Neuronal wiring diagram of an adult brain.

Connections between neurons can be mapped by acquiring and analysing electron microscopic brain images. In recent years, this approach has been applied to chunks of brains to reconstruct local connectivity maps that are highly informative1-6, but nevertheless inadequate for understanding brain function more globally. Here we present a neuronal wiring diagram of a whole brain containing 5 × 107 chemical synapses7 between 139,255 neurons reconstructed from an adult female Drosophila melanogaster8,9. The resource also incorporates annotations of cell classes and types, nerves, hemilineages and predictions of neurotransmitter identities10-12. Data products are available for download, programmatic access and interactive browsing and have been made interoperable with other fly data resources. We derive a projectome-a map of projections between regions-from the connectome and report on tracing of synaptic pathways and the analysis of information flow from inputs (sensory and ascending neurons) to outputs (motor, endocrine and descending neurons) across both hemispheres and between the central brain and the optic lobes. Tracing from a subset of photoreceptors to descending motor pathways illustrates how structure can uncover putative circuit mechanisms underlying sensorimotor behaviours. The technologies and open ecosystem reported here set the stage for future large-scale connectome projects in other species.

SLEAP: A deep learning system for multi-animal pose tracking.

The desire to understand how the brain generates and patterns behavior has driven rapid methodological innovation in tools to quantify natural animal behavior. While advances in deep learning and computer vision have enabled markerless pose estimation in individual animals, extending these to multiple animals presents unique challenges for studies of social behaviors or animals in their natural environments. Here we present Social LEAP Estimates Animal Poses (SLEAP), a machine learning system for multi-animal pose tracking. This system enables versatile workflows for data labeling, model training and inference on previously unseen data. SLEAP features an accessible graphical user interface, a standardized data model, a reproducible configuration system, over 30 model architectures, two approaches to part grouping and two approaches to identity tracking. We applied SLEAP to seven datasets across flies, bees, mice and gerbils to systematically evaluate each approach and architecture, and we compare it with other existing approaches. SLEAP achieves greater accuracy and speeds of more than 800 frames per second, with latencies of less than 3.5 ms at full 1,024 × 1,024 image resolution. This makes SLEAP usable for real-time applications, which we demonstrate by controlling the behavior of one animal on the basis of the tracking and detection of social interactions with another animal.

FlyWire: online community for whole-brain connectomics.

Due to advances in automated image acquisition and analysis, whole-brain connectomes with 100,000 or more neurons are on the horizon. Proofreading of whole-brain automated reconstructions will require many person-years of effort, due to the huge volumes of data involved. Here we present FlyWire, an online community for proofreading neural circuits in a Drosophila melanogaster brain and explain how its computational and social structures are organized to scale up to whole-brain connectomics. Browser-based three-dimensional interactive segmentation by collaborative editing of a spatially chunked supervoxel graph makes it possible to distribute proofreading to individuals located virtually anywhere in the world. Information in the edit history is programmatically accessible for a variety of uses such as estimating proofreading accuracy or building incentive systems. An open community accelerates proofreading by recruiting more participants and accelerates scientific discovery by requiring information sharing. We demonstrate how FlyWire enables circuit analysis by reconstructing and analyzing the connectome of mechanosensory neurons.

Predictive whisker kinematics reveal context-dependent sensorimotor strategies.

Animals actively move their sensory organs in order to acquire sensory information. Some rodents, such as mice and rats, employ cyclic scanning motions of their facial whiskers to explore their proximal surrounding, a behavior known as whisking. Here, we investigated the contingency of whisking kinematics on the animal's behavioral context that arises from both internal processes (attention and expectations) and external constraints (available sensory and motor degrees of freedom). We recorded rat whisking at high temporal resolution in 2 experimental contexts-freely moving or head-fixed-and 2 spatial sensory configurations-a single row or 3 caudal whiskers on each side of the snout. We found that rapid sensorimotor twitches, called pumps, occurring during free-air whisking carry information about the rat's upcoming exploratory direction, as demonstrated by the ability of these pumps to predict consequent head and body locomotion. Specifically, pump behavior during both voluntary motionlessness and imposed head fixation exposed a backward redistribution of sensorimotor exploratory resources. Further, head-fixed rats employed a wide range of whisking profiles to compensate for the loss of head- and body-motor degrees of freedom. Finally, changing the number of intact vibrissae available to a rat resulted in an alteration of whisking strategy consistent with the rat actively reallocating its remaining resources. In sum, this work shows that rats adapt their active exploratory behavior in a homeostatic attempt to preserve sensorimotor coverage under changing environmental conditions and changing sensory capacities, including those imposed by various laboratory conditions.

Review Article: Gastrointestinal Bleeding Risk with Direct Oral Anticoagulants.

PURPOSE: Although direct oral anticoagulants (DOACs) are associated with an overall favourable safety profile, the risk of gastrointestinal bleeding with DOACs compared with vitamin K antagonists (VKAs) remains controversial. Accordingly, we aimed to provide a focused overview of the risk of gastrointestinal bleeding associated with dabigatran, rivaroxaban, apixaban and edoxaban and its management. METHODS: We reviewed published studies reporting on DOACs with gastrointestinal bleeding as an outcome, including randomised controlled trials (RCTs), retrospective database studies and large-scale prospective cohort studies. RESULTS: Cumulative evidence confirms no notable difference in major gastrointestinal bleeding risk between DOACs and VKAs. Moreover, gastrointestinal bleeding in DOAC-treated patients seems less severe and requires less intensive management. The main cause of upper gastrointestinal bleeding in DOAC-treated patients appears to be gastroduodenal ulcers, whereas lower gastrointestinal bleedings are mainly due to diverticula followed by angiodysplasia and haemorrhoids. The lack of head-to-head RCTs with DOACs precludes drawing conclusions on the DOAC with the lowest gastrointestinal bleeding risk. Prescribing physicians should be aware of risk factors for DOAC-related gastrointestinal bleeding (e.g. age > 65, heavy alcohol use, uncontrolled hypertension, hepatic or renal dysfunction, active cancer, anaemia) and adopt preventive measures accordingly. Management of DOAC-associated major gastrointestinal bleeding involves temporary discontinuation of the DOAC, investigation of the bleeding source and treatment of bleeding with fluid resuscitation combined with transfusion and endoscopic haemostasis. CONCLUSION: DOACs as a class do not increase the risk of major gastrointestinal bleeding compared to VKAs, which supports their continued use for different anticoagulant indications.

Abdominal Pain Severity Is Mainly Associated with Bloating Severity in Patients with Functional Bowel Disorders and Functional Abdominal Pain.

PURPOSE: Abdominal pain is a cardinal sign of functional bowel disorders (FBD), in favor of irritable bowel syndrome (IBS). However, the determinants of abdominal pain severity (APS) are unknown. The present study aimed to search the relationships between APS and demographic, psychological, and clinical parameters in tertiary care FBD outpatients. PATIENTS AND METHODS: In this retrospective study, we included 2043 new outpatients with FBD or functional abdominal pain. They fulfilled the Rome III questionnaire, psychological evaluation, and four 10-points Likert scale for the perceived severity of constipation, diarrhea, bloating, and abdominal pain. Linear regression was performed for each phenotype to model the severity of abdominal pain with demographic, psychological parameters, and symptoms severity. RESULTS: APS was positively associated with bloating severity in all phenotypes, but APS was also associated with other variables according to gender and phenotype. APS was negatively associated with age and positively with depression, constipation severity, and diarrhea severity in female patients. In male patients, APS was associated with state anxiety, constipation severity, and diarrhea severity. APS severity was associated with bloating severity and transit severity in IBS patients, while in non-IBS patients, APS was only associated with bloating severity. CONCLUSION: Perceived abdominal pain severity is always associated with perceived bloating severity in FBD and FAP patients.

Self-Perceived Stress Is Associated With Chest Pain and Personality in Patients With Refractory Functional Gastrointestinal Disorders.

ABSTRACT: Stressful events are frequently associated with functional gastrointestinal disorders (FGID). This study aims to determine if the severity of self-perceived stress is associated with specific FGID and personality characteristics in 822 patients with FGID who have filled a Rome III questionnaire, Minnesota Multiphasic Personality Inventory 2 (MMPI-2), and a 10-point Likert scale for self-perceived stress. According to stress severity, the patients were divided into three groups: low (<4; n = 183), moderate (4-6; n = 283), and severe stress (>6; n = 356). Female sex was more frequent in the severe stress group than in the low stress group (p = 0.001). Stress severity was strongly correlated with the two MMPI-2 posttraumatic stress scales. Clinically, chest pain was more frequently reported by severe stress patients than moderate stress patients. MMPI-2 clinical scales vary significantly according to the severity of stress, and "mild stress" patients have increased hysteria and depression scales and showed a higher frequency of irritable bowel syndrome-diarrhea. This study shows that severe stress severity is associated with a higher frequency of noncardiac chest pain and correlated with most personality items.

Panel gene profiling of small bowel adenocarcinoma: Results from the NADEGE prospective cohort.

Small bowel adenocarcinoma (SBA) is a rare tumour. Large genomic analyses with prognostic assessments are lacking. The NADEGE cohort has enrolled 347 patients with all stage SBA from 2009 to 2012. Next-generation sequencing investigates the presence of 740 hotspot somatic mutations in a panel of 46 genes involved in carcinogenesis. The mismatch repair (MMR) status was assessed by immunochemistry. We have collected 196 tumour samples and 125 had conclusive results for mutation analysis. The number of mutations was 0 in 9.6% of tumours, only 1 in 32.0%, 2 in 26.4% and ≥3 in 32.0%. Overall, at least one genomic alteration was observed in 90.4% of tumour. The most frequent genomic alteration was in KRAS (44.0%), TP53 (38.4%), PIK3CA (20.0%), APC (18.4%), SMAD4 (14.4%) and ERBB2 (7.2%) genes. KRAS mutations were more frequent in synchronous metastatic tumours than in localised tumours (72.7% vs 38.2%, P = .003). There was no significant difference in the mutation rates according to primary location for the most frequently altered gene. ATM, FGFR3 and FGFR1 gene alterations were associated with Lynch syndrome and IDH1 mutations with Crohn disease. dMMR tumours were associated with younger age, localised tumours, less KRAS but more SMARCB1 mutations. No genomic alteration was associated with overall survival. There is a trend for better survival in patient with dMMR tumours. In conclusion, there is a different genomic alteration profile in SBA according to predisposing diseases. No association between genomic alterations and prognoses was observed except for a trend of better prognoses associated with dMMR.

Personality of patients with fecal incontinence.

BACKGROUND/AIMS: Although idiopathic fecal incontinence (FI) patients have some psychological characteristics, the personality of FI patients was not described. The present study aims to describe the clinical and personality characteristics of FI patients. PATIENTS AND METHODS: This retrospective observational study included 996 outpatients, 72 with fecal incontinence. They filled out the Rome III diagnostic questionnaire, the personality inventory MMPI-2, the questionnaires for urological and sexual disorders, and Likert scales for bowel disorders perceived symptom severity. The main outcome measures were the presence in FI patients of functional gastrointestinal disorders, the self-reported symptom severity, and the personality profile. RESULTS: Patients were mainly females (72%). FI patients were characterized by higher age (P = 0.015), and by a higher prevalence of functional diarrhea (P = 0.001), urological (P = 0.001), and sexual disorders (P = 0.005). These patients also report higher diarrhea severity (P < 0.001) and lower abdominal pain severity (P = 0.009). The personality of FI patients is distinguished by a higher score for psychopathic deviate (P = 0.006), social responsibility (P = 0.003), Mac Andrew revised scale (P = 0.005), and antisocial practice (P = 0.007), and a lower score for type A behavior (P = 0.005). CONCLUSION: FI patients are characterized not only by older age, and a high prevalence of diarrhea but also by a specific personality profile characterized by an unfavorable comparison with others.

Characteristics of patients with overlap functional gastrointestinal disorders.

BACKGROUND AND AIM: Functional gastrointestinal disorders (FGIDs) are frequently overlapped. The present study was designed to (i) search the clinical differences between patients with single FGID and overlap FGIDs and (ii) define the most common FGIDs associations to identify homogenous subgroups of patients. METHODS: A total of 3555 outpatients with FGID filled out the Rome III adult diagnostic questionnaire, Bristol stool form, and four 10-point Likert scales to report the severity of constipation, diarrhea, bloating, and abdominal pain. An unsupervised algorithm was used to estimate the number of groups directly from the data. A classification tree separated patients into different subgroups, according to FGIDs. Multinomial logistic regression was used to characterize the groups of patients with overlap disorders. RESULTS: Patients reported 3.3 ± 1.9 FGIDs (range 1-10, median = 3); 736 reported only one FGID, while 2819 reported more than one FGID (3.8 ± 1.7). Patients with single FGID had higher body mass index (P < 0.001), never report irritable bowel syndrome (IBS), and rarely report fecal incontinence and anorectal pain (< 1% for each disorder). The non-supervised clustering of the 2819 patients with overlap FGIDs divided this population into 23 groups, including five groups associated with only one disorder (IBS-diarrhea, dysphagia, functional constipation, levator ani syndrome, and IBS-unspecified). Ten groups were related to two overlap disorders and eight groups to three or more disorders. Three disorders were not explicitly associated with a given group: IBS-mixed, proctalgia fugax, and nonspecific anorectal pain. CONCLUSION: Patients with FGID mostly report overlap disorders in a limited number of associations, each significantly associated with a few disorders.

Biopsychosocial Model and Perceived Constipation Severity According to the Constipation Phenotype.

PURPOSE: Constipation is a frequent complaint of patients with functional bowel disorders. The present study aimed to evaluate the relationship between the perceived constipation severity with demographics, clinical, physiological, and psychological parameters in constipated patients. PATIENTS AND METHODS: Four hundred seven constipated patients were included and had clinical, physiological, and psychological evaluation. The self-reported severity of constipation was analyzed using stepwise linear regression in the total population and within each clinical group. RESULTS: The patients were mainly of female gender (81%) and were 47.4 ± 16.5 years old. They complained of IBS (65%), and 62% had defecation disorders. The depression scale was abnormal in 200 patients (49%). The relationships of the constipation severity varied according to the Rome IV phenotype. In all phenotypes, it was positively associated with bloating severity, and negatively with Bristol stool form. In IBS patients, perceived constipation severity was also associated with abdominal pain severity. CONCLUSION: Our data support the hypothesis that perceived constipation severity is associated with clinical and physiological factors but not demographics and psychological factors. Besides, the relationships of perceived constipation severity with these factors vary according to clinical phenotypes.

The association of metabolic syndrome and COVID-19 deterioration.

BACKGROUND AND AIMS: To evaluate the prevalence and prognostic value of metabolic syndrome (MetS) in patients admitted for coronavirus disease 2019 (COVID-19). METHODS AND RESULTS: In this monocentric cohort retrospective study, we consecutively included all adult patients admitted to COVID-19 units between April 9 and May 29, 2020 and between February 1 and March 26, 2021. MetS was defined when at least three of the following components were met: android obesity, high HbA1c, hypertension, hypertriglyceridemia, and low HDL cholesterol. COVID-19 deterioration was defined as the need for nasal oxygen flow ≥6 L/min within 28 days after admission. We included 155 patients (55.5% men, mean age 61.7 years old, mean body mass index 29.8 kg/m2). Fifty-six patients (36.1%) had COVID-19 deterioration. MetS was present in 126 patients (81.3%) and was associated with COVID-19 deterioration (no-MetS vs MetS: 13.7% and 41.2%, respectively, p < 0.01). Logistic regression taking into account MetS, age, gender, ethnicity, period of inclusion, and Charlson Index showed that COVID-19 deterioration was 5.3 times more likely in MetS patients (95% confidence interval 1.3-20.2) than no-MetS patients. CONCLUSIONS: Over 81.3% of patients hospitalized in COVID-19 units had MetS. This syndrome appears to be an independent risk factor of COVID-19 deterioration.

Platelet-Rich Plasma as a Treatment for Androgenetic Alopecia.

BACKGROUND: Platelet-rich plasma (PRP) treatment may encourage hair growth by promoting cellular maturation, differentiation, and proliferation. OBJECTIVE: The objective of this study was to evaluate the effectiveness of PRP as a treatment for androgenetic alopecia (AGA). MATERIALS AND METHODS: A literature search combined with meta-analysis was used to calculate the overall standardized mean difference (SMD) in hair density in patients treated with PRP injections in comparison with baseline and placebo treatment. Chi squared analysis and Fisher exact test were used to investigate variation in protocols. RESULTS: The overall SMD in hair density was 0.58 (95% confidence interval [CI]: 0.35-0.80) and 0.51 (95% CI: 0.23-0.80, p < .0004) in favor of PRP treatment when compared with baseline and placebo treatment, respectively. CONCLUSION: Platelet-rich plasma is beneficial in the treatment of AGA. It is recommended that 3 monthly sessions of PRP (once monthly ×3 treatments) be used followed by a 3- to 6-month maintenance period.

Relationship Between Colonic Transit Response to Eating With Self-reported Constipation Severity in Constipated Patients According to the Phenotype.

Background/Aims: Eating is the major synchronizer of gastrointestinal motility and secretions. The present study aims to evaluate the interplay between self-perceived constipation severity (CS) and colonic response to eating in constipated patients according to the phenotype. Methods: We included 387 consecutive outpatients complaining of Rome IV chronic idiopathic constipation. Likert scales for CS, abdominal pain severity, bloating severity, depression and anxiety assessment, total and segmental colonic transit time (CTT), and colonic transit response to eating (CTRE) were performed in all patients. Results: Of the 387 patients included (49.7 ± 16.4 years), 320 (83%) were female, 203 had irritable bowel syndrome with constipation (IBS-C), 184 as functional constipation (FC), and 283 had defecation disorders (DD). The female gender was characterized by increased bloating severity (P = 0.011) and decreased Bristol stool form (P = 0.002). In IBS-C and FC patients, CS was related with bloating severity (P < 0.001 in both groups) and total CTT (P = 0.007 in IBS-constipation, P = 0.040 in FC). In IBS-C patients, CS was also associated with abdominal pain severity (P = 0.003) and Bristol stool form (P = 0.004). In contrast, in FC, CS was only related to left CTRE (P = 0.006), and in patients with DD, CS was associated with total CTT (P < 0.001) and left CTRE (P = 0.002). Conclusion: Colonic transit response to eating was not associated to CS in IBS-C patients, but left CTRE was associated with constipation severity in FC and DD patients.

Successful Treatment of Recurrent Pyloric Stenosis Using Balloon Dilation.

Infantile hypertrophic pyloric stenosis is a common surgical disease in infants, with an incidence of 2 to 5 cases per 1000 live births. It often presents with nonbilious projectile vomiting after feeding and a mid-epigastric mass in infants between the third and eighth weeks of life. Ramstedt pyloromyotomy remains the gold standard of treatment. Postoperative emesis is common; however, further evaluation for incomplete pyloromyotomy and recurrent pyloric stenosis should be conducted with prolonged, or new-onset postoperative emesis. While repeat pyloromyotomy is the standard of care for infants presenting with incomplete pyloric stenosis, treatment for the rare development of recurrent pyloric stenosis is not clearly outlined. Here, we report a successful balloon dilation procedure in an 8-week-old female with recurrent pyloric stenosis three and a half weeks after the initial laparoscopic pyloromyotomy.

Neuronal wiring diagram of an adult brain.

Connections between neurons can be mapped by acquiring and analyzing electron microscopic (EM) brain images. In recent years, this approach has been applied to chunks of brains to reconstruct local connectivity maps that are highly informative, yet inadequate for understanding brain function more globally. Here, we present the first neuronal wiring diagram of a whole adult brain, containing 5×107 chemical synapses between ~130,000 neurons reconstructed from a female Drosophila melanogaster. The resource also incorporates annotations of cell classes and types, nerves, hemilineages, and predictions of neurotransmitter identities. Data products are available by download, programmatic access, and interactive browsing and made interoperable with other fly data resources. We show how to derive a projectome, a map of projections between regions, from the connectome. We demonstrate the tracing of synaptic pathways and the analysis of information flow from inputs (sensory and ascending neurons) to outputs (motor, endocrine, and descending neurons), across both hemispheres, and between the central brain and the optic lobes. Tracing from a subset of photoreceptors all the way to descending motor pathways illustrates how structure can uncover putative circuit mechanisms underlying sensorimotor behaviors. The technologies and open ecosystem of the FlyWire Consortium set the stage for future large-scale connectome projects in other species.

Flexibility of neural circuits regulating mating behaviors in mice and flies.

Mating is essential for the reproduction of animal species. As mating behaviors are high-risk and energy-consuming processes, it is critical for animals to make adaptive mating decisions. This includes not only finding a suitable mate, but also adapting mating behaviors to the animal's needs and environmental conditions. Internal needs include physical states (e.g., hunger) and emotional states (e.g., fear), while external conditions include both social cues (e.g., the existence of predators or rivals) and non-social factors (e.g., food availability). With recent advances in behavioral neuroscience, we are now beginning to understand the neural basis of mating behaviors, particularly in genetic model organisms such as mice and flies. However, how internal and external factors are integrated by the nervous system to enable adaptive mating-related decision-making in a state- and context-dependent manner is less well understood. In this article, we review recent knowledge regarding the neural basis of flexible mating behaviors from studies of flies and mice. By contrasting the knowledge derived from these two evolutionarily distant model organisms, we discuss potential conserved and divergent neural mechanisms involved in the control of flexible mating behaviors in invertebrate and vertebrate brains.

Everettian relative states in the Heisenberg picture.

Everett's relative-state construction in quantum theory has never been satisfactorily expressed in the Heisenberg picture. What one might have expected to be a straightforward process was impeded by conceptual and technical problems that we solve here. The result is a construction which, unlike Everett's one in the Schrödinger picture, makes manifest the locality of Everettian multiplicity, its inherently approximative nature and its origin in certain kinds of entanglement and locally inaccessible information. (By Everettian, we are referring not only to Everett's own work, but also to versions of quantum theory that elaborate and refine his. The notion of relative states first appeared in Everett (Everett 1973 In The many worlds interpretation of quantum mechanics (eds BS DeWitt, N Graham)). We are proposing a formalism for relative states that is more detailed and more illuminating than Everett's.) Our construction also allows us to give a more precise definition of an Everett 'universe', under which it is fully quantum, not quasi-classical, and we compare the Everettian decomposition of a quantum state with the foliation of a space-time.