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Background and Study Aim: Data from the AWARE study (A Worldwide Antihistamine-Refractory chronic urticaria patient Evaluation) illustrate a substantial disease burden in German patients with H1-antihistamine (-H1-AH)-refractory chronic spontaneous urticaria (CSU). Detrimental effects on patients' quality of life, poor disease control and impairment in the ability to work and perform other daily activities are reported. Based on these findings, this study aims to quantify the epidemiological and socio-economic burden of H1-AH-refractory CSU in Germany., Methods: To determine the epidemiological burden of H1-AH-refractory CSU, the age- and gender-specific prevalence of CSU and the proportion of H1-AH-refractory patients in Germany anonymized data from the InGef research database have been used. In a second step, the socio-economic burden in terms of lost numbers of hours in paid and unpaid work was calculated by extrapolating the age- and gender-specific work productivity and activity impairment (WPAI) observed in AWARE to the H1-AH-refractory CSU population in Germany. Finally, productivity losses in paid and unpaid work were monetized using the human capital and the friction cost approach respectively. Moreover, socio-economic burden was calculated depending on symptom control of the patients (measured by urticaria control test [UCT])., Results: In Germany, over 203,000 patients (20 years or older) had H1-AH-refractory CSU in 2018. The avoided lost paid and unpaid work hours attributable to H1-AH-refractory CSU summed up to over 100 million. Overall, the socio-economic burden of H1-AH-refractory CSU in monetary terms was evaluated at € 2.2 billion and the majority of this was due to unpaid work loss. Patients with poor disease control, as indicated by UCT score < 12, were more likely to suffer from high impairment than patients with controlled disease, resulting in a higher socio-economic burden., Conclusions: The results of our analyses picture the substantial socio-economic burden of H1-AH-refractory CSU and therefore the tremendous impact it has on daily lives of individuals and society overall., (© 2024 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Objective: Idiopathic intracranial hypertension (IIH) is a neurometabolic disease with an increasing incidence. The pathophysiology is unknown, but improvement of diagnosis and management requires discovery of novel biomarkers. Our objective was to identify such candidate biomarkers in IIH, and secondarily, test for associations between identified metabolites and disease severity., Methods: This is a prospective case-control study with collection of cerebrospinal fluid (CSF), serum, and clinical data from new-onset, treatment-naïve patients with IIH (n = 60). Patients were included consecutively from 2 tertiary headache centers in Denmark, and age, sex, and body mass index (BMI) -matched healthy controls (n = 35) were recruited. Clinical data were retrieved at ocular remission (n = 55). Samples were analyzed using non-targeted mass spectrometry., Results: Serum sphingosine 1-phosphate (S1P), adenosine, and glutamate were 0.46-fold (q < 0.0001), 0.25-fold (q = 0.0048), and 0.44-fold (q < 0.0001) lower, respectively, in IIH. CSF stearoyl-lysophosphatidylcholine (LysoPC-18) and 2-palmitoyl-lysophosphatidylcholine (LysoPC-16) were 0.42 (q = 0.0025) and 0.37 (q < 0.001) -fold lower. LysoPC-18 was higher in patients with moderate-severe versus mild papilledema (p = 0.022). LysoPC-18 correlated positively with retinal nerve fiber layer thickness (p = 0.0012, r = 0.42) and inversely with mean deviation on automated perimetry (p = 0.01, r = -0.35). Higher baseline serum S1P (p = 0.018) and lower CSF LysoPC-16 (p = 0.003) were associated with optic nerve atrophy at ocular remission. Pathway analysis suggests dysregulated lipid metabolism and redox disturbances in new-onset IIH., Interpretation: We identify perturbed metabolism in new-onset IIH. S1P and LysoPC-16 demonstrate potential prognostic value due to association with subsequent optic nerve atrophy. This association between specific, differential metabolites and outcome provides substantial evidence for novel biomarkers of clinical significance that should be the focus of further targeted studies. ANN NEUROL 2024;96:595-607., (© 2024 The Author(s). Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Physical activity can worsen migraine, leading to reduced activity levels in adults with chronic migraine. This study investigated the change in average steps per day, as a surrogate marker of physical activity, in adults with chronic migraine successfully treated with monoclonal antibodies against calcitonin gene-related peptide or its receptor. Data were obtained from adults with chronic migraine, who were classified as responders to preventive treatment with monoclonal antibodies. The primary endpoint was the difference in a mean number of steps per day between the 3 months prior to treatment initiation and the first 3 months after treatment initiation. The secondary endpoint was the correlation between the change in steps per day and the change in monthly migraine days. Twenty-two (20 females) participants with a median age of 48.5 years were enrolled. The median number of steps per day increased from 4421 at baseline to 5241 after treatment (P = 0.039). We found a positive correlation between the increase in steps per day and the treatment response (P = 0.013). In conclusion, an increase in physical activity, based on steps per day, positively correlated with treatment response to monoclonal antibodies. Automatically registered daily step count data might be used to monitor physical activity as a response to preventive treatment in adults with chronic migraine., (© 2024. The Author(s).)

Background: Glucagon-like peptide-1 (GLP-1) plays a crucial role in metabolic disorders by enhancing insulin secretion, inhibiting glucagon release, and slowing gastric emptying, thereby improving glycemic control. In recent years, GLP-1 role in neuronal pathways has expanded its therapeutic potential. We aim to comprehensively evaluate the relevance of GLP-1 in headache and pain disorders., Methods: A systematic literature search was conducted on PubMed and Embase (Ovid) databases using the search terms "GLP-1" and "pain". Animal and human studies published in English language were included. Abstracts, reviews, and articles on other disorders than "pain" were excluded., Results: The search strategy identified 833 hits, of which 42 studies were included in the final review. The studies were categorized into four groups: inflammatory pain and osteoarthritis, headaches, neuropathic pain and diabetic neuropathy, and visceral pain and irritable bowel syndrome. GLP-1 receptor (GLP-1R) agonists, like liraglutide, have shown analgesic effects by modulating pain hypersensitivity in animal models of inflammatory and neuropathic pain. GLP-1 is involved in migraine mechanisms and GLP-1R agonists are beneficial in individuals with idiopathic intracranial hypertension. Additionally, GLP-1R agonists reduce visceral hypersensitivity and ameliorate symptoms in patients with irritable bowel syndrome., Conclusions: The therapeutic scope of GLP-1R agonists is expanding beyond traditional metabolic targets, highlighting its potential for headache and pain disorders. Engineering bimodal molecules that integrate GLP-1R agonism with specific pain-related mechanisms may offer innovative therapeutic options., (© 2024. The Author(s).)

Introduction: Atogepant is a selective calcitonin gene-related peptide (CGRP) receptor antagonist that is utilized in adults for the prevention of episodic and chronic migraine. Cumulative findings support the involvement of CGRP in migraine pathophysiology, and atogepant functions by competitively antagonizing CGRP receptors, which results in the inhibition of trigeminovascular nociception. The mechanism of action addresses the cause of migraine pain, providing an effective preventive treatment option., Areas Covered: The key milestones in its development, including preclinical achievements, phase I, II, and III clinical trials, and regulatory approvals are reviewed. Additionally, clinical efficacy, safety profile, and tolerability of atogepant are discussed. The literature review is based on a comprehensive search of English peer-reviewed articles from various electronic databases, including PubMed and ClinicalTrials.gov., Expert Opinion: The development of atogepant represents a significant breakthrough in migraine prevention, particularly due to its improved safety profile that reduces the risk of liver injury, which was a major limitation of first-generation gepants. Drug-drug interaction studies with atogepant highlight the necessity for more inclusive study populations. Given that migraine disproportionately affects females, future clinical development programs should include diverse patient demographics to ensure the findings are generalizable to all individuals suffering from migraine.

Importance: The magnetic resonance imaging (MRI) criteria currently used to diagnose idiopathic intracranial hypertension (IIH) are based on expert opinion and have limited accuracy. Additional neuroimaging signs have been proposed and used with contradictory results; thus, prospective evidence is needed to improve diagnostic accuracy., Objective: To provide evidence-based, accurate MRI signs for IIH diagnosis., Design, Setting, and Participants: This prospective cohort study was conducted from January 2018 to May 2021 with 3 validation cohorts at 2 Danish headache centers and with 3 independent international cohorts. Consecutive patients with suspected IIH were enrolled. Eligibility required the clinical suspicion of IIH, age 18 years or older, and written informed consent. The validation cohorts comprised patients with confirmed IIH from Austria and the US, and patients without IIH from the US. Data analysis was performed from December 2021 to August 2023., Exposure: Standardized diagnostic workup was performed to classify cases according to current criteria, and blinded evaluation of cerebral radiological diagnostics and papilledema was performed., Main Outcomes and Measures: The primary outcomes were MRI signs associated with IIH as assessed by univariate analyses. An MRI score estimating papilledema was calculated using machine learning. Internal validation of associations with lumbar puncture opening pressure and outcome and external validation of accuracy were performed in 3 cohorts., Results: Of 192 eligible patients (185 women [96.4%]; median [IQR] age, 28.0 [23.0-35.0] years), 110 were classified as having IIH, 4 as having probable IIH, and 1 as having suspected IIH without papilledema; 77 did not have IIH and served as controls, with corresponding age, sex, and weight. Papilledema at diagnosis was associated with perioptic subarachnoid space distension (56 patients [68.3%] vs 21 patients [41.2%]), posterior globe flattening (53 patients [66.3%] vs 10 patients [21.3%]), optic nerve disc protrusion (35 patients [30.4%] vs 2 patients [2.3%]), and transverse sinus venous stenosis (75 patients [79.8%] vs 29 patients [46.8%]). The papilledema-estimating MRI score showed optimal balance between sensitivity (49%) and specificity (87%) when 2 of the 3 latter signs were present and was associated with the lumbar puncture opening pressure and ophthalmological outcome. The score showed strong diagnostic accuracy in the external validation cohorts (587 patients; area under the receiver operating characteristic curve, 0.86) and outperformed the current (2013) diagnostic MRI criteria., Conclusions and Relevance: The findings of this cohort study of patients with IIH and controls suggest that an evidence-based MRI score including posterior globe flattening, optic nerve disc protrusion, and transverse sinus stenosis can estimate the presence of papilledema more accurately than the current diagnostic criteria.

Background: Idiopathic intracranial hypertension is a secondary headache disorder potentially causing visual loss. Neurofilament light chain is a candidate, prognostic biomarker, but further studies of neuronal biomarkers are needed. Our objective was to investigate neurofilament light chain in cerebrospinal fluid (cNfL) and plasma (pNfL), amyloid-beta 42 (Aβ-42), total-tau and phosphorylated-tau in cerebrospinal fluid in new-onset idiopathic intracranial hypertension., Methods: Prospective case-control study including new-onset idiopathic intracranial hypertension and age, sex and BMI matched controls. Biomarkers were compared between patients and controls and related to papilledema, visual fields and opening pressure., Results: We included 37 patients and 35 controls. Patients had higher age-adjusted cNfL (1.4 vs. 0.6 pg/mL, p-adjusted < 0.001), pNfL (0.5 vs. 0.3 pg/mL, p-adjusted < 0.001) and total-tau/Aβ-42 (0.12 vs. 0.11, p-adjusted = 0.039). Significant, positive linear correlations were found between cNfL, pNfL, total-tau/Aβ-42 and opening pressure. Patients with severe papilledema had elevated cNfL compared to mild-moderate papilledema (median cNfL: 4.3 pg/mL (3.7) versus 1.0 pg/mL (1.4), p-adjusted = 0.009). cNFL was inversely associated with perimetric mean deviation (r = -0.47, p-adjusted < 0.001)., Conclusions: cNfL, pNfL and total-tau/Aβ-42 were elevated in new-onset idiopathic intracranial hypertension. cNfL was associated with severity of papilledema and visual field defects at diagnosis. This indicates early axonal damage. Neurofilament light chain is a candidate biomarker for disease severity., Competing Interests: Declaration of conflicting interestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: KS: No conflicts of interest. JJK: Received funding from the Lundbeck Foundation, Rigshospitalet-Glostrup and Odense University Hospital. RHJ: Paid lectures for Pfizer, Eli-Lilly, Merck, TEVA, Novartis, Lundbeck and Allergan. Investigator in clinical trials with Eli-Lilly, Novartis and Lundbeck; Director of Danish Headache Center, Lifting The Global Burden of Headache and Founder of Master of Headache Disorders at University of Copenhagen. Recived research funding from University of Copenhagen, Rigshospitalet, Lundbeck Foundation, The Medical Society in Copenhagen, NovoNordisk Foundation and Tryg Foundation. TP: No conflicts of interest. CSK: No conflicts of interest. SGH: No conflicts of interest. SMH: No conflicts of interest. EAW: Medical Advisory Board for StatuManu ICP ApS. Received research funding from Øjenforeningen (Fight for Sight, Denmark) and the Synoptik Foundation. LDM: No conflicts of interest. DB: Presentations (TEVA, Novartis, Pfizer), Travel Support (Allergan, TEVA, Pfizer, Abbvie), Advisory Boards (Novartis, Lilly, Teva, Lundbeck, Pfizer, Abbvie) and Participations in clinical trials (TEVA, Lundbeck, Novartis, Lilly, Novo Nordic Foundation) outside the submitted work (other headache disorders), receiving grants from Odense University Hospital and Rigshospitalet, University of Copenhagen during the conduction of the work.

Background: Data are limited regarding guideline-directed medical therapy (GDMT) treatment patterns in patients with worsening heart failure (HF)., Methods: We used administrative claims databases in Germany and the USA to conduct a retrospective cohort study of patients with worsening HF. Two cohorts of patients with prevalent HF and a HF hospitalization (HFH) from 2016 to 2019, alive at discharge (N = 75,140 USA; N = 47,003 Germany) were identified. Index date was the first HFH during the study period. One-year HF rehospitalization and mortality rates were calculated and a composite endpoint of both outcomes assessed using Kaplan-Meier estimation. We evaluated HF medication patterns in the 6 months before and after the index date. New users of a HF medication (at discharge/after index HFH) were followed for 1 year to evaluate persistence (no treatment gaps > 2 months) RESULTS: One-year HF rehospitalization rates were 36.2% (USA) and 47.7% (Germany). One year mortality rates were 30.0% (USA) and 23.0% (Germany), and the composite endpoint (mortality/HF rehospitalization) was reached in 55.1 % (USA) and 56.6% (Germany). Kaplan-Meier plots showed the risk for the composite endpoint was high in the early post discharge period. Comparison of patterns pre- and postindex HFH showed some increase in use of mineralocorticoid receptor antagonists (MRAs), angiotensin receptor-neprilysin inhibitor (ARNI), and triple therapy; use of angiotensin-converting enzyme (ACE) inhibitor/ angiotensin receptor blocker (ARB) plus beta-blockers remained constant/slightly declined; < 20% patients received triple therapy (ACE inhibitor/ARB plus beta-blocker plus MRA). A third of patients were new users; 1 year persistence rates were often low., Conclusions: Morbidity, mortality, and rehospitalization risk is high among patients with worsening HF; uptake and continuation of GDMT is suboptimal., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Aim: Seasonal influenza poses a significant burden of disease, affecting not only older adults but also individuals under the age of 60. It carries a high economic burden, mainly driven by influenza-associated productivity losses in the working population. Conventional egg-based influenza vaccines may have reduced effectiveness due to antigen adaptation in eggs. In contrast, cell-based influenza vaccines are less likely to be affected by such antigen adaptation. This review aims to present real-world data (RWD) comparing the effectiveness of quadrivalent cell-based (QIVc) and egg-based (QIVe) influenza vaccines over three consecutive seasons., Methods: A comprehensive review was conducted, analyzing RWD from retrospective cohort and case-control studies on the relative vaccine effectiveness (rVE) of QIVc versus QIVe during the 2017/18-2019/20 seasons., Results: This study included six retrospective cohort studies and one case-control study, with a combined total of approximately 29 million participants. A cohort study involving people aged ≥4 years during the 2017/18 season showed a statistically significant rVE of QIVc compared to QIVe in preventing influenza-like illness, with a value of 36.2%. QIVc demonstrated statistically significant superiority over QIVe in preventing outpatient and inpatient medical encounters as observed in two cohort studies conducted during the 2018/19 and 2019/20 seasons. The rVE of QIVc compared to QIVe was found to be 7.6% in individuals aged ≥4 years and 9.5% in individuals aged ≥18 years. Three additional cohort studies conducted between 2017/18-2019/20 reported a statistically significant improvement in rVE (5.3-14.4%) of QIVc compared to QIVe in preventing influenza-related hospitalizations and emergency department visits due to influenza in individuals aged 4-64 years. In a case-control study across all three seasons, QIVc showed statistically significantly higher effectiveness compared to QIVe in preventing test-confirmed influenza, with rVEs of 10.0-14.8%., Conclusions: RWD from the 2017/18-2019/20 seasons demonstrated that QIVc is more effective than QIVe in preventing influenza-related outcomes in individuals aged 4-64 years. Preferential use of cell-based influenza vaccines, as opposed to conventional egg-based vaccines, could reduce the burden of influenza-related symptoms on individuals and alleviate the economic impact on the German population under 60 years of age., Competing Interests: CSL Seqirus GmbH funded the publication.Dr. Dietmar Beier: Advisory Board for CSL Seqirus.Prof. Dr. Barbara C. Gärtner: Advisory Board and honoraria for lectures for CSL Seqirus, Sanofi, GSK, Moderna, BioNTech, Pfizer, Viatris.Dr. Gunther Gosch: Lecturing activities and participation in advisory boards for AstraZeneca, CLS Seqirus, GSK, MSD, Pfizer, Sanofi Aventis. Prof. Dr. Klaus Wahle: Lectures and participation in advisory boards on behalf of or for SPMSD, CSL Seqirus, Pfizer, GSK, BioNTech. Dr. Luise Wendt: -Dr. Laura-Christin Förster is employed by CSL Seqirus GmbH.Kim J. Schmidt is employed by Xcenda GmbH, which received funding from CSL Seqirus GmbH for the preparation of this manuscript.Prof. Dr. Tino F. Schwarz: Honoraria for consulting and lectures for Alexion, AstraZeneca, Bavarian Nordic, Biogen, BioNTech, GSK, Janssen-Cilag, Merck-Serono, Moderna, MSD, Novavax, Pfizer, Roche, Sanofi-Aventis, CSL Seqirus, Synlab, Takeda and va-Q-tec., (Copyright © 2024 Gärtner et al.)

Background: Headache burden is substantial in idiopathic intracranial hypertension. The classification of idiopathic intracranial hypertension headache by the International Classification of Headache Disorders (ICHD) is an important tool for research and clinical purposes., Methods: We phenotyped headaches and tested sensitivity and specificity of the ICHD-3 criteria for idiopathic intracranial hypertension headache in a prospective cohort of patients suspected of idiopathic intracranial hypertension at two tertiary headache centers., Results: Sensitivity was 93% and specificity was 100% of ICHD-3 criteria for idiopathic intracranial hypertension-related headache validated in idiopathic intracranial hypertension ( n  = 140) and patients in whom idiopathic intracranial hypertension was suspected but disproven ( n =  103). The phenotype of new/worsened headaches related to idiopathic intracranial hypertension suspicion was equally migraine-like (p = 0.76) and tension-type-like (p = 0.08). Lumbar puncture opening pressure was higher ( p  < 0.0001) and pulsatile tinnitus more frequent ( p  < 0.0001) in idiopathic intracranial hypertension patients, but neither improved the applicability of the headache criteria, nor did papilledema., Conclusion: Headache phenotype is not distinct in idiopathic intracranial hypertension. ICHD-3 criteria for idiopathic intracranial hypertension headache are sensitive and specific, but simplicity can be improved without compromising accuracy. We propose that a new or worsened headache temporally related to active idiopathic intracranial hypertension is a sufficient criterion for idiopathic intracranial hypertension headache regardless of headache phenotype or accompanying symptoms, and that elements of idiopathic intracranial hypertension diagnostics (papilledema and opening pressure) be segregated from headache criteria. Trial Registration: ClinicalTrials.gov Identifier: NCT04032379., Competing Interests: Declaration of conflicting interestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: NSH received funding from the Novo Nordic Foundation during the conduction of the work and gave lectures for Pfizer, University of Southern Denmark, and University of Copenhagen. JJK received funding from the Lundbeck Foundation, Rigshospitalet-Glostrup, and Odense University hospital for the duration of the study. HMY received support from Abbvie for participation in non-related courses. RHJ gave lectures for Pfizer, Eli-Lilly, Merck, TEVA, Novartis, Lundbeck and Allergan; was investigator in clinical trials with Eli-Lilly, Novartis and Lundbeck. She is the Director of Danish Headache Center, Lifting The Global Burden of Headache and Founder of Master of Headache Disorders at University of Copenhagen and received research funding from University of Copenhagen, Rigshospitalet, Lundbeck Foundation, The Medical Society in Copenhagen, NovoNordisk Foundation and Tryg Foundation. DB gave lectures for TEVA, Novartis, Pfizer. Received travel support from Allergan, TEVA, Pfizer, Abbvie; was in advisory boards for Novartis, Lilly, Teva, Lundbeck, Pfizer, Abbvie and participated in clinical trials for TEVA, Lundbeck, Novartis, Lilly, Novo Nordic Foundation outside the submitted work. Received grants from Odense University Hospital and Rigshospitalet, University of Copenhagen during the conduction of the work.

Background: Idiopathic intracranial hypertension (IIH) occurs more frequently in obese females of childbearing age. A link between eating disorders and poor outcome has been suggested but remains unproven., Methods: This prospective field study at two tertiary headache centers included patients with clinically suspected IIH after standardized diagnostic work-up. Eating disorders were evaluated using validated questionnaires (EDQs). Primary outcome was the impact of eating disorders on IIH severity and outcome, secondary outcome was the prevalence and type of eating disorders in IIH compared to controls., Results: We screened 326 patients; 143 patients replied to the EDQs and were classified as 'IIH' or 'non-IIH' patients. The demographic profile of EDQ-respondents and non-respondents was similar. Presence of an eating disorder did not impact IIH severity (lumbar puncture opening pressure (p = 0.63), perimetric mean deviation (p = 0.18), papilledema (Frisén grad 1-3; p = 0.53)) nor IIH outcome (optic nerve atrophy (p = 0.6), impaired visual fields (p = 0.18)). Moreover, we found no differences in the prevalence and type of eating disorders when comparing IIH with non-IIH patients (p = 0.09)., Conclusion: Eating disorders did not affect IIH severity or outcome. We found the same prevalence and distribution pattern of eating disorders in IIH and non-IIH patients advocating against a direct link between IIH and eating disorders., Competing Interests: Declaration of conflicting interestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: T.W.: No conflicts of interest. J.L.: No conflicts of interest. M.B.L.: No conflicts of interest. N.S.H.: Received funding from the Novo Nordic Foundation (NNF20OC0065926) during the conduction of the work and gave lectures for Pfizer, University of Southern Denmark, and University of Copenhagen. J.J.K.: Received funding from the Lundbeck Foundation, Odense University Hospital and Rigshospitalet during the study. L.H.: No conflicts of interest. S.M.H.: Received grants from Fight for Sight, Denmark and the Synoptik Foundation. L.D.M.: No conflicts of interest. R.H.J.: Gave lectures for Pfizer, Eli-Lilly, ATI, Merck, TEVA, Novartis, Lundbeck and Allergan. Investigator in clinical trials with ATI, Eli-Lilly, Novartis and Lundbeck. Director of Danish Headache Center, Lifting The Global Burden of Headache and Founder of Master of Headache Disorders at University of Copenhagen. Recived research funding from University of Copenhagen, Rigshospitalet, ATI, Lundbeck Foundation, The Medical Society in Copenhagen, NovoNordisk Foundation and Tryg Foundation. D.B.: Participated in clinical trials and served with lectures as well as on advisory or speaker boards for Novartis, Eli Lilly, Lundbeck, Pfizer, Abbvie and Teva outside the submitted work (migraine). Received grants from Odense University Hospital and Rigshospitalet, University of Copenhagen during the conduct of the study.

Background and Objectives: Idiopathic intracranial hypertension (IIH) is a syndrome of increased intracranial pressure without an identifiable cause that mostly affects obese persons of childbearing age. In this prospective case series, we have evaluated the overall outcome of pregnancy and birth in participants with IIH and their newborn children. We also provide a proposal for the management of pregnant persons with IIH., Methods: In this observational study, neuro-ophthalmological findings, the course of IIH-related symptoms, disease management, and pregnancy outcomes were evaluated. The participants were divided into 3 groups according to the course of the disease during pregnancy: stable, worsened, and new diagnosed. Furthermore, the type of delivery and outcome of newborn children such as gestational age, weight at birth, and the presence of asphyxia were compared between the groups., Results: We observed 47 pregnancies in 42 participants; 2 had spontaneous abortions. There were 19 (47%) participants in the stable, 18 (45%) in the worsened, and 3 (8%) in the new diagnosed groups, respectively. A relapse of IIH occurred in 2 (5%). Worsening of IIH-related symptoms was experienced by 18/37 (49%) participants: headache by 17/18 (94%), tinnitus by 11/18 (61%), and vision by 7/18 (39%) (mostly in the first and second trimester). In 8/18 (44%), the symptoms were transient or alleviated in the second and third trimester. Body mass index before and after pregnancy did not significantly differ among the groups. A total of 8 participants were treated with acetazolamide. The frequency of cesarean section was 17/40 (43%). Preterm delivery occurred in 22%. No increased risk of asphyxia was observed, and all infants, but one, were healthy., Discussion: Worsening of headache, tinnitus, and/or vision were experienced by half of pregnant participants with IIH, mostly transient in the first and second trimester, rarely required specific treatment, and were not identified as a relapse of IIH. There was no difference in gestational age and weight at birth in children among the groups, and no perinatal asphyxia was noted. Weight gain in the participants was not identified as a risk factor for relapse of IIH in pregnancy. The rate of cesarean and preterm delivery was higher than in the non-IIH population. A proposal for the management of IIH in pregnancy is provided., Competing Interests: V. Vukovic-Cvetkovic: lectures for Novartis, Merck, and MSD and investigator in clinical trials with Lundbeck and Allergan. D. Beier: advisory board of Pfizer, Lundbeck, AbbVie, Novartis, Eli Lilly and Company, and Teva and participation in clinical trials of Teva, Lundbeck, and Novartis. L. Buchgreitz: lecture for AbbVie/Allergan. J.J. Korsbæk: funding from Lundbeck of Candy Foundation. R. Jensen: lectures for Pfizer, Eli Lilly and Company, Merck, TEVA, Novartis, Lundbeck, and Allergan; investigator in clinical trials with Eli Lilly and Company, Novartis, and Lundbeck; director of Danish Headache Center and Lifting The Global Burden of Headache; founder of Master of Headache Disorders at the University of Copenhagen; and received research funding from the University of Copenhagen, Rigshospitalet, Lundbeck Foundation, The Medical Society in Copenhagen, The Capital Region, Novo Nordisk Foundation, and Tryg Foundation. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp., (© 2024 American Academy of Neurology.)

The population < 60 years of age is also affected by a significant disease burden from seasonal influenza. It carries a high economic burden, mainly driven by influenza-associated productivity losses in the working population. Conventional egg-based influenza vaccines may experience reduced effectiveness due to antigen adaptation in eggs. In contrast, cell-based influenza vaccines are less likely to be affected by antigenic adaptations to the host system and showed better effectiveness in individuals 4-64 years old over several seasons compared to conventional egg-based influenza vaccines under real-world conditions. Preferential use of cell-based influenza vaccines, as opposed to conventional egg-based vaccines, could reduce the burden of influenza-related symptoms on individuals and alleviate the economic impact on the German population < 60 years of age., (© 2024. The Author(s).)

Background and Aims: The treatment of hepatocellular carcinoma (HCC) is undergoing a historic transformation with the approval of several new systemic therapies in the last few years. This study aimed to examine the impact of this changing landscape on survival and costs in a Western nationwide, real-world cohort., Methods: A nationwide representative claims database (InGef) was screened for HCC cases between 2015 and 2020. Survival in an era with only sorafenib (period A, January 2015 to July 2018) and after approval of lenvatinib and other systemic treatments (period B, August 2018 to December 2020) was analysed. Health care costs were assessed., Results: We identified 2876 individuals with HCC in the study period. The proportion of patients receiving systemic therapy increased significantly over time, from 11.8% in 2015 to 15.1% in 2020 (p < 0.0001). The median overall survival in period B was 6.5 months (95% confidence interval [CI]: 4.9-8.9) and in period A was 5.3 months (95% CI: 4.5-6.3; p = 0.046). In period B, the median overall survival with lenvatinib was 9.7 months (95% CI: 6.3-18.4) versus 4.8 months with sorafenib (95% CI: 4.0-7.1, p = 0.008). Costs for prescription drugs per patient increased from €6150 in 2015 to €9049 in 2020 (p < 0.0001), and costs for outpatient care per patient increased from €1646 to €2149 (p = 0.0240)., Conclusion: The approval of new systemic therapies resulted in a survival benefit in patients with HCC. The magnitude of the effect is modest and associated with a moderate increase in health costs., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships, which may be considered as potential competing interests: N.B.K. has received reimbursement of meeting attendance fees and travel expenses from EISAI and a lecture honorarium from Falk. B.M. has served as a paid consultant for Roche Diagnostics GmbH and Roche Pharma AG. D.B. and D.P.P. are employed by InGef, which received funding from LMU University for the contribution to the study. F.P.R. has received honoraria for lectures and travel support from the Falk Foundation, Gilead, Ipsen, and Novartis. A.T. has received honoraria, travel support, or/and scientific funding from Ipsen Pharma GmbH, Gilead Sciences, AbbVie Deutschland GmbH & Co. KG, F. Hoffmann-La Roche AG, Eisai GmbH, Bayer AG, Novartis AG, Intercept Pharmaceuticals, Inc., Lilly Deutschland GmbH, Alpen Pharma (Schweiz), Dr. Falk Pharma GmbH, Astra Zeneca, Sanofi-Aventis Deutschland GmbH, and Orphalan. D.R. advises Bayer and advises and has received grants from Ipsen. I.K. served as a paid consultant for Alnylam and Roche and received lecture honorarium from Takeda. U.E. has received honoraria for lectures from AstraZeneca, the Falk Foundation, IPSEN, and Novartis and travel support from AstraZeneca. She has served as advisory board or steering committee member to AstraZeneca, Bayer, EISAI, and MSD. C.M.L. has received advisory and speaker honoraria from AbbVie, AstraZeneca, Boston Scientific, CSL Behring, Eisai, Falk, Gilead, MSD, Norgine, Novartis, Roche, Shionogi, and Sobi. K.B. received a research grant from Roche Pharma AG. E.D.T. has served as a paid consultant for AstraZeneca, Bayer, BMS, EISAI, Eli Lilly & Co, Pfizer, IPSEN, and Roche. He has received reimbursement of meeting attendance fees and travel expenses from Arqule, AstraZeneca, BMS, Bayer, Celsion, and Roche and lecture honoraria from BMS and Falk. In addition, he has received third-party funding for scientific research from Arqule, AstraZeneca, BMS, Bayer, Eli Lilly, and Roche. S.M. received a research grant from Ipsen, BMBF, and the Bavarian Ministry of economic affairs and media. All the other authors have no conflicts of interest to declare., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Patients with inflammatory bowel disease are at increased risk of colorectal and extra-intestinal cancer. However, the overall cancer risk in patients with Crohn's disease (CD) with perianal fistulas (PF) (CPF) and those with CD without PF (non-PF CD) is unclear., Objective: To describe the prevalence and incidence of cancer in patients with CPF and non-PF CD, and to estimate incidence rate ratio (IRR) of cancer between CPF and non-PF CD groups., Methods: A retrospective cohort study was conducted using the German InGef (Institute for Applied Health Research Berlin) research database. Patients with a CD record and PF from 1 January 2013 to 31 December 2014 were identified and followed up from 1 January 2015 until the first occurrence of cancer, end of health insurance contributing data, death, or end of study period (31 December 2020). Prevalence of any type of cancer including patients with CD diagnosed with cancer in the selection period and incidence of cancer excluding patients with CD diagnosed with cancer in the selection period were calculated., Results: In total, 10,208 patients with CD were identified. Of 824 patients with CPF (8.1%), 67 had had a malignancy (6-year period crude malignancy prevalence 8.13% [95% confidence interval (CI) 6.36%-10.21%]), which was lower than patients with non-PF CD (19.8% [95% CI 19%-20.6%]). Incidence (per 100,000 person-years) in patients with CPF was 1184 (95% CI 879-1561) and in non-PF CD was 2365 (95% CI 2219-2519). There was no significant difference in the adjusted IRR of cancer for the CPF group compared with the non-PF CD group (0.83 [95% CI 0.62-1.10]; p = 0.219)., Conclusion: There was no significant difference in the incidence of any cancer in patients with CPF compared with non-PF CD. However, patients with CPF had a higher numerical risk of cancer than the general German population., (© 2023 Takeda Pharmaceuticals and The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.)

Introduction: Clostridioides difficile infection (CDI) is increasingly recognized as a public health threat at the community level in addition to being one of the most common causes of healthcare-associated infections. In Germany, the epidemiology of CDI is primarily informed by national hospital-based CDI surveillance. We used health claims data from Germany to obtain valuable insights on population-level disease burden and risk factors for CDI., Methods: This was a retrospective cohort study using a representative sample from the InGef research database. Overall and age- and sex-stratified CDI incidence rates were estimated for German adults from 2013 to 2017 using different case definitions (i.e., main, broad, strict), and further stratified by setting (inpatient versus outpatient). Risk factors for CDI were assessed for the 2013-2016 period., Results: The CDI incidence rate was high but declined by 15.3% from 2013 [141 (95% confidence interval, CI 137-145) cases/100,000 person-years] to 2017 [120 (95% CI 116-123)]. Annual CDI incidence rates were higher in female patients and the elderly. The most important risk factors for CDI were chronic inflammatory bowel disease [odds ratio (OR) 4.7, 95% CI 4.0-5.5], chemotherapy (OR 4.7, 95% CI 4.1-5.2), chronic kidney disease (OR 2.9, 95% CI 2.6-3.3), and ciprofloxacin receipt (OR 2.6, 95% CI 2.4-2.8)., Conclusions: Despite prevention strategies leading to declining incidence, CDI remains an important public health threat in Germany, with a high burden in the hospital setting and an outpatient epidemiology that is poorly understood. These findings, which are relevant both regionally and globally, can be used as a basis for further research on the full burden of CDI in Germany., (© 2023. The Author(s).)

Seasonal influenza causes a significant burden of disease in the German population and is associated with high societal costs. Persons aged 60 years and older are particularly at risk due to immunosenescence and chronic disease and account for a large proportion of influenza-associated hospitalizations and deaths. Adjuvanted, high-dose, recombinant and cell-based influenza vaccines have been developed to improve the effectiveness compared with conventional vaccines. Recent observational studies show better effectiveness of adjuvanted vaccine over conventional vaccines and similar effectiveness to the high-dose vaccine in older adults. Some countries have already considered the new evidence in their vaccination recommendations for the current or earlier seasons. The availability of the vaccines for older adults should also be ensured in Germany to guarantee a high level of vaccination protection., Competing Interests: Die Durchführung der Publikation wurde finanziell von der Seqirus GmbH unterstützt. Dr. Markus Frühwein: – Vorträge/Beratung: Astra Zeneca, Bavarian, Nordic, Biontech, Janßen, GSK, Moderna, MSD, Pfizer, Sanofi, Seqirus, Takeda, Viatris. Prof. Dr. Jörg Schelling: – Beratungshonorare von AstraZeneca, Bavarian Nordic, der GSK Unternehmensgruppe, Sanofi Pasteur, Pfizer, Johnson & Johnson, MSD, BioNTech, Seqirus, Takeda, Viatris – Zahlungen oder Honorare für Vorlesungen, Präsentationen, Rednerbüros, Manuskripterstellung oder Bildungsveranstaltungen von GSK, Sanofi Pasteur, Pfizer, Johnson & Johnson, MSD, BioNTech, Seqirus, Takeda, Viatris – Unterstützung für die Teilnahme an Sitzungen und/oder Reisen von Sanofi Pasteur und Pfizer und Aktienbesitz von Valneva außerhalb der eingereichten Arbeit. Prof. Dr. Klaus Wahle: – Vortragstätigkeiten und Teilnahme an Advisory Boards im Auftrag bzw. für die Firmen SPMSD, Seqirus, Pfizer, GSK, Biontech. Dr. Dietmar Beier: – Advisory Board für Seqirus. Dr. Anja Kwetkat: – Forschungsunterstützung: Robert-Bosch-Stiftung – Forschungskolleg Geriatrie, Pfizer Pharma GmbH – Beratungs-/Gutachtertätigkeit: Projekt Grippeschutz – Seqirus, Advisory Board Prävention Herpes Zoster – GlaxoSmithKline GmbH & Co. KG, Advisory Board Sektorenübergreifendes Impfmanagement – Pfizer Pharma GmbH, Advisory Board Hochdosis Influenza Impfstoff – Sanofi-Pasteur, Advisory Board COVID-19 Impfstoff AZD1222 – AstraZeneca – Vortragstätigkeit: Pfizer Pharma GmbH, Fa. MSD, Fa. Novartis, Fa. Daiichi-Sankyo, Fa. Bristol-Myers Squibb, Fa. Sanofi-Pasteur – Ehrenämter: Sprecherin der AG Impfen der Deutschen Gesellschaft für Geriatrie e. V. (DGG e. V.), Mitglied DRG-Projektgruppe des Bundesverbandes Geriatrie e. V. (BVG e. V.). Prof. Dr. Tino Schwarz: – Honorare für Beratung und Vorträge: Biogen, Merck-Serono, GSK, Sanofi-Aventis, Pfizer, Seqirus, Synlab, AstraZeneca, Roche, MSD, va-Q-tec, Bavarian Nordic, Janssen-Cilag, Alexion, Takeda, Biontech, MSD, Moderna, (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Background: Since the introduction of higher valency pneumococcal conjugate vaccines in 2009, recent estimates on the economic burden of pediatric pneumococcal disease (PD) in Germany have been lacking. This study estimates healthcare resource utilization (HCRU) and medical cost associated with PDs in children < 16 years old in Germany from 2014-2019., Methods: A nationally representative sample from the Institute for Applied Health Research (InGef) German claims database was used, covering approximately 5% of the total German population. Episodes of pneumococcal pneumonia (PP), all-cause pneumonia (ACP), invasive pneumococcal disease (IPD), and acute otitis media (AOM) in children aged < 16 years were identified using ICD-10-GM codes. HCRU was estimated from annual rates of outpatient visits, outpatient antibiotic prescriptions and inpatient admissions, divided by person-years (PY) at-risk. Average direct medical costs per episode were estimated as the total cost of all HCRU, divided by the total number of episodes. The Mann-Kendall test was used to assess monotonic time trends from 2014-2019., Results:  During 2014-2019, 916,805 children aged < 16 years were followed up for a total of 3,608,716 PY. The average costs per episode for out-versus inpatient care associated with PP and ACP were €67 (95% CI 58-76) versus €2,606 (95% CI 1,338-3,873), and €63 (95% CI 62-63) versus €620 (95% CI 598-641), respectively. For IPD, the average medical cost per episode for out-versus inpatients were €30 (95% CI 19-42) versus €6,051 (95% CI 3,323-8,779), respectively. There were no significant trends in HCRU or costs for IPD or pneumonia over the study period, except for a significant reduction in ACP outpatient visits. A significant decrease in rate of outpatient visits and antibiotic prescribing for recurrent AOM was observed, in addition to an increase in rates of hospital admissions for simple AOM. This was paralleled by a significant increase in inpatient costs per episode for treating AOM overall, and simple AOM, over the study period., Conclusions:  The HCRU and cost per episode of pneumonia and IPD did not vary significantly from 2014-2019, but increased for AOM. The economic burden of pneumonia, IPD, and AOM remains substantial in Germany., (© 2023. Merck & Co., Inc., Rahway, NJ, USA and its affiliates.)

Background: Based on expert opinion, abducens nerve palsy and a neuroimaging criterion (≥3 neuroimaging signs suggestive of elevated intracranial pressure) were added to the diagnostic criteria for idiopathic intracranial hypertension. Our objective was to validate this., Methods: This prospective study included patients with new-onset idiopathic intracranial hypertension for a standardized work-up: interview, neuro-ophthalmological exam, lumbar puncture, neuroimaging. Neuroimaging was evaluated by a blinded neuroradiologist., Results: We included 157 patients classified as idiopathic intracranial hypertension (56.7%), probable idiopathic intracranial hypertension (1.9%), idiopathic intracranial hypertension without papilledema (idiopathic intracranial hypertension-without papill edema; 0%), suggested idiopathic intracranial hypertension-without papill edema (4.5%), or non-idiopathic intracranial hypertension (36.9%). Moderate suprasellar herniation was more common in idiopathic intracranial hypertension than non-idiopathic intracranial hypertension (71.4% versus 47.4%, p < 0.01), as was perioptic nerve sheath distension (69.8% versus 29.3%, p < 0.001), flattening of the globe (67.1% versus 11.1%, p < 0.001) and transverse sinus stenosis (60.2% versus 18.9%, p < 0.001). Abducens nerve palsy was of no diagnostic significance. Sensitivity of ≥3 neuroimaging signs was 59.5% and specificity was 93.5%., Conclusion: Moderate suprasellar herniation, distension of the perioptic nerve sheath, flattening of the globe and transverse sinus stenosis were associated with idiopathic intracranial hypertension. We propose that idiopathic intracranial hypertension can be defined by two out of three objective findings (papilledema, opening pressure ≥25 cm cerebrospinal fluid and ≥3 neuroimaging signs).

Introduction: Retinal vessel dynamics analysis has proven to be a viable, non-invasive surrogate marker for increased intracranial pressure. We aimed to test this method in patients with suspected idiopathic intracranial hypertension., Methods: Patients with suspected idiopathic intracranial hypertension were prospectively enrolled for hand-held fundus-videography during diagnostic lumbar puncture. After extracting optic disc images, peripapillary arteriole-to-venule-ratios were measured using machine-learning algorithms with manual identification control. A general linear model was applied to arteriole-to-venule-ratios and corresponding lumbar opening pressures to estimate cerebrospinal fluid pressure., Results: Twenty-five patients were included with a significant difference in arteriole-to-venule-ratio between patients with ( n  = 17) and without ( n  = 8) idiopathic intracranial hypertension (0.78 ± 0.10 vs 0.90 ± 0.08, p  = 0.006). Arteriole-to-venule-ratio correlated inversely with lumbar opening pressure (slope regression estimate -0.0043 (95% CI -0.0073 to -0.0023), p  = 0.002) and the association was stronger when lumbar opening pressure exceeded 15 mm Hg (20 cm H 2 O) (slope regression estimate -0.0080 (95% CI -0.0123 to -0.0039), p  < 0.001). Estimated cerebrospinal fluid pressure predicted increased lumbar opening pressure >20 mm Hg (27 cm H 2 O) with 78% sensitivity and 92% specificity (AUC 0.81, p  = 0.02). A stand-alone arteriole-to-venule-ratio measurement predicting lumbar opening pressure >20 mm Hg (27 cm H 2 O) was inferior with a 48% sensitivity and 92% specificity (AUC 0.73, p =  0.002)., Conclusion: Retinal vessel dynamics analysis with the described model for estimating cerebrospinal fluid pressure is a promising non-invasive method with a high sensitivity and specificity for detecting elevated intracranial pressure at follow-up assessments of patients with confirmed idiopathic intracranial hypertension if initial lumbar opening pressure and arteriole-to-venule-ratio data are available.

Small bacterial regulatory RNAs (sRNAs) have been implicated in the regulation of numerous metabolic pathways. In most of these studies, sRNA-dependent regulation of mRNAs or proteins of enzymes in metabolic pathways has been predicted to affect the metabolism of these bacteria. However, only in a very few cases has the role in metabolism been demonstrated. Here, we performed a combined transcriptome and metabolome analysis to define the regulon of the sibling sRNAs NgncR&#95;162 and NgncR&#95;163 (NgncR&#95;162/163) and their impact on the metabolism of Neisseria gonorrhoeae. These sRNAs have been reported to control genes of the citric acid and methylcitric acid cycles by posttranscriptional negative regulation. By transcriptome analysis, we now expand the NgncR&#95;162/163 regulon by several new members and provide evidence that the sibling sRNAs act as both negative and positive regulators of target gene expression. Newly identified NgncR&#95;162/163 targets are mostly involved in transport processes, especially in the uptake of glycine, phenylalanine, and branched-chain amino acids. NgncR&#95;162/163 also play key roles in the control of serine-glycine metabolism and, hence, probably affect biosyntheses of nucleotides, vitamins, and other amino acids via the supply of one-carbon (C 1 ) units. Indeed, these roles were confirmed by metabolomics and metabolic flux analysis, which revealed a bipartite metabolic network with glucose degradation for the supply of anabolic pathways and the usage of amino acids via the citric acid cycle for energy metabolism. Thus, by combined deep RNA sequencing (RNA-seq) and metabolomics, we significantly extended the regulon of NgncR&#95;162/163 and demonstrated the role of NgncR&#95;162/163 in the regulation of central metabolic pathways of the gonococcus. IMPORTANCE Neisseria gonorrhoeae is a major human pathogen which infects more than 100 million people every year. An alarming development is the emergence of gonococcal strains that are resistant against virtually all antibiotics used for their treatment. Despite the medical importance and the vanishing treatment options of gonococcal infections, the bacterial metabolism and its regulation have been only weakly defined until today. Using RNA-seq, metabolomics, and 13 C-guided metabolic flux analysis, we here investigated the gonococcal metabolism and its regulation by the previously studied sibling sRNAs NgncR&#95;162/163. The results demonstrate the regulation of transport processes and metabolic pathways involved in the biosynthesis of nucleotides, vitamins, and amino acids by NgncR&#95;162/163. In particular, the combination of transcriptome and metabolic flux analyses provides a heretofore unreached depth of understanding the core metabolic pathways and their regulation by the neisserial sibling sRNAs. This integrative approach may therefore also be suitable for the functional analysis of a growing number of other bacterial metabolic sRNA regulators.

Background: A high degree of adherence to direct oral anticoagulants is essential for reducing the risk of ischaemic stroke and systemic embolism in patients with atrial fibrillation, owing to the rapid decline in anticoagulation activity when doses are omitted (i.e. rebound effect)., Objective: We aimed to assess the relationship between non-adherence and non-persistence with direct oral anticoagulants and the incidence of ischaemic stroke in patients with atrial fibrillation., Methods: A nested case-control study was conducted in the Netherlands, Italy and Germany among patients with atrial fibrillation starting direct oral anticoagulants between the drug approval date and the end of database availability. Patients with an ischaemic stroke during the follow-up were selected as cases and compared with matched controls (matched on age ± 5 years, sex, year of cohort entry date and CHA 2 DS 2 -VASc-score at cohort entry date). The cohort entry date was the first dispensing date. Study patients were those aged ≥ 45 years, with ≥ 1 year database history, ≥ 1 year follow-up and at least two direct oral anticoagulant dispensings after the cohort entry date. Adherence and persistence to direct oral anticoagulant treatment were defined as the proportion of days covered ≥ 80% or direct oral anticoagulant continuous use between the cohort entry date and the index date (i.e. date of ischaemic stroke), respectively., Results: In The Netherlands, Italy and Germany, 105 cases and 395 controls, 1580 cases and 6248 controls, and 900 cases and 3570 controls were included, respectively. Odds ratios (ORs) for stroke among current users who were non-adherent compared to adherent users were 0.43 (95% confidence interval [CI] 0.09-1.96) in The Netherlands, 1.11 (95% CI 0.98-1.26) in Italy and 1.21 (95% CI 1.01-1.45) in Germany. The risk of stroke was significantly higher among non-persistent users compared with persistent users in all three databases [OR 1.56 (95% CI 1.00-2.44), OR 1.48 (1.32-1.65) and OR 1.91 (95% CI 1.64-2.22), respectively]. In The Netherlands and Germany, the risk of stroke was higher the longer a patient had stopped using direct oral anticoagulants., Conclusions: Both non-adherence (in Germany) and non-persistence increased the risk of stroke, either using a once-daily or twice-daily regime., (© 2022. The Author(s).)

Objective: To identify the most frequent causes of secondary pseudotumor cerebri syndrome and compare phenotype, clinical presentation, and symptoms of secondary pseudotumor cerebri syndrome to the primary form of pseudotumor cerebri syndrome, idiopathic intracranial hypertension., Methods: The study was a prospective cohort study including patients with new-onset pseudotumor cerebri syndrome. Diagnostic work up was standardized. Patients were diagnosed with secondary pseudotumor cerebri syndrome or idiopathic intracranial hypertension according to the revised Friedman criteria. Secondary pseudotumor cerebri syndrome patients were categorized into five causes: medication, systemic causes, sleep apnea, cerebrovascular causes, and several competing causes. Phenotype, clinical presentation, symptoms and neuroimaging were compared between groups., Results: Out of 278 cases, 28 secondary pseudotumor cerebri syndrome and 120 idiopathic intracranial hypertension patients were included. The most frequent causes of secondary pseudotumor cerebri syndrome were medication (n  =  8, 28.6%) and systemic causes (n = 8, 28.6%), followed by sleep apnea (n = 5, 17.9%), cerebrovascular causes (n = 4, 14.3%) and several competing causes (n = 3, 10.7%). Secondary pseudotumor cerebri syndrome and idiopathic intracranial hypertension patients were phenotypically alike and predominately female, premenopausal, and obese. Symptoms and objective findings at disease onset were similar between groups., Conclusion: Secondary pseudotumor cerebri syndrome should be considered in all patients with suspected pseudotumor cerebri syndrome as secondary pseudotumor cerebri syndrome and idiopathic intracranial hypertension patients are phenotypically and clinically alike. A thorough diagnostic workup is needed as treatment of idiopathic intracranial hypertension and secondary pseudotumor cerebri syndrome is markedly different.

This study assessed the incidence rate of all-cause pneumonia (ACP) and invasive pneumococcal disease (IPD) and associated medical costs among individuals aged ≥16 in the German InGef database from 2016 to 2019. Incidence rate was expressed as the number of episodes per 100 000 person-years (PY). Healthcare resource utilisation was investigated by age group and by risk group (healthy, at-risk, high-risk). Direct medical costs per ACP/IPD episode were estimated as the total costs of all inpatient and outpatient visits. The overall incidence rate of ACP was 1345 (95% CI 1339-1352) and 8.25 (95% CI 7.76-8.77) per 100 000 PY for IPD. For both ACP and IPD, incidence rates increased with age and were higher in the high-risk and at-risk groups, in comparison to the healthy group. ACP inpatient admission rate increased with age but remained steady across age-groups for IPD. The mean direct medical costs per episode were €8075 (95% CI 7121-9028) for IPD and €1454 (95% CI 1426-1482) for ACP. The aggregate direct medical costs for IPD and ACP episodes were estimated to be €8.5 million and €248.9 million respectively. The clinical and economic burden of IPD and ACP among German adults is substantial regardless of age.

Background: Despite recommendations from the German Standing Committee on Vaccination (STIKO), pneumococcal vaccination coverage remains low in vulnerable populations. This study estimated the pneumococcal vaccination coverage rate (VCR) and timing among individuals aged 16-59 years in Germany who were recommended to receive pneumococcal vaccination, according to STIKO., Methods: A retrospective cohort analysis was conducted using the German InGef database. Individuals aged 16 to 59 years diagnosed with at least one "at-risk" (chronic disease) or "high-risk" (e.g., immunocompromising) condition considered to be at-risk of pneumococcal infection were identified at the time of first diagnosis, between January 1, 2016 and December 31, 2018, and followed up until December 31, 2019. The percentage of cumulative pneumococcal VCR with 95% confidence interval (CI) was reported for each calendar year of follow-up., Results: There were 334,292 individuals followed for a median of 2.38 (interquartile range (IQR) 1.63-3.13) person years. For individuals aged 16-59 years diagnosed with an incident risk condition in 2016, pneumococcal VCR increased from 0.44% (95% CI 0.41-0.48) in 2016 to 1.24% (95% CI 1.18-1.30) in 2019. In 2019, VCRs were higher in individuals with high-risk conditions compared with at-risk conditions (2.24% (95% CI 2.09-2.40) vs. 0.90% (95% CI 0.85-0.96)). In 2019, VCRs were higher in individuals aged 50 to 59 years compared with individuals aged 16 to 49 years (2.25% (95% CI 2.10-2.41) vs. 0.90% (95% CI 0.84-0.96)). Similar trends were observed in individuals with newly diagnosed risk conditions identified in 2017 and in 2018. Older age, influenza vaccination and increasing number of risk conditions increased the likelihood of pneumococcal vaccination. Median time to vaccination from diagnosis of the risk condition was shorter for high-risk conditions (369.5 days (IQR 155.8-702.0)) compared to at-risk conditions (435.5 days (IQR 196.3-758.8))., Conclusion: Despite recommendations from STIKO, pneumococcal vaccination coverage remains very low and with long delays in vulnerable individuals aged 16-59 in Germany. Further efforts are required to increase immunization levels and shorten time to vaccination among individuals 16-59 years of age developing conditions with higher susceptibility to pneumococcal infection., (© 2022. The Author(s).)

Background and Objectives: Psychiatric disease is a frequent comorbidity in idiopathic intracranial hypertension (IIH) and has been associated with a poor subjective outcome. No prospective studies have investigated psychiatric comorbidities in new-onset IIH. Our primary aim was to investigate disease severity in IIH depending on comorbid psychiatric disease. Important secondary outcomes were disease severity after 6 months and prevalence of psychiatric diseases in IIH., Methods: This prospective, observational cohort study consecutively included patients with clinically suspected, new-onset IIH from 2 headache centers. A standardized diagnostic workup was completed to confirm or exclude IIH according to the revised Friedman criteria: semi-structured interview, neurologic and neuro-ophthalmologic examination, lumbar puncture with opening pressure (OP), and neuroimaging. Exclusion criteria were known IIH, secondary intracranial hypertension, missing data, and pregnancy. Disease severity was evaluated based on papilledema, visual fields, OP, and headache in patients with IIH without psychiatric disease (IIH-P) compared with patients with IIH with psychiatric disease (IIH+P). A blinded neuro-ophthalmologist assessed visual outcomes. Age- and sex-matched prevalence rates of psychiatric diseases in the general population were found in national reports., Results: A total of 258 patients were screened; 69 were excluded. A total of 189 patients with clinically suspected IIH were then evaluated with the diagnostic workup and IIH was confirmed in 111 patients (58.7%). A total of 45% of patients with IIH had a psychiatric comorbidity. Visual fields were worse in patients with IIH+P at baseline (-8.0 vs -6.0 dB; p = 0.04) and after 6 months (-5.5 vs -4.0 dB; p < 0.01) compared with IIH-P. Highly prevalent psychiatric disorders were major depressive disorder (24.3%; n = 27), anxiety or stress-related disorders (24.3%; n = 27), and emotionally unstable personality disorder (6.3%; n = 7). Substance abuse (1.8%), schizophrenia (0.9%), and bipolar disorder (0.9%) were rare. In the general population, prevalence estimates of major depressive disorder and emotionally unstable personality disorder were 1.8%-3.3% and 2%, respectively., Discussion: Visual fields were significantly worse at baseline and 6 months in IIH+P compared with IIH-P. Psychiatric comorbidities, particularly depression and emotionally unstable personality disorder, were highly prevalent in IIH. Increased awareness of psychiatric disease as a marker for worse visual status may improve patient care., (© 2022 American Academy of Neurology.)

Importance: Early prediction of long-term mortality in status epilepticus is important given the high fatality rate in the years after diagnosis., Objective: To improve prognostication of long-term mortality after status epilepticus diagnosis., Design, Settings, and Participants: This retrospective, multicenter, multinational cohort study analyzed adult patients who were diagnosed with and treated for status epilepticus at university hospitals in Odense, Denmark, between January 1, 2008, and December 31, 2017, as well as in Oslo, Norway; Marburg, Germany; and Frankfurt, Germany. They were aged 18 years or older and had first-time, nonanoxic status epilepticus. A new scoring system, called the ACD score, for predicting 2-year (long-term) mortality after hospital discharge for status epilepticus was developed in the Danish cohort and validated in the German and Norwegian cohorts. The ACD score represents age at onset, level of consciousness at admission, and duration of status epilepticus. Data analysis was performed between September 1, 2019, and March 31, 2020., Exposures: Long-term follow-up using data from national and local civil registries in Denmark, Norway, and Germany., Main Outcomes and Measures: The predefined end point was 2-year survival for all patients and for a subgroup of patients with status epilepticus causes that were not damaging or were less damaging to the brain. Neurological deficits before and after onset, demographic characteristics, etiological categories of status epilepticus, comorbidities, survival, time points, treatments, and prognostic scores for different measures were assessed., Results: A total of 261 patients (mean [SD] age, 67.2 [14.8] years; 132 women [50.6%]) were included, of whom 145 patients (mean [SD] age, 66.3 [15.0] years; 78 women [53.8%]) had status epilepticus causes that were not damaging or were less damaging to the brain. The validation cohort comprised patients from Norway (n = 139) and Germany (n = 906). At hospital discharge, 29.8% of patients (n = 64 of 215) had new moderate to severe neurological deficits compared with baseline. New neurological deficits were a major predictor of 2-year survival after hospital discharge (odds ratio, 5.1; 95% CI, 2.2-11.8); this association was independent of etiological category. Nonconvulsive status epilepticus in coma and duration of status epilepticus were associated with development of new neurological deficits, and a simple 3-factor score (ACD score) combining these 2 risk factors with age at onset was developed to estimate survival after status epilepticus diagnosis. The ACD score had a linear correlation with 2-year survival (Pearson r2 = 0.848), especially in the subset of patients with a low likelihood of brain damage., Conclusions and Relevance: This study found that age, long duration, and nonconvulsive type of status epilepticus in coma were associated with the development of new neurological deficits, which were predictors of long-term mortality. Accounting for risk factors for new neurological deficits using the ACD score is a reliable method of prediction of long-term outcome in patients with status epilepticus causes that were not damaging or were less damaging to the brain.

Background: There is an urgent need for improved influenza vaccines especially for older adults due to the presence of immunosenescence. It is therefore highly relevant to compare enhanced influenza vaccines with traditional influenza vaccines with respect to their effectiveness., Objective: To compare vaccine efficacy and effectiveness of adjuvanted influenza vaccines (aTIV/aQIV) vs. non-adjuvanted standard-dose (TIV/QIV) and high-dose (TIV-HD/QIV-HD) influenza vaccines regarding influenza-related outcomes in older adults, complementing findings from the European Centre for Disease Prevention and Control (ECDC)'s systematic review of enhanced seasonal influenza vaccines from February 2020., Methods: A systematic literature search was conducted in Embase and MEDLINE to identify randomised controlled trials, observational studies and systematic reviews, published since ECDC's systematic review (between 7 February 2020 and 6 September 2021). Included studies were appraised with either the Cochrane Risk of Bias tool, ROBINS-I or AMSTAR 2., Results: Eleven analyses from nine real-world evidence (RWE) studies comprising ∼53 million participants and assessing the relative vaccine effectiveness (rVE) of aTIV vs. TIV, QIV and/or TIV-HD in adults aged ≥65 years over the 2006/07-2008/09 and 2011/12-2019/20 influenza seasons were identified. Nine analyses found that aTIV was significantly more effective than TIV and QIV in reducing influenza-related outcomes by clinical setting and suspected influenza outbreaks (rVE ranging from 7.5% to 25.6% for aTIV vs. TIV and 7.1% to 36.3% for aTIV vs. QIV). Seven analyses found similar effectiveness of aTIV vs. TIV-HD in reducing influenza-related medical encounters, inpatient stays and hospitalisations/emergency room visits. In three analyses, aTIV was significantly more effective than TIV-HD in reducing influenza-related medical encounters and office visits (rVE ranging from 6.6% to 16.6%). Risk of bias of identified studies was moderate to high., Conclusions: Our study suggests that both adjuvanted and high-dose vaccines are effective alternatives for vaccination programmes in older adults and preferable over conventional standard-dose vaccines., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: TW, KW, AK, DB and TFS have received honoraria from Seqirus GmbH for their contribution to this work. KJS was employed by Xcenda GmbH which received funding from Seqirus GmbH., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Acute otitis media (AOM) remains a common infection in children despite the introduction of pneumococcal conjugate vaccines. This study estimated AOM incidence rates (IRs) over time in children < 16 years old in Germany following PCV13 introduction., Methods: AOM episodes were identified in the InGef healthcare claims database from 2014-2019 in children aged < 16 years. Each AOM episode was classified as either simple or recurrent. Recurrent AOM was defined as 3 or more episodes identified within a 6-month period; or 4 or more episodes within a 12-month period with at least one episode in the prior 6 months. AOM-related surgical procedures within 12 months and complications within 21 days of an AOM episode were also identified. Annual IRs were calculated as number of episodes/child-years (CY) at risk. 95% Confidence intervals (95%CI) were calculated using the Wilson method. The Mann-Kendall test was used to assess trends over time., Results: Between 2014 and 2019, the study population comprised 916,805 children with 327,726 AOM episodes, of which 15% (49,011) of all episodes were identified as recurrent AOM and 85% (278,715) as simple AOM. There were significant declines in AOM (p = 0.003) in the study population overall and in all age groups over the study period; from 101 (95%CI 101-102)/1000 CY to 79 (95%CI 78-80)/1000 CY in the total study population, from 209 (95%CI 206-212)/1000 CY to 147 (95%CI 145-150)/1000 CY in < 2-year-olds, from 239 (95%CI 237-242) to 179 (95%CI 177-182)/1000 CY in 2-4-year-olds, and from 50 (95%CI 49-50) to 38 (95%CI 37-39)/1000 CY in 5-15-year-olds. No significant trends were identified for AOM-related surgical procedures over the study period; however, AOM-related complications overall increased (p = 0.003)., Conclusion: Between 2014 and 2019, AOM incidence overall declined in children aged 0-15 years in Germany. Over the study period, the incidence of complicated AOM cases increased, however the incidence of AOM-related surgical procedures remained constant. Despite the impact of PCV13, the burden associated with AOM in Germany remains substantial., (© 2022. The Author(s).)

Migraine and tension-type headache are among the most frequent diseases of the world. As pharmacological treatment often is associated with distinct side effects, there is an increasing need for non-pharmacological treatment options. However, there has been a striking lack of evidence with regards to the efficacy of the huge variety of non-pharmacological interventions. In this review, we present the available evidence for the most common non-pharmacological treatment options with focus on the national clinical guideline for non-pharmacological treatment of headache disorders published in 2021.

Background: Many people suffering from migraine combine pharmacological and non-pharmacological treatments. The purpose of this systematic review is to provide an updated guideline for some widely used non-pharmacological treatment options for migraine., Methods: We conducted a systematic literature review of randomized studies of adults with migraine treated with manual joint mobilisation techniques, supervised physical activity, psychological treatment, acupuncture and patient education. The main outcomes measured were days with headache and quality of life. Recommendations were formulated based on the Grade of Recommendation, Assessment, Development and Evaluation (GRADE) approach including patient preferences based on expert opinion and questionnaire data., Results: The overall level of certainty of the evidence was low to very low. Manual therapy techniques and psychological treatment did not change the studied outcomes. Supervised physical activity might have a positive impact on quality of life, acupuncture on headache frequency, intensity, quality of life and the use of attack-medicine. Patient education might improve self-rated health and quality of life and increase the number of well-informed patients., Conclusion: Based on observed effects, the lack of serious adverse events, and patients' preferences, we make weak recommendations for considering the investigated interventions as a supplement to standard treatment. Protocol registration: Prospero CRD42020220132.

Non-coding regulatory RNAs mediate post-transcriptional gene expression control by a variety of mechanisms relying mostly on base-pairing interactions with a target mRNA. Though a plethora of putative non-coding regulatory RNAs have been identified by global transcriptome analysis, knowledge about riboregulation in the pathogenic Neisseriae is still limited. Here we report the initial characterization of a pair of sRNAs of N. gonorrhoeae , TfpR1 and TfpR2, which exhibit a similar secondary structure and identical single-stranded seed regions, and therefore might be considered as sibling sRNAs. By combination of in silico target prediction and sRNA pulse expression followed by differential RNA sequencing we identified target genes of TfpR1 which are involved in type IV pilus biogenesis and DNA damage repair. We provide evidence that members of the TfpR1 regulon can also be targeted by the sibling TfpR2.

Background: Tension-type headache (TTH) has been ranked the second most prevalent health condition worldwide. Non-pharmacological treatments for TTH are widely used as a supplement or an alternative to medical treatment. However, the evidence for their effects are limited. Therefore, the aim of this study was to review the evidence for manual joint mobilisation techniques, supervised physical activity, psychological treatment, acupuncture and patient education as treatments for TTH on the effect of headache frequency and quality of life., Methods: A systematic literature search was conducted from February to July 2020 for clinical guidelines, systematic reviews, and individual randomised controlled trials (RCT). The primary outcomes measured were days with headache and quality of life at the end of treatment along with a number of secondary outcomes. Meta-analyses were performed on eligible RCTs and pooled estimates of effects were calculated using the random-effect model. The overall certainty of evidence was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation approach (GRADE). In addition, patient preferences were included in the evaluation., Results: In all, 13 RCTs were included. Acupuncture might have positive effects on both primary outcomes. Supervised physical activity might have a positive effect on pain intensity at the end of treatment and headache frequency at follow-up. Manual joint mobilisation techniques might have a positive effect on headache frequency and quality of life at follow-up. Psychological treatment might have a positive effect on stress symptoms at the end of treatment. No relevant RCTs were identified for patient education. The overall certainty of evidence was downgraded to low and very low. No serious adverse events were reported. A consensus recommendation was made for patient education and weak recommendations for the other interventions., Conclusion: Based on identified benefits, certainty of evidence, and patient preferences, manual joint mobilisation techniques, supervised physical activity, psychological treatment, acupuncture, and patient education can be considered as non-pharmacological treatment approaches for TTH. Some positive effects were shown on headache frequency, quality of life, pain intensity and stress symptoms. Few studies and low sample sizes posed a challenge in drawing solid conclusions. Therefore, high-quality RCTs are warranted., (© 2021. The Author(s).)

Idiopathic intracranial hypertension (IIH) is a challenging disease characterized by an increase in intracranial pressure which occurs without any known cause. The disease is mainly seen in obese females of child-bearing age. While originally described as rare, the incidence is increasing in parallel with pandemic obesity, and clinicians in all fields are increasingly likely to meet patients with IIH. The condition causes major morbidity due to chronic headache and visual loss if untreated. In the past ten years new diagnostic criteria and guidelines for management have been published.

The diagnosis and management of idiopathic intracranial hypertension (IIH) can be difficult and multiple medical subspecialities are often involved. Several national and international guidelines regarding the investigations and management of IIH have been published in recent years but still there is no consensus about the optimal organization of IIH-care. The objective of this review was to propose and describe a referral pathway and an organization scheme for diagnosis and management of IIH. An extensive search of existing literature was conducted and summarized. In total, 237 IIH-articles were identified and hereof 43 included. The clinical practice in our specialized IIH-clinic is characterized and described. We conclude that an educational campaign involving medical care providers and patients with chronic headaches is necessary. A detailed organizational proposal for a referral pathway and management of IIH patients based on the literature search and our clinical experience from a highly specialized IIH outpatient clinic is suggested and discussed.

Medulloblastoma is a rare brain malignancy. Patients after puberty are rare and bear an intermediate prognosis. Standard treatment consists of maximal resection plus radio-chemotherapy. Treatment toxicity is high and produces disabling long-term side effects. The sonic hedgehog (SHH) subgroup is highly overrepresented in the post-pubertal and adult population and can be targeted by smoothened (SMO) inhibitors. No practice-changing prospective randomized data have been generated in adults. The EORTC 1634-BTG/NOA-23 trial will randomize patients between standard-dose vs. reduced-dosed craniospinal radiotherapy and SHH-subgroup patients between the SMO inhibitor sonidegib (Odomzo TM , Sun Pharmaceuticals Industries, Inc., New York, USA) in addition to standard radio-chemotherapy vs. standard radio-chemotherapy alone to improve outcomes in view of decreased radiotherapy-related toxicity and increased efficacy. We will further investigate tumor tissue, blood, and cerebrospinal fluid as well as magnetic resonance imaging and radiotherapy plans to generate information that helps to further improve treatment outcomes. Given that treatment side effects typically occur late, long-term follow-up will monitor classic side effects of therapy, but also health-related quality of life, cognition, social and professional outcome, and reproduction and fertility. In summary, we will generate unprecedented data that will be translated into treatment changes in post-pubertal patients with medulloblastoma and will help to design future clinical trials.

Background: In 2019, 1.5 billion international tourist trips were counted worldwide. Germany, with 70.8 million vacations lasting ≥ 5 days, was one of the populations most willing to travel. These days, even elderly and multimorbid persons regularly travel long-distance, which can be associated with significant health risks. By advising travelers and implementing preventive measures, the risk of illness can be reduced significantly., Methods: A selective survey of PubMed was performed to identify publications on medical advice for travelers between 2000 and 2020. We included guidelines, studies, and recommendations that mainly deal with the preventive aspects of travel medicine and have a high level of practical relevance and the highest possible level of evidence. Previously published guidelines (based on the GRADE criteria) were adopted, and recommendations not based on the results of scientific studies were characterized as Good Clinical Practice (GCP)., Results: Many medical recommendations for travelers still rely on individualized, experience-based, or consensus-based assessments. Apart from a review of medical history and vaccination status, a risk analysis is performed, travel fitness is evaluated individually, and a prevention plan is designed. Particular attention is devoted to malaria prophylaxis, vector protection, and traveler's diarrhea. Medical advice before travel is especially important for the elderly, children, pregnant women, the chronically ill, long-term and adventure travelers as well as migrants from malaria-endemic areas who are returning home., Conclusion: The health risks associated with travel can be minimized by specialist medical advice. Many recommendations are empirical in nature and require further research.

Spontaneous intracranial hypotension (SIH) is a secondary headache disorder due to leakage of cerebrospinal fluid without a history of dural trauma. If not diagnosed in time, patients may develop invalidating headaches or even life-threatening complications. SIH diagnosis can be challenging as the presentation of the disease may vary significantly. In this case report of a classic course of disease in a 62-year-old woman, we illustrate challenges according to the diagnosis emphasising the importance to consider SIH as a differential diagnosis in cases of orthostatic but also atypical chronic headache.

Purpose: To inform high-quality rehabilitation services, this study investigates if patients with glioma located in the right- or left-hemisphere present with different health-related quality of life, symptomatology, and functional performance in the early disease state., Material and Methods: Between 2013 and 2017, 81 adult patients were assessed during the first week of chemo-radiation, following resection. Patients were stratified into two groups depending on a right- or left-hemispheric lesion. Independent t-tests analyzed potential differences regarding health-related quality of life, symptomatology, and functional performance., Results: Forty-five patients (56%) had a tumor located in the right hemisphere, whereas 36 patients (44%) had a tumor in the left hemisphere. Except for more patients with tumors in the left hemisphere having their tumor located in eloquent brain areas, the groups were well matched. No group differences were found in health-related quality of life. Group differences were found in communication deficits ( Δ -10.9, 95%CI -19.1; -2.3, p  = 0.01), which were more frequent in patients with left-sided lesions, and of headaches ( Δ 13.9, 95%CI 1.8; 25.9, p  = 0.02), which were more frequent in patients with right-hemispheric lesions, who also had significantly greater difficulties with process-skills when performing everyday life tasks ( Δ -0.3, 95%CI -0.5; -0.1, p  < 0.01). Also, weak evidence suggests that patients with Glioblastoma Multiforme located in the right hemisphere are more affected by fatigue compared to their left-hemispheric comparisons ( Δ 14.6, 95%CI 0.19; 29.0, p  < 0.05)., Conclusions: The hemispheric location of a glial-cell brain tumor has no consequence for health-related quality of life at the beginning of chemo-radiation treatments. However, findings of tumor-location dependent conditions of communication, headache, patients' ability to perform executive functions, and fatigue should be considered in rehabilitation situations when designing an intervention to potentially improve executive functions and relieve the symptoms.Implications for rehabilitationIt is unclear if laterality impact glioma patients health-related quality of life and functional performance, which might implicate differentiated rehabilitation interventions.The hemispheric location of a glial-cell brain tumor has no consequence for the health-related quality of life at the beginning of chemo-radiation, following surgery.Tumor-location dependent conditions of communication, headache, fatigue, and patients' ability to perform executive functions should be considered when designing an intervention to improve executive functions and symptom-relieve.In rehabilitation interventions, tumor laterality is not a factor that needs to be considered before recommending aerobic training to improve the functional capacity of patients with glioma.

Headache and facial pain are among the most common, disabling and costly diseases in Europe, which demands for high quality health care on all levels within the health system. The role of the Danish Headache Society is to educate and advocate for the needs of patients with headache and facial pain. Therefore, the Danish Headache Society has launched a third version of the guideline for the diagnosis, organization and treatment of the most common types of headaches and facial pain in Denmark. The second edition was published in Danish in 2010 and has been a great success, but as new knowledge and treatments have emerged it was timely to revise the guideline. The recommendations for the primary headaches and facial pain are largely in accordance with the European guidelines produced by the European Academy of Neurology. The guideline should be used a practical tool for use in daily clinical practice for primary care physicians, neurologists with a common interest in headache, as well as other health-care professionals treating headache patients. The guideline first describes how to examine and diagnose the headache patient and how headache treatment is organized in Denmark. This description is followed by sections on the characteristics, diagnosis and treatment of each of the most common primary and secondary headache disorders and trigeminal neuralgia. The guideline includes many tables to facilitate a quick overview. Finally, the particular challenges regarding migraine and female hormones as well as headache in children are addressed.

Background: Tick-borne encephalitis (TBE) is an arboviral infection of the central nervous system. As there is no causal treatment of TBE, disease prevention by vaccination is especially important. Immunization consists of a three-dose primary vaccination schedule, followed by regular booster doses. In Germany, the Standing Committee on Vaccination (STIKO) at the Robert Koch-Institute recommends TBE vaccination for all those at high risk of contracting TBE. This includes individuals living in, traveling to and/or working in risk areas, and being exposed to ticks. To our knowledge, there are currently no reliable data on TBE vaccination rates in Germany available., Methods: This retrospective cohort study based on anonymized German health claims data was conducted to determine vaccination rates of TBE primary immunization in 2012 to 2015 by federal state, compliance with the vaccination schedule, and TBE vaccination uptake for the 2011 birth cohort. Vaccination protection rates for each federal state were simulated based on a compartmental model., Results: Vaccination rates of an initiated primary immunization ranged from about 3% in the southern federal states to <1% in the northern federal states. Across all federal states, compliance with the vaccination schedule decreased with each subsequent vaccination. Slightly higher TBE vaccination uptake was determined in the 2011 birth cohort, as compared to the German school entry health examination statistics in 2017. Simulated vaccination protection rates for each federal state ranged from 10% in Hamburg to 51% in Baden-Wuerttemberg., Conclusions: While there was an overall low vaccination uptake and a discrepancy between areas of high vs. low TBE risk, this study also indicates a concerning decline in vaccination compliance. Vaccinating physicians should address the importance of adherence upon initiation of TBE vaccination., Competing Interests: Declaration of Competing Interest K. Schley and J. Schiffner-Rohe are employees of Pfizer Deutschland GmbH. C. Malerczyk and C. von Eiff  are employees of Pfizer Pharma GmbH. D. Häckl is employed by WIG2 which received funding from Pfizer Deutschland GmbH for the execution of the study and manuscript preparation. D. Beier is employed by InGef which acted as subcontractor and received funding from WIG2 for the execution of the study and manuscript preparation. J. Süß has no competing interest in regard with the content of this study., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Damage of the optic nerve is the major complication of idiopathic intracranial hypertension. A biomarker indicative for optic nerve damage would help identifying high-risk patients requiring surgical procedures. Here, we studied the potential of cerebrospinal fluid neurofilament to predict idiopathic intracranial hypertension-induced optic nerve damage., Methods: In two centers, serum and cerebrospinal fluid of 61 patients with clinically suspected idiopathic intracranial hypertension were prospectively collected. Neurofilament concentrations were measured and related to ophthalmological assessment., Results: The average cerebrospinal fluid neurofilament concentration in patients with moderate and severe papilledema was increased compared to patients with minor and no papilledema (1755 ± 3507 pg/ml vs. 244 ± 102 pg/ml; p  < 0.001). Cerebrospinal fluid neurofilament concentrations correlated with the maximal lumbar puncture opening pressure (r = 0.67, p  < 0.001). In patients fulfilling the Friedman criteria for idiopathic intracranial hypertension with or without papilledema (n = 35), development of bilateral visual field defects and bilateral atrophy of the optic nerve were associated with increased average age-adjusted cerebrospinal fluid neurofilament concentrations. At last follow-up (n = 30), 8/13 of patients with increased, but only 3/17 with normal, cerebrospinal fluid neurofilament had developed bilateral visual field defects and/or bilateral optic nerve atrophy resulting in a sensitivity of 72.7% and a specificity of 73.7% of cerebrospinal fluid neurofilament to detect permanent optic nerve damage., Conclusions: Cerebrospinal fluid neurofilament is a putative biomarker for optical nerve damage in idiopathic intracranial hypertension.

Background: Combined radiochemotherapy followed by maintenance chemotherapy with cisplatin, lomustine and vincristine within the NOA-07 study resulted in considerable short-term toxicity in adult medulloblastoma patients. Here we investigated the long-term impact of this treatment, focusing on neurocognitive functioning and health-related quality of life (HRQoL)., Methods: Neurocognitive functioning and HRQoL scores over time were determined, and differences between the post-treatment and follow-up assessments were calculated up to 18 months for neurocognition and 60 months for HRQoL., Results: 28/30 patients were analyzed. The three preselected HRQoL scales (role, social and cognitive functioning) showed improved scores, to a clinically relevant extent (≥ 10 points), compared to post-treatment levels up to 30 months, but decreased afterwards. Z-scores for verbal working memory were worse during follow-up compared to post-treatment scores and remained impaired during 18 months follow-up (i.e. z-score below - 1 standard deviation). Attention was impaired post-treatment, and remained impaired to a clinically relevant extent during follow-up. Coordination/processing speed and lexical verbal fluency improved compared to post-treatment scores, and remained within the normal range thereafter. Other tests of verbal fluency were stable over time, with z-scores within the normal range., Conclusions: This long-term follow-up study showed that the NOA-07 treatment regimen was not associated with a deterioration in HRQoL in the post-treatment period. Verbal working memory deteriorated, while other neurocognitive domains did not seem to be impacted negatively by the treatment.

Cardiac fibrosis in response to injury is a physiological response to wound healing. Efforts have been made to study and target fibroblast subtypes that mitigate fibrosis. However, fibroblast research has been hindered due to the lack of universally acceptable fibroblast markers to identify quiescent as well as activated fibroblasts. Fibroblasts are a heterogenous cell population, making them difficult to isolate and characterize. The presented protocol describes three different methods to enrich fibroblasts and myofibroblasts from uninjured and injured mouse hearts. Using a standard and reliable protocol to isolate fibroblasts will enable the study of their roles in homeostasis as well as fibrosis modulation.

Background: It is recommended that people with gliomas engage in rehabilitation, but high-quality evidence to support this recommendation is lacking., Objective: This study assesses the effectiveness of a physical therapy- and occupational therapy-based rehabilitation intervention compared with usual rehabilitation care for quality of life (QoL) during active anticancer treatment., Design: This study was a randomized controlled trial., Setting: The study took place in Odense University Hospital, Denmark., Participants: The trial included people with gliomas who were functionally independent., Intervention: The participants were randomly assigned to a supervised rehabilitation intervention or usual rehabilitation care during the active anticancer period. The supervised rehabilitation included physical therapy and occupational therapy-based interventions., Measurements: The primary outcome was the between-group difference in the overall QoL from baseline to the 6-week follow-up. It was self-rated with the global health status (GHS)/QoL domains from the European Organization for Research and Treatment of Cancer Questionnaire. Eighty-eight participants per group were required to find a 10% between-group difference from baseline to the 6-week follow-up. Secondary outcomes were the health-related QoL domains, symptomatology, and functional performance., Results: A total of 64 participants were included (32 in the intervention group and 32 in the control group). At follow-up, the intervention group self-rated a nonsignificantly better score for GHS/QoL than the control group (adjusted mean difference = 8.7% [95% confidence interval = -4.36 to 21.79]). Compared with the control group, the intervention group had consistently better results on self-rated secondary outcomes, including cognitive functioning (β = 16.2) and fatigue (β = -13.4), and objectively measured aerobic power (β = 2.6)., Limitations: The number of participants and duration of follow-up were inadequate to determine if the intervention was superior to the current usual rehabilitation care., Conclusions: The physical therapy- and occupational therapy-based rehabilitation intervention did not affect GHS/QoL. However, the trial found promising significant effects on both objective and self-reported secondary outcomes, making rehabilitation efforts during active anticancer treatment promising., (© 2020 American Physical Therapy Association.)

Purpose: Isocitrate dehydrogenase 1 (IDH1) mutations are associated with improved survival in gliomas. Depending on the IDH1 status, TERT promoter mutations affect prognosis. IDH1 mutations are associated with alpha-thalassemia/mental retardation syndrome X-linked (ATRX) mutations and alternative lengthening of telomeres (ALT), suggesting an interaction between IDH1 and telomeres. However, little is known how IDH1 mutations affect telomere maintenance., Methods: We analyzed cell-specific telomere length (CS-TL) on a single cell level in 46 astrocytoma samples (WHO II-IV) by modified immune-quantitative fluorescence in situ hybridization, using endothelial cells as internal reference. In the same samples, we determined IDH1/TERT promoter mutation status and ATRX expression. The interaction of IDH1 R132H mutation and CS-TL was studied in vitro using an IDH1 R132H doxycycline-inducible glioma cell line system., Results: Virtually all ALT positive astrocytomas had normal TERT promoter and lacked ATRX expression. Further, all ALT positive samples had IDH1 R132H mutations, resulting in a significantly longer CS-TL of IDH1 R132H gliomas, when compared to their wildtype counterparts. Conversely, TERT promotor mutations were associated with IDH wildtype , ATRX expression, lack of ALT and short CS-TL. ALT, TERT promoter mutations, and CS-TL remained without prognostic significance, when correcting for IDH1 status. In vitro, overexpression of IDH R132H in the glioma cell line LN319 resulted in downregulation of ATRX and rapid TERT-independent telomere lengthening consistent with ALT., Conclusion: ALT is the major telomere maintenance mechanism in IDH R132H mutated astrocytomas, while TERT promoter mutations were associated with IDH wildtype glioma. IDH1 R132H downregulates ATRX expression in vitro resulting in ALT, which may contribute to the strong association of IDH1 R132H mutations, ATRX loss, and ALT.

Background: Huntington's disease (HD) is a rare, genetic, neurodegenerative and ultimately fatal disease with no cure or progression-delaying treatment currently available. HD is characterized by a triad of cognitive, behavioural and motor symptoms. Evidence on epidemiology and management of HD is limited, especially for Germany. This study aims to estimate the incidence and prevalence of HD and analyze the current routine care based on German claims data., Methods: The source of data was a sample of the Institute for Applied Health Research Berlin (InGef) Research Database, comprising data of approximately four million insured persons from approximately 70 German statutory health insurances. The study was conducted in a retrospective cross-sectional design using 2015 and 2016 as a two-year observation period. At least two outpatient or inpatient ICD-10 codes for HD (ICD-10: G10) during the study period were required for case identification. Patients were considered incident if no HD diagnoses in the 4 years prior to the year of case identification were documented. Information on outpatient drug dispensations, medical aids and remedies were considered to describe the current treatment situation of HD patients., Results: A 2-year incidence of 1.8 per 100,000 persons (95%-Confidence interval (CI): 1.4-2.4) and a 2-year period prevalence of 9.3 per 100,000 persons (95%-CI: 8.3-10.4) was observed. The prevalence of HD increased with advancing age, peaking at 60-69 years (16.8 per 100,000 persons; 95%-CI: 13.4-21.0) and decreasing afterwards. The most frequently observed comorbidities and disease-associated symptoms in HD patients were depression (42.9%), dementia (37.7%), urinary incontinence (32.5%), extrapyramidal and movement disorders (30.5%), dysphagia (28.6%) and disorders of the lipoprotein metabolism (28.2%). The most common medications in HD patients were antipsychotics (66.9%), followed by antidepressants (45.1%). Anticonvulsants (16.6%), opioids (14.6%) and hypnotics (9.7%) were observed less frequently. Physical therapy was the most often used medical aid in HD patients (46.4%). Nursing services and speech therapy were used by 27.9 and 22.7% of HD patients, respectively, whereas use of psychotherapy was rare (3.2%)., Conclusions: Based on a representative sample, this study provides new insights into the epidemiology and routine care of HD patients in Germany, and thus, may serve as a starting point for further research.