Connectome-driven neural inventory of a complete visual system.

Vision provides animals with detailed information about their surroundings, conveying diverse features such as color, form, and movement across the visual scene. Computing these parallel spatial features requires a large and diverse network of neurons, such that in animals as distant as flies and humans, visual regions comprise half the brain's volume. These visual brain regions often reveal remarkable structure-function relationships, with neurons organized along spatial maps with shapes that directly relate to their roles in visual processing. To unravel the stunning diversity of a complex visual system, a careful mapping of the neural architecture matched to tools for targeted exploration of that circuitry is essential. Here, we report a new connectome of the right optic lobe from a male Drosophila central nervous system FIB-SEM volume and a comprehensive inventory of the fly's visual neurons. We developed a computational framework to quantify the anatomy of visual neurons, establishing a basis for interpreting how their shapes relate to spatial vision. By integrating this analysis with connectivity information, neurotransmitter identity, and expert curation, we classified the ~53,000 neurons into 727 types, about half of which are systematically described and named for the first time. Finally, we share an extensive collection of split-GAL4 lines matched to our neuron type catalog. Together, this comprehensive set of tools and data unlock new possibilities for systematic investigations of vision in Drosophila, a foundation for a deeper understanding of sensory processing.

Limited Axial Interpretation of Coronary CT Angiography in the Emergency Department Setting.

PURPOSE: Incorporating coronary CT angiographic (CCTA) imaging into emergency department (ED) workflows has been limited by the need for 24/7 real-time postprocessing. The aim of this study was to determine whether interpretation of transaxial CCTA images alone (limited axial interpretation [LI]) is noninferior to interpretation of combined transaxial and multiplanar reformation images (full interpretation [FI]) in assessing patients with acute chest pain in the ED. METHODS: CCTA examinations from 74 patients were evaluated by two radiologists, one without dedicated CCTA training and one with basic CCTA experience. Each examination was evaluated three times in separate sessions, once by LI and twice by FI, in random order. Nineteen coronary artery segments were rated as having significant stenoses (≥50%) or not. Interreader agreement was assessed using Cohen's κ statistic. The primary analysis was whether the accuracy of LI for detecting significant stenosis was noninferior to that of FI at the patient level (margin = -10%). Secondary analyses included similar analyses of sensitivity and specificity, at both the patient and vessel levels. RESULTS: Interreader agreement for significant stenosis was good for both LI and FI (κ = 0.72 vs 0.70, P = .74). Average accuracy for significant stenosis at the patient level was 90.5% for LI and 91.9% for FI, with a difference of -1.4%. The accuracy of LI was noninferior to FI, because the confidence interval did not include the noninferiority margin. Noninferiority was also found for patient-level sensitivity and for accuracy, sensitivity, and specificity at the vessel level. CONCLUSIONS: LI of the coronary arteries using transaxial CCTA images may be sufficient for the detection of significant coronary artery disease in the ED setting.

Gene Variants Implicated in Steatotic Liver Disease: Opportunities for Diagnostics and Therapeutics.

Non-alcoholic fatty liver disease (NAFLD) describes a steatotic (or fatty) liver occurring as a consequence of a combination of metabolic, environmental, and genetic factors, in the absence of significant alcohol consumption and other liver diseases. NAFLD is a spectrum of conditions. Steatosis in the absence of inflammation is relatively benign, but the disease can progress into more severe forms like non-alcoholic steatohepatitis (NASH), liver cirrhosis, and hepatocellular carcinoma. NAFLD onset and progression are complex, as it is affected by many risk factors. The interaction between genetic predisposition and other factors partially explains the large variability of NAFLD phenotype and natural history. Numerous genes and variants have been identified through large-scale genome-wide association studies (GWAS) that are associated with NAFLD and one or more subtypes of the disease. Among them, the largest effect size and most consistent association have been patatin-like phospholipase domain-containing protein 3 (PNPLA3), transmembrane 6 superfamily member 2 (TM6SF2), and membrane-bound O-acyltransferase domain containing 7 (MBOAT7) genes. Extensive in vitro and in vivo studies have been conducted on these variants to validate these associations. The focus of this review is to highlight the genetics underpinning the molecular mechanisms driving the onset and progression of NAFLD and how they could potentially be used to improve genetic-based diagnostic testing of the disease and develop personalized, targeted therapeutics.

Telemedicine vs Face-to-Face for Nursing Home Residents With Acute Presentations: A Noninferiority Study.

OBJECTIVES: Telemedicine and face-to-face outreach services to nursing homes (NHs) have been used to reduce hospital utilization rates for acute presentations. However, how these modalities compare against each other is unclear. This article examines if the management of acute presentations in NHs with care involving telemedicine is noninferior to care delivered face-to-face. DESIGN: A noninferiority study was conducted on a prospective cohort. Face-to-face intervention involved on-site assessment by a geriatrician and aged care clinical nurse specialist (CNS). Telemedicine intervention involved on-site assessment by an aged care CNS with telemedicine input by a geriatrician. SETTING AND PARTICIPANTS: A total of 438 NH residents with acute presentations from 17 NHs between November 2021 and June 2022. METHODS: Between-group differences in proportion of residents successfully managed on-site and mean number of encounters were evaluated using bootstrapped multiple linear regression; 95% CIs were compared against predefined noninferiority margins with noninferiority P values calculated. RESULTS: In the adjusted models, care involving telemedicine demonstrated noninferiority in the difference in proportion of residents successfully managed on-site (95% CI lower limit -6.2% to -1.4% vs -10% noninferiority margin; P < .001 for noninferiority) but not in the difference in mean number of encounters (95% CI upper limit 1.42 to 1.50 encounters vs 1 encounter noninferiority margin; P = .7 for noninferiority). CONCLUSIONS AND IMPLICATIONS: In our model of care, care that involved telemedicine was noninferior to care delivered face-to-face in managing NH residents with acute presentations on-site. However, additional encounters may be required. Application of telemedicine ought to be tailored to fit the needs and preferences of stakeholders.

The Quality and Safety of Sedation and Monitoring in Adults Undergoing Nonoperative Transesophageal Echocardiography.

Sedation is an essential component of the transesophageal echocardiography (TEE) procedure for patient comfort. The use and the clinical implications of cardiologist-supervised (CARD-Sed) versus anesthesiologist-supervised sedation (ANES-Sed) are unknown. We reviewed nonoperative TEE records from a single academic center over a 5-year period and identified CARD-Sed and ANES-Sed cases. We evaluated the impact of patient co-morbidities, cardiac abnormalities on transthoracic echocardiogram, and the indication for TEE on sedation practice. We analyzed the use of CARD-Sed versus ANES-Sed in light of institutional guidelines; the consistency in the documentation of preprocedural risk stratification; and the incidence of cardiopulmonary events, including hypotension, hypoxia, and hypercarbia. A total of 914 patients underwent TEE, with 475 patients (52%) receiving CARD-Sed and 439 patients (48%) receiving ANES-Sed. The presence of obstructive sleep apnea (p = 0.008), a body mass index of >45 kg/m2 (p <0.001), an ejection fraction of <30% (p <0.001), and pulmonary artery systolic pressure of more than 40 mm Hg (p = 0.015) were all associated with the use of ANES-Sed. Of the 178 patients (19.5%) with at least 1 caution to nonanesthesiologist-supervised sedation by the institutional screening guideline, 65 patients (36.5%) underwent CARD-Sed. In the ANES-Sed group, where intraprocedural vital signs and medications were documented in all cases, hypotension (n = 91, 20.7%), vasoactive medication use (n = 121, 27.6%), hypoxia (n = 35, 8.0%), and hypercarbia (n = 50, 11.4%) were noted. This single-center study revealed that 48% of the nonoperative TEE used ANES-Sed over 5 years. Sedation-related hemodynamic changes and respiratory events were not infrequently encountered during ANES-Sed.

Sudden cardiac death as a consequence of Cor triatriatum sinistrum in an adult.

Cor triatriatum sinistrum (CTS) is a rare congenital cardiac malformation in which the left atrium is divided by a fenestrated membrane, which can restrict blood flow and cause symptoms of congestive heart failure. Rarely, the condition can present in adulthood. This case report illustrates a case of sudden cardiac death (SCD) due to the sequelae of untreated CTS. To date, there are no reported cases of SCD attributable to CTS. Learning objectives: Cor triatriatum sinistrum is among the rarest of congenital heart diseases. In this case report, we describe the prevalence, etiology, diagnosis, and management of this disease.

The need for unbiased genetic screens to dissect aggression in Drosophila melanogaster.

Aggression is an evolutionarily conserved behavior present in most animals and is necessary for survival when competing for limited resources and mating partners. Studies have shown that aggression is modulated both genetically and epigenetically, but details of how the molecular and cellular mechanisms interact to determine aggressive behavior remain to be elucidated. In recent decades, Drosophila melanogaster has emerged as a powerful model system to understand the mechanisms that regulate aggression. Surprisingly most of the findings discovered to date have not come from genetic screens despite the fly's long and successful history of using screens to unravel its biology. Here, we highlight the tools and techniques used to successfully screen for aggression-linked behavioral elements in Drosophila and discuss the potential impact future screens have in advancing our knowledge of the underlying genetic and neural circuits governing aggression.

Recurrent sudden cardiac death secondary to anomalous right coronary artery: Insights into prevalence and management.

A 32-year-old woman presented after ventricular fibrillation arrest requiring three defibrillations. The episode coincided with an upper respiratory infection and physical exertion. Eight years prior, she survived another cardiac arrest of unknown cause during childbirth. This time, imaging revealed an anomalous right coronary artery connecting to the left coronary cusp, with a small, slit-like osteal orifice coursing between the aorta and pulmonary artery. Surgical exploration revealed an intramural segment of the right coronary artery, which was surgically unroofed with improvement in cardiac function. An implantable cardioverter-defibrillator was implanted for secondary prevention of sudden cardiac death. Surgery is recommended for malignant anomalous coronary arteries, with a very low risk of recurrence of arrhythmia and sudden cardiac death after surgery. However, with growing evidence for persistent risk of arrhythmia and sudden cardiac death even after surgical correction of the anomalous coronary arteries, more experts choose to take secondary prevention measures as a component of initial management.

A pathogenic mechanism associated with myopathies and structural birth defects involves TPM2-directed myogenesis.

Nemaline myopathy (NM) is the most common congenital myopathy, characterized by extreme weakness of the respiratory, limb, and facial muscles. Pathogenic variants in Tropomyosin 2 (TPM2), which encodes a skeletal muscle-specific actin binding protein essential for sarcomere function, cause a spectrum of musculoskeletal disorders that include NM as well as cap myopathy, congenital fiber type disproportion, and distal arthrogryposis (DA). The in vivo pathomechanisms underlying TPM2-related disorders are unknown, so we expressed a series of dominant, pathogenic TPM2 variants in Drosophila embryos and found 4 variants significantly affected muscle development and muscle function. Transient overexpression of the 4 variants also disrupted the morphogenesis of mouse myotubes in vitro and negatively affected zebrafish muscle development in vivo. We used transient overexpression assays in zebrafish to characterize 2 potentially novel TPM2 variants and 1 recurring variant that we identified in patients with DA (V129A, E139K, A155T, respectively) and found these variants caused musculoskeletal defects similar to those of known pathogenic variants. The consistency of musculoskeletal phenotypes in our assays correlated with the severity of clinical phenotypes observed in our patients with DA, suggesting disrupted myogenesis is a potentially novel pathomechanism of TPM2 disorders and that our myogenic assays can predict the clinical severity of TPM2 variants.

Long-Term Outcomes and Risk Stratification of Patients With Heart Failure With Recovered Ejection Fraction.

This study aimed to understand the long-term outcomes of patients with heart failure with recovered ejection fraction, identify predictors of adverse events, and develop a risk stratification model. From an academic healthcare system, we retrospectively identified 133 patients (median age 66, 38% female, 30% ischemic etiology) who had an improvement in left ventricular ejection fraction (LVEF) from <40% to ≥53%. Significant predictors of all-cause mortality, hospitalization, and future reduction in LVEF were identified through Cox regression analysis. Kaplan-Meier survival was 70% at 5 years. Freedom from hospitalization was 58% at 1 year, and the risk of future LVEF reduction to <40% was 28% at 3 years. Diuretic dose and B-type natriuretic peptide (BNP) at the time of LVEF recovery were the strongest predictors of mortality and hospitalization in multivariate-adjusted analysis (BNP hazard ratio 1.13 per 100 pg/ml increase [p <0.01]; furosemide-equivalent dose hazard ratio 1.19 per 40 mg increase [p = 0.02]). An all-cause mortality Cox proportional hazard risk model incorporating New York Heart Association functional class, BNP and diuretic dose at the time of recovery showed excellent risk discrimination (c-statistic 0.79) and calibration. In conclusion, patients with heart failure with recovered ejection fraction have heterogenous clinical outcomes and are not "cured." A risk model using New York Heart Association functional class, BNP, and diuretic dose can accurately stratify mortality risk.

Relation of Progression of Coronary Artery Calcium to Dementia (from the Multi-Ethnic Study of Atherosclerosis).

Baseline coronary artery calcification has been shown to be associated with dementia. However, the value of coronary artery calcium (CAC) progression in the prediction of dementia remains unclear. In this study, we examined the association between CAC progression and dementia in the Multi-Ethnic Study of Atherosclerosis. The Multi-Ethnic Study of Atherosclerosis is a prospective study consisting of 6,814 participants 45 to 84 years of age, free of overt cardiovascular disease at baseline. A total of 5,570 subjects had baseline and follow-up CAC scans approximately 2.5 years apart and were included this analysis. A total of 4,173 of these participants completed cognitive testing with the Cognitive Abilities Screening Instrument (CASI) approximately 10 years after the baseline CAC scan. Dementia diagnoses were identified using International Classification of Diseases codes from hospitalizations, death certificates, and medications used to treat dementia. The absolute change between baseline and follow-up CAC was used to assess CAC progression. Cox proportional hazards and multivariable linear regression models were used to examine the association of CAC progression with incident dementia and with CASI score. Over a median follow-up of 13.2 (interquartile range: 11.2 to 15.3) years, 350 participants developed incident dementia. CAC progression showed no association with dementia risk after adjustment for age, gender, race/ethnicity, vascular risk factors, and baseline CAC score. There was no association of CAC progression with CASI score in any adjusted model. In conclusion, progression of CAC over approximately 2.5 years was not associated with increased risk of dementia after adjustment for demographic variables, vascular risk factors, and baseline CAC.

Outcomes in Takotsubo Syndrome Following Left Ventricular Ejection Fraction Improvement.

Takotsubo syndrome (TTS) is evaluated by monitoring of left ventricular (LV) ejection fraction (LVEF); however, there are limited data to correlate echocardiographic findings with long-term outcomes. This study assessed clinical outcomes in patients with TTS and their association with echocardiographic parameters. Echocardiographic parameters at the time of diagnosis and on first follow-up were collected for 115 consecutive patients (58.5 ± 15.2 years, 74.8% women) diagnosed with TTS. The primary clinical end points were all-cause mortality and time to first readmission. Cox proportional hazard analysis was used to assess the association between echocardiographic parameters and clinical end points. Mean baseline LVEF and global longitudinal strain (GLS) were 37.1 ± 10.7% and -8.5 ± 3.4%, respectively. On follow-up echocardiogram at median of 14 days, LVEF and GLS improved to 58.7 ± 9.3% and -14.2 ± 4.0%, respectively. Most patients (83%) experienced normalization of LVEF (>50%), whereas only 20% had normalization of LV-GLS (<-18%). A total of 99 patients had clinical follow-up after the second echocardiogram with a median follow-up time of 1.3 years. Estimated Kaplan-Meier survival at 2 years was 80% (95% confidence interval 69% to 88%), and median time to readmission was 226 days. There was no significant association between any of the echocardiographic parameters (including LV end-diastolic diameter and baseline, follow-up, and differential LVEF and GLS) and our clinical end points. Zero deaths and only 10.4% of first readmissions were from cardiovascular causes. This suggests that although cardiology follow-up with repeat imaging is important after TTS, additional follow-up with noncardiology specialists is essential to improve outcomes.

Transesophageal echocardiography simulation: A review of current technology.

Transesophageal echocardiography (TEE) has experienced tremendous increase in interest and demand alongside the rapid growth of transcatheter structural cardiac interventions. TEE instruction prolongs the procedure, increasing the risk of probe malfunction from overheating and patient complications from prolonged sedation. Echocardiographic simulation programs have been developed to hone the procedural skills of novice operators in a time-unrestricted, low-pressure environment before they perform TEEs on real patients. Simulators likely benefit training in interventional TEE for the same reasons. We searched PubMed, basic Google, and Google Scholar for currently marketed TEE simulators, including foreign as well as US companies. We queried the vendors regarding features of the simulators that pertain to effective instructional design for diagnostic TEE. We also queried regarding the simulators' applicability to training in interventional TEE. The vendors' responses are reported here. In addition, we discuss the specific training needs for structural heart interventions, for which echocardiographic simulation could be a powerful educational tool. Lastly, we discuss the role of simulation for formative and summative assessment, and the advances required to improve training in complex procedures within the field of interventional echocardiography.

Cancer: The role of iron and ferroptosis.

Iron is an essential element for virtually all living things. Body iron levels are tightly controlled as both increased iron levels and iron deficiency are associated with many clinical conditions. Increased iron levels are associated with a worse prognosis in some cancers, so understanding the role of iron in cancer development has thus been an active area of research. Regulated forms of cell death are important in development and disease pathogenesis. In this Medicine in Focus review article, we discuss the role of iron in cancer, and ferroptosis, a new form of iron-regulated cell death triggered by increased iron and peroxidation of lipids. We also review the pathogenesis of cancer, potential therapeutics for targeting the increased requirement of iron, as well as how ferroptosis activation may have a role in treatment of cancers.

A genetic screen for regulators of muscle morphogenesis in Drosophila.

The mechanisms that determine the final topology of skeletal muscles remain largely unknown. We have been developing Drosophila body wall musculature as a model to identify and characterize the pathways that control muscle size, shape, and orientation during embryogenesis. Our working model argues muscle morphogenesis is regulated by (1) extracellular guidance cues that direct muscle cells toward muscle attachment sites, and (2) contact-dependent interactions between muscles and tendon cells. While we have identified several pathways that regulate muscle morphogenesis, our understanding is far from complete. Here, we report the results of a recent EMS-based forward genetic screen that identified a myriad of loci not previously associated with muscle morphogenesis. We recovered new alleles of known muscle morphogenesis genes, including back seat driver, kon-tiki, thisbe, and tumbleweed, arguing our screen had the depth and precision to uncover myogenic genes. We also identified new alleles of spalt-major, barren, and patched that presumably disrupt independent muscle morphogenesis pathways. Equally as important, our screen shows that at least 11 morphogenetic loci remain to be mapped and characterized. Our screen has developed exciting new tools to study muscle morphogenesis, which may provide future insights into the mechanisms that regulate skeletal muscle topology.

Cardiac Arrest during Transesophageal Echocardiogram (TEE) due to Acute Right Ventricular Failure.

The case of a patient who suffered cardiac arrest while undergoing transesophageal echocardiography (TEE) is presented here. A 75-year-old man with moderate right ventricular (RV) dysfunction and pulmonary hypertension became bradycardic and hypotensive after receiving propofol for procedural sedation. His profound hypotension ultimately led to a pulseless electrical activity (PEA) cardiac arrest. TEE images captured immediately prior to cardiac arrest show a severely dilated and hypokinetic RV, consistent with acute right ventricular failure. This case highlights the potentially fatal consequences of procedural sedation in patients with RV dysfunction and pulmonary hypertension.

A connectome and analysis of the adult Drosophila central brain.

The neural circuits responsible for animal behavior remain largely unknown. We summarize new methods and present the circuitry of a large fraction of the brain of the fruit fly Drosophila melanogaster. Improved methods include new procedures to prepare, image, align, segment, find synapses in, and proofread such large data sets. We define cell types, refine computational compartments, and provide an exhaustive atlas of cell examples and types, many of them novel. We provide detailed circuits consisting of neurons and their chemical synapses for most of the central brain. We make the data public and simplify access, reducing the effort needed to answer circuit questions, and provide procedures linking the neurons defined by our analysis with genetic reagents. Biologically, we examine distributions of connection strengths, neural motifs on different scales, electrical consequences of compartmentalization, and evidence that maximizing packing density is an important criterion in the evolution of the fly's brain.

Animal brains of all sizes, from the smallest to the largest, work in broadly similar ways. Studying the brain of any one animal in depth can thus reveal the general principles behind the workings of all brains. The fruit fly Drosophila is a popular choice for such research. With about 100,000 neurons ­ compared to some 86 billion in humans ­ the fly brain is small enough to study at the level of individual cells. But it nevertheless supports a range of complex behaviors, including navigation, courtship and learning. Thanks to decades of research, scientists now have a good understanding of which parts of the fruit fly brain support particular behaviors. But exactly how they do this is often unclear. This is because previous studies showing the connections between cells only covered small areas of the brain. This is like trying to understand a novel when all you can see is a few isolated paragraphs. To solve this problem, Scheffer, Xu, Januszewski, Lu, Takemura, Hayworth, Huang, Shinomiya et al. prepared the first complete map of the entire central region of the fruit fly brain. The central brain consists of approximately 25,000 neurons and around 20 million connections. To prepare the map ­ or connectome ­ the brain was cut into very thin 8nm slices and photographed with an electron microscope. A three-dimensional map of the neurons and connections in the brain was then reconstructed from these images using machine learning algorithms. Finally, Scheffer et al. used the new connectome to obtain further insights into the circuits that support specific fruit fly behaviors. The central brain connectome is freely available online for anyone to access. When used in combination with existing methods, the map will make it easier to understand how the fly brain works, and how and why it can fail to work correctly. Many of these findings will likely apply to larger brains, including our own. In the long run, studying the fly connectome may therefore lead to a better understanding of the human brain and its disorders. Performing a similar analysis on the brain of a small mammal, by scaling up the methods here, will be a likely next step along this path.