Natural history of eukaryotic DNA viruses with double jelly-roll major capsid proteins.

The phylum Preplasmiviricota (kingdom Bamfordvirae, realm Varidnaviria) is a broad assemblage of diverse viruses with comparatively short double-stranded DNA genomes (<50 kbp) that produce icosahedral capsids built from double jelly-roll major capsid proteins. Preplasmiviricots infect hosts from all cellular domains, testifying to their ancient origin and, in particular, are associated with six of the seven supergroups of eukaryotes. Preplasmiviricots comprise four major groups of viruses, namely, polintons, polinton-like viruses (PLVs), virophages, and adenovirids. We employed protein structure modeling and analysis to show that protein-primed DNA polymerases (pPolBs) of polintons, virophages, and cytoplasmic linear plasmids encompass an N-terminal domain homologous to the terminal proteins (TPs) of prokaryotic PRD1-like tectivirids and eukaryotic adenovirids that are involved in protein-primed replication initiation, followed by a viral ovarian tumor-like cysteine deubiquitinylase (vOTU) domain. The vOTU domain is likely responsible for the cleavage of the TP from the large pPolB polypeptide and is inactivated in adenovirids, in which TP is a separate protein. Many PLVs and transpovirons encode a distinct derivative of polinton-like pPolB that retains the TP, vOTU and pPolB polymerization palm domains but lacks the exonuclease domain and instead contains a supefamily 1 helicase domain. Analysis of the presence/absence and inactivation of the vOTU domains, and replacement of pPolB with other DNA polymerases in eukaryotic preplasmiviricots enabled us to outline a complete scenario for their origin and evolution.

Natural history of eukaryotic DNA viruses with double jelly-roll major capsid proteins.

The phylum Preplasmiviricota (kingdom Bamfordvirae, realm Varidnaviria) is a broad assemblage of diverse viruses with comparatively short double-stranded DNA genomes (<50 kbp) that produce icosahedral capsids built from double jelly-roll major capsid proteins. Preplasmiviricots infect hosts from all cellular domains, testifying to their ancient origin, and, in particular, are associated with six of the seven supergroups of eukaryotes. Preplasmiviricots comprise four major groups of viruses, namely, polintons, polinton-like viruses (PLVs), virophages, and adenovirids. We used protein structure modeling and analysis to show that protein-primed DNA polymerases (pPolBs) of polintons, virophages, and cytoplasmic linear plasmids encompass an N-terminal domain homologous to the terminal proteins (TPs) of prokaryotic PRD1-like tectivirids and eukaryotic adenovirids that are involved in protein-primed replication initiation, followed by a viral ovarian tumor-like cysteine deubiquitinylase (vOTU) domain. The vOTU domain is likely responsible for the cleavage of the TP from the large pPolB polypeptide and is inactivated in adenovirids, in which TP is a separate protein. Many PLVs and transpovirons encode a distinct derivative of polinton-like pPolB that retains the TP, vOTU, and pPolB polymerization palm domains but lacks the exonuclease domain and instead contains a superfamily 1 helicase domain. Analysis of the presence/absence and inactivation of the vOTU domains and replacement of pPolB with other DNA polymerases in eukaryotic preplasmiviricots enabled us to outline a complete scenario for their origin and evolution.

Isolation of Diverse Simian Arteriviruses Causing Hemorrhagic Disease.

Genetically diverse simian arteriviruses (simarteriviruses) naturally infect geographically and phylogenetically diverse monkeys, and cross-species transmission and emergence are of considerable concern. Characterization of most simarteriviruses beyond sequence analysis has not been possible because the viruses fail to propagate in the laboratory. We attempted to isolate 4 simarteriviruses, Kibale red colobus virus 1, Pebjah virus, simian hemorrhagic fever virus, and Southwest baboon virus 1, by inoculating an immortalized grivet cell line (known to replicate simian hemorrhagic fever virus), primary macaque cells, macrophages derived from macaque induced pluripotent stem cells, and mice engrafted with macaque CD34+-enriched hematopoietic stem cells. The combined effort resulted in successful virus isolation; however, no single approach was successful for all 4 simarteriviruses. We describe several approaches that might be used to isolate additional simarteriviruses for phenotypic characterization. Our results will expedite laboratory studies of simarteriviruses to elucidate virus-host interactions, assess zoonotic risk, and develop medical countermeasures.

Comparative analysis of radiomics and deep-learning algorithms for survival prediction in hepatocellular carcinoma.

To examine the comparative robustness of computed tomography (CT)-based conventional radiomics and deep-learning convolutional neural networks (CNN) to predict overall survival (OS) in HCC patients. Retrospectively, 114 HCC patients with pretherapeutic CT of the liver were randomized into a development (n = 85) and a validation (n = 29) cohort, including patients of all tumor stages and several applied therapies. In addition to clinical parameters, image annotations of the liver parenchyma and of tumor findings on CT were available. Cox-regression based on radiomics features and CNN models were established and combined with clinical parameters to predict OS. Model performance was assessed using the concordance index (C-index). Log-rank tests were used to test model-based patient stratification into high/low-risk groups. The clinical Cox-regression model achieved the best validation performance for OS (C-index [95% confidence interval (CI)] 0.74 [0.57-0.86]) with a significant difference between the risk groups (p = 0.03). In image analysis, the CNN models (lowest C-index [CI] 0.63 [0.39-0.83]; highest C-index [CI] 0.71 [0.49-0.88]) were superior to the corresponding radiomics models (lowest C-index [CI] 0.51 [0.30-0.73]; highest C-index [CI] 0.66 [0.48-0.79]). A significant risk stratification was not possible (p > 0.05). Under clinical conditions, CNN-algorithms demonstrate superior prognostic potential to predict OS in HCC patients compared to conventional radiomics approaches and could therefore provide important information in the clinical setting, especially when clinical data is limited.

Lymphoepithelial cyst mimicking malignant pancreatic signs: a case report.

BACKGROUND: A lymphoepithelial cyst of the pancreas is a rare benign lesion that is difficult to diagnose preoperatively and challenging in distinguishing from potentially malignant cystic pancreatic neoplasms. A diagnostic step-up approach is recommended to clarify the lesion's dignity and specify a treatment plan. CASE PRESENTATION: Here, we describe a case of a 51-year-old male European with a lymphoepithelial cyst of the pancreas mimicking malignant features in a mid-age male patient with abdominal pain and unintended weight loss. CONCLUSION: Patients with indeterminate cystic pancreatic lesions should be examined by a multidisciplinary diagnostic team in a step-up approach to clarify the lesion's entity. In the case of incidentally found lymphoepithelial cysts of the pancreas, a watchful waiting strategy might be clinically reasonable if the diagnosis is proven.

Prediction of clinically relevant postoperative pancreatic fistula using radiomic features and preoperative data.

Clinically relevant postoperative pancreatic fistula (CR-POPF) can significantly affect the treatment course and outcome in pancreatic cancer patients. Preoperative prediction of CR-POPF can aid the surgical decision-making process and lead to better perioperative management of patients. In this retrospective study of 108 pancreatic head resection patients, we present risk models for the prediction of CR-POPF that use combinations of preoperative computed tomography (CT)-based radiomic features, mesh-based volumes of annotated intra- and peripancreatic structures and preoperative clinical data. The risk signatures were evaluated and analysed in detail by visualising feature expression maps and by comparing significant features to the established CR-POPF risk measures. Out of the risk models that were developed in this study, the combined radiomic and clinical signature performed best with an average area under receiver operating characteristic curve (AUC) of 0.86 and a balanced accuracy score of 0.76 on validation data. The following pre-operative features showed significant correlation with outcome in this signature ([Formula: see text]) - texture and morphology of the healthy pancreatic segment, intensity volume histogram-based feature of the pancreatic duct segment, morphology of the combined segment, and BMI. The predictions of this pre-operative signature showed strong correlation (Spearman correlation co-efficient, [Formula: see text]) with the intraoperative updated alternative fistula risk score (ua-FRS), which is the clinical gold standard for intraoperative CR-POPF risk stratification. These results indicate that the proposed combined radiomic and clinical signature developed solely based on preoperatively available clinical and routine imaging data can perform on par with the current state-of-the-art intraoperative models for CR-POPF risk stratification.

Viriforms-A New Category of Classifiable Virus-Derived Genetic Elements.

The International Committee on Taxonomy of Viruses (ICTV) recently accepted viriforms as a new polyphyletic category of classifiable virus-derived genetic elements, juxtaposed to the polyphyletic virus, viroid, and satellite nucleic acid categories. Viriforms are endogenized former viruses that have been exapted by their cellular hosts to fulfill functions important for the host's life cycle. While morphologically resembling virions, particles made by viriforms do not package the viriform genomes but instead transport host genetic material. Known viriforms are highly diverse: members of family Polydnaviriformidae (former Polydnaviridae) have thus far been found exclusively in the genomes of braconid and ichneumonid parasitoid wasps, whereas the completely unrelated gene transfer agents (GTAs) are widely distributed among prokaryotes. In addition, recent discoveries likely extend viriforms to mammalian genomes. Here, we briefly outline the properties of these viriform groups and the first accepted and proposed ICTV frameworks for viriform classification.

Definition of age-dependent reference values for the diameter of the common bile duct and pancreatic duct on MRCP: a population-based, cross-sectional cohort study.

OBJECTIVE: Changes of the pancreaticobiliary ducts herald disease. Magnetic resonance cholangiopancreatography (MRCP) allows accurate duct visualisation. Data on reliable upper reference ranges are missing. DESIGN: Cross-sectional whole body MRI data from the population-based Study of Health in Pomerania were analysed. The width of the common bile duct (CBD) and the pancreatic duct (PD) was determined. We aimed to describe the distribution of physiological duct diameters on MRCP in a population of healthy subjects and to identify factors influencing duct size. RESULTS: After excluding pre-existing pancreaticobiliary conditions, CBD and PD diameters from 938 and 774 healthy individuals, respectively, showed a significant increase with age (p<0.0001) and exceeded the conventional upper reference limit of normal in 10.9% and 18.2%, respectively. Age-dependent upper reference limits of duct diameters were delineated with non-parametric quantile regression, defined as 95th percentile: for CBD up to 8 mm in subjects <65 years and up to 11 mm in subjects ≥65 years. For the PD reference diameters were up to 3 mm in subjects <65 years and up to 4 mm in subjects ≥65 years. CONCLUSIONS: This is the first population-based study delineating age-adjusted upper reference limits of CBD and PD on MRCP. We showed that up to 18.2% of healthy volunteers would have needed diagnostic workup, if the conventional reference values were used. The utilisation of the adapted reference levels may help to avoid unnecessary investigations and thus to reduce healthcare expenditure and test-related adverse events.

Quantification of Liver Iron Overload with MRI: Review and Guidelines from the ESGAR and SAR.

Accumulation of excess iron in the body, or systemic iron overload, results from a variety of causes. The concentration of iron in the liver is linearly related to the total body iron stores and, for this reason, quantification of liver iron concentration (LIC) is widely regarded as the best surrogate to assess total body iron. Historically assessed using biopsy, there is a clear need for noninvasive quantitative imaging biomarkers of LIC. MRI is highly sensitive to the presence of tissue iron and has been increasingly adopted as a noninvasive alternative to biopsy for detection, severity grading, and treatment monitoring in patients with known or suspected iron overload. Multiple MRI strategies have been developed in the past 2 decades, based on both gradient-echo and spin-echo imaging, including signal intensity ratio and relaxometry strategies. However, there is a general lack of consensus regarding the appropriate use of these methods. The overall goal of this article is to summarize the current state of the art in the clinical use of MRI to quantify liver iron content and to assess the overall level of evidence of these various methods. Based on this summary, expert consensus panel recommendations on best practices for MRI-based quantification of liver iron are provided.

Four principles to establish a universal virus taxonomy.

A universal taxonomy of viruses is essential for a comprehensive view of the virus world and for communicating the complicated evolutionary relationships among viruses. However, there are major differences in the conceptualisation and approaches to virus classification and nomenclature among virologists, clinicians, agronomists, and other interested parties. Here, we provide recommendations to guide the construction of a coherent and comprehensive virus taxonomy, based on expert scientific consensus. Firstly, assignments of viruses should be congruent with the best attainable reconstruction of their evolutionary histories, i.e., taxa should be monophyletic. This fundamental principle for classification of viruses is currently included in the International Committee on Taxonomy of Viruses (ICTV) code only for the rank of species. Secondly, phenotypic and ecological properties of viruses may inform, but not override, evolutionary relatedness in the placement of ranks. Thirdly, alternative classifications that consider phenotypic attributes, such as being vector-borne (e.g., "arboviruses"), infecting a certain type of host (e.g., "mycoviruses," "bacteriophages") or displaying specific pathogenicity (e.g., "human immunodeficiency viruses"), may serve important clinical and regulatory purposes but often create polyphyletic categories that do not reflect evolutionary relationships. Nevertheless, such classifications ought to be maintained if they serve the needs of specific communities or play a practical clinical or regulatory role. However, they should not be considered or called taxonomies. Finally, while an evolution-based framework enables viruses discovered by metagenomics to be incorporated into the ICTV taxonomy, there are essential requirements for quality control of the sequence data used for these assignments. Combined, these four principles will enable future development and expansion of virus taxonomy as the true evolutionary diversity of viruses becomes apparent.

Connectivity in deep brain stimulation for self-injurious behavior: multiple targets for a common network?

Self-injurious behavior (SIB) is associated with diverse psychiatric conditions. Sometimes (e.g., in patients with autism spectrum disorder or acquired brain injuries), SIB is the most dominant symptom, severely restricting the psychosocial functioning and quality of life of the patients and inhibiting appropriate patient care. In severe cases, it can lead to permanent physical injuries or even death. Primary therapy consists of medical treatment and if implementable, behavioral therapy. For patients with severe SIB refractory to conventional therapy, neuromodulation can be considered as a last recourse. In scientific literature, several successful lesioning and deep brain stimulation targets have been described that can indicate a common underlying neuronal pathway. The objectives of this study were to evaluate the short- and long-term clinical outcome of patients with severe, therapy refractory SIB who underwent DBS with diverse underlying psychiatric disorders and to correlate these outcomes with the activated connectivity networks. We retrospectively analyzed 10 patients with SIB who underwent DBS surgery with diverse psychiatric conditions including autism spectrum disorder, organic personality disorder after hypoxic or traumatic brain injury or Tourette syndrome. DBS targets were chosen according to the underlying disorder, patients were either stimulated in the nucleus accumbens, amygdala, posterior hypothalamus, medial thalamus or ventrolateral thalamus. Clinical outcome was measured 6 months after surgery and at long-term follow-up after 10 or more years using the Early Rehabilitation Barthel index (ERBI) and time of restraint. Connectivity patterns were analyzed using normative connectome. Based on previous literature the orbitofrontal cortex, superior frontal gyrus, the anterior cingulate cortex, the amygdala and the hippocampus were chosen as regions of interest. This analysis showed a significant improvement in the functionality of the patients with DBS in the short- and long-term follow-up. Good clinical outcome correlated with higher connectivity to the amygdala and hippocampus. These findings may suggest a common pathway, which can be relevant when planning a surgical procedure in patients with SIB.

Value of Clinical Information on Radiology Reports in Oncological Imaging.

Radiological reporting errors have a direct negative impact on patient treatment. The purpose of this study was to investigate the contribution of clinical information (CI) in radiological reporting of oncological imaging and the dependence on the radiologists' experience level (EL). Sixty-four patients with several types of carcinomas and twenty patients without tumors were enrolled. Computed tomography datasets acquired in primary or follow-up staging were independently analyzed by three radiologists (R) with different EL (R1: 15 years; R2: 10 years, R3: 1 year). Reading was initially performed without and 3 months later with CI. Overall, diagnostic accuracy and sensitivity for primary tumor detection increased significantly when receiving CI from 77% to 87%; p = 0.01 and 73% to 83%; p = 0.01, respectively. All radiologists benefitted from CI; R1: 85% vs. 92%, p = 0.15; R2: 77% vs. 83%, p = 0.33; R3: 70% vs. 86%, p = 0.02. Overall, diagnostic accuracy and sensitivity for detecting lymphogenous metastases increased from 80% to 85% (p = 0.13) and 42% to 56% (p = 0.13), for detection of hematogenous metastases from 85% to 86% (p = 0.61) and 46% to 60% (p = 0.15). Specificity remained stable (>90%). Thus, CI in oncological imaging seems to be essential for correct radiological reporting, especially for residents, and should be available for the radiologist whenever possible.

The image-based preoperative fistula risk score (preFRS) predicts postoperative pancreatic fistula in patients undergoing pancreatic head resection.

Clinically relevant postoperative pancreatic fistula (CR-POPF) is a common severe surgical complication after pancreatic surgery. Current risk stratification systems mostly rely on intraoperatively assessed factors like manually determined gland texture or blood loss. We developed a preoperatively available image-based risk score predicting CR-POPF as a complication of pancreatic head resection. Frequency of CR-POPF and occurrence of salvage completion pancreatectomy during the hospital stay were associated with an intraoperative surgical (sFRS) and image-based preoperative CT-based (rFRS) fistula risk score, both considering pancreatic gland texture, pancreatic duct diameter and pathology, in 195 patients undergoing pancreatic head resection. Based on its association with fistula-related outcome, radiologically estimated pancreatic remnant volume was included in a preoperative (preFRS) score for POPF risk stratification. Intraoperatively assessed pancreatic duct diameter (p < 0.001), gland texture (p < 0.001) and high-risk pathology (p < 0.001) as well as radiographically determined pancreatic duct diameter (p < 0.001), gland texture (p < 0.001), high-risk pathology (p = 0.001), and estimated pancreatic remnant volume (p < 0.001) correlated with the risk of CR-POPF development. PreFRS predicted the risk of CR-POPF development (AUC = 0.83) and correlated with the risk of rescue completion pancreatectomy. In summary, preFRS facilitates preoperative POPF risk stratification in patients undergoing pancreatic head resection, enabling individualized therapeutic approaches and optimized perioperative management.

Association between hepatic iron overload assessed by magnetic resonance imaging and glucose intolerance states in the general population.

BACKGROUND AND AIM: While there is evidence that iron overload disorders are associated with type 2 diabetes, the relationship between hepatic iron overload and prediabetes remains unclear. We aimed to investigate the association between hepatic iron overload, as assessed by magnetic resonance imaging (MRI), and different glucose intolerance states in the population-based Study. METHODS AND RESULTS: We included data from 1622 individuals with MRI data, who did not have known type 2 diabetes (T2DM). Using an oral glucose tolerance testing, participants were classified as having isolated impaired fasting glucose (i-IFG), isolated impaired glucose tolerance (i-IGT), combined IFG and IGT (IFG + IGT) or previously unknown T2DM. Hepatic iron and fat contents were assessed through quantitative MRI. We undertook linear and multinomial logistic regression models adjusted for potential confounders and MRI-assessed hepatic fat content to examine the association of hepatic iron overload with different glucose intolerance states or continuous markers of glucose metabolism. MRI-assessed hepatic iron overload was positively associated only with both 2-h plasma glucose (ß = 0.32; 95%CI 0.04-0.60) and the combined IFG + IGT category (relative risk ratio = 1.87; 95%CI 1.15-3.06). No significant associations were found between hepatic iron overload and other glucose intolerance states or biomarkers of glucose metabolism, independently of potential confounders. CONCLUSIONS: MRI-assessed hepatic iron overload was associated with higher 2-h glucose concentrations and the combined IFG + IGT category, but not with other glucose intolerance states. Our findings suggest a weak adverse impact of hepatic iron overload on glucose metabolism, but further studies are needed to confirm these findings.

Association between thyroid function and assessment of hepatic fat and iron contents by magnetic resonance imaging.

The associations of thyroid function parameters with non-alcoholic fatty liver disease (NAFLD) and hepatic iron overload are not entirely clear. We have cross-sectionally investigated these associations among 2734 participants of two population-based cross-sectional studies of the Study of Health in Pomerania. Serum levels of thyroid-stimulating hormone (TSH), free tri-iodothyronine (fT3), and free thyroxine (fT4) levels were measured. Liver fat content (by proton-density fat fraction) as well as hepatic iron content (by transverse relaxation rate; R2*) were assessed by quantitative MRI. Thyroid function parameters were associated with hepatic fat and iron contents by median and logistic regression models adjusted for confounding. There were no associations between serum TSH levels and liver fat content, NAFLD, or hepatic iron overload. Serum fT4 levels were inversely associated with liver fat content, NAFLD, hepatic iron contents, and hepatic iron overload. Serum fT3 levels as well as the fT3 to fT4 ratio were positively associated with hepatic fat, NAFLD, hepatic iron contents, but not with hepatic iron overload. Associations between fT3 levels and liver fat content were strongest in obese individuals, in which we also observed an inverse association between TSH levels and NAFLD. These findings might be the result of a higher conversion of fT4 to the biologically active form fT3. Our results suggest that a subclinical hyperthyroid state may be associated with NAFLD, particularly in obese individuals. Furthermore, thyroid hormone levels seem to be more strongly associated with increased liver fat content compared to hepatic iron content.

Sangivamycin is highly effective against SARS-CoV-2 in vitro and has favorable drug properties.

Sangivamycin is a nucleoside analog that is well tolerated by humans and broadly active against phylogenetically distinct viruses, including arenaviruses, filoviruses, and orthopoxviruses. Here, we show that sangivamycin is a potent antiviral against multiple variants of replicative severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with half-maximal inhibitory concentration in the nanomolar range in several cell types. Sangivamycin suppressed SARS-CoV-2 replication with greater efficacy than remdesivir (another broad-spectrum nucleoside analog). When we investigated sangivamycin's potential for clinical administration, pharmacokinetic; absorption, distribution, metabolism, and excretion (ADME); and toxicity properties were found to be favorable. When tested in combination with remdesivir, efficacy was additive rather than competitive against SARS-CoV-2. The proven safety in humans, long half-life, potent antiviral activity (compared to remdesivir), and combinatorial potential suggest that sangivamycin is likely to be efficacious alone or in combination therapy to suppress viremia in patients. Sangivamycin may also have the ability to help combat drug-resistant or vaccine-escaping SARS-CoV-2 variants since it is antivirally active against several tested variants. Our results support the pursuit of sangivamycin for further preclinical and clinical development as a potential coronavirus disease 2019 therapeutic.

Diagnostic performance of 18F-fluorodeoxyglucose-PET/MRI versus MRI alone in the diagnosis of pelvic recurrence of rectal cancer.

PURPOSE: To compare the diagnostic performance of 18F-fluorodeoxyglucose-PET/MRI and MRI in the diagnosis of pelvic recurrence of rectal cancer. METHODS: All PET/MRIs of patients in the follow-up of rectal cancer performed between 2011 and 2018 at our institution were retrospectively reviewed. Recurrence was confirmed/excluded either by histopathology or imaging follow-up (> 4 months). Four groups of readers (groups 1/2: one radiologist each, groups 3/4: one radiologist/one nuclear medicine physician) independently interpreted MRI and PET/MRI. The likelihood of recurrence was scored on a 5-point-scale. Inter-reader agreement, sensitivity, specificity, PPV/NPV and accuracy were assessed. ROC curve analyses were performed. RESULTS: Fourty-one PET/MRIs of 40 patients (mean 61 years ± 10.9; 11 women, 29 men) were included. Sensitivity of PET/MRI in detecting recurrence was 94%, specificity 88%, PPV/NPV 97% and 78%, accuracy 93%. Sensitivity of MRI was 88%, specificity 75%, PPV/NPV 94% and 60%, accuracy 85%. ROC curve analyses showed an AUC of 0.97 for PET/MRI and 0.92 for MRI, but the difference was not statistically significant (p = 0.116). On MRI more cases were scored as equivocal (12% versus 5%). Inter-reader agreement was substantial for PET/MRI and MRI (0.723 and 0.656, respectively). CONCLUSION: 18F-FDG-PET/MRI and MRI are accurate in the diagnosis of locally recurrent rectal cancer. Sensitivity, specificity, PPV, NPV and accuracy are comparable for both modalities, but PET/MRI increases readers' confidence levels and reduces the number of equivocal cases.

Thalamic deep brain stimulation for Tourette Syndrome: A naturalistic trial with brief randomized, double-blinded sham-controlled periods.

BACKGROUND: There is still a lack of controlled studies to prove efficacy of thalamic deep brain stimulation for Tourette's Syndrome. OBJECTIVES: In this controlled trial, we investigated the course of tic severity, comorbidities and quality of life during thalamic stimulation and whether changes in tic severity can be assigned to ongoing compared to sham stimulation. METHODS: We included eight adult patients with medically refractory Tourette's syndrome. Bilateral electrodes were implanted in the centromedian-parafascicular-complex and the nucleus ventro-oralis internus. Tic severity, quality of life and comorbidities were assessed before surgery as well as six and twelve months after. Short randomized, double-blinded sham-controlled crossover sequences with either active or sham stimulation were implemented at both six- and twelve-months' assessments. The primary outcome measurement was the difference in the Yale Global Tic Severity Scale tic score between active and sham stimulation. Adverse events were systematically surveyed for all patients to evaluate safety. RESULTS: Active stimulation resulted in significantly higher tic reductions than sham stimulation (F = 79.5; p = 0.001). Overall quality of life and comorbidities improved significantly in the open-label-phase. Over the course of the trial two severe adverse events occurred that were resolved without sequelae. CONCLUSION: Our results provide evidence that thalamic stimulation is effective in improving tic severity and overall quality of life. Crucially, the reduction of tic severity was primarily driven by active stimulation. Further research may focus on improving stimulation protocols and refining patient selection to improve efficacy and safety of deep brain stimulation for Tourette's Syndrome.