavior, a policy based decision making algorithm for NCTI waveform selection is explained, using CPOMDPs.

Introduction Escherichia coli and Staphylococcus aureus are important causes of severe diseases like blood stream infections. This study comparatively assessed potential differences in their impact on disease severity in local and systemic infections. Methods Over a 5-year interval, patients in whom either E. coli or S. aureus was detected in superficial or primary sterile compartments were assessed for the primary endpoint death during hospital stay and the secondary endpoints duration of hospital stay and infectious disease as the main diagnosis. Results Significance was achieved for the impacts as follows: Superficial infection with S. aureus was associated with an odds ratio of 0.27 regarding the risk of death and of 1.42 regarding infectious disease as main diagnosis. Superficial infection with E. coli was associated with a reduced duration of hospital stay by –2.46 days and a reduced odds ratio of infectious diseases as main diagnosis of 0.04. The hospital stay of patients with E. coli was increased due to third-generation cephalosporin and ciprofloxacin resistance, and in the case of patients with S. aureus due to tetracycline and fusidic acid resistance. Conclusions Reduced disease severity of superficial infections due to both E. coli and S. aureus and resistance-driven prolonged stays in hospital were confirmed, while other outcome parameters were comparable.

Bacterial infections of vascular grafts represent a major burden in cardiovascular medicine, which is related to an increase in morbidity and mortality. Different factors that are associated with this medical field such as patient frailty, biofilm formation, or immunosuppression negatively influence antibiotic treatment, inhibiting therapy success. Thus, further treatment strategies are required. Bacteriophage antibacterial properties were discovered 100 years ago, but the focus on antibiotics in Western medicine since the mid-20th century slowed the further development of bacteriophage therapy. Therefore, the experience and knowledge gained until then in bacteriophage mechanisms of action, handling, clinical uses, and limitations were largely lost. However, the parallel emergence of antimicrobial resistance and individualized medicine has provoked a radical reassessment of this approach and cardiovascular surgery is one area in which phages may play an important role to cope with this new scenario. In this context, bacteriophages might be applicable for both prophylactic and therapeutic use, serving as a stand-alone therapy or in combination with antibiotics. From another perspective, standardization of phage application is also required. The ideal surgical bacteriophage application method should be less invasive, enabling highly localized concentrations, and limiting bacteriophage distribution to the infection site during a prolonged time lapse. This review describes the latest reports of phage therapy in cardiovascular surgery and discusses options for their use in implant and vascular graft infections.

Secondary immunodeficiencies (SIDs) are acquired conditions that may occur as sequelae of immune therapy. In recent years a number of disease-modifying therapies (DMTs) has been approved for multiple sclerosis and related disorders such as neuromyelitis optica spectrum disorders, some of which are frequently also used in- or off-label to treat conditions such as chronic inflammatory demyelinating polyneuropathy (CIDP), myasthenia gravis, myositis, and encephalitis. In this review, we focus on currently available immune therapeutics in neurology to explore their specific modes of action that might contribute to SID, with particular emphasis on their potential to induce secondary antibody deficiency. Considering evidence from clinical trials as well as long-term observational studies related to the patients’ immune status and risks of severe infections, we delineate long-term anti-CD20 therapy, with the greatest data availability for rituximab, as a major risk factor for the development of SID, particularly through secondary antibody deficiency. Alemtuzumab and cladribine have relevant effects on circulating B-cell counts; however, evidence for SID mediated by antibody deficiency appears limited and urgently warrants further systematic evaluation. To date, there has been no evidence suggesting that treatment with fingolimod, dimethyl fumarate, or natalizumab leads to antibody deficiency. Risk factors predisposing to development of SID include duration of therapy, increasing age, and pre-existing low immunoglobulin (Ig) levels. Prevention strategies of SID comprise awareness of risk factors, individualized treatment protocols, and vaccination concepts. Immune supplementation employing Ig replacement therapy might reduce morbidity and mortality associated with SIDs in neurological conditions. In light of the broad range of existing and emerging therapies, the potential for SID warrants urgent consideration among neurologists and other healthcare professionals.

A 71‐year‐old Caucasian man presented with dysarthria and fluctuating hypoesthesia of the right upper limb in early 2019. Brain magnetic resonance imaging (MRI) demonstrated T2/fluid attenuated inversion recovery hyperintense lesions in the left parietal cortical grey matter and adjacent white matter compatible with embolic stroke of undetermined source. Eight weeks later, symptoms had further progressed with loss of adequate communication, disturbance of fine motor skills, ataxia and neuropsychiatric symptoms. Widespread disease on brain MRI and the detection of JC polyomavirus (JCPyV) DNA from cerebrospinal fluid (CSF) confirmed the diagnosis of progressive multifocal leukoencephalopathy (PML) [1]. Bone marrow biopsy revealed normal findings, and no underlying cause of reduced immunocompetence was identified. Despite rehabilitation, treatment with mirtazapine and two cycles of interleukin‐2 (IL‐2) (1 mio IE/m² sc once per day for 7 days) administered 2 weeks apart [1, 2], symptoms and MRI lesions further progressed, with complete immobility and severe dysphagia. Nine weeks after definite PML diagnosis and 4 weeks after the last IL‐2 dose, a total of three cycles of monthly infusions of pembrolizumab were applied. At the initiation of the third cycle of pembrolizumab, cognitive performance and fine motor skills had temporarily improved, and the patient had regained the ability to walk a few steps with assistance. On MRI, no increase in lesion load and no signs of an immune reconstitution inflammatory syndrome were noted. JCPyV DNA, after a decline that started already following the IL‐2 therapy, was no longer detected in CSF, collectively suggesting PML remission (Fig. 1). Enzyme‐linked immunosorbent assays revealed increasing JCPyV‐specific antibody titers in blood and CSF (AIJCPyV > 1.5 [3]). A pembrolizumab effect was indicated by reduced programmed cell death protein 1 (PD‐1) expression on peripheral CD4+ and CD8+ T cells after the treatment. Also, during the disease course of PML and following pembrolizumab treatment, proportions of innate immune cells (CD56dimCD16‐cytotoxic NK cells, CD14+ CD16 classical and CD14dim CD16+ non‐classical monocytes and CD11+ dendritic cells) and pro‐inflammatory cytokines and chemokine increased (Appendix S1, Table S1). Four weeks following the last infusion with pembrolizumab, aspiration pneumonia was suspected, and the patient received intravenous piperacillin/tazobactam 4/0.5 g three times per day for 7 days with temporary relief of symptoms. No causative bacteria were detected from blood cultures. Six weeks post‐pembrolizumab treatment, respiratory distress occurred again, and the general clinical condition further deteriorated. The patient and his legal custodians decided not to receive further hospital care, upon considering the severe and persistent disability, and the patient died shortly thereafter. As an autopsy was not performed, alternative causes of respiratory distress, such as autoimmune pneumonitis that might occur as an adverse event of pembrolizumab therapy, could not be ruled out.