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Objective: To evaluate the effects of a multifaceted Treatment for Social cognition and Emotion regulation (T-ScEmo) in patients with a traumatic brain injury. Participants: Sixty-one patients with moderate to severe traumatic brain injury randomly assigned to an experimental T-ScEmo intervention or a Cogniplus control condition. Interventions: T-ScEmo is a compensatory strategy training for impairments in emotion recognition, theory of mind, and social behavioral skills. Cogniplus is a computerized cognitive function training. Both interventions were given in 16 to 20 weekly 1-hour sessions. Main Measures: Social cognition tests and questionnaires for social behavior (self-and proxy-rated) administered at baseline, immediately posttreatment, and at 3 to 5 months of follow-up. Results: Compared with the Cogniplus group, the T-ScEmo group improved significantly on facial affect recognition, theory of mind, proxy-rated empathic behavior, societal participation, and treatment goal attainment, which lasted up to 5 months after treatment. At follow-up, the T-ScEmo group also reported higher quality of life and their life partners rated relationship quality to be higher than the Cogniplus group. Conclusion: This study shows that impairments in social cognition can be effectively dealt with by using a comprehensive treatment protocol, leading to improvements in everyday life social functioning.

Objective The objectives of this study were to model more homogeneous subgroups within autism spectrum disorder (ASD) based on early trajectories of core symptoms; and to further characterize these subgroups in terms of trajectories of language, cognition, co-occurring (attention-deficit/hyperactivity disorder [ADHD]–related) traits and clinical outcome diagnosis. Method Children (N = 203) referred for possible ASD at ages 1 to 4 years were assessed at three time points at intervals ranging from 9 months to 3 years. Assessments included standardized measures for ASD (Autism Diagnostic Observation Schedule [ADOS]), language (ADOS-language item), nonverbal IQ (NV-IQ; different tests adequate to chronological/mental age), and parent-reported behavioral problems (Infant-Toddler Social and Emotional Assessment, Child Behavior Checklist). Results Latent-class growth curve analysis with ADOS total scores led to the identification of three main stable and two small improving groups: a severe–stable group (19.5% of sample)—the only group without considerable language improvement—showed persistent low NV-IQ and marked increase in attention problems over time; a moderate–stable group (21.7%) with below-average increasing NV-IQ; and a mild–stable group (48%) with stable–average NV-IQ and the highest scores on ADHD-related traits, whose ASD outcome diagnoses increased despite stable–low ASD scores. Two groups (each 5.4%) improved: one moved from severe to moderate ASD scores, and the other moved from moderate to mild/nonspectrum scores. Both of these groups improved on language, NV-IQ, and ADHD-related traits. Conclusion Results support the high stability of ASD symptoms into various severity levels, but also highlight the significant contribution of non-ASD domains in defining and explaining the different ASD trajectories.

Background and Purpose— High blood pressure (BP) is associated with poor outcome and the occurrence of symptomatic intracranial hemorrhage in acute ischemic stroke. Whether BP influences the benefit or safety of intra-arterial treatment (IAT) is not known. We aimed to assess the relation of BP with functional outcome, occurrence of symptomatic intracranial hemorrhage and effect of IAT. Methods— This is a post hoc analysis of the MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment of Acute Ischemic Stroke in the Netherlands). BP was measured at baseline, before IAT or stroke unit admission. We estimated the association of baseline BP with the score on the modified Rankin Scale at 90 days and safety parameters with ordinal and logistic regression analysis. Effect of BP on the effect of IAT was tested with multiplicative interaction terms. Results— Systolic BP (SBP) had the best correlation with functional outcome. This correlation was U-shaped; both low and high baseline SBP were associated with poor functional outcome. Higher SBP was associated with symptomatic intracranial hemorrhage (adjusted odds ratio, 1.25 for every 10 mm Hg higher SBP [95% confidence interval, 1.09–1.44]). Between SBP and IAT, there was no interaction for functional outcome, symptomatic intracranial hemorrhage, or other safety parameters; the absolute benefit of IAT was evident for the whole SBP range. The same was found for diastolic BP. Conclusions— BP does not affect the benefit or safety of IAT in patients with acute ischemic stroke caused by proximal intracranial vessel occlusion. Our data provide no arguments to withhold or delay IAT based on BP. Clinical Trial Registration— URL: http://www.isrctn.com . Unique identifier: ISRCTN10888758.

Background In a previous feasibility study (APROPOS) in a single municipality of the Netherlands, we showed that a locally tailored preconception care (PCC) approach has the potential to positively affect preconceptional lifestyle behaviours. Therefore, we designed a second study (APROPOS-II) to obtain a more robust body of evidence: a larger group of respondents, more municipalities, randomization, and a more comprehensive set of (clinical) outcomes. The aim of this study is to assess the effectiveness and the implementation process of a local PCC-approach on preconceptional lifestyle behaviours, health outcomes and the reach of PCC among prospective parents and healthcare providers. Methods This study is an effectiveness-implementation hybrid type 2 trial. This involves a stepped-wedge cluster randomized controlled trial design aiming to include over 2000 future parents from six municipalities in the Netherlands. The intervention has a dual-track approach, focusing on both the uptake of PCC among future parents and the provision of PCC by healthcare providers. The PCC-approach consists of 1) a social marketing strategy directed towards prospective parent(s) and 2) a local care pathway to improve interdisciplinary collaboration. Data will be collected before and after the introduction of the intervention through questionnaires and medical records in each of the participating municipalities. The primary outcome of this study is change in lifestyle behaviours (e.g. folic acid use, smoking and alcohol use). Secondary outcomes are pregnancy outcomes (e.g. miscarriage, preterm birth, gestational diabetes) and the uptake of PCC. Moreover, a process evaluation will be performed, providing information on the efficacy, feasibility, barriers and facilitators regarding the implementation of the intervention. Discussion The APROPOS-II study introduces a locally tailored PCC-approach in six municipalities in the Netherlands that will contribute to the body of evidence regarding the effectiveness of PCC and its implementation. If this intervention has a positive effect on lifestyle behaviour changes, leading to improved pregnancy outcomes and the future health of prospective parents and their offspring, it could subsequently be upscaled to (inter)national implementation. Trial registration Dutch Trial register: NL7784 (Registered June 6th, 2019).

The Dutch Parelsnoer Institute-Cerebrovascular accident (CVA) Study is part of the Parelsnoer Institute (PSI), initiated in 2007 by the Netherlands Federation of University Medical Centers (NFU). PSI is a cooperation of all eight Dutch University Medical Centers (UMCs) and aims at building large prospectively collected datasets with uniformly and standardized storage of biomaterials for complex diseases. Currently, PSI covers 18 disease-specific cohorts called ‘Pearls’, and this number is still growing. One of these cohorts is the Stroke or CVA Pearl. For each of the cohorts, PSI offers the UMCs an infrastructure and standard procedures for storing the specific biomaterials in their certified biobanks. Clinical data are stored in a central database after being pseudonymized to ensure patient privacy. For the Parelsnoer Institute-CVA Study, blood for genetic analysis, serum and plasma are collected according to nationally agreed standards. Currently (November 2017) the Stroke Pearl has stored blood samples with prospectively obtained clinical data of around 6000 patients in all UMCs combined. Blood samples and data are available for all researchers with a methodologically valid research proposal. Funding statement: PSI was founded in 2007 with a five year grant from the Dutch Government. From 2011 until now PSI is funded and facilitated by the Netherlands Federation of University Medical Centers (NFU) and its member institutions, independent of external funds. Additional funds from governmental sources, industry sponsors and charity are used for the analysis on the existing data and the expansion of PSI with new diseases.

Background Patients with migraine might be more susceptible of spreading depolarizations, which are known to affect vascular and neuronal function and penumbra recovery after stroke. We investigated whether these patients have more severe stroke progression and less favorable outcomes after recanalization therapy. Methods We included patients from a prospective multicenter ischemic stroke cohort. Lifetime migraine history was based on the International Classification of Headache Disorders II criteria. Patients without confirmed migraine diagnosis were excluded. Patients underwent CT angiography and CT perfusion Results We included 600 patients of whom 43 had migraine. There were no differences between patients with or without migraine in presence of a perfusion deficit on admission (aRR: 0.98, 95%CI: 0.77–1.25), infarct core volume (aB: -10.8, 95%CI: -27.04–5.51), penumbra volume (aB: -11.6, 95%CI: -26.52–3.38), mean blood brain barrier permeability (aB: 0.08, 95%CI: -3.11–2.96), malignant edema (0% vs. 5%), hemorrhagic transformation (aRR: 0.26, 95%CI: 0.04–1.73), final infarct volume (aB: -14.8, 95%CI: 29.9–0.2) or outcome after recanalization therapy (mRS > 2, aRR: 0.50, 95%CI: 0.21–1.22). Conclusion Elderly patients with a history of migraine do not seem to have more severe stroke progression and have similar treatment outcomes compared with patients without migraine.

Highlights • Doppler imaging to measure cerebral blood flow is feasible during tilt testing. • Cerebral blood flow in ME/CFS patients is reduced during tilt testing. • 90% of ME/CFS patients show abnormal cerebral blood flow reduction on tilt testing. • Cerebral blood flow reduction correlates with symptoms of orthostatic intolerance., Objective The underlying hypothesis in orthostatic intolerance (OI) syndromes is that symptoms are associated with cerebral blood flow (CBF) reduction. Indirect CBF measurements (transcranial Doppler flow velocities), provide inconsistent support of this hypothesis. The aim of the study was to measure CBF during a 30 min head-up tilt test (HUT), using Doppler flow imaging of carotid and vertebral arteries, in individuals with chronic fatigue syndrome/myalgic encephalomyelitis (ME/CFS), a condition with a high prevalence of OI. Methods 429 ME/CFS patients were studied: 247 had a normal heart rate (HR) and blood pressure (BP) response to HUT, 62 had delayed orthostatic hypotension (dOH), and 120 had postural orthostatic tachycardia syndrome (POTS). We also studied 44 healthy controls (HC). CBF measurements were made at mid-tilt and end-tilt. Before mid-tilt, we administered a verbal questionnaire to ascertain for 15 OI symptoms. Results End-tilt CBF reduction was 7% in HC versus 26% in the overall ME/CFS group, 24% in patients with a normal HR/BP response, 28% in those with dOH, and 29% in POTS patients (all P

We report a case of ventricular septal defect causing congestive heart failure in a two-year-old, male common degu (Octodon degus). The patient presented for anorexia and dental disease, and a grade 4/6 holosystolic cardiac murmur was detected on physical exam. Thoracic radiographs showed cardiomegaly and a diffuse interstitial pulmonary pattern, consistent with congestive heart failure. Echocardiography was supportive of a perimembranous ventricular septal defect exhibiting low-velocity left-to-right shunting, and biatrial enlargement. These diagnoses were confirmed on post-mortem exam, along with pulmonary edema and cardiomyocyte hypertrophy, degeneration, and regeneration. This is the first published account of a ventricular septal defect and congestive heart failure in a degu.

Objectives We investigated the role of molecular markers in cervical cancer screening for South African women living with HIV (WLHIV). Methods South African WLHIV underwent cervical screening and colposcopy-directed biopsy with molecular screening. Data included cytology, HPV (high-risk), HPV (16/18) and histology. Detection of FAM19A4/miR124–2 hypermethylation was performed on DNA isolated from cervical scrapes. Diagnostic performance of cytology and HPV tests alone and combined with FAM19A4/miR124–2 hypermethylation was determined. Results 285 women were included in the analyses. Cytology provided the highest specificity (91.6%), but lowest sensitivity (59.3%), HPV (high-risk) provided the highest sensitivity (83.1%), but lowest specificity (66.4%). Combining cytology with methylation did not improve the performance of cytology alone, but triage of HPV (high-risk) with methylation, increased specificity (76.1%) while maintaining an acceptable sensitivity (72.9%). Similar performance was observed for HPV (16/18) with methylation triage (sensitivity 79.7%, specificity 74.8%). Number referred per CIN3+ was lowest for cytology (1.5), but only slightly higher for HPV (high-risk) or HPV (16/18) with methylation triage (2.3 and 2.2). Conclusions We report promising results using molecular triage of HPV positive WLHIV with methylation markers regarding sensitivity and specificity for CIN 3+.

Introduction: A recent study reported a favorable effect of vitamin B12 injections/oral folic acid support in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients. Recently, vitamin B12 nasal drops were developed as an alternative to the vitamin B12 injections. As no data are available on efficacy of this formulation, we studied vitamin B12 serum levels, the physical activity scale of the RAND-36, the number of steps on an activity meter, and the fatigue and concentration scales of the CIS20r questionnaires, before and after 3 months of treatment in ME/CFS patients. Methods and Results: Fifty-one patients completed all measurements. Forty-four were female. Mean age was 42 years, and mean disease duration was 16 years. Median vitamin B12 levels before treatment were 328 (244-429) pmol/l, and 973 (476-1,476) pmol/l after treatment. Thirty-four patients reported a favorable response to treatment. In the non-responders, only a small but significant increase in vitamin B12 levels was observed. In contrast, in responders, the number of steps, the physical activity scale of the RAND-36, and the vitamin B12 serum levels increased significantly. The CIS20r fatigue scale decreased significantly, and the CIS20r concentration scale was unchanged. Conclusions: Nasal drop vitamin B12 administration resulted in a significant increase in vitamin B12 serum levels and therefore may be effective. This pilot study suggest that the nasal drops may be used as an alternative to injections because two thirds of ME/CFS patients reported a positive effect, accompanied by an increased number of steps, improvement of the RAND-36 physical functioning scale and the CIS20r fatigue scale, and a significant increase in serum vitamin B12 levels.

In this study, the genetic structure of indigenous Tswana and Swazi goats using the Illumina Goat50K SNP array was investigated. Two South African commercial goat breeds were included to investigate admixture with the indigenous populations in southern Africa. A total of 144 DNA samples including Boer goats (n = 24), Kalahari Red (n = 24), Swazi (n = 48), and Tswana goats (n = 48) were genotyped. Statistical analysis was performed using PLINK version 1.07. Genetic diversity, measured as expected heterozygosity, was estimated at 0.390, 0.398, 0.413, and 0.387 for Boer, Kalahari Red, Tswana, and Swazi goats, respectively. The individual inbreeding coefficient varied from 0.019 ± 0.05 to 0.011 ± 0.06 for the Tswana and Swazi goats, respectively. The Principal component analysis clustered the populations according to geographical origin and breed type. Linkage disequilibrium (LD) for shorter intervals (0-10 kb) ranged from 0.44 to 0.56 and commercial breeds had higher values. Effective population sizes decreased with generations and at the 13th generation ranged between 87 for Boer to 266 for Tswana goats. The Tswana population exhibited the highest level of genetic variation and effective population size, which holds potential for improved production in marginal regions. A national strategy is required to maintain genetic diversity in communal goat production systems through well-structured breeding and conservation programs.

ObjectivesElectronic dance music (EDM) concerts are becoming increasingly popular. Strong stroboscopic light effects are commonly part of these shows, and may provoke seizures in individuals with photosensitive epilepsy. This study aims to examine the risk of epileptic seizures during EDM concerts.Setting28 EDM concerts taking place in The Netherlands.ParticipantsWe describe a young man who experienced a seizure during an EDM concert, and who later showed a positive electroencephalographic provocation test during exposure to video footage of the same concert. Subsequently, we performed a cohort study of 400 343 visitors to EDM concerts, divided in those exposed (concert occurring in darkness) versus unexposed (concert in daylight) to stroboscopic light effects.ResultsIn total, 400 343 EDM concert visitors were included: 241 543 (representing 2 222 196 person hours) in the exposed group and 158 800 (representing 2 334 360 person hours) in the control group. The incidence density ratio of epileptic seizures in exposed versus unexposed individuals was 3.5 (95% CI: 1.7 to 7.8; pConclusionStroboscopic light effects during EDM concerts occurring in darkness probably more than triple the risk of epileptic seizures. Concert organisers and audience should warn against the risk of seizures and promote precautionary measures in susceptible individuals.

We sought to determine the prevalence and clinical significance of right heart remodeling and right ventricular (RV) dysfunction in dogs with pulmonary valve stenosis (PS). We also sought to evaluate repeatability of several measurements of severity of PS, right heart size, and RV function in dogs with PS.Several indices of right atrial (RA) size and RV size and function were prospectively evaluated in 48 dogs with PS. Regression analysis was used to determine if indices of right heart size and function were independently associated with maximum transpulmonary pressure gradient (max PG) and adverse clinical findings (exercise intolerance, syncope, or right heart failure). Eight dogs underwent a second echocardiogram performed by the same operator to assess repeatability of the echocardiographic indices, which was quantified by coefficient of variation (CV) and repeatability coefficient.Increased RA size (81%), increased RV wall thickness (83%), and decreased tricuspid annular plane systolic excursion (TAPSE [81%]) were common. Right atrial size, end-diastolic RV area, and RV wall thickness were independently associated with max PG. Decreased TAPSE was independently associated with adverse clinical findings. All indices except RA area (18.6%) and RV systolic velocity (20.7%) had CVs15%. Repeatability coefficients are available to help distinguish a true change versus measurement variability during serially obtained exams.Right heart remodeling and RV dysfunction are common in dogs with PS and are associated with echocardiographic and clinical severity. Results support the quantitative assessment of right heart size and function in dogs with PS.

Pulmonary hypertension (PH) is a common clinical condition associated with morbidity and mortality in both humans and dogs. Sildenafil, a phosphodiesterase-5 (PDE5) inhibitor causing accumulation of cGMP, is frequently used for treatment of PH. The authors previously reported a PDE5A:E90K polymorphism in dogs that results in lower basal cyclic guanosine monophosphate (cGMP) concentrations than in wild-type dogs, which could contribute to variability in the efficacy of sildenafil. In this study, response to sildenafil therapy was evaluated in dogs with PH by comparing echocardiographic parameters, quality-of-life (QOL) score, and plasma cGMP concentrations before and after sildenafil therapy. Overall, tricuspid regurgitation estimated systolic pressure gradient (PG) and QOL score were significantly improved after sildenafil therapy, and the plasma cGMP concentration was significantly decreased. Dogs that had a heterozygous PDE5A status had a significantly worse QOL score when compared to the wildtype group after sildenafil treatment. The simple and multiple regression analyses revealed a significant but weak prediction for the percent reduction in QOL score with sildenafil treatment by plasma cGMP level and by the PDE5A:E90K polymorphic status. This study showed that sildenafil treatment improved PH in dogs, and the PDE5A:E90K polymorphism blunted the efficacy of sildenafil in terms of QOL improvement.

Subvalvular aortic stenosis (SAS) and valvular pulmonic stenosis (PS) are two of the most common congenital heart diseases of dogs. The aim of this study was to determine the prevalence and mode of inheritance of these congenital heart diseases in a large veterinary teaching hospital population. Case records of dogs presented to the University of California Davis, Veterinary Medical Teaching Hospital (UCD VMTH) between January 2008 to December 2017 were reviewed retrospectively and pedigree information was obtained when available. There were 259 unique SAS and 336 unique PS cases diagnosed during the study period. The prevalence of SAS was 0.3% of overall hospital admissions and 4.7% for all dogs seen by the cardiology service. The prevalence for PS was 0.41% of overall hospital admissions and 6.1% of dogs seen by the cardiology service. Bullmastiffs and Newfoundlands had the greatest prevalence (6.59 and 4.46%, respectively) and odds ratio (52.43 and 34.73, respectively) for SAS. Bulldogs and French Bulldogs had the greatest prevalence (4.8 and 2.7%, respectively) and odds ratio (13.32 and 7.52, respectively) for PS. The identified prevalence of SAS and PS is higher than previously reported. Pedigree analysis in SAS affected Bullmastiffs, Golden Retrievers, and Rottweilers suggested an autosomal recessive pattern of inheritance. The mode of inheritance for PS in Bulldogs, also appears to be autosomal recessive. The results of this study can be used to inform future selection of breeding pairs and genetic studies aimed at reducing the prevalence of these common congenital heart diseases.

Snakes of the genera Pseudocerastes and Eristicophis (Viperidae: Viperinae) are known as the desert vipers due to their association with the arid environments of the Middle East. These species have received limited research attention and little is known about their venom or ecology. In this study, a comprehensive analysis of desert viper venoms was conducted by visualising the venom proteomes via gel electrophoresis and assessing the crude venoms for their cytotoxic, haemotoxic, and neurotoxic properties. Plasmas sourced from human, toad, and chicken were used as models to assess possible prey-linked venom activity. The venoms demonstrated substantial divergence in composition and bioactivity across all experiments. Pseudocerastes urarachnoides venom activated human coagulation factors X and prothrombin and demonstrated potent procoagulant activity in human, toad, and chicken plasmas, in stark contrast to the potent neurotoxic venom of P. fieldi. The venom of E. macmahonii also induced coagulation, though this did not appear to be via the activation of factor X or prothrombin. The coagulant properties of P. fieldi and P. persicus venoms varied among plasmas, demonstrating strong anticoagulant activity in the amphibian and human plasmas but no significant effect in that of bird. This is conjectured to reflect prey-specific toxin activity, though further ecological studies are required to confirm any dietary associations. This study reinforces the notion that phylogenetic relatedness of snakes cannot readily predict venom protein composition or function. The significant venom variation between these species raises serious concerns regarding antivenom paraspecificity. Future assessment of antivenom is crucial.

Purpose: Many patients with mild traumatic brain injury do not fully return to work owing to persistent posttraumatic complaints. Research suggests that preventing chronic complaints might be prevented by giving cognitive behavioral therapy early after injury. Therefore, a new cognitive behavioral intervention (UPFRONT-intervention) was developed to not only prevent chronic complaints but to also establish a more successful return to work. The intervention is currently being evaluated in a multicenter randomized controlled trial design (trial number ISRCTN86191894) in mild traumatic brain injury patients who are at-risk of negative outcomes (patients with high numbers of early complaints). Two case examples are presented to demonstrate the application of the intervention. Rationale: Psychological factors, like cognitive appraisal and coping, play an important role in the persistence of posttraumatic complaints. Some patients are less able to adapt and thus to cope with the injury and its initial consequences than others. Dealing with the injury in a passive, avoidant way, focusing on negative feelings, will hamper recovery and is therefore a valuable target for an intervention. Theory into practice: The UPFRONT intervention is a short cognitive behavioral therapy intervention for patients that are at-risk of developing persistent posttraumatic complaints. Patients will undergo five sessions of cognitive behavioral therapy within 4–10 weeks after trauma. The intervention aims to enhance patients’ feeling of competency of dealing with the consequences of mild traumatic brain injury by providing psycho-education, identifying and challenging unrealistic illness perceptions and improving coping style (decreasing maladaptive coping and enhancing adaptive coping).

The aim of this study was to compare the American Gastroenterological Association guidelines (AGA criteria), the 2012 (Fukuoka criteria), and 2006 (Sendai criteria) International Consensus Guidelines for the diagnosis of advanced pancreatic cystic neoplasms. All patients who underwent surgical resection of a pancreatic cyst from August 2007 through January 2016 were retrospectively analyzed at a single tertiary academic center. Relevant clinical and imaging variables along with pathology results were collected to determine appropriate classification for each guideline. Advanced pancreatic cystic neoplasms were defined by the presence of either high-grade dysplasia or cystic adenocarcinoma. Diagnostic accuracy was measured by ROC analysis. A total of 209 patients were included. Both the AGA and Fukuoka criteria had a higher diagnostic accuracy for advanced neoplastic cysts than the Sendai criteria: AGA ROC 0.76 (95% CI 0.69–0.81), Fukuoka ROC 0.78 (95% CI 0.74–0.82), and Sendai ROC 0.65 (95% CI 0.61–0.69) (p

Background and Purpose— A high clot burden score (CBS) is associated with favorable outcome after intravenous treatment for acute ischemic stroke. The added benefit of intra-arterial treatment might be less in these patients. The aim of this exploratory post hoc analysis was to assess the relation of CBS with neurological improvement and endovascular treatment effect. Methods— For 499 of 500 patients in the MR CLEAN study (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands), the CBS was determined. Ordinal logistic regression models with and without main baseline prognostic variables were used to assess the association between CBS (continuous or dichotomized at CBS of 6) and a shift toward better outcome on the modified Rankin Scale. The model without main baseline prognostic variables only included treatment allocation and CBS. Models with and without a multiplicative interaction term of CBS and treatment were compared using the χ 2 test to assess treatment effect modification by CBS. Results— Higher CBS was associated with a shift toward better outcome on the modified Rankin Scale; adjusted common odds ratio per point CBS was 1.12 (95% confidence interval, 1.04–1.20]. Dichotomized CBS had an adjusted common odds ratio of 1.67 (95% confidence interval, 1.12–2.51). Both effect estimates were slightly attenuated by adding baseline prognostic variables. The addition of the interaction terms did not significantly improve the fit of the models. There was a small and insignificant increase of intra-arterial treatment efficacy in the high CBS group. Conclusions— A higher CBS is associated with improved outcome and may be used as a prognostic marker. We found no evidence that CBS modifies the effect of intra-arterial treatment. Clinical Trial Registration— URL: http://www.trialregister.nl . Unique identifier: NTR1804. URL: http://www.controlled-trials.com . Unique identifier: ISRCTN10888758.

// Evelyn Kidess-Sigal 1, 2, * , Haiyan E. Liu 3, * , Melanie M. Triboulet 2 , James Che 3 , Vishnu C. Ramani 2 , Brendan C. Visser 2 , George A. Poultsides 2 , Teri A. Longacre 4 , Andre Marziali 5 , Valentina Vysotskaia 6 , Matthew Wiggin 5 , Kyra Heirich 2 , Violet Hanft 2 , Ulrich Keilholz 7 , Ingeborg Tinhofer 8 , Jeffrey A. Norton 2 , Mark Lee 9 , Elodie Sollier-Christen 3 , Stefanie S. Jeffrey 2 1 Department of Medicine, Division of Hepatology and Gastroenterology, Charite University Hospital, Berlin, Germany 2 Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA 3 Vortex BioSciences, Inc., Menlo Park, CA, USA 4 Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA 5 Boreal Genomics, Vancouver, BC, Canada 6 Counsyl Inc., San Francisco, CA, USA 7 Comprehensive Cancer Center Charite, Berlin, Germany 8 Department of Radiooncology and Radiotherapy, Charite University Hospital, Berlin, Germany 9 GRAIL, Redwood City, CA, USA * These authors have contributed equally to this work Correspondence to: Stefanie S. Jeffrey, email: ssj@stanford.edu Keywords: colorectal cancer, circulating tumor cells, circulating tumor DNA, liquid biopsy, Vortex Received: June 30, 2016 Accepted: October 26, 2016 Published: November 15, 2016 ABSTRACT Treatment of advanced colorectal cancer (CRC) requires multimodal therapeutic approaches and need for monitoring tumor plasticity. Liquid biopsy biomarkers, including CTCs and ctDNA, hold promise for evaluating treatment response in real-time and guiding therapeutic modifications. From 15 patients with advanced CRC undergoing liver metastasectomy with curative intent, we collected 41 blood samples at different time points before and after surgery for CTC isolation and quantification using label-free Vortex technology. For mutational profiling, KRAS, BRAF, and PIK3CA hotspot mutations were analyzed in CTCs and ctDNA from 23 samples, nine matched liver metastases and three primary tumor samples. Mutational patterns were compared. 80% of patient blood samples were positive for CTCs, using a healthy baseline value as threshold (0.4 CTCs/mL), and 81.4% of captured cells were EpCAM+ CTCs. At least one mutation was detected in 78% of our blood samples. Among 23 matched CTC and ctDNA samples, we found a concordance of 78.2% for KRAS, 73.9% for BRAF and 91.3% for PIK3CA mutations. In several cases, CTCs exhibited a mutation that was not detected in ctDNA, and vice versa. Complementary assessment of both CTCs and ctDNA appears advantageous to assess dynamic tumor profiles.

The risk of postoperative adverse events in patients with underlying cardiac disease undergoing major hepatectomy remains poorly characterized.The NSQIP database was used to identify patients undergoing hemihepatectomy and trisectionectomy. Patient characteristics and postoperative outcomes were evaluated.From 2005 to 2012, 5227 patients underwent major hepatectomy. Of those, 289 (5.5%) had prior major cardiac disease: 5.6% angina, 3.1% congestive heart failure, 1% myocardial infarction, 54% percutaneous coronary intervention, and 46% cardiac surgery. Thirty-day mortality was higher in patients with cardiac comorbidity (6.9% vs. 3.7%, P = 0.008), including the incidence of postoperative cardiac arrest requiring cardiopulmonary resuscitation (3.8% vs. 1.2%, P = 0.001) and myocardial infarction (1.7% vs. 0.4%, P = 0.011). Multivariate analysis revealed that functional impairment, older age, and malnutrition, but not cardiac comorbidity, were significant predictors of 30-day mortality. However, prior percutaneous coronary intervention was independently associated with postoperative cardiac arrest (OR 2.999, P = 0.008).While cardiac comorbidity is not a predictor of mortality after major hepatectomy, prior percutaneous coronary intervention is independently associated with postoperative cardiac arrest. Careful patient selection and preoperative optimization is fundamental in patients with prior percutaneous coronary intervention being considered for major hepatectomy as restrictive fluid management and low central venous pressure anesthesia may not be tolerated well by all patients.

Introduction: Fluoxetine is a selective serotonin reuptake inhibitor and long-lived open channel blocker of the acetylcholine receptor often used in the treatment of slow-channel congenital myasthenic syndromes (CMS). Methods: We report a 42-year woman who had a history of episodic limb weakness that worsened after initiation of fluoxetine for treatment of depression. Genetic testing for CMS revealed a homozygous pathogenic mutation in the rapsyn (RAPSN) gene (p.Asn88Lys). Electrodiagnostic testing was performed prior to and 1 month after discontinuation of fluoxetine. Results: Two-Hz repetitive nerve stimulation of the fibular and spinal accessory nerves showed a baseline decrement of 36% and 14%, respectively. One month after discontinuing fluoxetine, the spinal accessory nerve decrement was no longer present, and the decrement in the fibular nerve was improved at 17%. Conclusion: This case demonstrates worsening of both clinical and electrophysiologic findings in a patient with CMS secondary to a RAPSN mutation treated with fluoxetine. This article is protected by copyright. All rights reserved.

Objective: In chronic fatigue syndrome (CFS), only a few imaging and histopathological studies have previously assessed either cardiac dimensions/function or myocardial tissue, suggesting smaller left ventricular (LV) dimensions, LV wall motion abnormalities and occasionally viral persistence that may lead to cardiomyopathy. The present study with cardiac magnetic resonance (CMR) imaging is the first to use a contrast-enhanced approach to assess cardiac involvement, including tissue characterisation of the LV wall. Methods: CMR measurements of 12 female CFS patients were compared with data of 36 age-matched, healthy female controls. With cine imaging, LV volumes, ejection fraction (EF), mass, and wall motion abnormalities were assessed. T2-weighted images were analysed for increased signal intensity, reflecting oedema (i. e. inflammation). In addition, the presence of contrast enhancement, reflecting fibrosis (i. e. myocardial damage), was analysed. Results: When comparing CFS patients and healthy controls, LVEF (57.9 ± 4.3 % vs. 63.7 ± 3.7 %; p < 0.01), end-diastolic diameter (44 ± 3.7 mm vs. 49 ± 3.7 mm; p < 0.01), as well as body surface area corrected LV end-diastolic volume (77.5 ± 6.2 ml/m2 vs. 86.0 ± 9.3 ml/m2; p < 0.01), stroke volume (44.9 ± 4.5 ml/m2 vs. 54.9 ± 6.3 ml/m2; p < 0.001), and mass (39.8 ± 6.5 g/m2 vs. 49.6 ± 7.1 g/m2; p = 0.02) were significantly lower in patients. Wall motion abnormalities were observed in four patients and contrast enhancement (fibrosis) in three; none of the controls showed wall motion abnormalities or contrast enhancement. None of the patients or controls showed increased signal intensity on the T2-weighted images. Conclusion: In patients with CFS, CMR demonstrated lower LV dimensions and a mildly reduced LV function. The presence of myocardial fibrosis in some CFS patients suggests that CMR assessment of cardiac involvement is warranted as part of the scientific exploration, which may imply serial non-invasive examinations

Minimally invasive liver surgery is a growing field, and a small number of recent reports have suggested that laparoscopic liver resection (LLR) is feasible even in patients with cirrhosis. However, parenchymal transection of the cirrhotic liver is challenging due to fibrosis and portal hypertension. There is a paucity of data regarding the technical modifications necessary to safely transect the diseased parenchyma. Patients undergoing LLR by a single surgeon between 2008 and 2015 were reviewed. Patients with cirrhosis were compared to those without cirrhosis to examine differences in surgical technique, intraoperative characteristics, and outcomes (including liver-related morbidity and general postoperative complication rates). A total of 167 patients underwent LLR during the study period. Forty-eight (29 %) had cirrhosis, of which 43 (90 %) had hepatitis C. Most had Child–Pugh class A disease (85 %). Compared to noncirrhotics, patients with cirrhosis were older, had more comorbidities, and were more likely to have hepatocellular carcinoma. Precoagulation before parenchymal transection was used more frequently in cirrhotics (65 vs. 15 %, P

Key Points Question What are the outcomes of patients who undergo aggressive resection of locally advanced pancreatic neuroendocrine tumors (PNETs)? Findings In this case series, 99 patients with locally advanced (T3/T4) PNETs and no known distant metastatic disease who underwent resection had a recurrence rate of 35%, but their quality of life remained high, and the overall 5-year survival was 91%. Meaning These findings suggest that locally advanced PNETs warrant aggressive surgical resection, including local organs and blood vessels, if necessitated by tumor invasion., This case series examines data from 2003 to 2018 regarding patients who underwent aggressive resection operative treatment for locally advanced pancreatic neuroendocrine tumors and their outcomes in terms of disease recurrence, quality of life, and overall 5-year survival., Importance Although outcome of surgical resection of liver metastases from pancreatic neuroendocrine tumors (PNETs) has been extensively studied, little is known about surgery for locally advanced PNETs; it was listed recently by the European neuroendocrine tumor society as a major unmet need. Objective To evaluate the outcome of patients who underwent surgery for locally aggressive PNETs. Design, Setting, and Participants This retrospective single-center case series reviewed consecutive patients who underwent resection of T3/T4 PNETs at a single academic institution. Data collection occurred from 2003 to 2018. Data analysis was performed in August 2019. Main Outcomes and Measures Disease-free survival (primary outcome) and overall mortality (secondary outcome) were assessed with Kaplan-Meier analysis. Recurrence risk (secondary outcome, defined as identification of tumor recurrence on imaging) was assessed with Cox proportional hazard models adjusting for covariates. Results In this case series, 99 patients with locally advanced nondistant metastatic PNET (56 men [57%]) with a mean (SEM) age of 57.0 (1.4) years and a mean (SEM) follow-up of 5.3 (0.1) years underwent surgically aggressive resections. Of those, 4 patients (4%) underwent preoperative neoadjuvant treatment (including peptide receptor radionuclide therapy and chemotherapy); 18 patients (18%) underwent pancreaticoduodenectomy, 68 patients (69%) had distal or subtotal pancreatic resection, 10 patients (10%) had total resection, and 3 patients (3%) had other pancreatic procedures. Additional organ resection was required in 86 patients (87%): spleen (71 patients [71%]), major blood vessel (17 patients [17%]), bowel (2 patients [2%]), stomach (4 patients [4%]), and kidney (2 patients [2%]). Five-year disease-free survival was 61% (61 patients) and 5-year overall survival was 91% (91 patients). Of those living, 75 patients (76%) had an Eastern Cooperative Oncology Group score of less than or equal to 1 at last followup. Lymph node involvement (HR, 7.66; 95% CI, 2.78-21.12; P

Background. Eight-and-a-half syndrome is a rare condition comprising one-and-a-half syndrome and cranial nerve VII palsy caused by a single unilateral lesion in the lower pontine tegmentum, of varying etiology. Case presentation. A 67-year-old woman presented at our emergency department with diplopia, vertigo, headache, nausea and vomiting. Physical examination revealed a left horizontal gaze palsy, left internuclear ophthalmoplegia and left facial palsy. Upon the clinical findings eight-and-a-half syndrome was suspected. Cerebral computed tomography showed no signs of recent haemorrhage or ischaemia, but MRI showed a hyperintense lesion located at the left dorsal pons, confirming the diagnosis. Conclusions. Our case illustrates the value of a thorough physical examination combined with the clinical presentation to precisely localize a single lesion causing a complex clinical syndrome.

Introduction: Effort intolerance along with a prolonged recovery from exercise and post-exertional exacerbation of symptoms are characteristic features of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The gold standard to measure the degree of physical activity intolerance is cardiopulmonary exercise testing (CPET). Multiple studies have shown that peak oxygen consumption is reduced in the majority of ME/CFS patients, and that a 2-day CPET protocol further discriminates between ME/CFS patients and sedentary controls. Limited information is present on ME/CFS patients with a severe form of the disease. Therefore, the aim of this study was to compare the effects of a 2-day CPET protocol in female ME/CFS patients with a severe grade of the disease to mildly and moderately affected ME/CFS patients. Methods and results: We studied 82 female patients who had undergone a 2-day CPET protocol. Measures of oxygen consumption (VO2), heart rate (HR) and workload both at peak exercise and at the ventilatory threshold (VT) were collected. ME/CFS disease severity was graded according to the International Consensus Criteria. Thirty-one patients were clinically graded as having mild disease, 31 with moderate and 20 with severe disease. Baseline characteristics did not differ between the 3 groups. Within each severity group, all analyzed CPET parameters (peak VO2, VO2 at VT, peak workload and the workload at VT) decreased significantly from day-1 to day-2 (p-Value between 0.003 and &lt, 0.0001). The magnitude of the change in CPET parameters from day-1 to day-2 was similar between mild, moderate, and severe groups, except for the difference in peak workload between mild and severe patients (p = 0.019). The peak workload decreases from day-1 to day-2 was largest in the severe ME/CFS group (&minus, 19 (11) %). Conclusion: This relatively large 2-day CPET protocol study confirms previous findings of the reduction of various exercise variables in ME/CFS patients on day-2 testing. This is the first study to demonstrate that disease severity negatively influences exercise capacity in female ME/CFS patients. Finally, this study shows that the deterioration in peak workload from day-1 to day-2 is largest in the severe ME/CFS patient group.

Background CT perfusion (CTP) and diffusion or perfusion MRI might assist patient selection for endovascular thrombectomy. We aimed to establish whether imaging assessments of irreversibly injured ischaemic core and potentially salvageable penumbra volumes were associated with functional outcome and whether they interacted with the treatment effect of endovascular thrombectomy on functional outcome.Methods In this systematic review and meta-analysis, the HERMES collaboration pooled patient-level data from all randomised controlled trials that compared endovascular thrombectomy (predominantly using stent retrievers) with standard medical therapy in patients with anterior circulation ischaemic stroke, published in PubMed from Jan 1,2010, to May 31, 2017. The primary endpoint was functional outcome, assessed by the modified Rankin Scale (mRS) at 90 days after stroke. Ischaemic core was estimated, before treatment with either endovascular thrombectomy or standard medical therapy, by CTP as relative cerebral blood flow less than 30% of normal brain blood flow or by MRI as an apparent diffusion coefficient less than 620 mu m(2)/s. Critically hypoperfused tissue was estimated as the volume of tissue with a CTP time to maximum longer than 6 s. Mismatch volume (ie, the estimated penumbral volume) was calculated as critically hypoperfused tissue volume minus ischaemic core volume. The association of ischaemic core and penumbral volumes with 90-day mRS score was analysed with multivariable logistic regression (functional independence, defined as mRS score 0-2) and ordinal logistic regression (functional improvement by at least one mRS category) in all patients and in a subset of those with more than 50% endovascular reperfusion, adjusted for baseline prognostic variables. The meta-analysis was prospectively designed by the HERMES executive committee, but not registered.Findings We identified seven studies with 1764 patients, all of which were included in the meta-analysis. CTP was available and assessable for 591 (34%) patients and diffusion MRI for 309 (18%) patients. Functional independence was worse in patients who had CTP versus those who had diffusion MRI, after adjustment for ischaemic core volume (odds ratio [OR] 0.47 [95% CI 0.30-0.72], p=0.0007), so the imaging modalities were not pooled. Increasing ischaemic core volume was associated with reduced likelihood of functional independence (CTP OR 0.77 [0.69-0.86] per 10 mL, p(interaction)=0.29; diffusion MRI OR 0.87 [0.81-0.94] per 10 mL, p(interaction)=0.94). Mismatch volume, examined only in the CTP group because of the small numbers of patients who had perfusion MRI, was not associated with either functional independence or functional improvement. In patients with CTP with more than 50% endovascular reperfusion (n=186), age, ischaemic core volume, and imaging-to-reperfusion time were independently associated with functional improvement. Risk of bias between studies was generally low.Interpretation Estimated ischaemic core volume was independently associated with functional independence and functional improvement but did not modify the treatment benefit of endovascular thrombectomy over standard medical therapy for improved functional outcome. Combining ischaemic core volume with age and expected imagingto-reperfusion time will improve assessment of prognosis and might inform endovascular thrombectomy treatment decisions. Copyright (C) 2018 Elsevier Ltd. All rights reserved.

The slippery slope framework of tax compliance emphasizes the importance of trust in authorities as a substantial determinant of tax compliance alongside traditional enforcement tools like audits and fines. Using data from an experimental scenario study in 44 nations from five continents (N = 14,509), we find that trust in authorities and power of authorities, as defined in the slippery slope framework, increase tax compliance intentions and mitigate intended tax evasion across societies that differ in economic, sociodemographic, political, and cultural backgrounds. We also show that trust and power foster compliance through different channels: trusted authorities (those perceived as benevolent and enhancing the common good) register the highest voluntary compliance, while powerful authorities (those perceived as effectively controlling evasion) register the highest enforced compliance. In contrast to some previous studies, the results suggest that trust and power are not fully complementary, as indicated by a negative interaction effect. Despite some between-country variations, trust and power are identified as important determinants of tax compliance across all nations. These findings have clear implications for authorities across the globe that need to choose best practices for tax collection. © 2019

Advances in precision molecular imaging promise to transform our ability to detect, diagnose and treat disease. Here, we describe the engineering and validation of a new cystine knot peptide (knottin) that selectively recognizes human integrin αvβ6 with single-digit nanomolar affinity. We solve its 3D structure by NMR and x-ray crystallography and validate leads with 3 different radiolabels in pre-clinical models of cancer. We evaluate the lead tracer’s safety, biodistribution and pharmacokinetics in healthy human volunteers, and show its ability to detect multiple cancers (pancreatic, cervical and lung) in patients at two study locations. Additionally, we demonstrate that the knottin PET tracers can also detect fibrotic lung disease in idiopathic pulmonary fibrosis patients. Our results indicate that these cystine knot PET tracers may have potential utility in multiple disease states that are associated with upregulation of integrin αvβ6., Knottin is a cystine knot peptide. Here, the authors develop a knottin-based tracer for positron emission tomography and demonstrate its ability to detect cancer and idiopathic pulmonary fibrosis through selective binding to integrin αvβ6.

Background: Many patients with moderate to severe traumatic brain injury have deficits in social cognition. Social cognition refers to the ability to perceive, interpret, and act upon social information. Few studies have investigated the effectiveness of treatment for impairments of social cognition in patients with traumatic brain injury. Moreover, these studies have targeted only a single aspect of the problem. They all reported improvements, but evidence for transfer of learned skills to daily life was scarce. We evaluated a multifaceted treatment protocol for poor social cognition and emotion regulation impairments (called T-ScEmo) in patients with traumatic brain injury and found evidence for transfer to participation and quality of life. Purpose: In the current paper, we describe the theoretical underpinning, the design, and the content of our treatment of social cognition and emotion regulation (T-ScEmo). Theory into practice: The multifaceted treatment that we describe is aimed at improving social cognition, regulation of social behavior and participation in everyday life. Some of the methods taught were already evidence-based and derived from existing studies. They were combined, modified, or extended with newly developed material. Protocol design: T-ScEmo consists of 20 one-hour individual sessions and incorporates three modules: (1) emotion perception, (2) perspective taking and theory of mind, and (3) regulation of social behavior. It includes goal-setting, psycho-education, function training, compensatory strategy training, self-monitoring, role-play with participation of a significant other, and homework assignments. Recommendations: It is strongly recommended to offer all three modules, as they build upon each other. However, therapists can vary the time spent per module, in line with the patients’ individual needs and goals. In future, development of e-learning modules and virtual reality sessions might shorten the treatment.

Introduction: Conflicting data have been published on the reduction of circulating blood volume in adults with Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The aim of the present study was to compare blood volumes based on the presence or absence of orthostatic symptoms.Methods and results: Twenty consecutive adults with ME/CFS participated in the study. All underwent dual isotope blood volume measurement and were evaluated for a clinical suspicion of orthostatic intolerance (OI). The mean age was 34 (10) years, and median duration of disease was 7.5 (6–10) years. The mean (SD) absolute blood volume was 59 (8) ml/kg, a value −11 (7) ml/kg below the reference blood volume. Of the 12 patients, 4 had no OI and 8 had a clinical suspicion of OI. In 8 patients with OI, absolute blood volumes were significantly lower than for the 4 without OI (56 [2] vs. 66 [5]; p < 0.05) as were the differences between the measured and the reference blood volume (−14 [2]; vs. −4 [3]; p < 0.02).Conclusions: Adults with ME/CFS had a significantly lower blood volume if they had a clinical suspicion of OI compared to those without a clinical suspicion of OI, as well as a significantly lower blood volume compared to the expected value. The data suggest that accounting for symptoms of OI could enhance the detection of the subset with reduced blood volume.

Introduction: Orthostatic intolerance is common among individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). In some ME/CFS case definitions, orthostatic intolerance is considered a core feature of the disorder. Some studies have employed tilt table tests lasting 2–5 min to diagnose one common form of orthostatic intolerance, postural tachycardia syndrome (POTS). We examined the diagnostic yield of abbreviated durations of tilt testing in adults meeting criteria for ME/CFS, and identified the proportion with POTS misdiagnosed using testing of

OBJECTIVE To describe vertebral left atrial size (VLAS), a quantitative method to estimate left atrial (LA) size radiographically, and to determine its diagnostic value for prediction of echocardiographic LA enlargement in dogs with myxomatous mitral valve disease (MMVD) of varying severity. DESIGN Prospective observational study. ANIMALS 103 client-owned dogs with a left-sided systolic murmur. PROCEDURES For each dog, 3-view thoracic radiographs were obtained within 24 hours of an echocardiographic examination. The VLAS was measured on right and left lateral thoracic radiographs and compared with the left atrium-to-aortic root ratio acquired from short-axis (LA:AoSx) and long-axis (LA:AoLx) echocardiographic images. Left atrial enlargement was defined as an LA:AoLx ≥ 2.6 or LA:AoSx ≥ 1.6. Dogs were allocated to 4 groups on the basis of MMVD severity. RESULTS Of the 103 dogs, 15, 40, 26, and 22 were assigned to the control (no echocardiographic abnormalities), stage B1 (hemodynamically irrelevant MMVD), B2 (hemodynamically relevant MMVD), and C-D (MMVD with congestive heart failure) groups, respectively. Median VLAS, LA:AoSx, and LA:AoLx for the stage B2 and C-D groups were significantly greater than the corresponding medians for the control and stage B1 groups. There was a moderate positive correlation between VLAS and both LA:AoSx and LA:AoLx. Receiver operating characteristic analyses revealed that a VLAS ≥ 2.3 vertebrae was a useful predictor of LA enlargement. Intraobserver and interobserver agreements for VLAS measurements were high. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated VLAS was a repeatable and useful radiographic measurement for prediction of LA enlargement in dogs with MMVD.

Background Sotalol is a commonly used antiarrhythmic drug that may alter ventricular function. Objective To determine the effect of sotalol on echocardiographic indices of ventricular systolic function in dogs with ventricular arrhythmias. Animals Thirty-five client-owned dogs with ventricular arrhythmias. Methods Dogs with ventricular arrhythmias (n = 27) had an echocardiogram and 5-minute ECG performed at baseline and 2-4 hours post-sotalol (2-2.5 mg/kg PO once). Eight additional dogs underwent the same protocol but did not receive sotalol (within-day variability controls). Left ventricular (LV) internal dimension at end-systole normalized to bodyweight (LVIDs_N), LV ejection fraction (LV EF), LV shortening area, LV fractional shortening, tricuspid annular plane systolic excursion (TAPSE), and right ventricular systolic myocardial velocity were evaluated as indices of systolic function. Results All indices except TAPSE had mild decreases in systolic function post-sotalol (all P ≤ .0007) compared with baseline but only the percent change in LVIDs_N and LV EF were significantly (P ≤ .0079) different from the percent change of the same indices in control dogs. Sinus heart rate, ventricular premature complexes/5-minutes, and arrhythmia grade also were decreased post-sotalol (all P ≤ .01) compared with baseline when assessed by a 5-minutes ECG. No dog experienced an adverse event post-sotalol, including dogs with systolic dysfunction or atrial enlargement. Conclusions and clinical importance A single dose of sotalol may cause a mild decrease in LV systolic function in dogs with ventricular arrhythmias. Sotalol appears to be well tolerated, even in dogs with atrial enlargement or systolic dysfunction.

Venoms from snakes are rich sources of highly active proteins with potent affinity towards a variety of enzymes and receptors. Of the many distinct toxicities caused by envenomation, neurotoxicity plays an important role in the paralysis of prey by snakes as well as by venomous sea snails and insects. In order to improve the analytical discovery component of venom toxicity profiling, this paper describes the implementation of microfluidic high-resolution screening (HRS) to obtain neurotoxicity fingerprints from venoms that facilitates identification of the neurotoxic components of envenomation. To demonstrate this workflow, 47 snake venoms were profiled using the acetylcholine binding protein (AChBP) to mimic the target of neurotoxic proteins, in particular nicotinic acetylcholine receptors (nAChRs). In the microfluidic HRS system, nanoliquid chromatographic (nanoLC) separations were on-line connected to both AChBP profiling and parallel mass spectrometry (MS). For virtually all neurotoxic elapid snake venoms tested, we obtained bioactivity fingerprints showing major and minor bioactive zones containing masses consistent with three-finger toxins (3FTxs), whereas, viperid and colubrid venoms showed little or no detectable bioactivity. Our findings demonstrate that venom interactions with AChBP correlate with the severity of neurotoxicity observed following human envenoming by different snake species. We further, as proof of principle, characterized bioactive venom peptides from a viperid (Daboia russelli) and an elapid (Aspidelaps scutatus scutatus) snake by nanoLC-MS/MS, revealing that different toxin classes interact with the AChBP, and that this binding correlates with the inhibition of α7-nAChR in calcium-flux cell-based assays. The on-line post-column binding assay and subsequent toxin characterization methodologies described here provide a new in vitro analytic platform for rapidly investigating neurotoxic snake venom proteins.