Miracle-dz/UniFAR-FTUs huggingface dataset:
Distinct brain structural‐functional network topological coupling explains different outcomes in tinnitus patients treated with sound therapy

Topological properties, which serve as the core of the neural network, and their couplings can reflect different therapeutic effects in tinnitus patients. We hypothesized that tinnitus patients with different outcomes after sound therapy (narrowband noise) would have distinct brain network topological alterations. Diffusion tensor imaging and resting‐state functional magnetic resonance imaging (fMRI) were prospectively performed in 60 patients with idiopathic tinnitus and 57 healthy controls (HCs). Graph‐theoretical network analyses of structural connectivity (SC), functional connectivity (FC), and SC and FC coupling were performed. Associations between clinical performance and graph‐theoretical features were also analyzed. Treatment was effective (effective group; EG) in 28 patients and ineffective (ineffective group; IG) in 32 patients. For FC, the patients in the EG showed higher local efficiency than patients in the IG. For SC, patients in both the EG and IG displayed lower normalized characteristic path length, characteristic path length, and global efficiency than the HCs. More importantly, patients in the IG had higher coupling than the HCs, whereas there was no difference in coupling between patients in the EG and HCs. Additionally, there were significant associations between the SC features and clinical performance in patients in the EG. Our findings demonstrate that tinnitus patients exhibited significant brain network topological alterations, especially in the structural brain network. More importantly, patients who demonstrated different curative effects showed distinct SC‐FC topological coupling properties. SC‐FC coupling could be an indicator that could be used to predict prognoses in patients with idiopathic tinnitus before sound therapy.
A Multicenter Study on the Impact of Gender, Age, and Dual Diagnosis on Substance Consumption and Mental Health Status in Outpatients Treated for Substance Use Disorders During COVID-19 Lockdown

Abstract Objective COVID-19 and lockdown measures impacted mental health globally and had a particular impact on patients with substance use disorders (SUD). However, the impact of gender, age, and dual diagnosis on consumption patterns and mental health during COVID-19 lockdown among patients with SUD has not been analyzed in depth. Therefore, this study aimed to examine substance use and mental health status during COVID-19 lockdown considering gender, age, and previous dual diagnosis in patients with SUD treated in different outpatient addiction clinics in Catalonia. Methods: Thirteen clinics participated and 588 patients were enrolled in the study, of whom 70.7% were men and 29.3% were women. The mean age was 48 ± 11.3 years, and 63.2% had dual diagnoses. Results: Men reported significantly more frequent alcohol and cocaine consumption during lockdown, while women experienced more anxiety and depressive symptoms. Younger patients more frequently reported consuming cocaine and cannabis, breaking the lockdown rule, worsened family relationships, and reduced incomes. Older patients more frequently reported maintaining abstinence. Previous dual diagnosis was more often associated with benzodiazepine use disorder, less active working during lockdown, and more anxiety and depressive symptoms than not having previous dual diagnosis. Conclusions: Both new psychiatric symptoms and general worsening of existing symptoms were frequent during the lockdown. Differences based on the gender, age, and dual diagnosis of outpatients treated for substance use disorders should be considered in the planning of protection measures such as home confinement.
Personalized drug testing in human pheochromocytoma/paraganglioma primary cultures.

Aggressive pheochromocytomas and paragangliomas (PPGLs) are difficult to treat, and molecular targeting is being increasingly considered, but with variable results. This study investigates established and novel molecular-targeted drugs and chemotherapeutic agents for the treatment of PPGLs in human primary cultures and murine cell line spheroids. In PPGLs from 33 patients, including 7 metastatic PPGLs, we identified germline or somatic driver-mutations in 79% of cases, allowing us to assess potential differences in drug responsivity between pseudohypoxia-associated cluster 1- (n=10) and kinase signaling-associated cluster 2-related (n=14) PPGL primary cultures. Single anti-cancer drugs were either more effective in cluster 1 (cabozantinib, selpercatinib, 5-FU) or similarly effective in both clusters (everolimus, sunitinib, alpelisib, trametinib, niraparib, entinostat, gemcitabine, AR-A014418, high-dose zoledronic acid). High-dose estrogen and low-dose zoledronic acid were the only single substances more effective in cluster 2. Neither cluster 1- nor cluster 2-related patient primary cultures responded to HIF-2α inhibitors, temozolomide, dabrafenib, or octreotide. We showed particular efficacy of targeted combination treatments (cabozantinib/everolimus, alpelisib/everolimus, alpelisib/trametinib) in both clusters, with higher efficacy of some targeted combinations in cluster 2 and overall synergistic effects (cabozantinib/everolimus, alpelisib/trametinib) or synergistic effects in cluster 2 (alpelisib/everolimus). Cabozantinib/everolimus combination therapy, gemcitabine, and high-dose zoledronic acid appear to be promising treatment options with particularly high efficacy in SDHB-mutant and metastatic tumors. In conclusion, only minor differences regarding drug responsivity were found between cluster 1 and cluster 2: some single anti-cancer drugs were more effective in cluster 1 and some targeted combination treatments were more effective in cluster 2.
Efficacy and Safety of a Krabbe Disease Gene Therapy

Krabbe disease is a lysosomal storage disease caused by mutations in the gene that encodes galactosylceramidase, in which galactosylsphingosine (psychosine) accumulation drives demyelination in the central and peripheral nervous systems, ultimately progressing to death in early childhood. Gene therapy, alone or in combination with transplant, has been developed for almost two decades in mouse models, with increasing therapeutic benefit paralleling the improvement of next-generation adeno-associated virus (AAV) vectors. This effort has recently shown remarkable efficacy in the canine model of the disease by two different groups that used either systemic or cerebrospinal fluid (CSF) administration of AAVrh10 or AAV9. Building on our experience developing CSF-delivered, AAV-based drug products for a variety of neurodegenerative disorders, we conducted efficacy, pharmacology, and safety studies of AAVhu68 delivered to the CSF in two relevant natural Krabbe animal models, and in nonhuman primates. In newborn Twitcher mice, the highest dose (1 × 1011 genome copies [GC]) of AAVhu68.hGALC injected into the lateral ventricle led to a median survival of 130 days compared to 40.5 days in vehicle-treated mice. When this dose was administered intravenously, the median survival was 49 days. A single intracisterna magna injection of AAVhu68.cGALC at 3 × 1013 GC into presymptomatic Krabbe dogs increased survival for up to 85 weeks compared to 12 weeks in controls. It prevented psychosine accumulation in the CSF, preserved peripheral nerve myelination, ambulation, and decreased brain neuroinflammation and demyelination, although some regions remained abnormal. In a Good Laboratory Practice-compliant toxicology study, we administered the clinical candidate into the cisterna magna of 18 juvenile rhesus macaques at 3 doses that displayed efficacy in mice. We observed no dose-limiting toxicity and sporadic minimal degeneration of dorsal root ganglia (DRG) neurons. Our studies demonstrate the efficacy, scalability, and safety of a single cisterna magna AAVhu68 administration to treat Krabbe disease. ClinicalTrials.Gov ID: NCT04771416.
Understanding the impact of COVID‐19 pandemic on teleworkers' experiences of perceived threat and professional isolation: The moderating role of friendship

Abstract Drawing from conservation of resource theory and the social support resource theory, this study examines how the severity of an exogenous disruptive event – the COVID‐19 pandemic – in one's community influences teleworkers' well‐being outcomes indirectly through their perceptions of pandemic‐related threat and experience of professional isolation, as well as the buffering effect of friendship on these relationships. Utilizing time‐lagged data from participants of a two‐wave survey panel (N = 351) and objective data of COVID‐19 severity from counties around the United States, we found that perceived threat, but not professional isolation, mediated the negative effect of proportion of confirmed COVID‐19 cases in the community on teleworkers' well‐being outcomes. Further, consistent with our predictions, support from friends significantly weakened the negative effects of threat and professional isolation on well‐being. Key theoretical and practical implications of this study are discussed.
Minority Stress and Mental Health of Gay Men in Turkey: The Mediator Roles of Shame and Forgiveness of Self

ABSTRACT Proximal minority stressors (i.e., internalized homonegativity, anticipation of rejection, and concealment of sexual identity) lead to depression and anxiety. General psychological factors mediate the association of proximal stressors with depression and anxiety. Based on this, the present study aimed to investigate the sequential mediating roles of shame and forgiveness of self on the relations of proximal stressors with depression and anxiety in a sample of self-identified gay men in Turkey (N = 200). The findings revealed that proximal stressors significantly predicted depression and anxiety indirectly through shame and self-forgiveness. Thus, the link between minority stress and shame should be considered in clinical practice, and self-forgiveness should be integrated into intervention programs to eliminate the negative impacts of shame on depression and anxiety among this population. Limitations and directions for future studies are presented.
Invertible Modeling of Bidirectional Relationships in Neuroimaging With Normalizing Flows: Application to Brain Aging

Many machine learning tasks in neuroimaging aim at modeling complex relationships between a brain’s morphology as seen in structural MR images and clinical scores and variables of interest. A frequently modeled process is healthy brain aging for which many image-based brain age estimation or age-conditioned brain morphology template generation approaches exist. While age estimation is a regression task, template generation is related to generative modeling. Both tasks can be seen as inverse directions of the same relationship between brain morphology and age. However, this view is rarely exploited and most existing approaches train separate models for each direction. In this paper, we propose a novel bidirectional approach that unifies score regression and generative morphology modeling and we use it to build a bidirectional brain aging model. We achieve this by defining an invertible normalizing flow architecture that learns a probability distribution of 3D brain morphology conditioned on age. The use of full 3D brain data is achieved by deriving a manifold-constrained formulation that models morphology variations within a low-dimensional subspace of diffeomorphic transformations. This modeling idea is evaluated on a database of MR scans of more than 5000 subjects. The evaluation results show that our bidirectional brain aging model (1) accurately estimates brain age, (2) is able to visually explain its decisions through attribution maps and counterfactuals, (3) generates realistic age-specific brain morphology templates, (4) supports the analysis of morphological variations, and (5) can be utilized for subject-specific brain aging simulation.
Analysis of Telomere Length and Its Implication in Neurocognitive Functions in Elderly Women

During the normal aging process, a series of events occur, such as a decrease in telomere length and a decrease in various cognitive functions, such as attention, memory, or perceptual-motor speed. Several studies have attempted to establish a correlation between both variables; however, there is considerable controversy in the scientific literature. The aim of our study was to establish a correlation between the scores obtained in the following different cognitive tests: the Mini-Mental State Examination, the Benton Visual Retention Test, the Trail Making Test, the Rey Auditory Verbal Learning Test, the Stroop Test, and the measurement of telomere length. The sample consisted of a total of 41 physically active, healthy women, with a mean age of 71.21 (±4.32) and of 33 physically inactive, healthy women, with a mean age of 72.70 (±4.13). Our results indicate that there is no correlation between the scores obtained by the women in either group and their telomere length. Therefore, it is not possible to conclude that telomere length can be correlated with cognitive performance.
Overall survival and registration of cutaneous T-cell lymphoma patients in Sweden: a multi-center cohort and validation study

Julia Nenonen, Anna H. Winther, Ellinor Leijonhufvud, Emma Belfrage, Karin E. Smedby and Hanna Brauner Division of Rheumatology, Department of Medicine, Solna and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden; Dermato-Venereology Clinic, Karolinska University Hospital, Stockholm, Sweden; Dermato-Venereology Clinic, Uppsala Academic University Hospital, Uppsala, Sweden; Dermato-Venereology Clinic, Skåne university hospital, Lund, Sweden; Department of Clinical Sciences, Lund University, Lund, Sweden; Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, and Department of Hematology, Karolinska University Hospital, Stockholm, Sweden
Evaluation of the Relationship between Medication Adherence and Tacrolimus Coefficient of Variation

Introduction: High tacrolimus intrapatient variability is associated with poor outcomes following transplantation. A commonly hypothesized cause of this variability is medication non-adherence, but this has not been conclusively demonstrated. Research Question: The purpose of this study was to evaluate the relationship between medication adherence and tacrolimus intrapatient variability. Design: This was a retrospective cohort study of kidney transplant recipients. Adherence was assessed at the 12-month clinic visit as a composite of patient self-report, pharmacist assessment, and lab monitoring frequency. Tacrolimus intrapatient variability was calculated as the coefficient of variation (CV). Linear regression and receiver operating curve (ROC) analysis were used to assess the relationship between adherence and CV. Results: Nonadherence was identified in 37.5% of patients. The median CV was 27.1% for adherent patients and 29.8% for non-adherent patients (P = 0.051). In the multivariable analysis, the only significant predictor of CV was the incidence of dose changes (P = 0.002). ROC analysis demonstrated poor discriminant power with an AUC of 0.597. Discussion: The results fail to support a clinically meaningful relationship between medication adherence and tacrolimus CV. There is very little evidence at this time that adherence is the primary contributing factor to tacrolimus intrapatient variability and, by extension, that CV can be used as a surrogate for adherence.
P3 latency as a biomarker for the complexity of migraine with aura: Event-related potential study

Abstract Background This study aimed to compare the P3 component between patients who have migraines with aura and healthy subjects, and to compare different subtypes of migraine with aura relative to the complexity of migraine aura. Methods Average Migraine Aura Complexity Score was calculated for each MwA patient. Visual oddball paradigm was used to elicit the P3 component. P3 amplitudes and latencies elicited from frequent and rare stimuli, as well as from difference wave, were compared with healthy subjects. Subsequently, subtypes of migraine with aura were compared and Average Migraine Aura Complexity Score was used to explore the connection between features of the P3 and complexity of migraine with aura. Results 37 patients who have migraine with aura (16 with simple aura and 21 with complex aura) patients and 28 healthy subjects were studied. Patients who have migraine with aura had significantly prolonged latencies compared to healthy subjects (411 ± 39 ms vs 372 ± 34 ms, p < 0.001) relative to a rare condition. Patients who have complex aura significantly differs from patients who have simple aura (427 ± 34 ms vs 389 ± 35 ms, p = 0.004) and healthy subjects (372 ± 34 ms, p < 0.001) relative to P3 latency in a rare condition and the patients who have complex aura significantly differs from healthy subjects (442 ± 37 ms vs 394 ± 33 ms, p < 0.001) relative to P3 latency in difference wave. P3 latency from rare condition positively correlated with the Average Migraine Aura Complexity Score (p < 0.001). Conclusions Visual oddball paradigm, particularly rare stimuli, could serve as a potential new tool for deep profiling of different clinical complexities among patients who have migraine with aura. Also, the present pattern of P3 components provided new evidence for the cognitive dysfunctions in patients who have migraine with aura.
Acceptance and commitment therapy for individuals with depressive and anxiety symptoms following acquired brain injury: A non-concurrent multiple baseline design across four cases

ABSTRACT Patients with acquired brain injury (ABI) often experience symptoms of anxiety and depression. Until now, evidence-based treatment is scarce. This study aimed to investigate the effectiveness of Acceptance and Commitment Therapy (ACT) for patients with ABI. To evaluate the effect of ACT for people with ABI, a non-concurrent multiple baseline design across four cases was used. Participants were randomly assigned to a baseline period, followed by treatment and then follow-up phases. Anxiety and depressive symptoms were repeatedly measured. During six measurement moments over a year, participants filled in questionnaires measuring anxiety, depression, stress, participation, quality of life, and ACT-related processes. Randomization tests and NAP scores were used to calculate the level of change across phases. Clinically significant change was defined with the Reliable Change Index. Three out of four participants showed medium to large decreases in anxiety and depressive symptoms (NAP = 0.85 till 0.99). Furthermore, participants showed improvements regarding stress, cognitive fusion, and quality of life. There were no improvements regarding psychological flexibility, value-driven behaviour, or social participation. This study shows that ACT is possibly an effective treatment option for people experiencing ABI-related anxiety and depression symptoms. Replication with single case or large scale group studies is needed to confirm these findings.
Magnetic resonance imaging contrast-enhancement with superparamagnetic iron oxide nanoparticles amplifies macrophage foam cell apoptosis in human and murine atherosclerosis

Abstract Aims (Ultra) Small superparamagnetic iron oxide nanoparticles, (U)SPIO, are widely used as magnetic resonance imaging contrast media and assumed to be safe for clinical applications in cardiovascular disease. As safety tests largely relied on normolipidaemic models, not fully representative of the clinical setting, we investigated the impact of (U)SPIOs on disease-relevant endpoints in hyperlipidaemic models of atherosclerosis. Methods and results RAW264.7 foam cells, exposed in vitro to ferumoxide (dextran-coated SPIO), ferumoxtran (dextran-coated USPIO), or ferumoxytol [carboxymethyl (CM) dextran-coated USPIO] (all 1 mg Fe/mL) showed increased apoptosis and reactive oxygen species accumulation for ferumoxide and ferumoxtran, whereas ferumoxytol was tolerated well. Pro-apoptotic (TUNEL+) and pro-oxidant activity of ferumoxide (0.3 mg Fe/kg) and ferumoxtran (1 mg Fe/kg) were confirmed in plaque, spleen, and liver of hyperlipidaemic ApoE−/− (n = 9/group) and LDLR−/− (n = 9–16/group) mice that had received single IV injections compared with saline-treated controls. Again, ferumoxytol treatment (1 mg Fe/kg) failed to induce apoptosis or oxidative stress in these tissues. Concomitant antioxidant treatment (EUK-8/EUK-134) largely prevented these effects in vitro (−68%, P < 0.05) and in plaques from LDLR−/− mice (−60%, P < 0.001, n = 8/group). Repeated ferumoxtran injections of LDLR−/− mice with pre-existing atherosclerosis enhanced plaque inflammation and apoptosis but did not alter plaque size. Strikingly, carotid artery plaques of endarterectomy patients who received ferumoxtran (2.6 mg Fe/kg) before surgery (n = 9) also showed five-fold increased apoptosis (18.2 vs. 3.7%, respectively; P = 0.004) compared with controls who did not receive ferumoxtran. Mechanistically, neither coating nor particle size seemed accountable for the observed cytotoxicity of ferumoxide and ferumoxtran. Conclusions Ferumoxide and ferumoxtran, but not ferumoxytol, induced apoptosis of lipid-laden macrophages in human and murine atherosclerosis, potentially impacting disease progression in patients with advanced atherosclerosis.
BDNF blood levels after electroconvulsive therapy in patients with mood disorders: An updated systematic review and meta-analysis

Abstract Objectives Studies have suggested Brain-Derived Neurotrophic Factors (BDNF) increase after electroconvulsive therapy (ECT) although they were methodologically limited and enrolled small sample sizes. We aimed at updating a systematic review and meta-analysis to explore BDNF changes after ECT for the treatment of depression. Methods PubMed, PsycInfo, Embase and Global health were searched (March, 2021). Clinical trials that measured BDNF in the blood before and after ECT in adults (≥ 18 years old) with depression (major depressive disorder or bipolar disorder) were eligible. Data were pooled through random-effects meta-analyses. Results Twenty-eight studies involving 778 participants were included. Meta-analysis showed a significant increase in BDNF levels after ECT (Hedges’ g = 0.28; 95% CI: 0.10, 0.46) while there was evidence of significant heterogeneity (I2 = 67.64%) but not publication bias/small-study effect. Subgroup analyses and meta-regressions were underpowered to detect significant differences. Meta-analysis of depression severity scores demonstrated a considerable larger treatment effect in reducing depressive symptoms after ECT (Hedge’s g = −3.72 95% CI: −4.23, −3.21). Conclusion This updated review showed that BDNF blood levels increased after ECT treatment. However, there was still evidence of substantial heterogeneity and there were limited sample sizes to investigate factors driving the variability of effects across studies. Importantly, the increase in BDNF levels was substantially smaller than the observed in depressive symptomatology, which could be indicative that the former was independent than the latter. Additional studies with larger sample sizes are currently required.