Decompressive craniectomy plus best medical treatment versus best medical treatment alone for spontaneous severe deep supratentorial intracerebral haemorrhage: a randomised controlled clinical trial.

BACKGROUND: It is unknown whether decompressive craniectomy improves clinical outcome for people with spontaneous severe deep intracerebral haemorrhage. The SWITCH trial aimed to assess whether decompressive craniectomy plus best medical treatment in these patients improves outcome at 6 months compared to best medical treatment alone. METHODS: In this multicentre, randomised, open-label, assessor-blinded trial conducted in 42 stroke centres in Austria, Belgium, Finland, France, Germany, the Netherlands, Spain, Sweden, and Switzerland, adults (18-75 years) with a severe intracerebral haemorrhage involving the basal ganglia or thalamus were randomly assigned to receive either decompressive craniectomy plus best medical treatment or best medical treatment alone. The primary outcome was a score of 5-6 on the modified Rankin Scale (mRS) at 180 days, analysed in the intention-to-treat population. This trial is registered with ClincalTrials.gov, NCT02258919, and is completed. FINDINGS: SWITCH had to be stopped early due to lack of funding. Between Oct 6, 2014, and April 4, 2023, 201 individuals were randomly assigned and 197 gave delayed informed consent (96 decompressive craniectomy plus best medical treatment, 101 best medical treatment). 63 (32%) were women and 134 (68%) men, the median age was 61 years (IQR 51-68), and the median haematoma volume 57 mL (IQR 44-74). 42 (44%) of 95 participants assigned to decompressive craniectomy plus best medical treatment and 55 (58%) assigned to best medical treatment alone had an mRS of 5-6 at 180 days (adjusted risk ratio [aRR] 0·77, 95% CI 0·59 to 1·01, adjusted risk difference [aRD] -13%, 95% CI -26 to 0, p=0·057). In the per-protocol analysis, 36 (47%) of 77 participants in the decompressive craniectomy plus best medical treatment group and 44 (60%) of 73 in the best medical treatment alone group had an mRS of 5-6 (aRR 0·76, 95% CI 0·58 to 1·00, aRD -15%, 95% CI -28 to 0). Severe adverse events occurred in 42 (41%) of 103 participants receiving decompressive craniectomy plus best medical treatment and 41 (44%) of 94 receiving best medical treatment. INTERPRETATION: SWITCH provides weak evidence that decompressive craniectomy plus best medical treatment might be superior to best medical treatment alone in people with severe deep intracerebral haemorrhage. The results do not apply to intracerebral haemorrhage in other locations, and survival is associated with severe disability in both groups. FUNDING: Swiss National Science Foundation, Swiss Heart Foundation, Inselspital Stiftung, and Boehringer Ingelheim.

Functional annotation of a divergent genome using sequence and structure-based similarity.

BACKGROUND: Microsporidia are a large taxon of intracellular pathogens characterized by extraordinarily streamlined genomes with unusually high sequence divergence and many species-specific adaptations. These unique factors pose challenges for traditional genome annotation methods based on sequence similarity. As a result, many of the microsporidian genomes sequenced to date contain numerous genes of unknown function. Recent innovations in rapid and accurate structure prediction and comparison, together with the growing amount of data in structural databases, provide new opportunities to assist in the functional annotation of newly sequenced genomes. RESULTS: In this study, we established a workflow that combines sequence and structure-based functional gene annotation approaches employing a ChimeraX plugin named ANNOTEX (Annotation Extension for ChimeraX), allowing for visual inspection and manual curation. We employed this workflow on a high-quality telomere-to-telomere sequenced tetraploid genome of Vairimorpha necatrix. First, the 3080 predicted protein-coding DNA sequences, of which 89% were confirmed with RNA sequencing data, were used as input. Next, ColabFold was used to create protein structure predictions, followed by a Foldseek search for structural matching to the PDB and AlphaFold databases. The subsequent manual curation, using sequence and structure-based hits, increased the accuracy and quality of the functional genome annotation compared to results using only traditional annotation tools. Our workflow resulted in a comprehensive description of the V. necatrix genome, along with a structural summary of the most prevalent protein groups, such as the ricin B lectin family. In addition, and to test our tool, we identified the functions of several previously uncharacterized Encephalitozoon cuniculi genes. CONCLUSION: We provide a new functional annotation tool for divergent organisms and employ it on a newly sequenced, high-quality microsporidian genome to shed light on this uncharacterized intracellular pathogen of Lepidoptera. The addition of a structure-based annotation approach can serve as a valuable template for studying other microsporidian or similarly divergent species.

Y-Linked Copy Number Polymorphism of Target of Rapamycin Is Associated with Sexual Size Dimorphism in Seed Beetles.

The Y chromosome is theorized to facilitate evolution of sexual dimorphism by accumulating sexually antagonistic loci, but empirical support is scarce. Due to the lack of recombination, Y chromosomes are prone to degenerative processes, which poses a constraint on their adaptive potential. Yet, in the seed beetle, Callosobruchus maculatus segregating Y linked variation affects male body size and thereby sexual size dimorphism (SSD). Here, we assemble C. maculatus sex chromosome sequences and identify molecular differences associated with Y-linked SSD variation. The assembled Y chromosome is largely euchromatic and contains over 400 genes, many of which are ampliconic with a mixed autosomal and X chromosome ancestry. Functional annotation suggests that the Y chromosome plays important roles in males beyond primary reproductive functions. Crucially, we find that, besides an autosomal copy of the gene target of rapamycin (TOR), males carry an additional TOR copy on the Y chromosome. TOR is a conserved regulator of growth across taxa, and our results suggest that a Y-linked TOR provides a male specific opportunity to alter body size. A comparison of Y haplotypes associated with male size difference uncovers a copy number variation for TOR, where the haplotype associated with decreased male size, and thereby increased sexual dimorphism, has two additional TOR copies. This suggests that sexual conflict over growth has been mitigated by autosome to Y translocation of TOR followed by gene duplications. Our results reveal that despite of suppressed recombination, the Y chromosome can harbor adaptive potential as a male-limited supergene.

Ion Mobility Mass Spectrometry-Based Disaccharide Analysis of Glycosaminoglycans.

Glycosaminoglycans (GAGs) are linear and acidic polysaccharides. They are ubiquitous molecules, which are involved in a wide range of biological processes. Despite being structurally simple at first glance, with a repeating backbone of alternating hexuronic acid and hexosamine dimers, GAGs display a highly complex structure, which predominantly results from their heterogeneous sulfation patterns. The commonly applied method for compositional analysis of all GAGs is "disaccharide analysis." In this process, GAGs are enzymatically depolymerized into disaccharides, derivatized with a fluorescent label, and then analysed through liquid chromatography. The limiting factor in the high throughput analysis of GAG disaccharides is the time-consuming liquid chromatography. To address this limitation, we here utilized trapped ion mobility-mass spectrometry (TIM-MS) for the separation of isomeric GAG disaccharides, which reduces the measurement time from hours to a few minutes. A full set of disaccharides comprises twelve structures, with eight possessing isomers. Most disaccharides cannot be differentiated by TIM-MS in underivatized form. Therefore, we developed chemical modifications to reduce sample complexity and enhance differentiability. Quantification is performed using stable isotope labelled standards, which are easily available due to the nature of the performed modifications.

Acquired hypothalamic obesity: A clinical overview and update.

Hypothalamic obesity (HO) is a rare and complex disorder that confers substantial morbidity and excess mortality. HO is a unique subtype of obesity characterized by impairment in the key brain pathways that regulate energy intake and expenditure, autonomic nervous system function, and peripheral hormonal signalling. HO often occurs in the context of hypothalamic syndrome, a constellation of symptoms that follow from disruption of hypothalamic functions, for example, temperature regulation, sleep-wake circadian control, and energy balance. Genetic forms of HO, including the monogenic obesity syndromes, often impact central leptin-melanocortin pathways. Acquired forms of HO occur as a result of tumours impacting the hypothalamus, such as craniopharyngioma, surgery or radiation to treat those tumours, or other forms of hypothalamic damage, such as brain injury impacting the region. Risk for severe obesity following hypothalamic injury is increased with larger extent of hypothalamic damage or lesions that contain the medial and posterior hypothalamic nuclei that support melanocortin signalling pathways. Structural damage in these hypothalamic nuclei often leads to hyperphagia, central insulin and leptin resistance, decreased sympathetic activity, low energy expenditure, and increased energy storage in adipose tissue, the collective effect of which is rapid weight gain. Individuals with hyperphagia are perpetually hungry. They do not experience fullness at the end of a meal, nor do they feel satiated after meals, leading them to consume larger and more frequent meals. To date, most efforts to treat HO have been disappointing and met with limited, if any, long-term success. However, new treatments based on the distinct pathophysiology of disturbed energy homeostasis in acquired HO may hold promise for the future.

As fast as an X-ray: real-time magnetic resonance imaging for diagnosis of idiopathic scoliosis in children and adolescents.

BACKGROUND: Idiopathic scoliosis is common in adolescence. Due to the rapid growth of the spine, it must be monitored closely with radiographs to ensure timely intervention when therapy is needed. As these radiographs continue into young adulthood, patients are repeatedly exposed to ionizing radiation. OBJECTIVE: This study aimed to investigate whether real-time magnetic resonance imaging (MRI) is equivalent to conventional radiography in juvenile idiopathic scoliosis for determining curvature, rotation and the Risser stage. Additionally, the time requirement should be quantified. MATERIALS AND METHODS: Children with idiopathic scoliosis who had postero-anterior whole-spine radiography for clinical indications were included in this prospective study. A real-time spine MRI was performed at 3 tesla in the supine position, capturing images in both the coronal and sagittal planes. The scoliosis was assessed using Cobb angle, rotation was evaluated based on Nash and Moe criteria, and the Risser stage was determined for each modality. The correlations between modalities and a correction factor for the Cobb angle between the standing and supine position were calculated. RESULTS: A total of 33 children (aged 5-17 years), who met the inclusion criteria, were recruited. The Cobb angle (R2 = 0.972; P < 0.01) was positively correlated with a correction factor of 1.07 between modalities. Additionally, the degree of rotation (R2 = 0.92; P < 0.01) and the Risser stage (R2 = 0.93; P < 0.01) demonstrated a strong correlation. CONCLUSION: Real-time MRI is equivalent to conventional radiography in determining baseline parameters. Furthermore, it is radiation-free and less time-consuming.

Outcomes After Decompressive Surgery for Severe Cerebral Venous Sinus Thrombosis Associated or Not Associated with Vaccine-Induced Immune Thrombosis with Thrombocytopenia: A Multicenter Cohort Study.

BACKGROUND: Clinical observations indicated that vaccine-induced immune thrombosis with thrombocytopenia (VITT)-associated cerebral venous sinus thrombosis (CVST) often has a space-occupying effect and thus necessitates decompressive surgery (DS). While comparing with non-VITT CVST, this study explored whether VITT-associated CVST exhibits a more fulminant clinical course, different perioperative and intensive care unit management, and worse long-term outcome. METHODS: This multicenter, retrospective cohort study collected patient data from 12 tertiary centers to address priorly formulated hypotheses concerning the clinical course, the perioperative management with related complications, extracerebral complications, and the functional outcome (modified Rankin Scale) in patients with VITT-associated and non-VITT CVST, both with DS. RESULTS: Both groups, each with 16 patients, were balanced regarding demographics, kind of clinical symptoms, and radiological findings at hospital admission. Severity of neurological symptoms, assessed with the National Institute of Health Stroke Scale, was similar between groups at admission and before surgery, whereas more patients with VITT-associated CVST showed a relevant midline shift (≥ 4 mm) before surgery (100% vs. 68.8%, p = 0.043). Patients with VITT-associated CVST tended to undergo DS early, i.e., ≤ 24 h after hospital admission (p = 0.077). Patients with VITT-associated CVST more frequently received platelet transfusion, tranexamic acid, and fibrinogen perioperatively. The postoperative management was comparable, and complications were evenly distributed. More patients with VITT-associated CVST achieved a favorable outcome (modified Rankin Scale ≤ 3) at 3 months (p = 0.043). CONCLUSIONS: Although the prediction of individual courses remains challenging, DS should be considered early in VITT-associated CVST because an overall favorable outcome appears achievable in these patients.

Consultation Requests and Satisfaction with a Telehealth Network for Epilepsy: Longitudinal Analysis of the Epilepsy Network Hessen Evaluation.

Background: Telemedicine improves access to specialized medical expertise, as required for paroxysmal disorders. The Epilepsy Network Hessen Evaluation (ENHE) is a pilot cross-sectoral teleconsultation network connecting primary neurologists and pediatricians with epilepsy centers in Hessen, a federal German state. Methods: We prospectively and longitudinally evaluated telehealthcare in the ENHE. Participating physicians rated each consultation for satisfaction and impact on further management. The survey was administered at each consultation and 3 months later. Results: We analyzed 129 consultations involving 114 adult and pediatric patients. Their mean age was 34 years (standard deviation: 26, range: 0.1-91 years), 48% were female, and 34% were children and adolescents. The most common consultation requests were co-evaluation of an electroencephalogram (electroencephalogram [EEG]; 76%) and therapeutic (33%) and differential diagnosis (24%) concerns. Physicians transmitted one paraclinical examination on average (range: 1-4), predominantly EEG (85%), followed by magnetic resonance imaging (17%) and written records (9%). Response rates were 72% for the initial and 67% for the follow-up survey. Across respondents, 99% (n = 92) were satisfied with the ENHE. Overall, 80% of the consultations contributed to the diagnosis, and 90% were considered helpful for treatment, influencing it in 71% of cases. Seizure frequency had decreased more often (96%) than increased (4%) at 3 months. The initial diagnosis was confirmed in 78% of patients. Discussion: In this pilot teleconsultation network for paroxysmal disorders, diagnostic and therapeutic advice was perceived as helpful. Clinical outcomes were largely positive, suggesting tele-epileptology is viable for paroxysmal (seizure) disorders.

Comparative Effectiveness of Upper Limb Exercise Interventions in Individuals With Stroke: A Network Meta-Analysis.

BACKGROUND: Although numerous effective exercise interventions can treat upper limb motor impairments after stroke, it remains unknown as to which are the most effective. The objective of the present study was to investigate the comparative effectiveness of various exercise interventions of the upper limb for individuals with an acute or subacute stroke. METHODS: For this systematic review with network meta-analysis, we searched PubMed/MEDLINE, Cochrane Library CENTRAL and Web of Science from database inception to September 2021 for randomized controlled trials examining individuals within 6 months of stroke onset, active upper limb exercise interventions, and any kind of control intervention. The primary outcome was upper limb motor function, secondary outcomes were activities of daily living and social participation, both assessed at post-intervention and follow-up. Nonspecific/multimodal active upper limb therapy was the standard comparator. Standardized mean differences, that is, Hedge's g, were the effect size estimators. We calculated Frequentist-based network meta-analysis for the comparative effectiveness calculations using the R package netmeta. Main analyses were network plotting to display the geometry of the network and P-scores to summarize the intervention hierarchy. Results were derived from direct within-study and indirect between-study evidence comparisons. The Cochrane risk-of-bias tool II assessed all risk of bias domains. RESULTS: This review involved 145 randomized controlled trial on 6432 participants and 45 different treatment categories. The network meta-analysis analyzed 119 randomized controlled trials on 5553 participants and 41 different treatment categories. Electrical stimulation combined with task-specific training (standardized mean difference, 1.03 [95% CI, 0.51-1.55]; P<0.0001, P-score=0.11), high-volume constraint-induced movement therapy (0.86 [0.4-1.32]; P=0.0003, P-score=0.18), and strength training (0.65 [0.17-1.13]; P=0.01, P-score=0.28) were the most effective interventions (each k=107). CONCLUSIONS: Electrical stimulation combined with task-specific training (low evidence), high-volume constraint-induced movement therapy (moderate evidence), and strength training (low evidence) were the most effective interventions in improving upper limb motor function in individuals with a stroke. As the results were sensitive against a high risk of bias, likewise, these interventions should receive more attention in research and practice. Due to the heterogeneous use, electrical stimulation in combination with task-specific training should be further investigated in well-designed studies alongside other successful interventions (eg, constraint-induced movement therapy). REGISTRATION: URL: https://www.crd.york.ac.uk/prospero/; Unique identifier: CRD42021284064.

Resistance training volume does not influence lean mass preservation during energy restriction in trained males.

This study investigated the effects of a relatively high- versus moderate-volume resistance training program on changes in lean mass during caloric restriction. Thirty-eight resistance-trained males were randomized to perform either a high-volume (HVG; 5 sets/exercise) or a moderate-volume (MVG; 3 sets/exercise) resistance training program. Both groups were supervised during lower body training. Participants consumed 30 kcal/kg for 6 weeks after 1 week of weight maintenance (45 kcal/kg), with protein intake fixed at 2.8 g/kg fat-free mass. Muscle thickness of the m. rectus femoris, body composition, contractile properties, stiffness, mood, and sleep status were assessed at pre-, mid-, and post-study. No significant group × time interaction was observed for muscle thickness of the m. rectus femoris at 50% (∆ [post-pre] 0.36 ± 0.93 mm vs. ∆ -0.01 ± 1.59 mm; p = 0.226) and 75% length (∆ -0.32 ± 1.12 mm vs. ∆ 0.08 ± 1.14 mm; p = 0.151), contractility, sleep, and mood in the HVG and MVG, respectively. Body mass (HVG: ∆ -1.69 ± 1.12 kg vs. MVG: ∆ -1.76 ± 1.76 kg) and lean mass (∆ -0.51 ± 2.30 kg vs. ∆ -0.92 ± 1.59 kg) decreased significantly in both groups (p = 0.022), with no between-group difference detected (p = 0.966). High-volume resistance training appears to have neither an advantage nor disadvantage over moderate-volume resistance training in terms of maintaining lean mass or muscle thickness. Given that both groups increased volume load and maintained muscle contractility, sleep quality, and mood, either moderate or higher training volumes conceivably can be employed by resistance-trained individuals to preserve muscle during periods of moderate caloric restriction.

Effects of muscle fatigue on exercise-induced hamstring muscle damage: a three-armed randomized controlled trial.

PURPOSE: Hamstring injuries in soccer reportedly increase towards the end of the matches' halves as well as with increased match frequency in combination with short rest periods, possibly due to acute or residual fatigue. Therefore, this study aimed to investigate the effects of acute and residual muscle fatigue on exercise-induced hamstring muscle damage. METHODS: A three-armed randomized-controlled trial, including 24 resistance-trained males, was performed allocating subjects to either a training group with acute muscle fatigue + eccentric exercise (AF/ECC); residual muscle fatigue + eccentric exercise (RF/ECC) or a control group with only eccentric exercise (ECC). Muscle stiffness, thickness, contractility, peak torque, range of motion, pain perception, and creatine kinase were assessed as muscle damage markers pre, post, 1 h post, and on the consecutive three days. RESULTS: Significant group × time interactions were revealed for muscle thickness (p = 0.02) and muscle contractility parameters radial displacement (Dm) and contraction velocity (Vc) (both p = 0.01), with larger changes in the ECC group (partial η2 = 0.4). Peak torque dropped by an average of 22% in all groups; stiffness only changed in the RF/ECC group (p = 0.04). Muscle work during the damage protocol was lower for AF/ECC than for ECC and RF/ECC (p = 0.005). CONCLUSION: Hamstring muscle damage was comparable between the three groups. However, the AF/ECC group resulted in the same amount of muscle damage while accumulating significantly less muscle work during the protocol of the damage exercise. TRIAL REGISTRATION: This study was preregistered in the international trial registration platform (WHO; registration number: DRKS00025243).

Chest examinations in children with real-time magnetic resonance imaging: first clinical experience.

BACKGROUND: Real-time magnetic resonance imaging (MRI) based on a fast low-angle shot technique 2.0 (FLASH 2.0) is highly effective against artifacts caused due to the bulk and pulmonary and cardiac motions of the patient. However, to date, there are no reports on the application of this innovative technique to pediatric lung MRI. OBJECTIVE: This study aimed to identify the limits of resolution and image quality of real-time lung MRI in children and to assess the types and minimal size of lesions with these new sequences. MATERIALS AND METHODS: In this retrospective study, pathological lung findings in 87 children were classified into 6 subgroups, as detected on conventional MRI: metastases and tumors, consolidation, scars, hyperinflation, interstitial pathology and bronchiectasis. Subsequently, the findings were grouped according to size (4-6 mm, 7-9 mm and ≥ 10 mm) and evaluated for visual delineation of the findings (0 = not visible, 1 = hardly visible and 2 = well visualized). RESULTS: Real-time MRI allows for diagnostic, artifact-free thorax images to be obtained, regardless of patient movements. The delineation of findings strongly correlates with the size of the pathology. Metastases, consolidation and scars were visible at 100% when larger than 9 mm. In the 7-9 mm subgroup, the visibility was 83% for metastases, 88% for consolidation and 100% for scars in T2/T1 weighting. Though often visible, smaller pathological lesions of 4-6 mm in size did not regularly meet the expected diagnostic confidence: The visibility of metastases was 18%, consolidation was 64% and scars was 71%. Diffuse interstitial lung changes and hyperinflation, known as "MR-minus pathologies," were not accessible to real-time MRI. CONCLUSION: The method provides motion robust images of the lung and thorax. However, the lower sensitivity for small lung lesions is a major limitation for routine use of this technique. Currently, the method is adequate for diagnosing inflammatory lung diseases, atelectasis, effusions and lung scarring in children with irregular breathing patterns or bulk motion on sedation-free MRI. A medium-term goal is to improve the diagnostic accuracy of small nodules and interstitial lesions.

Salivary Pellicle Formed on Dental Composites Evaluated by Mass Spectrometry-An In Situ Study.

(1) Background: In the oral environment, sound enamel and dental restorative materials are immediately covered by a pellicle layer, which enables bacteria to attach. For the development of new materials with repellent surface functions, information on the formation and maturation of salivary pellicles is crucial. Therefore, the present in situ study aimed to investigate the proteomic profile of salivary pellicles formed on different dental composites. (2) Methods: Light-cured composite and bovine enamel samples (controls) were exposed to the oral cavity for 30, 90, and 120 min. All samples were subjected to optical and mechanical profilometry, as well as SEM surface evaluation. Acquired pellicles and unstimulated whole saliva samples were analyzed by SELDI-TOF-MS. The significance was determined by the generalized estimation equation and the post-hoc bonferroni adjustment. (3) Results: SEM revealed the formation of homogeneous pellicles on all test and control surfaces. Profilometry showed that composite surfaces tend to be of higher roughness compared to enamel. SELDI-TOF-MS detected up to 102 different proteins in the saliva samples and up to 46 proteins in the pellicle. Significant differences among 14 pellicle proteins were found between the composite materials and the controls. (4) Conclusions: Pellicle formation was material- and time-dependent. Proteins differed among the composites and to the control.

Inositol 1,4,5-trisphosphate receptor type 1 autoantibody (ITPR1-IgG/anti-Sj)-associated autoimmune cerebellar ataxia, encephalitis and peripheral neuropathy: review of the literature.

BACKGROUND: In 2014, we first described novel autoantibodies to the inositol 1,4,5-trisphosphate receptor type 1 (ITPR1-IgG/anti-Sj) in patients with autoimmune cerebellar ataxia (ACA) in this journal. Here, we provide a review of the available literature on ITPR1-IgG/anti-Sj, covering clinical and paraclinical presentation, tumour association, serological findings, and immunopathogenesis. METHODS: Review of the peer-reviewed and PubMed-listed English language literature on ITPR1-IgG/anti-Sj. In addition, we provide an illustrative report on a new patient with ITPR1-IgG-associated encephalitis with cognitive decline and psychosis. RESULTS: So far, at least 31 patients with serum ITPR1-IgG/anti-Sj have been identified (clinical information available for 21). The most common manifestations were ACA, encephalopathy with seizures, myelopathy, and (radiculo)neuropathy, including autonomic neuropathy. In 45% of cases, an underlying tumour was present, making the condition a facultative paraneoplastic neurological disorder. The neurological syndrome preceded tumour diagnosis in all but one case. In most cases, immunotherapy had only moderate or no effect. The association of ITPR1-IgG/anti-Sj with manifestations other than ACA is corroborated by the case of a 48-year-old woman with high-titre ITPR1-IgG/anti-Sj antibodies and rapid cognitive decline, affecting memory, attention and executive function, and psychotic manifestations, including hallucinations, investigated here in detail. FDG-PET revealed right-temporal glucose hypermetabolism compatible with limbic encephalitis. Interestingly, ITPR1-IgG/anti-Sj mainly belonged to the IgG2 subclass in both serum and cerebrospinal fluid (CSF) in this and further patients, while it was predominantly IgG1 in other patients, including those with more severe outcome, and remained detectable over the entire course of disease. Immunotherapy with intravenous methylprednisolone, plasma exchange, and intravenous immunoglobulins, was repeatedly followed by partial or complete recovery. Long-term treatment with cyclophosphamide was paralleled by relative stabilization, although the patient noted clinical worsening at the end of each treatment cycle. CONCLUSIONS: The spectrum of neurological manifestations associated with ITPR1 autoimmunity is broader than initially thought. Immunotherapy may be effective in some cases. Studies evaluating the frequency of ITPR1-IgG/anti-Sj in patients with cognitive decline and/or psychosis of unknown aetiology are warranted. Tumour screening is essential in patients presenting with ITPR1-IgG/anti-Sj.

Energy balance in hypothalamic obesity in response to treatment with a once-weekly GLP-1 receptor agonist.

BACKGROUND/OBJECTIVES: Hypothalamic obesity (HO) frequently occurs following suprasellar tumors from a combination of decreased energy expenditure and increased energy intake. Glucagon-like peptide-1 receptor agonist (GLP1RA) therapy is associated with increased satiety and energy expenditure. We hypothesized GLP1RA therapy in patients with HO would cause both lower energy intake and increased energy expenditure. SUBJECTS/METHODS: Forty-two patients aged 10-26 years (median 16 years) with HO with suprasellar tumors were randomized to GLP1RA (exenatide extended release once-weekly, ExQW, n = 23) or placebo (n = 19). Thirty seven (81%) patients completed the 36-week double-blind placebo-controlled trial. Total energy expenditure (TEE) was measured with doubly labeled water, physical activity was assessed with actigraphy, and intake was estimated with ad libitum buffet meal. Results are presented as adjusted mean between-group difference. RESULTS: As compared with treatment with placebo, treatment with ExQW was associated with decreased energy intake during a buffet meal (-1800 kJ (-430 kcal), 95% CI -3 184 to -418 kJ, p = 0.02). There were no significant differences in physical activity between groups. ExQW (vs. placebo) treatment was associated with a decrease in TEE (-695 kJ/day (-166 kcal/day), 95% CI -1 130 to -264 kJ/day, p < 0.01, adjusted for baseline TEE). The treatment effect was still significant after further adjustment for change in body composition (-372 kJ/day (-89 kcal/day), 95% CI -699 to -42 kJ/day, p = 0.04) or change in leptin (-695 kJ/day (-166 kcal/day), 95% CI -1 130 to -264 kJ/day, p < 0.01). This decrease in TEE occurred despite an increase in lean mass and fat mass (1.7 vs. 1.3 kg lean mass, p = 0.88 and 1.5 vs. 4.6 kg fat mass, p = 0.04, ExQW vs. placebo). CONCLUSIONS: Treatment with a GLP1RA was associated with a decrease in food intake but also a decrease in TEE that was disproportionate to change in body composition.

Early Tracheostomy Is Associated With Shorter Ventilation Time and Duration of ICU Stay in Patients With Myasthenic Crisis-A Multicenter Analysis.

BACKGROUND: Myasthenic crisis (MC) requiring mechanical ventilation (MV) is a rare and serious complication of myasthenia gravis. Here we analyzed the frequency of performed tracheostomies, risk factors correlating with a tracheostomy, as well as the impact of an early tracheostomy on ventilation time and ICU length of stay (LOS) in MC. METHODS: Retrospective chart review on patients treated for MC in 12 German neurological departments between 2006 and 2015 to assess demographic/diagnostic data, rates and timing of tracheostomy and outcome. RESULTS: In 107 out of 215 MC (49.8%), a tracheostomy was performed. Patients without tracheostomy were more likely to have an early-onset myasthenia gravis (27 [25.2%] vs 12 [11.5%], p = 0.01). Patients receiving a tracheostomy, however, were more frequently suffering from multiple comorbidities (20 [18.7%] vs 9 [8.3%], p = 0.03) and also the ventilation time (34.4 days ± 27.7 versus 7.9 ± 7.8, p < 0.0001) and ICU-LOS (34.8 days ± 25.5 versus 12.1 ± 8.0, p < 0.0001) was significantly longer than in non-tracheostomized patients. Demographics and characteristics of the course of the disease up to the crisis were not significantly different between patients with an early (within 10 days) compared to a late tracheostomy. However, an early tracheostomy correlated with a shorter duration of MV at ICU (26.2 days ± 18.1 versus 42.0 ± 33.1, p = 0.006), and ICU-LOS (26.2 days ± 14.6 versus 42.3 ± 33.0, p = 0.003). CONCLUSION: Half of the ventilated patients with MC required a tracheostomy. Poorer health condition before the crisis and late-onset MG were associated with a tracheostomy. An early tracheostomy (≤ day 10), however, was associated with a shorter duration of MV and ICU-LOS by 2 weeks.

Novel Long-Acting Oxytocin Analog with Increased Efficacy in Reducing Food Intake and Body Weight.

Oxytocin (OXT) analogues have been designed to overcome the limitation of the short half-life of the native OXT peptide. Here, we tested ASK2131 on obesity related outcomes in diet-induced obese (DIO) Sprague Dawley rats. In vitro function assays were conducted. The effects of daily subcutaneous injections of ASK2131 vs. OXT and pair-feeding were assessed on food intake and body weight in vivo. ASK2131 is a longer-lasting OXT analog with improved pharmacokinetics compared to OXT (T1/2: 2.3 vs. 0.12 h). In chronic 22-day administration, ASK2131 was administered at 50 nmol/kg, while OXT doses were titrated up to 600 nmol/kg because OXT appeared to be less effective at reducing energy intake relative to ASK2131 at equimolar doses. After 22 days, vehicle-treated animals gained 4.5% body weight, OXT rats maintained their body weight, while those treated with ASK2131 declined in weight continuously over the 22-day period, leading to a 6.6 ± 1.3% reduction (mean ± standard error) compared to baseline. Compared to their pair-fed counterparts, ASK2131-treated rats showed a more pronounced reduction in body weight through most of the study. In summary, ASK2131 is a promising OXT-based therapeutic, with extended in vivo stability and improved potency leading to a profound reduction in body weight partly explained by reduced food intake.

Systematic Evaluation of Fluorination as Modification for Peptide-Based Fusion Inhibitors against HIV-1 Infection.

With the emergence of novel viruses, the development of new antivirals is more urgent than ever. A key step in human immunodeficiency virus type 1 (HIV-1) infection is six-helix bundle formation within the envelope protein subunit gp41. Selective disruption of bundle formation by peptides has been shown to be effective; however, these drugs, exemplified by T20, are prone to rapid clearance from the patient. The incorporation of non-natural amino acids is known to improve these pharmacokinetic properties. Here, we evaluate a peptide inhibitor in which a critical Ile residue is replaced by fluorinated analogues. We characterized the influence of the fluorinated analogues on the biophysical properties of the peptide. Furthermore, we show that the fluorinated peptides can block HIV-1 infection of target cells at nanomolar levels. These findings demonstrate that fluorinated amino acids are appropriate tools for the development of novel peptide therapeutics.

Congenital cervical spine malformation due to bi-allelic RIPPLY2 variants in spondylocostal dysostosis type 6.

RIPPLY2 is an essential part of the formation of somite patterning during embryogenesis and in establishment of rostro-caudal polarity. Here, we describe three individuals from two families with compound-heterozygous variants in RIPPLY2 (NM_001009994.2): c.238A > T, p.(Arg80*) and c.240-4 T > G, p.(?), in two 15 and 20-year-old sisters, and a homozygous nonsense variant, c.238A > T, p.(Arg80*), in an 8 year old boy. All patients had multiple vertebral body malformations in the cervical and thoracic region, small or absent rib involvement, myelopathies, and common clinical features of SCDO6 including scoliosis, mild facial asymmetry, spinal spasticity and hemivertebrae. The nonsense variant can be classified as likely pathogenic based on the ACMG criteria while the splice variants must be classified as a variant of unknown significance. With this report on two further families, we confirm RIPPLY2 as the gene for SCDO6 and broaden the phenotype by adding myelopathy with or without spinal canal stenosis and spinal spasticity to the symptom spectrum.

MRI measures of hypothalamic injury are associated with glucagon-like peptide-1 receptor agonist treatment response in people with hypothalamic obesity.

AIM: To evaluate whether neuroimaging-delineated regions of hypothalamic injury are associated with a differential treatment response to a glucagon-like peptide-1 receptor agonist (GLP-1RA) in patients with hypothalamic obesity (HO). MATERIALS AND METHODS: We performed a prespecified secondary analysis of a randomized, multicentre, double-blind, placebo-controlled trial of people aged 10-25 years with hypothalamic injury and HO randomized to the GLP-1RA exenatide once-weekly (ExQW) or placebo for 36 weeks. Subjects underwent MRI prior to enrolment and the degree of hypothalamic damage was assessed using an integrative hypothalamic lesion score (HLS). Mammillary body (MB) damage was specifically determined. The main clinical endpoints were % change in body mass index (BMI) and change in % body fat. Nested ANCOVA models including a treatment × imaging measure interaction were compared using partial F-tests to assess whether the effect of ExQW treatment differed by severity of hypothalamic damage. RESULTS: Complete data were available in 35/42 randomized participants (placebo, n = 15; ExQW, n = 20). ExQW-treated patients with worse HLS or bilateral MB damage had greater reductions in % body fat at 36 weeks (interaction coefficient estimates for HLS: -0.9%, 95% CI -1.6% to -0.2%, p = .02; for MB damage: -7.4%, 95% CI -10.1% to -4.7%, p < .001, respectively) but not for BMI % change. Similarly, patients with more damaged and smaller MB cross-sectional areas had greater reductions in % body fat following ExQW (interaction coefficient estimate 0.3%, 95% CI 0.2%-0.4%, p < .001). CONCLUSIONS: In people with HO, greater hypothalamic damage as determined by MRI, in particular MB injury, is associated with greater reductions in adiposity following GLP-1RA treatment.