Functional long-term outcome following endovascular thrombectomy in patients with acute ischemic stroke.

Endovascular thrombectomy (EVT) is the most effective treatment for acute ischemic stroke caused by large vessel occlusion (LVO). Yet, long-term outcome (LTO) and health-related quality of life (HRQoL) in these patients have rarely been addressed, as opposed to modified Rankin scale (mRS) recordings. We analysed demographic data, treatment and neuroimaging parameters in 694 consecutive stroke patients in a maximum care hospital. In 138 of these patients with respect on receipt of written informed consent, LTO and HRQoL were collected over a period of 48 months after EVT using a standardised telephone survey (median 2.1 years after EVT). Age < 70 years (OR 4.82), lower NIHSS on admission (OR 1.11), NIHSS ≤ 10 after 24 h (OR 11.23) and complete recanalisation (mTICI3) (OR 7.79) were identified as independent predictors of favourable LTO. Occurrence of an infection requiring treatment within the first 72 h was recognised as a negative predictor for good long-term outcome (OR 0.22). Patients with mRS > 2 according to the telephone survey more often had complaints regarding mobility, self-care, and usual activity domains of the HRQoL. Our results underline a sustainable positive effect of effective EVT on the quality of life in LVO stroke. Additionally, predictive parameters of outcome were identified, that may support clinical decision making in LVO stroke.

Sex, Genotype, and Liver Volume Progression as Risk of Hospitalization Determinants in Autosomal Dominant Polycystic Liver Disease.

BACKGROUND & AIMS: Autosomal dominant polycystic liver disease is a rare condition with a female preponderance, based mainly on pathogenic variants in 2 genes, PRKCSH and SEC63. Clinically, autosomal dominant polycystic liver disease is characterized by vast heterogeneity, ranging from asymptomatic to highly symptomatic hepatomegaly. To date, little is known about the prediction of disease progression at early stages, hindering clinical management, genetic counseling, and the design of randomized controlled trials. To improve disease prognostication, we built a consortium of European and US centers to recruit the largest cohort of patients with PRKCSH and SEC63 liver disease. METHODS: We analyzed an international multicenter cohort of 265 patients with autosomal dominant polycystic liver disease harboring pathogenic variants in PRKCSH or SEC63 for genotype-phenotype correlations, including normalized age-adjusted total liver volumes and polycystic liver disease-related hospitalization (liver event) as primary clinical end points. RESULTS: Classifying individual total liver volumes into predefined progression groups yielded predictive risk discrimination for future liver events independent of sex and underlying genetic defects. In addition, disease severity, defined by age at first liver event, was considerably more pronounced in female patients and patients with PRKCSH variants than in those with SEC63 variants. A newly developed sex-gene score was effective in distinguishing mild, moderate, and severe disease, in addition to imaging-based prognostication. CONCLUSIONS: Both imaging and clinical genetic scoring have the potential to inform patients about the risk of developing symptomatic disease throughout their lives. The combination of female sex, germline PRKCSH alteration, and rapid total liver volume progression is associated with the greatest odds of polycystic liver disease-related hospitalization.

Long-term functional outcome and quality of life 2.5 years after thrombolysis in acute ischemic stroke.

BACKGROUND: Evaluation of outcome after stroke is largely based on assessment of gross function 3 months after stroke onset using scales such as mRS. Cognitive or social functions, level of symptom burden or emotional health are not usually assessed, nor are data available on long-term functional outcomes years after stroke. METHODS: Analysis of 1141 patients with AIS treated with IVT from two major German university hospitals between 2017 and 2020. Patient characteristics and short-term outcome were analysed from patient records. Long-term outcome of 228 patients with prior written informed consent was assessed via telephone survey using mRS and PROMs (EQ-5D-5L, EQ-VAS) 2.5 years after stroke. RESULTS: Predictors of excellent to good long-term outcome were younger age, event to door time ≤ 2 h, NIHSS ≤ 6 on admission and NIHSS ≤ 6 after IVT. Stroke recurrence was a negative predictor. Predictors of excellent quality of life at 2.5 years included age < 73 years, lower NIHSS after IVT, absence of hypertension. Quality of life was rated in all dimensions with a medium score of 1 and a medium EQ-VAS of 70, representing the good general health status of this stroke population. CONCLUSION: Main predictors of an excellent to good long-term outcome and excellent QoL 2.5 years after stroke are younger age, lower NIHSS, and event to door time ≤ 2 h. Research on long-term outcome after disease and treatment is of utmost importance, as it has the ability to reveal the patient true functional outcome and quality of life and to provide information on the status of independence and self-esteem.

Modelling polycystic liver disease progression using age-adjusted liver volumes and targeted mutational analysis.

Background & Aims: Polycystic liver disease (PLD) manifests as numerous fluid-filled cysts scattered throughout the liver parenchyma. PLD most commonly develops in females, either as an extra-renal manifestation of autosomal-dominant polycystic kidney disease (ADPKD) or as isolated autosomal-dominant polycystic liver disease (ADPLD). Despite known genetic causes, clinical variability challenges patient counselling and timely risk prediction is hampered by a lack of genotype-phenotype correlations and prognostic imaging classifications. Methods: We performed targeted next-generation sequencing and multiplex ligation-dependent probe amplification to identify the underlying genetic defect in a cohort of 80 deeply characterized patients with PLD. Identified genotypes were correlated with total liver and kidney volume (assessed by CT or MRI), organ function, co-morbidities, and clinical endpoints. Results: Monoallelic diagnostic variants were identified in 60 (75%) patients, 38 (48%) of which pertained to ADPKD-gene variants (PKD1, PKD2, GANAB) and 22 (27%) to ADPLD-gene variants (PRKCSH, SEC63). Disease severity defined by age at waitlisting for liver transplantation and first PLD-related hospitalization was significantly more pronounced in mutation carriers compared to patients without genetic diagnoses. While current imaging classifications proved unable to differentiate between severe and moderate courses, grouping by estimated age-adjusted total liver volume progression yielded significant risk discrimination. Conclusion: This study underlines the predictive value of providing a molecular diagnosis for patients with PLD. In addition, we propose a novel risk-classification model based on age- and height-adjusted total liver volume that could improve individual prognostication and personalized clinical management. Lay summary: Polycystic liver disease (PLD) is a highly variable condition that can be asymptomatic or severe. However, it is currently difficult to predict clinical outcomes such as hospitalization, symptom burden, and need for transplantation in individual patients. In the current study, we aimed to investigate the clinical value of genetic confirmation and an age-adjusted total liver volume classification for individual disease prediction. While genetic confirmation generally pointed to more severe disease, estimated age-adjusted increases in liver volume could be useful for predicting clinical outcomes.

Transient Global Amnesia (TGA): Sex-Specific Differences in Blood Pressure and Cerebral Microangiopathy in Patients with TGA.

Transient global amnesia (TGA) is defined by an acute memory disturbance of unclear aetiology for a period of less than 24 h. Observed psychological, neuroanatomical and hormonal differences between the sexes in episodic memory suggest sex-specific differences in memory disorders such as TGA. The aim of this study was to determine sex-specific differences in cardiovascular risk profiles, recurrences and magnetic resonance imaging (MRI). In total, 372 hospitalised TGA patients between 01/2011 and 10/2021 were retrospectively analysed. Comparisons were made between female and male TGA patients and compared to 216 patients with acute stroke. In our sample, women were overrepresented (61.8%), especially compared to the general population in the 65−74 age category (χ2 = 10.6, p < 0.02). On admission, female TGA patients had significantly higher systolic blood pressure values and a higher degree of cerebral microangiopathy compared to male TGA patients, whereas acute stroke patients did not. No sex-specific differences were observed with respect to recurrences or hippocampal DWI lesions. Our data demonstrate sex-specific differences in TGA. The higher blood pressure on admission and different degree of cerebral microangiopathy in female TGA patients supports the theory of blood pressure dysregulation as a disease trigger. Distinct precipitating events in female and male patients could lead to differences in the severity and duration of blood pressure abnormalities, possibly explaining the higher incidence in female patients.

A dopamine-gated learning circuit underpins reproductive state-dependent odor preference in Drosophila females.

Motherhood induces a drastic, sometimes long-lasting, change in internal state and behavior in many female animals. How a change in reproductive state or the discrete event of mating modulates specific female behaviors is still incompletely understood. Using calcium imaging of the whole brain of Drosophila females, we find that mating does not induce a global change in brain activity. Instead, mating modulates the pheromone response of dopaminergic neurons innervating the fly's learning and memory center, the mushroom body (MB). Using the mating-induced increased attraction to the odor of important nutrients, polyamines, we show that disruption of the female fly's ability to smell, for instance the pheromone cVA, during mating leads to a reduction in polyamine preference for days later indicating that the odor environment at mating lastingly influences female perception and choice behavior. Moreover, dopaminergic neurons including innervation of the ß'1 compartment are sufficient to induce the lasting behavioral increase in polyamine preference. We further show that MB output neurons (MBON) of the ß'1 compartment are activated by pheromone odor and their activity during mating bidirectionally modulates preference behavior in mated and virgin females. Their activity is not required, however, for the expression of polyamine attraction. Instead, inhibition of another type of MBON innervating the ß'2 compartment enables expression of high odor attraction. In addition, the response of a lateral horn (LH) neuron, AD1b2, which output is required for the expression of polyamine attraction, shows a modulated polyamine response after mating. Taken together, our data in the fly suggests that mating-related sensory experience regulates female odor perception and expression of choice behavior through a dopamine-gated learning circuit.

Progressive liver, kidney, and heart degeneration in children and adults affected by TULP3 mutations.

Organ fibrosis is a shared endpoint of many diseases, yet underlying mechanisms are not well understood. Several pathways governed by the primary cilium, a sensory antenna present on most vertebrate cells, have been linked with fibrosis. Ciliopathies usually start early in life and represent a considerable disease burden. We performed massively parallel sequencing by using cohorts of genetically unsolved individuals with unexplained liver and kidney failure and correlated this with clinical, imaging, and histopathological analyses. Mechanistic studies were conducted with a vertebrate model and primary cells. We detected bi-allelic deleterious variants in TULP3, encoding a critical adaptor protein for ciliary trafficking, in a total of 15 mostly adult individuals, originating from eight unrelated families, with progressive degenerative liver fibrosis, fibrocystic kidney disease, and hypertrophic cardiomyopathy with atypical fibrotic patterns on histopathology. We recapitulated the human phenotype in adult zebrafish and confirmed disruption of critical ciliary cargo composition in several primary cell lines derived from affected individuals. Further, we show interaction between TULP3 and the nuclear deacetylase SIRT1, with roles in DNA damage repair and fibrosis, and report increased DNA damage ex vivo. Transcriptomic studies demonstrated upregulation of profibrotic pathways with gene clusters for hypertrophic cardiomyopathy and WNT and TGF-ß signaling. These findings identify variants in TULP3 as a monogenic cause for progressive degenerative disease of major organs in which affected individuals benefit from early detection and improved clinical management. Elucidation of mechanisms crucial for DNA damage repair and tissue maintenance will guide novel therapeutic avenues for this and similar genetic and non-genomic diseases.

Transient Global Amnesia (TGA): Younger Age and Absence of Cerebral Microangiopathy Are Potentially Predisposing Factors for TGA Recurrence.

Background: Transient global amnesia (TGA) is defined by an acute memory disturbance of unclear etiology for a period of less than 24 h. TGA occurs as a single event in most cases. Prevalence rates of recurrent TGA vary widely from 5.4 to 27.1%. This retrospective study aimed to determine predictors for TGA recurrence. Methods: Cardiovascular risk profile and magnetic resonance imaging (MRI) of 340 hospitalized TGA patients between 2011 and 2020 were retrospectively analyzed. The median follow-up period amounted to 4.5 ± 2.7 years. Comparisons were made between TGA patients with and without subsequent recurrence. Results: TGA patients with subsequent recurrence were significantly younger (recurrent vs. single episode, 63.6 ± 8.6 years vs. 67.3 ± 10.5 years, p = 0.032) and showed a lower degree of cerebral microangiopathy compared to TGA patients without recurrence. The mean latency to recurrence was 3.0 years ± 2.1 years after the first episode. In a subgroup analysis, patients with at least five years of follow-up (N = 160, median follow-up period 7.0 ± 1.4 years) had a recurrence rate of 11.3%. A 24.5% risk of subsequent TGA recurrence in the following five years was determined for TGA patients up to 70 years of age without microangiopathic changes on MRI (Fazekas' score 0). Conclusion: Younger TGA patients without significant microangiopathy do have an increased recurrence risk. In turn, pre-existing cerebrovascular pathology, in the form of chronic hypertension and cerebral microangiopathy, seems to counteract TGA recurrence.

Transient Global Amnesia (TGA): Influence of Acute Hypertension in Patients Not Adapted to Chronic Hypertension.

Objective: Transient global amnesia (TGA) is defined by an acute memory disturbance of unclear etiology for a period of <24 h. Several studies showed differences in vascular risk factors between TGA compared to transient ischemic attack (TIA) or healthy controls with varying results. This retrospective and cross-sectional study compares the cardiovascular risk profile of TGA patients with that of acute stroke patients. Methods: Cardiovascular risk profile and MR imaging of 277 TGA patients was retrospectively analyzed and compared to 216 acute ischemic stroke patients (26% TIA). Results: TGA patients were significantly younger and predominantly female compared to stroke patients. A total of 90.6% of TGA patients underwent MRI, and 53% of those showed hippocampal diffusion-weighted imaging (DWI) lesions. Scores for cerebral microangiopathy were lower in TGA patients compared to stroke patients. After statistical correction for age, TGA patients had higher systolic and diastolic blood pressure, higher cholesterol levels, lower HbA1c, as well as blood glucose levels, and lower CHA2DS2-VASc scores. Stroke patients initially displayed higher CRP levels than TIA and TGA patients. TGA patients without DWI lesions were older and showed higher CHA2DS2-VASc scores compared to TGA patients with DWI lesions. Conclusion: This study revealed significant differences between TGA and stroke patients in regard to the cardiovascular risk profile. Our main findings show a strong association between acute hypertensive peaks and TGA in patients not adapted to chronic hypertension, indicating a vascular cause of the disease.

The Coxiella burnetii effector protein CaeB modulates endoplasmatic reticulum (ER) stress signalling and is required for efficient replication in Galleria mellonella.

The obligate intracellular pathogen Coxiella burnetii is the causative agent of the zoonosis Q fever. C. burnetii infection can have severe outcomes due to the development of chronic infection. To establish and maintain an infection, C. burnetii depends on a functional type IVB secretion system (T4BSS) and, thus, on the translocation of effector proteins into the host cell. Here, we showed that the C. burnetii T4BSS effector protein CaeB targets the conserved endoplasmatic reticulum (ER) stress sensor IRE1 during ER stress in mammalian and plant cells. CaeB-induced upregulation of IRE1 RNase activity was essential for CaeB-mediated inhibition of ER stress-induced cell death. Our data reveal a novel role for CaeB in ER stress signalling modulation and demonstrate that CaeB is involved in pathogenicity in vivo. Furthermore, we provide evidence that C. burnetii infection leads to modulation of the ER stress sensors IRE1 and PERK, but not ATF6 during ER stress. While the upregulation of the RNase activity of IRE1 during ER stress depends on CaeB, modulation of PERK is CaeB independent, suggesting that C. burnetii encodes several factors influencing ER stress during infection.

Genomes of the wild beets Beta patula and Beta vulgaris ssp. maritima.

We present draft genome assemblies of Beta patula, a critically endangered wild beet endemic to the Madeira archipelago, and of the closely related Beta vulgaris ssp. maritima (sea beet). Evidence-based reference gene sets for B. patula and sea beet were generated, consisting of 25 127 and 27 662 genes, respectively. The genomes and gene sets of the two wild beets were compared with their cultivated sister taxon B. vulgaris ssp. vulgaris (sugar beet). Large syntenic regions were identified, and a display tool for automatic genome-wide synteny image generation was developed. Phylogenetic analysis based on 9861 genes showing 1:1:1 orthology supported the close relationship of B. patula to sea beet and sugar beet. A comparative analysis of the Rz2 locus, responsible for rhizomania resistance, suggested that the sequenced B. patula accession was rhizomania susceptible. Reference karyotypes for the two wild beets were established, and genomic rearrangements were detected. We consider our data as highly valuable and comprehensive resources for wild beet studies, B. patula conservation management, and sugar beet breeding research.

Sleep better, feel better? Effects of a CBT-I and HT-I sleep training on mental health, quality of life and stress coping in university students: a randomized pilot controlled trial.

BACKGROUND: The SWIS sleep training for university students showed promising results regarding subjective and objective sleep parameters. As sleep disorders and impaired sleep quality are closely related to various aspects of mental health, the current study examines the effects of the SWIS sleep training on mental health in university students. METHODS: Fifty six university students (M = 25.84, SD = 5.06) participated in the study, 68% were women. Forty one were randomly assigned to the SWIS treatment (pre-post-follow-up), 15 to a Waiting List Control condition (WLC, pre-post). Besides sleep-related measures, the students completed four online questionnaires measuring mental health, quality of life and stress coping strategies. Effect sizes for the pre-post data were compared between the conditions, long-term effects were calculated with repeated measures ANOVA or Friedman ANOVA. Long-term clinical changes were analyzed with the Reliable Change Index (RCI). RESULTS: The pre-post comparisons between SWIS and WLC revealed lower depression scores in both conditions, a better physical state in the SWIS condition and less maladaptive stress coping strategies in the WLC students. The long-term results of SWIS provided significant improvements regarding the students' somatic complaints, reduced anxiety, an improved physical state and a better quality of life with moderate to large effect sizes. Most of the significant improvements occurred between pre- and follow-up measurement. These statistically significant results were also reflected in clinically significant changes from pre- to follow-up-test. CONCLUSIONS: SWIS and WLC condition both improved in two mental health variables immediately after the training. These findings may be explained by unspecific treatment expectation effects in the WLC. Interestingly, most mental health outcomes showed significant improvements after 3 months, but not immediately after the training. These positive long-term effects of the SWIS training on mental health indicate that the transfer of strategies might simply need more time to affect the students' mental health. TRIAL REGISTRATION: The current study was retrospectively registered at German Clinical Trials Register (ID: DRKS00014338 , registration date: 20.04.2018, enrolment of first participant: 14.04.2015).

Inhibition of oxidative stress in cholinergic projection neurons fully rescues aging-associated olfactory circuit degeneration in Drosophila.

Loss of the sense of smell is among the first signs of natural aging and neurodegenerative diseases such as Alzheimer's and Parkinson's. Cellular and molecular mechanisms promoting this smell loss are not understood. Here, we show that Drosophila melanogaster also loses olfaction before vision with age. Within the olfactory circuit, cholinergic projection neurons show a reduced odor response accompanied by a defect in axonal integrity and reduction in synaptic marker proteins. Using behavioral functional screening, we pinpoint that expression of the mitochondrial reactive oxygen scavenger SOD2 in cholinergic projection neurons is necessary and sufficient to prevent smell degeneration in aging flies. Together, our data suggest that oxidative stress induced axonal degeneration in a single class of neurons drives the functional decline of an entire neural network and the behavior it controls. Given the important role of the cholinergic system in neurodegeneration, the fly olfactory system could be a useful model for the identification of drug targets.

Let's talk about sleep: a systematic review of psychological interventions to improve sleep in college students.

Sleep problems are a common occurrence in college students. Insomnia, nightmares and impaired sleep quality lead to several mental health issues, as well as impaired academic performance. Although different sleep programmes exist, a systematic overview comparing their effectiveness is still missing. This systematic review aims to provide an overview of psychological interventions to improve sleep in college students. Seven databases were searched from November to December 2016 (MEDLINE, EMBASE, PsycINFO, Cinahl, Cochrane Library, PubMed, OpenSigle). The search string included search terms from three different topics: sleep, intervention and college students. Outcome measures included subjective as well as objective measures and focused on sleep, sleep-related and mental health variables. Twenty-seven studies met the inclusion criteria. They were assigned to four intervention categories: (1) sleep hygiene, (2) cognitive-behavioural therapy (CBT), (3) relaxation, mindfulness and hypnotherapy and (4) other psychotherapeutic interventions. Fifteen studies were randomized controlled trials. While sleep hygiene interventions provided small to medium effects, the CBTs showed large effects. The variability of the effect sizes was especially large in the relaxation category, ranging from very small to very large effect sizes. Other psychotherapeutic interventions showed medium effects. CBT approaches provided the best effects for the improvement of different sleep variables in college students. Five studies included insomnia patients. The other three intervention categories also showed promising results with overall medium effects. In the future, CBT should be combined with relaxation techniques, mindfulness and hypnotherapy. Furthermore, the interventions should broaden their target group and include more sleep disorders.

Sleep problems in university students - an intervention.

INTRODUCTION: Up to 60% of all college students suffer from a poor sleep quality, and 7.7% meet all criteria of an insomnia disorder. Sleep problems have a great impact on the students' daily life, for example, the grade point average. Due to irregular daytime routines, chronotype changes, side jobs and exam periods, they need specialized treatments for improving sleep. "Studieren wie im Schlaf" (SWIS; (studying in your sleep)) is a multicomponent sleep training that combines Cognitive Behavioral Therapy for Insomnia and Hypnotherapy for Insomnia to improve students' sleep, insomnia symptoms and nightmares. The aim of the present study is to evaluate the acceptance, feasibility and the first effects of SWIS. METHODS: Twenty-seven students (mean =24.24, standard deviation =3.57) participated in a study of pre-post design. The acceptance and feasibility were measured with questionnaires. In addition, the Pittsburgh Sleep Quality Index (PSQI), sleep logs and actigraphy were implemented. Further variables encompassed daytime sleepiness, sleep-related personality traits and cognitions about sleep. RESULTS: Seventy-four percent of the participants reported symptoms of an insomnia disorder, and 51.9% fulfilled all criteria of an insomnia disorder according to the Diagnostic and Statistical Manual of Mental Disorders (fifth edition). Correspondingly, the students suffered from clinically relevant sleep problems according to the PSQI. The SWIS sleep training is a well-accepted and feasible program. Significant improvements were observed in the subjective sleep quality and sleep-related personality traits, as well as clinical improvements in objective sleep measures. DISCUSSION: Findings showed that SWIS is a feasible program for the treatment of sleep problems in college and university students due to its various effects on sleep and cognitive outcomes. Further evaluation of follow-up measurements and additional variables, that is, cognitive performance and mental health, is needed.

Modulation of host cell apoptotic pathways by intracellular pathogens.

Nearly all steps of the host cell apoptotic cascade can be subverted by intracellular microorganisms. Some pathogens modulate early steps and interfere with sensing of extracellular signals, cellular stress or signal transduction; others target Bcl-2 proteins, caspases, or inhibitor of apoptosis proteins (IAPs). In many cases the exact molecular mechanisms leading to interference with the host cell apoptotic cascade are still unknown. However, there are some examples where bacterial factors that modulate host cell death have been identified. In this review we will summarize recent findings on how intracellular pathogens or their secreted proteins alter the intrinsic and/or extrinsic host cell apoptotic pathways.

Direct neural pathways convey distinct visual information to Drosophila mushroom bodies.

Previously, we demonstrated that visual and olfactory associative memories of Drosophila share mushroom body (MB) circuits (Vogt et al., 2014). Unlike for odor representation, the MB circuit for visual information has not been characterized. Here, we show that a small subset of MB Kenyon cells (KCs) selectively responds to visual but not olfactory stimulation. The dendrites of these atypical KCs form a ventral accessory calyx (vAC), distinct from the main calyx that receives olfactory input. We identified two types of visual projection neurons (VPNs) directly connecting the optic lobes and the vAC. Strikingly, these VPNs are differentially required for visual memories of color and brightness. The segregation of visual and olfactory domains in the MB allows independent processing of distinct sensory memories and may be a conserved form of sensory representations among insects.

A Higher Brain Circuit for Immediate Integration of Conflicting Sensory Information in Drosophila.

Animals continuously evaluate sensory information to decide on their next action. Different sensory cues, however, often demand opposing behavioral responses. How does the brain process conflicting sensory information during decision making? Here, we show that flies use neural substrates attributed to odor learning and memory, including the mushroom body (MB), for immediate sensory integration and modulation of innate behavior. Drosophila melanogaster must integrate contradictory sensory information during feeding on fermenting fruit that releases both food odor and the innately aversive odor CO2. Here, using this framework, we examine the neural basis for this integration. We have identified a local circuit consisting of specific glutamatergic output and PAM dopaminergic input neurons with overlapping innervation in the MB-ß'2 lobe region, which integrates food odor and suppresses innate avoidance. Activation of food odor-responsive dopaminergic neurons reduces innate avoidance mediated by CO2-responsive MB output neurons. We hypothesize that the MB, in addition to its long recognized role in learning and memory, serves as the insect's brain center for immediate sensory integration during instantaneous decision making.