Effects of acute atrial fibrillation and cardioversion on left and right atrial pressures in a dog.

The occurrence of right-sided congestive heart failure (CHF) in dogs with left-sided heart disease is well-recognized, but its mechanisms are incompletely understood. A 12-year-old Maltese dog was admitted to the clinic for left atrial decompression to treat recurrent CHF due to severe myxomatous mitral valve disease (MMVD). Left atrial decompression was successful but atrial fibrillation (AF) occurred during the procedure. Electric cardioversion restored normal sinus rhythm (NSR) and the dog's recovery was uneventful. This sequence of events made it possible to study intracameral pressures individually in each atrium in a dog with naturally occurring MMVD during AF and again during NSR. Although pressures in both atria declined following cardioversion, the right atrial pressure declined to a greater degree. These findings indicated a disproportionate effect of AF on right atrial pressure. This difference was noteworthy given the long-standing clinical observation that dogs with MMVD have a higher prevalence of right-sided CHF when AF is present. Key clinical message: A dog with MMVD had a greater reduction in right atrial pressure than in left atrial pressure when its AF was cardioverted as part of a cardiac catheterization procedure. This observation proposed a mechanism for the well-known but unexplained observation that dogs with MMVD manifest right-sided CHF disproportionately more often when they have AF.

Effets de la fibrillation auriculaire aiguë et de la cardioversion sur les pressions auriculaires gauche et droite chez un chien. La présence d'une insuffisance cardiaque congestive du côté droit (ICC) chez les chiens atteints d'une cardiopathie du côté gauche est bien connue, mais ses mécanismes ne sont pas complètement compris. Un chien maltais de 12 ans a été admis à la clinique pour une décompression auriculaire gauche afin de traiter une ICC récurrente due à une grave maladie myxomateuse de la valvule mitrale (MMVD). La décompression auriculaire gauche a réussi, mais une fibrillation auriculaire (FA) s'est produite pendant la procédure. La cardioversion électrique a rétabli le rythme sinusal normal (NSR) et la récupération du chien s'est déroulée sans incident. Cette séquence d'événements a permis d'étudier les pressions individuellement dans chaque oreillette chez un chien atteint de MMVD d'origine naturelle pendant la FA et à nouveau pendant la NSR. Bien que les pressions dans les deux oreillettes aient diminué après la cardioversion, la pression de l'oreillette droite a diminué dans une plus grande mesure. Ces résultats ont indiqué un effet disproportionné de la FA sur la pression auriculaire droite. Cette différence était remarquable compte tenu de l'observation clinique de longue date selon laquelle les chiens atteints de MMVD ont une prévalence plus élevée d'ICC du côté droit en cas de FA.Message clinique clé :Un chien atteint de MMVD présentait une réduction plus importante de la pression auriculaire droite que de la pression auriculaire gauche lorsque sa FA était cardiovertie dans le cadre d'une procédure de cathétérisme cardiaque. Cette observation propose un mécanisme pour l'observation bien connue mais inexpliquée selon laquelle les chiens atteints de MMVD manifestent une ICC du côté droit de manière disproportionnée plus souvent lorsqu'ils souffrent de FA.(Traduit par Dr Serge Messier).

Real-World Clinical Performance of a DNA-Based Comprehensive Genomic Profiling Assay for Detecting Targetable Fusions in Nonsquamous NSCLC.

BACKGROUND: Genomic fusions are potent oncogenic drivers across cancer types and many are targetable. We demonstrate the clinical performance of DNA-based comprehensive genomic profiling (CGP) for detecting targetable fusions. MATERIALS AND METHODS: We analyzed targetable fusion genes in >450 000 tissue specimens profiled using DNA CGP (FoundationOne CDx, FoundationOne). Using a de-identified nationwide (US-based) non-small cell lung cancer (NSCLC) clinico-genomic database, we assessed outcomes in patients with nonsquamous NSCLC (NonSqNSCLC) who received matched therapy based on a fusion identified using DNA CGP. Lastly, we modeled the added value of RNA CGP for fusion detection in NonSqNSCLC. RESULTS: We observed a broad diversity of fusion partners detected with DNA CGP in conjunction with targetable fusion genes (ALK, BRAF, FGFR2, FGFR3, NTRK1/2/3, RET, and ROS1). In NonSqNSCLC with oncogenic ALK, NTRK, RET, and ROS1 fusions detected by DNA CGP, patients treated with a matched tyrosine kinase inhibitor had better real-world progression-free survival than those receiving alternative treatment regimens and benefit was observed regardless of the results of orthogonal fusion testing. An estimated 1.3% of patients with NonSqNSCLC were predicted to have an oncogenic driver fusion identified by RNA, but not DNA CGP, according to a model that accounts for multiple real-world factors. CONCLUSION: A well-designed DNA CGP assay is capable of robust fusion detection and these fusion calls are reliable for informing clinical decision-making. While DNA CGP detects most driver fusions, the clinical impact of fusion detection is substantial for individual patients and exhaustive efforts, inclusive of additional RNA-based testing, should be considered when an oncogenic driver is not clearly identified.

Circulating Tumor DNA Enables Sensitive Detection of Actionable Gene Fusions and Rearrangements Across Cancer Types.

PURPOSE: Genomic rearrangements can generate potent oncogenic drivers or disrupt tumor suppressor genes. This study examines the landscape of fusions and rearrangements detected by liquid biopsy (LBx) of circulating tumor DNA (ctDNA) across different cancer types. EXPERIMENTAL DESIGN: LBx from 53,842 patients with 66 solid tumor types were profiled using FoundationOneLiquid CDx, a hybrid-capture sequencing platform that queries 324 cancer-related genes. Tissue biopsies (TBx) profiled using FoundationOneCDx were used as a comparator. RESULTS: Among all LBx, 7,377 (14%) had ≥1 pathogenic rearrangement detected. A total of 3,648 (6.8%) LBx had ≥1 gain-of-function (GOF) oncogene rearrangement, and 4,428 (8.2%) LBx had ≥1 loss-of-function rearrangement detected. Cancer types with higher prevalence of GOF rearrangements included those with canonical fusion drivers: prostate cancer (19%), cholangiocarcinoma (6.4%), bladder (5.5%), and non-small cell lung cancer (4.4%). Although the prevalence of driver rearrangements was lower in LBx than TBx overall, the frequency of detection was comparable in LBx with a tumor fraction (TF) ≥1%. Rearrangements in FGFR2, BRAF, RET, and ALK, were detected across cancer types, but tended to be clonal variants in some cancer types and potential acquired resistance variants in others. CONCLUSIONS: In contrast to some prior literature, this study reports detection of a wide variety of rearrangements in ctDNA. The prevalence of driver rearrangements in tissue and LBx was comparable when TF ≥1%. LBx presents a viable alternative when TBx is not available, and there may be less value in confirmatory testing when TF is sufficient.

Emergency Medical Services Compliance With Prehospital Stroke Quality Metrics Is Associated With Faster Stroke Evaluation and Treatment.

BACKGROUND: Emergency medical services (EMS) is an important link in the stroke chain of recovery. Various prehospital quality metrics have been proposed for prehospital stroke care, but their individual impact is uncertain. We sought to measure associations between EMS quality metrics and downstream stroke care. METHODS: This is a retrospective analysis of a cohort of EMS-transported stroke patients assembled through a linkage between Michigan's EMS and stroke registries. We used multivariable regression to quantify the independent associations between EMS quality metric compliance (dispatch within 90 seconds of 911 call, prehospital stroke screen documentation [Prehospital stroke scale], glucose check, last known well time, maintenance of scene times ≤15 minutes, hospital prenotification, and intravenous line placement) and shorter door-to-CT times (door-to-CT ≤25), accounting for EMS recognition, age, sex, race, stroke subtype, severity, and duration of symptoms. We then developed a simple EMS quality score based on metrics associated with early CT and examined its associations with hospital stroke evaluation times, treatment, and patient outcomes. RESULTS: Five thousand seven hundred seven EMS-transported stroke cases were linked to prehospital records from January 2018 through June 2019. In multivariable analysis, prehospital stroke scale documentation (adjusted odds ratio, 1.4 [1.2-1.6]), glucose check (1.3 [1.1-1.6]), on-scene time ≤15 minutes (1.6 [1.4-1.9]), hospital prenotification ([2.0 [1.4-2.9]), and intravenous line placement (1.8 [1.5-2.1]) were independently associated with a door-to-CT ≤25 minutes. A 5-point quality score (1 point for each element) was therefore developed. In multivariable analysis, a 1-point higher EMS quality score was associated with a shorter time from EMS contact to CT (-9.2 [-10.6 to -7.8] minutes; P<0.001) and thrombolysis (-4.3 [-6.4 to -2.2] minutes; P<0.001), and higher odds of discharge to home (adjusted odds ratio, 1.1 [1.0-1.2]; P=0.002). CONCLUSIONS: Five EMS actions recommended by national guidelines were associated with rapid CT imaging. A simple quality score derived from these measures was also associated with faster stroke evaluation, greater odds of reperfusion treatment, and discharge to home.

Effects of Prior Robot Experience, Speed, and Proximity on Psychosocial Reactions to a Soft Growing Robot.

OCCUPATIONAL APPLICATIONSAfter viewing video vignettes of human interactions with a novel soft growing robot, we found that participants reported fewer perceived safety hazards, less anxiety and fear about robots, reduced social hesitancy about human-robot collaboration (HRC), and lower technology-induced fears of job insecurity. Unlike prior research with traditional rigid manipulators, we found that the manipulated proximity of the human-robot interactions was unrelated to any of these outcomes, suggesting closer interactions may be possible without adverse psychological resistance. On the other hand, fear of robots, perceived hazards, technology-induced job insecurity, and robot anxiety were all significantly lower when human-robot interactions were slower. Interestingly, participants with more extensive prior robot experience displayed preferences for faster HRC interactions. Many occupations are ripe for automation within the next two decades, yet technical and psychological barriers to adoption remain. Our research suggests that novel soft growing flexible robots may be a fruitful area for future advancements.

Background A growing body of literature exists on the determinants of psychosocial reactions to human-robot collaboration (HRC), including prior experience working with robots, speed of human-robot interactions, and the level of proximity between the human and the robot. However, the results from this emerging literature and implications for occupational settings have largely been based on research involving traditional rigid robots.Purpose Advancements in novel soft growing flexible robots necessitate evaluating how and whether such prior research generalizes to this new class of robots.Methods By manipulating the speed and proximity of an HRC task, and by measuring psychosocial robot-related attitudes pre- and post-task among research participants (N = 112), we evaluated the main and interactive effects of speed, proximity, and prior robot experience on perceived safety hazards, fear of robots, robot anxiety, technology-induced job insecurity, and social hesitancy toward robots.Results Following observations of HRC with the novel soft robot, participants perceived fewer safety hazards associated with working with robots, expressed less anxiety and fear about robots, reported less social hesitancy about HRC, and had lower levels of technology-induced fears of job insecurity. Proximity was unrelated to any of these outcomes, whereas fear of robots, perceived hazards, technology-induced job insecurity, and robot anxiety were all significantly lower under slower speed conditions. Finally, participants with more extensive prior robot experience displayed preferences for faster HRC interactions.Conclusions Many occupations are ripe for automation, yet technical and psychological barriers to adoption remain. Our findings indicate potential advantages posed by novel soft growing robots relative to traditional rigid robots. Closer interactions without adverse effects on psychosocial reactions may be possible with this newer class of robots. Developing variable speed soft robots, which can be adjusted as user experience grows, may also be useful technical avenue to pursue.

Safety of TCMCB07, a melanocortin-4 antagonist peptide, in dogs with naturally occurring cachexia.

BACKGROUND: The melanocortin 4 antagonist TCMCB07 is safe and effective in reversing cachexia caused by sepsis or cancer in rodents. The safety and pharmacokinetics of TCMCB07 are demonstrated in healthy beagle dogs. HYPOTHESIS/OBJECTIVES: The objectives of this study were to investigate the safety, peak plasma concentrations, and potential for efficacy of TCMCB07 in pet dogs with naturally occurring cachexia over a 4-week time period. ANIMALS: Fourteen dogs with cachexia of any underlying cause, except cancer of the oral cavity or gastrointestinal tract, were eligible for enrollment with informed client consent. METHODS: This study was a prospective, 1-armed open-label trial. Physical examination, complete blood count, chemistry panel, and owner-assessed quality of life surveys were checked at weeks 1, 2, and 4. Due to potential for bradycardia and hypotension, Holter monitoring and blood pressure evaluations were scheduled at pre-enrollment and week 4. RESULTS: Fourteen dogs completed the trial. Significant changes detected included increased mean body weight (18.6-19.5 kg, P < .02), increased body condition score (median Tufts 5-point thin dog scale score P < .004 and WSAVA muscle condition score P < .02) and increased mean blood urea nitrogen (21.79-30.43 mg dL-1 , P < .004). On quality of life surveys, pet owners perceived their dog appeared to be panting less (P < .002) and that the general health improved (P < .03). Four dogs had a change in coat pigmentation. The peak plasma concentration of TCMCB07 in cachectic dogs was similar to that in healthy beagle dogs. CONCLUSIONS AND CLINICAL IMPORTANCE: TCMCB07 was safe and has potential efficacy in pet dogs with cachexia.

Activating IGF1R hotspot non-frameshift insertions define a novel, potentially targetable molecular subtype of adenoid cystic carcinoma.

Activation of the tyrosine kinase receptor IGF1R is targetable with existing tyrosine kinase inhibitors (TKIs) and monoclonal antibodies, but mutations in IGF1R have not been systematically characterized. Pan-cancer analysis of 326,911 tumors identified two distinct, activating non-frameshift insertion hotspots in IGF1R, which were significantly enriched in adenoid cystic carcinomas (ACCs). IGF1R alterations from 326,911 subjects were analyzed by variant effect prediction class, position within the gene, and cancer type. 6502 (2.0%) samples harbored one or more alterations in IGF1R. Two regions were enriched for non-frameshift insertions: codons 663-666 at the hinge region of the fibronectin type 3 domain and codons 1034-1049 in the tyrosine kinase domain. Hotspot insertions were highly enriched in ACCs (27.3-fold higher than in the remainder of the pan-cancer dataset; P = 2.3 × 10-17). Among salivary gland tumors, IGF1R hotspot insertions were entirely specific to ACCs. IGF1R alterations were most often mutually exclusive with other ACC drivers (9/15, 60%). Tumors with non-frameshift hotspot IGF1R insertions represent a novel, potentially targetable subtype of ACC. Additional studies are needed to determine whether these patients respond to existing IGF1R inhibitors.

Hyperbaric oxygen for the treatment of severe subcutaneous and mediastinal emphysema after Renuvion/J-Plasma therapy®.

Subcutaneous and mediastinal emphysema are known complications of liposuction and body sculpting procedures. Treatment options are limited, and recovery is often prolonged. We discuss a case of severe subcutaneous and mediastinal emphysema after a skin-tightening procedure involving helium gas. The patient received one treatment of hyperbaric oxygen and was followed until symptom resolution. We review the known literature on hyperbaric oxygen therapy as a treatment for subcutaneous emphysema.

Neurodiversity and Intelligence: Evaluating the Flynn Effect in Children with Autism Spectrum Disorder.

The Flynn Effect (FE) among child and adolescent populations indicates that intelligence scores improve by about three points per decade. Using nine years of data from the National Database for Autism Research, this study examined whether general intelligence changed significantly for nine cohorts with autism spectrum disorder (ASD; N = 671). Analyses demonstrated a downward trend such that Cohen's d from 1998 to 2006 was - 0.27. The mean IQ is 92.74 for years 1-3, 91.54 for years 4-6, and 87.34 for years 7-9, indicating a reverse FE of 5.4 points per decade. A linear regression revealed a significant negative FE comparable to the positive effect of age on IQ among those with ASD. Implications for research, practice, and law are discussed.

Left atrial decompression as a palliative minimally invasive treatment for congestive heart failure caused by myxomatous mitral valve disease in dogs: 17 cases (2018-2019).

OBJECTIVE: To determine whether left atrial decompression (LAD) would reduce left atrial pressure (LAP) in dogs with advanced myxomatous mitral valve disease (MMVD) and left-sided congestive heart failure (CHF) and to describe the LAD procedure and hemodynamic alterations and complications. ANIMALS: 17 dogs with advanced MMVD and left-sided CHF that underwent LAD. PROCEDURES: The medical record database was retrospectively reviewed for all LAD procedures attempted in dogs with MMVD and left-sided CHF between October 2018 and June 2019. Data were collected regarding signalment (age, breed, weight, and sex), clinical signs, treatment, physical examination findings, and diagnostic testing before and after LAD. Procedural data were also collected including approach, technique, hemodynamic data, complications, and outcome. RESULTS: 18 LAD procedures performed in 17 patients were identified. Dogs ranged in age from 7.5 to 16 years old (median, 11 years) and ranged in body weight from 2.9 to 11.6 kg (6.4 to 25.5 lb) with a median body weight of 7.0 kg (15.4 lb). Minimally invasive creation of an atrial septal defect for the purpose of LAD was successful in all dogs without any intraoperative deaths. Before LAD, mean LAP was elevated and ranged from 8 to 32 mm Hg with a median value of 14 mm Hg (reference value, < 10 mm Hg). Following LAD, there was a significant decrease in mean LAP (median decrease of 6 mm Hg [range, 1 to 15 mm Hg]). Survival time following LAD ranged from 0 to 478 days (median, 195 days). CONCLUSIONS AND CLINICAL RELEVANCE: For dogs with advanced MMVD and left-sided CHF, LAD resulted in an immediate and substantial reduction in LAP.

The characteristics of dockless electric rental scooter-related injuries in a large U.S. city.

OBJECTIVE: To describe the characteristics of dockless electric rental scooter ("e-scooter")-related injuries presenting to two emergency departments in one large U.S. city. METHODS: This observational cohort study utilized the city's public health syndromic surveillance system to prospectively identify patients with e-scooter-related injuries presenting between September and November 2018. The medical records for all adult patients treated at the two participating emergency departments were manually reviewed to extract demographic and clinical data. Cases involving mobility scooters or non-electric scooters were excluded. RESULTS: For the 124 included adult patients with e-scooter-related injuries, the median age was 30 years (IQR: 22-43), they were predominantly male (59.7%), and approximately half (51.6%) arrived by ambulance. Falling from the scooter (84.7%) was the most common mechanism; twelve patients (9.7%) had collided with a motor vehicle. Head and face injuries (45.5%) were common; only 2 patients (1.6%) were documented as wearing a helmet at the time of injury. Most patients (n = 112, 90.3%) required imaging, more than half (n = 78, 62.9%) required an emergency department procedure, and 26 (21.0%) required surgical intervention. Most patients were discharged home, but 35 (28.2%) were admitted to hospital. Two patients (1.6%) were admitted to the intensive care unit. CONCLUSIONS: E-scooters are an emerging transportation technology associated with a wide range of potentially serious injuries that consume substantial emergency department and hospital resources. Head injuries are a particular concern, as few e-scooter riders are wearing helmets at the time of injury.

Patients with NSCLCs Harboring Internal Inversions or Deletion Rearrangements of the ALK Gene Have Durable Responses to ALK Kinase Inhibitors.

BACKGROUND: ALK fusions are targetable drivers in non-small-cell lung cancer (NSCLC). However, patients with NSCLC harboring ALK rearrangements without a fusion partner identified in DNA have also been shown to respond to ALK inhibitors. We aimed to characterize complex ALK variants that may predict sensitivity to multiple approved ALK inhibitors. METHODS: Comprehensive genomic profiling (CGP) of DNA isolated from formalin-fixed paraffin-embedded (FFPE) tumor tissue or blood-based circulating tumor DNA was performed for 39,159 NSCLC patients during routine clinical care. For a subset of cases, RNA sequencing was performed, and prior ALK test results and clinical treatment information were collected from treating physicians. RESULTS: We queried the Foundation Medicine NSCLC database and identified ALK internal inversions, as well as internal deletions, as the sole ALK rearrangements in 6 (0.02%) and 3 (0.01%) of cases, respectively. In cases with ALK internal inversions, RNA testing identified an EML4-ALK fusion in 2/2 cases evaluated, and 3/3 patients treated with ALK inhibitors had durable responses. A single patient with an ALK internal deletion and clinical data available responded to multiple ALK inhibitors. RNA data available for a subset of non-NSCLC cases suggest that ALK internal deletions removing a portion of the N-terminus are drivers themselves and do not result in ALK fusions. Fluorescence in situ hybridization (FISH) results were inconsistent for both classes of DNA events. CONCLUSION: Rare internal inversions of ALK appear to be indicative of ALK fusions, which can be detected in RNA, and response to ALK inhibitors in patients with NSCLC. In contrast, ALK internal deletions are not associated with ALK fusions in RNA but likely represent targetable drivers themselves. These data suggest that CGP of DNA should be supplemented with immunohistochemistry or RNA-based testing to further resolve these events and match patients to effective therapies.

Graded balloon atrial septostomy for palliation of congenital pulmonary hypertension in a dog: A case report.

CASE DESCRIPTION: A 6-month-old intact female Maltese dog was presented for acute onset of syncope. CLINICAL FINDINGS: The dog was presented for collapse upon excitement and exercise. It collapsed at discharge and suffered cardiopulmonary arrest. Echocardiography after resuscitation indicated severe pulmonary hypertension without evidence of intracardiac or extracardiac shunting. A presumptive diagnosis of congenital pulmonary hypertension was made. TREATMENT AND OUTCOME: Initial treatment with sildenafil was effective at relieving syncope, but the extent of pulmonary hypertension as determined by serial echocardiography was unchanged. Graded balloon atrial septostomy was performed as a palliative procedure. Follow-up echocardiography identified a patent interatrial communication with bidirectional shunting. The dog remained asymptomatic 18 months after treatment. CLINICAL RELEVANCE: To the best of our knowledge, this study is the first report in the veterinary literature of graded balloon atrial septostomy performed for therapeutic purposes. Further studies are required to determine if this palliative procedure is a beneficial treatment option for dogs with congenital or severe refractory pulmonary hypertension.

SMARCA4 inactivation defines a subset of undifferentiated uterine sarcomas with rhabdoid and small cell features and germline mutation association.

A rare subset of aggressive SMARCA4-deficient uterine sarcomas has been recently proposed, with only a limited number of cases having been previously described. Here, we identify 16 additional cases of SMARCA4-deficient uterine sarcoma from the database of a large, CLIA-certified and CAP-accredited, reference molecular laboratory, and we expand on their clinicopathological and genomic features. Median patient's age was 49 years (range 32-70). Most tumors were aggressive with distant metastasis. SMARCA4-deficient uterine sarcoma demonstrated predominantly rhabdoid or large epithelioid cells with abundant cytoplasm, but also had varying degrees of small cell and spindle cell morphology. Tumors were microsatellite stable and exhibited no other or only few co-occurring genomic alterations by comprehensive genomic profiling. We discovered one patient, who developed SMARCA4-deficient uterine sarcoma at the age of 55, had a germline SMARCA4 mutation, whose daughter had previously died of small cell carcinoma of the ovary, hypercalcemic type, at the age of 32. Our data support the notion that SMARCA4 inactivation is the driver oncogenic event of a morphologically and molecularly distinct form of uterine sarcoma. Identification of SMARCA4-deficient uterine sarcomas may be clinically important due to their aggressive behavior, germline association, and emerging targeted therapies.

Identification of NTRK fusions in pediatric mesenchymal tumors.

BACKGROUND: NTRK fusions are known oncogenic drivers and have recently been effectively targeted by investigational agents in adults. We sought to assess the frequency of NTRK fusions in a large series of pediatric and adolescent patients with advanced cancers. PROCEDURE: Genomic profiles from 2,031 advanced cancers from patients less than 21 years old who were assayed with comprehensive genomic profiling were reviewed to identify NTRK fusions. RESULTS: Total of nine cases (0.44%) harbored NTRK fusions, including novel partners. Four of these cases were in children less than 2 years old for which infantile fibrosarcoma was considered as a diagnosis, and two harbored the canonical ETV6-NTRK3. The remaining cases carried other diagnoses, at least one that carried the diagnosis of inflammatory myofibroblastic tumor. CONCLUSIONS: NTRK fusions occur in a subset of young patients with mesenchymal or sarcoma-like tumors at a low frequency, and are eminently druggable targets via either investigational agents or approved drugs.

A Fatal Case of Neuroinvasive West Nile Virus Infection in an Immunocompromised Host.

The neuroinvasive form of West Nile disease is an uncommon manifestation of the viral infection. To date, documented cases in Michigan of neuroinvasive decompensation from this virus have been rare. Evaluation requires a broad differential diagnosis and treatment options are still quite limited. Objective evaluations entailing physical exam and radiographic and laboratory changes are nonspecific. Serologic testing of cerebrospinal fluid by enzyme immunoassay remains the gold standard for diagnosis. However, IgM antibodies typically do not develop until after the fourth to seventh day of symptom onset. This retrospective case report presents an immunocompromised male patient in his mid-70s in whom neuroinvasive West Nile virus was diagnosed postmortem. All information was obtained from the patient's electronic health record. This patient's immunocompromised state at the time of West Nile exposure made him more susceptible to neuroinvasive disease progression and ultimately influenced the outcome. Prior to withdrawing care, the patient was treated for methicillin sensitive staphylococcus aureus (MSSA) cellulitis and Type 1 Herpes Simplex virus. In this case, neuroinvasive West Nile virus was a less likely diagnosis given the patient's physical exam findings and the context of more likely alternative explanations for his cognitive decline. Treatment options for neuroinvasive forms of West Nile virus are still supportive and would not have altered the patient's hospital course. This case report demonstrates that clinicians must maintain an ongoing index of suspicion for infection in warmer climates where West Nile is becoming more prevalent. Given some patients' obscure physical exam findings and radiographic imaging results, a thorough history with laboratory conformation is required for a more conclusive diagnosis.

Comprehensive Genomic Profiling Identifies a Subset of Crizotinib-Responsive ALK-Rearranged Non-Small Cell Lung Cancer Not Detected by Fluorescence In Situ Hybridization.

INTRODUCTION: For patients with non-small cell lung cancer (NSCLC) to benefit from ALK inhibitors, sensitive and specific detection of ALK genomic rearrangements is needed. ALK break-apart fluorescence in situ hybridization (FISH) is the U.S. Food and Drug Administration approved and standard-of-care diagnostic assay, but identification of ALK rearrangements by other methods reported in NSCLC cases that tested negative for ALK rearrangements by FISH suggests a significant false-negative rate. We report here a large series of NSCLC cases assayed by hybrid-capture-based comprehensive genomic profiling (CGP) in the course of clinical care. MATERIALS AND METHODS: Hybrid-capture-based CGP using next-generation sequencing was performed in the course of clinical care of 1,070 patients with advanced lung cancer. Each tumor sample was evaluated for all classes of genomic alterations, including base-pair substitutions, insertions/deletions, copy number alterations and rearrangements, as well as fusions/rearrangements. RESULTS: A total of 47 patients (4.4%) were found to harbor ALK rearrangements, of whom 41 had an EML4-ALK fusion, and 6 had other fusion partners, including 3 previously unreported rearrangement events: EIF2AK-ALK, PPM1B-ALK, and PRKAR1A-ALK. Of 41 patients harboring ALK rearrangements, 31 had prior FISH testing results available. Of these, 20 were ALK FISH positive, and 11 (35%) were ALK FISH negative. Of the latter 11 patients, 9 received crizotinib based on the CGP results, and 7 achieved a response with median duration of 17 months. CONCLUSION: Comprehensive genomic profiling detected canonical ALK rearrangements and ALK rearrangements with noncanonical fusion partners in a subset of patients with NSCLC with previously negative ALK FISH results. In this series, such patients had durable responses to ALK inhibitors, comparable to historical response rates for ALK FISH-positive cases. IMPLICATIONS FOR PRACTICE: Comprehensive genomic profiling (CGP) that includes hybrid capture and specific baiting of intron 19 of ALK is a highly sensitive, alternative method for identification of drug-sensitive ALK fusions in patients with non-small cell lung cancer (NSCLC) who had previously tested negative using standard ALK fluorescence in situ hybridization (FISH) diagnostic assays. Given the proven benefit of treatment with crizotinib and second-generation ALK inhibitors in patients with ALK fusions, CGP should be considered in patients with NSCLC, including those who have tested negative for other alterations, including negative results using ALK FISH testing.

Training experts in family medicine teaching.

Family medicine teachers require specific educational skills. A framework for their professional development is essential for future development of the discipline in Europe. EURACT developed a framework on educational expertise, and subsequently applied it in a curriculum of teaching-skills courses of various levels. The aim of this article is to describe the development of the teaching framework, and of an international three-level course programme for 'teaching-the-teachers'. Furthermore, we describe our experiences and lessons learned, in particular with regard to the level-three programme for proficient teachers, which was new. We conclude that it is possible to develop a theoretical framework of family medicine teaching expertise and to apply it in an international high-level educational programme for future experts in family medicine education. Research evidence of the usefulness of this approach is needed, and the threats for its further development into a sustainable activity are its high teacher/student ratio associated with relatively high costs and difficulties in recruiting suitable participants.