Research priorities in single-ventricle heart conditions: a United Kingdom national study.

OBJECTIVE: To bring together stakeholders in the United Kingdom to establish national priorities for research in single-ventricle heart conditions. METHODS: This study comprised two surveys and a workshop. The initial public online survey asked respondents up to three questions they would like answered for research. Responses were classified as unanswered, already answered, or unable to be answered by scientific research. In the follow-up survey, unanswered questions were divided into categories and respondents were asked to rank categories and questions by priority. A stakeholder workshop attended by patients, parents, healthcare professionals, researchers, and charities was held to determine the final list of research priorities. RESULTS: A total of 128 respondents posed 344 research questions, of which 271 were classified as unanswered, and after removing duplicates, 204 questions remained, which were divided into 20 categories. In the second survey, 56 (49.1%) respondents successfully ranked categories and questions. A total of 39 participants attended the workshop, drawing up a list of 30 research priorities across nine priority categories. The nine priority categories are: Associated co-morbidities; Brain & neurodevelopment; Exercise; Fontan failure; Heart function; Living with a single ventricle heart condition; Management of the well-functioning Fontan circulation; Surgery & perioperative care; and Transplantation, mechanical support & novel therapies. CONCLUSIONS: Through a multi-stage process, we engaged a wide range of interested parties to establish a list of research priorities in single-ventricle heart conditions. This provides a platform for clinicians, researchers, and funders in the United Kingdom and elsewhere to address the most important questions and improve outcomes in these rare but high-impact CHDs.

Investigating flavour characteristics of British ale yeasts: techniques, resources and opportunities for innovation.

Five British ale yeast strains were subjected to flavour profiling under brewery fermentation conditions in which all other brewing parameters were kept constant. Significant variation was observed in the timing and quantity of flavour-related chemicals produced. Genetic tests showed no evidence of hybrid origins in any of the strains, including one strain previously reported as a possible hybrid of Saccharomyces cerevisiae and S. bayanus. Variation maintained in historical S. cerevisiae ale yeast collections is highlighted as a potential source of novelty in innovative strain improvement for bioflavour production.

Sustaining sleep spindles through enhanced SK2-channel activity consolidates sleep and elevates arousal threshold.

Sleep spindles are synchronized 11-15 Hz electroencephalographic (EEG) oscillations predominant during nonrapid-eye-movement sleep (NREMS). Rhythmic bursting in the reticular thalamic nucleus (nRt), arising from interplay between Ca(v)3.3-type Ca(2+) channels and Ca(2+)-dependent small-conductance-type 2 (SK2) K(+) channels, underlies spindle generation. Correlative evidence indicates that spindles contribute to memory consolidation and protection against environmental noise in human NREMS. Here, we describe a molecular mechanism through which spindle power is selectively extended and we probed the actions of intensified spindling in the naturally sleeping mouse. Using electrophysiological recordings in acute brain slices from SK2 channel-overexpressing (SK2-OE) mice, we found that nRt bursting was potentiated and thalamic circuit oscillations were prolonged. Moreover, nRt cells showed greater resilience to transit from burst to tonic discharge in response to gradual depolarization, mimicking transitions out of NREMS. Compared with wild-type littermates, chronic EEG recordings of SK2-OE mice contained less fragmented NREMS, while the NREMS EEG power spectrum was conserved. Furthermore, EEG spindle activity was prolonged at NREMS exit. Finally, when exposed to white noise, SK2-OE mice needed stronger stimuli to arouse. Increased nRt bursting thus strengthens spindles and improves sleep quality through mechanisms independent of EEG slow waves (<4 Hz), suggesting SK2 signaling as a new potential therapeutic target for sleep disorders and for neuropsychiatric diseases accompanied by weakened sleep spindles.

Deconvolution of clinical variance in CAR-T cell pharmacology and response.

Chimeric antigen receptor T cell (CAR-T) expansion and persistence vary widely among patients and predict both efficacy and toxicity. However, the mechanisms underlying clinical outcomes and patient variability are poorly defined. In this study, we developed a mathematical description of T cell responses wherein transitions among memory, effector and exhausted T cell states are coordinately regulated by tumor antigen engagement. The model is trained using clinical data from CAR-T products in different hematological malignancies and identifies cell-intrinsic differences in the turnover rate of memory cells and cytotoxic potency of effectors as the primary determinants of clinical response. Using a machine learning workflow, we demonstrate that product-intrinsic differences can accurately predict patient outcomes based on pre-infusion transcriptomes, and additional pharmacological variance arises from cellular interactions with patient tumors. We found that transcriptional signatures outperform T cell immunophenotyping as predictive of clinical response for two CD19-targeted CAR-T products in three indications, enabling a new phase of predictive CAR-T product development.

Barriers to atrial fibrillation ablation during mitral valve surgery.

BACKGROUND: Nearly 40% of patients with atrial fibrillation (AF) undergoing mitral valve surgery do not receive concomitant ablation despite societal guidelines. We assessed barriers to implementation of this evidence-based practice through a survey of cardiac surgeons in 2 statewide quality collaboratives. METHODS: Adult cardiac surgeons across 2 statewide collaboratives were surveyed on their knowledge and practice regarding AF ablation. Questions concerning experience, clinical practice, case scenarios, and barriers to implementation were included. RESULTS: Among 66 respondents (66 of 135; 48.9%), the majority reported "very comfortable/frequently use" cryoablation (53 of 66; 80.3%) and radiofrequency (55 of 66; 83.3%). Only 12.1% (8/66) were not aware of the recommendations. Approximately one-half of the respondents reported learning AF ablation in fellowship (50.0%; 33 of 66) or attending courses (47.0%; 31 of 66). Responses to clinical scenarios demonstrated wide variability in practice patterns. One-half of the respondents reported no barriers; others cited increased cross-clamp time, excessive patient risk, and arrhythmia incidence as obstacles. Desired interventions included cardiology/electrophysiology support, protocols, pacemaker rate information, and education in the form of site visits, videos and proctors. CONCLUSIONS: Knowledge of evidence-based recommendations and practice patterns vary widely. These data identify several barriers to implementation of concomitant AF ablation and suggest specific interventions (mentorship/support, protocols, research, and education) to overcome these barriers.

Lessons learned from the EACTS-MSTCVS quality fellowship: a call to action for continuous improvement of cardiothoracic surgery outcomes in Europe.

The Michigan Society of Thoracic and Cardiovascular Surgeons (MSTCVS), a pioneer in initiating and nurturing quality improvement strategies in statewide cardiothoracic surgery, has been running the Quality Collaborative (MSTCVS-QC) program since 2001. This initiative has significantly grown over the years, facilitating at least 4 in-person meetings annually. It actively engages cardiac and general thoracic surgeons, data managers and researchers from all 32 non-federally funded cardiothoracic surgery sites across Michigan. Broadening its influence on joint learning and clinical outcomes, the MSTCVS-QC formed a strategic partnership with Blue Cross Blue Shield of Michigan, the state's largest private insurer, to further promote its initiatives. The MSTCVS-QC, operating from a dedicated QC centre employs an STS-associated database with additional aspects for data collection and analysis. The QC centre also organizes audits, facilitates collaborative meetings, disseminates surgical outcomes and champions the development and implementation of quality improvement initiatives related to cardiothoracic surgery in Michigan. Recognizing the MSTCVS-QC's successful efforts in advancing quality improvement, the European Association for Cardiothoracic Surgery (EACTS) introduced a fellowship program in 2018, facilitated through the EACTS Francis Fontan Fund (FFF). This program allows early-career academic physicians to spend 4-6 months with the MSTCVS-QC team in Ann Arbor. This article chronicles the evolution and functionality of the MSTCVS-QC, enriched by the experiences of the inaugural 4 EACTS/FFF fellows. Our objective is to emphasize the critical importance of fostering a culture of quality improvement and patient safety in the field of cardiothoracic surgery with open discussion of audited, high-quality data points. This principle, while implemented locally, has implications and value extending far beyond Europe, resonating globally.

T-type Ca2+ channels, SK2 channels and SERCAs gate sleep-related oscillations in thalamic dendrites.

T-type Ca2+ channels (T channels) underlie rhythmic burst discharges during neuronal oscillations that are typical during sleep. However, the Ca2+-dependent effectors that are selectively regulated by T currents remain unknown. We found that, in dendrites of nucleus reticularis thalami (nRt), intracellular Ca2+ concentration increases were dominated by Ca2+ influx through T channels and shaped rhythmic bursting via competition between Ca2+-dependent small-conductance (SK)-type K+ channels and Ca2+ uptake pumps. Oscillatory bursting was initiated via selective activation of dendritically located SK2 channels, whereas Ca2+ sequestration by sarco/endoplasmic reticulum Ca2+-ATPases (SERCAs) and cumulative T channel inactivation dampened oscillations. Sk2-/- (also known as Kcnn2) mice lacked cellular oscillations, showed a greater than threefold reduction in low-frequency rhythms in the electroencephalogram of non-rapid-eye-movement sleep and had disrupted sleep. Thus, the interplay of T channels, SK2 channels and SERCAs in nRt dendrites comprises a specialized Ca2+ signaling triad to regulate oscillatory dynamics related to sleep.

Basic principles of cardiothoracic surgery training: a position paper by the European Association for Cardiothoracic Surgery Residents Committee.

OBJECTIVES: Across Europe there are significant variations in the fundamental structure and content of cardiothoracic surgery (CTS) training programmes. Previous efforts have been made to introduce a Unified European Training System, which outlined the fundamentals of the ideal programme and supported a paradigm shift from an apprenticeship to a competency-based model. This article's goal was to define key structural, administrative and executive details of such a programme to lay the foundations for the standardization of cardiothoracic surgical training across Europe. METHODS: The European Association for Cardiothoracic Surgery Residents Committee had previously conducted a residents' training survey across Europe in 2020. Training curricula from the twelve most represented countries across Europe were either searched online or obtained from the countries' national trainee representative and reviewed by the committee. Information was collated and placed into one of the following categories to develop the position paper: (i) selection of eligible candidates, (ii) guidance for an outcome-based syllabus, (iii) documentation and evaluation of training progress, (iv) mandatory rotations and training courses, (v) number of independent or assisted cases and (vi) requirements and quality assurance of teachers. RESULTS: An independent professional body should promote an outcome-based syllabus and take responsibility for the training programme's quality assurance. Trainees should be selected on merit by an open and transparent process. Training should be delivered within a defined period and supervised by an appointed training committee to ensure its implementation. This committee should review the trainees progression regularly, provide feedback and offer trainees the opportunity to experience various training environments and trainers. A common electronic portal be used by trainees to record their agreed objectives and to evidence their completion. Trainees should regularly attend specialty-relevant courses and conferences to promote professional and academic development. The end of training is reached when the formal requirements of the training programme are met and the trainee is able to perform at the level expected of a day-1 independent surgeon. CONCLUSIONS: This article defines the key structural, administrative, and executive principles for CTS training. Programmes are encouraged to review and modify their training curricula, if necessary, to ensure the delivery of high-quality, standardized, outcome-orientated CTS training across Europe.

Failure to rescue: variation in mortality after cardiac surgery.

OBJECTIVES: Measures to prevent surgical complications are critical components of optimal patient care, and adequate management when complications occur is equally crucial in efforts to reduce mortality. This study aims to elucidate clinical realities underlying in-hospital variations in failure to rescue (FTR) after cardiac surgery. METHODS: Using a statewide database for a quality improvement program, we identified 62 450 patients who had undergone adult cardiac surgery between 2011 and 2018 in 1 of the 33 Michigan hospitals performing adult cardiac surgery. The hospitals were first divided into tertiles according to their observed to expected (O/E) ratios of 30-day mortality: low-mortality tertile (O/E 0.46-0.78), intermediate-mortality tertile (O/E 0.79-0.90) and high-mortality tertile (O/E 0.98-2.00). We then examined the incidence of 15 significant complications and the rates of death following complications among the 3 groups. RESULTS: A total of 1418 operative deaths occurred in the entire cohort, a crude mortality rate of 2.3% and varied from 1.3% to 5.9% at the hospital level. The death rates also diverged significantly according to mortality score tertiles, from 1.6% in the low-mortality group to 3.2% in the high-mortality group (P < 0.001). Hospitals ranked in a high- or intermediate-mortality tertile had similar rates of overall complications (21.3% and 20.7%, P = 0.17), while low-mortality hospitals had significantly fewer complications (16.3%) than the other 2 tertiles (P < 0.001). FTR increased in a stepwise manner from low- to high-mortality hospitals (8.3% vs 10.0% vs 12.7%, P < 0.001, respectively). Differences in FTR were related to survival after cardiac arrest, multi-system organ failure, prolonged ventilation, reoperation for bleeding and severe acute kidney disease that requires dialysis. CONCLUSIONS: This study demonstrates that timely recognition and appropriate treatment of complications are as important as preventing complications to further reduce operative mortality in cardiac surgery. FTR tools may provide vital information for quality improvement initiatives.

Quality Improvement: Arterial Grafting Redux, 2010:2019.

BACKGROUND: The evidence base favoring utilization of multiple arterial conduits in coronary artery bypass grafting has strengthened in recent years. Nevertheless, utilization of arterial conduits in the US lags behind that of many European peers. We describe a statewide collaborative based approach to improving utilization. METHODS: Four metrics of arterial revascularization were devised. These were displayed and discussed at quarterly statewide quality collaborative meetings from January 2016 onwards, integrated with an educational program regarding attendant benefits. We undertook retrospective review of isolated coronary artery bypass grafting statewide from 2012-2019 to assess impact. RESULTS: A total of 38,523 cases met inclusion/exclusion criteria. Statewide incidence of multiple arterial grafting increased from 7.4% at baseline to 21.7% in 2019 (P < .001), implementation across hospitals varied widely, ranging from 67.6% to 0.0%. Utilization of total arterial revascularization increased 1.9% to 4.4% (P < .001) between time frames. Utilization of both radial artery and bilateral internal thoracic artery conduit increased significantly from 5.3% to 13.2% (P < .001) and 2.1% to 8.5% (P < .001), respectively; radial artery utilization was significantly higher than bilateral internal thoracic artery for each year (P < .001 for all comparisons). CONCLUSIONS: Our statewide quality improvement initiative improved rates of utilization of multiple arterial grafting by all metrics. Barriers to current utilization were identified to guide future quality improvement efforts. This reproducible approach is readily transferable to improve quality of care in other domains and geographical areas.

Genetic deficit of SK3 and IK1 channels disrupts the endothelium-derived hyperpolarizing factor vasodilator pathway and causes hypertension.

BACKGROUND: It has been proposed that activation of endothelial SK3 (K(Ca)2.3) and IK1 (K(Ca)3.1) K+ channels plays a role in the arteriolar dilation attributed to an endothelium-derived hyperpolarizing factor (EDHF). However, our understanding of the precise function of SK3 and IK1 in the EDHF dilator response and in blood pressure control remains incomplete. To clarify the roles of SK3 and IK1 channels in the EDHF dilator response and their contribution to blood pressure control in vivo, we generated mice deficient for both channels. METHODS AND RESULTS: Expression and function of endothelial SK3 and IK1 in IK1(-/-)/SK3(T/T) mice was characterized by patch-clamp, membrane potential measurements, pressure myography, and intravital microscopy. Blood pressure was measured in conscious mice by telemetry. Combined IK1/SK3 deficiency in IK1(-/-)/SK3(T/T) (+doxycycline) mice abolished endothelial K(Ca) currents and impaired acetylcholine-induced smooth muscle hyperpolarization and EDHF-mediated dilation in conduit arteries and in resistance arterioles in vivo. IK1 deficiency had a severe impact on acetylcholine-induced EDHF-mediated vasodilation, whereas SK3 deficiency impaired NO-mediated dilation to acetylcholine and to shear stress stimulation. As a consequence, SK3/IK1-deficient mice exhibited an elevated arterial blood pressure, which was most prominent during physical activity. Overexpression of SK3 in IK1(-/-)/SK3(T/T) mice partially restored EDHF- and nitric oxide-mediated vasodilation and lowered elevated blood pressure. The IK1-opener SKA-31 enhanced EDHF-mediated vasodilation and lowered blood pressure in SK3-deficient IK1(+/+)/SK3(T/T) (+doxycycline) mice to normotensive levels. CONCLUSIONS: Our study demonstrates that endothelial SK3 and IK1 channels have distinct stimulus-dependent functions, are major players in the EDHF pathway, and significantly contribute to arterial blood pressure regulation. Endothelial K(Ca) channels may represent novel therapeutic targets for the treatment of hypertension.

Functional roles of a Ca2+-activated K+ channel in atrioventricular nodes.

Since the first description of the anatomical atrioventricular nodes (AVNs), a large number of studies have provided insights into the heterogeneity of the structure as well as a repertoire of ion channel proteins that govern this complex conduction pathway between the atria and ventricles. These studies have revealed the intricate organization of multiple nodal and nodal-like myocytes contributing to the unique electrophysiology of the AVN in health and diseases. On the other hand, information regarding the contribution of specific ion channels to the function of the AVN remains incomplete. We reason that the identification of AVN-specific ion channels may provide a more direct and rational design of therapeutic target in the control of AVN conduction in atrial flutter/fibrillation, one of the most common arrhythmias seen clinically. In this study, we took advantage of 2 genetically altered mouse models with overexpression or null mutation of 1 of a small conductance Ca2+-activated K+ channel isoform, SK2 channel, and demonstrated robust phenotypes of AVN dysfunction in these experimental models. Overexpression of SK2 channels results in the shortening of the spontaneous action potentials of the AVN cells and an increase in the firing frequency. On the other hand, ablation of the SK2 channel results in the opposite effects on the spontaneous action potentials of the AVN. Furthermore, we directly documented the expression of SK2 channel in mouse AVN using multiple techniques. The new insights may have important implications in providing novel drug targets for the modification of AVN conduction in the treatment of atrial arrhythmias.

SK2 channels are required for function and long-term survival of efferent synapses on mammalian outer hair cells.

Cochlear hair cells use SK2 currents to shape responses to cholinergic efferent feedback from the brain. Using SK2(-/-) mice, we demonstrate that, in addition to their previously defined role in modulating hair cell membrane potentials, SK2 channels are necessary for long-term survival of olivocochlear fibers and synapses. Loss of the SK2 gene also results in loss of electrically driven olivocochlear effects in vivo, and down regulation of ryanodine receptors involved in calcium-induced calcium release, the main inducer of nAChR evoked SK2 activity. Generation of double-null mice lacking both the alpha10 nAChR gene, loss of which results in hypertrophied olivocochlear terminals, and the SK2 gene, recapitulates the SK2(-/-) synaptic phenotype and gene expression, and also leads to down regulation of alpha9 nAChR gene expression. The data suggest a hierarchy of activity necessary to maintain early olivocochlear synapses at their targets, with SK2 serving an epistatic, upstream, role to the nAChRs.

PODO447: a novel antibody to a tumor-restricted epitope on the cancer antigen podocalyxin.

BACKGROUND: The success of new targeted cancer therapies has been dependent on the identification of tumor-specific antigens. Podocalyxin (Podxl) is upregulated on tumors with high metastatic index and its presence is associated with poor outcome, thus emerging as an important prognostic and theragnostic marker in several human cancers. Moreover, in human tumor xenograft models, Podxl expression promotes tumor growth and metastasis. Although a promising target for immunotherapy, the expression of Podxl on normal vascular endothelia and kidney podocytes could hamper efforts to therapeutically target this molecule. Since pathways regulating post-translational modifications are frequently perturbed in cancer cells, we sought to produce novel anti-Podxl antibodies (Abs) that selectively recognize tumor-restricted glycoepitopes on the extracellular mucin domain of Podxl. METHODS: Splenic B cells were isolated from rabbits immunized with a Podxl-expressing human tumor cell line. Abs from these B cells were screened for potent reactivity to Podxl+ neoplastic cell lines but not Podxl+ primary endothelial cells. Transcripts encoding heavy and light chain variable regions from promising B cells were cloned and expressed as recombinant proteins. Tumor specificity was assessed using primary normal tissue and an ovarian cancer tissue microarray (TMA). Mapping of the tumor-restricted epitope was performed using enzyme-treated human tumor cell lines and a glycan array. RESULTS: One mAb (PODO447) showed strong reactivity with a variety of Podxl+ tumor cell lines but not with normal primary human tissue including Podxl+ kidney podocytes and most vascular endothelia. Screening of an ovarian carcinoma TMA (219 cases) revealed PODO447 reactivity with the majority of tumors, including 65% of the high-grade serous histotype. Subsequent biochemical analyses determined that PODO447 reacts with a highly unusual terminal N-acetylgalactosamine beta-1 (GalNAcß1) motif predominantly found on the Podxl protein core. Finally, Ab-drug conjugates showed specific efficacy in killing tumor cells in vitro. CONCLUSIONS: We have generated a novel and exquisitely tumor-restricted mAb, PODO447, that recognizes a glycoepitope on Podxl expressed at high levels by a variety of tumors including the majority of life-threatening high-grade serous ovarian tumors. Thus, tumor-restricted PODO447 exhibits the appropriate specificity for further development as a targeted immunotherapy.

The Role of Regional Collaboratives in Quality Improvement: Time to Organize, and How?

Over the last 12 years, surgeon representatives from the 33 participating hospitals of the Michigan Society of Thoracic and Cardiovascular Surgeons Quality Collaborative (MSTCVS-QC), along with data specialists, surgical and quality improvement (QI) teams, have met at least 4 times a year to improve health-care quality and outcomes of cardiac and general thoracic surgery patients. The MSTCVS-QC nature of interactive learning has allowed all members to examine current data from each site in an unblinded manner for benchmarking, learn from their findings, institute clinically meaningful changes in survival and health-related quality of life, and carefully follow the effects. These meetings have resulted in agreement on various interventions to improve patient selection, periprocedural strategies, and adherence with evidence-based directed medication regimens, Factors contributing to the quality movement across hospitals include statewide-recognized clinicians who are eager to involve themselves in QI initiatives, dedicated health-care professionals at the hospital level, trusting environments in which failure is only a temporary step on the way toward achieving QI goals, real-time analytics of accurate data, and payers who strongly support QI efforts designed to improve outcomes.

Ablation of a Ca2+-activated K+ channel (SK2 channel) results in action potential prolongation in atrial myocytes and atrial fibrillation.

Small conductance Ca(2+)-activated K(+) channels (SK channels) have been reported in excitable cells, where they aid in integrating changes in intracellular Ca(2+) (Ca(2+)(i)) with membrane potential. We have recently reported the functional existence of SK2 channels in human and mouse cardiac myocytes. Moreover, we have found that the channel is predominantly expressed in atria compared to the ventricular myocytes. We hypothesize that knockout of SK2 channels may be sufficient to disrupt the intricate balance of the inward and outward currents during repolarization in atrial myocytes. We further predict that knockout of SK2 channels may predispose the atria to tachy-arrhythmias due to the fact that the late phase of the cardiac action potential is highly susceptible to aberrant excitation. We take advantage of a mouse model with genetic knockout of the SK2 channel gene. In vivo and in vitro electrophysiological studies were performed to probe the functional roles of SK2 channels in the heart. Whole-cell patch-clamp techniques show a significant prolongation of the action potential duration prominently in late cardiac repolarization in atrial myocytes from the heterozygous and homozygous null mutant animals. Moreover, in vivo electrophysiological recordings show inducible atrial fibrillation in the null mutant mice but not wild-type animals. No ventricular arrhythmias are detected in the null mutant mice or wild-type animals. In summary, our data support the important functional roles of SK2 channels in cardiac repolarization in atrial myocytes. Genetic knockout of the SK2 channels results in the delay in cardiac repolarization and atrial arrhythmias.

Contextual memory deficits observed in mice overexpressing small conductance Ca2+-activated K+ type 2 (KCa2.2, SK2) channels are caused by an encoding deficit.

Hippocampal-dependent synaptic plasticity and memory are modulated by apamin-sensitive small conductance Ca2+-activated K+ (SK) channels. Transgenic mice overexpressing SK2 channels (SK2+/T mice) exhibit marked deficits in hippocampal memory and synaptic plasticity, as previously reported. Here, we examined whether SK2 overexpression affects the encoding or retention of contextual memory. Compared with wild-type littermates, SK2+/T mice exhibited significantly less context-dependent freezing 10 min and 24 h after conditioning. Interestingly, this contextual memory impairment was eliminated if SK2+/T mice were permitted longer pre-exposure to the conditioning chamber. These data support converging evidence that SK2 channels restrict the encoding of hippocampal memory.

Hot Off the Press: Hospital Observation Upon Reversal (HOUR) With Naloxone: A Prospective Clinical Prediction Rule Validation Study.

This is a prospective observational study looking to validate a previously derived decision rule designed to help safely discharge opioid overdose patients from the emergency department after 1 hour. They included a convenience sample of 538 adult patients who had received naloxone pre-hospital and compared the Hospital Observation Upon Reversal (HOUR) rule with clinical judgement. The primary outcome of interest was a broadly defined composite of adverse events. The HOUR rule had a sensitivity of 84.1% (95% CI 76.2-92.1%) and a specificity of 62.1% (95% CI 57.6-66.5%), which was very similar to clinical judgement. Clinical judgement would have missed 12 adverse events, while the HOUR rule would have missed 13, although most of those adverse events were probably minor.

A mouse model of episodic ataxia type-1.

Episodic ataxia type-1 (EA1) is a dominant human neurological disorder characterized by stress-induced attacks of ataxia. EA1 is caused by mutations in the voltage-gated potassium channel Kv1.1, and affected individuals are heterozygous. Here we introduced the V408A EA1 mutation into mice using homologous recombination. In contrast to Kv1.1 null mice, homozygous V408A/V408A mice died after embryonic day 3 (E3). V408A/+ mice showed stress-induced loss of motor coordination that was ameliorated by acetazolamide, a carbonic anhydrase inhibitor that minimizes EA1 symptoms in human patients. We made electrophysiological recordings from cerebellar Purkinje cells in both V408A/+ mice and their wild-type littermates. V408A/+ mice showed a greater frequency and amplitude of spontaneous GABAergic inhibitory postsynaptic currents (IPSCs) than did wild type; however, the amplitude or frequency of miniature IPSCs and the basket cell firing frequency did not differ between groups. The stress-induced motor dysfunction in V408A mice is similar to that of family members harboring the EA1 allele, and our findings suggest that these behavioral changes are linked to changes in GABA release.