AnFiSA: An open-source computational platform for the analysis of sequencing data for rare genetic disease.

Despite genomic sequencing rapidly transforming from being a bench-side tool to a routine procedure in a hospital, there is a noticeable lack of genomic analysis software that supports both clinical and research workflows as well as crowdsourcing. Furthermore, most existing software packages are not forward-compatible in regards to supporting ever-changing diagnostic rules adopted by the genetics community. Regular updates of genomics databases pose challenges for reproducible and traceable automated genetic diagnostics tools. Lastly, most of the software tools score low on explainability amongst clinicians. We have created a fully open-source variant curation tool, AnFiSA, with the intention to invite and accept contributions from clinicians, researchers, and professional software developers. The design of AnFiSA addresses the aforementioned issues via the following architectural principles: using a multidimensional database management system (DBMS) for genomic data to address reproducibility, curated decision trees adaptable to changing clinical rules, and a crowdsourcing-friendly interface to address difficult-to-diagnose cases. We discuss how we have chosen our technology stack and describe the design and implementation of the software. Finally, we show in detail how selected workflows can be implemented using the current version of AnFiSA by a medical geneticist.

[Psychopathological consequences of confinement]. / Conséquences psychopathologiques du confinement.

The psychological effects of isolation have already been described in the literature (polar expeditions, submarines, prison). Nevertheless, the scale of confinement implemented during the COVID-19 pandemic is unprecedented. In addition to reviewing the published studies, we need to anticipate the psychological problems that could arise during or at a distance from confinement. We have gone beyond the COVID-19 literature in order to examine the implications of the known consequences of confinement, like boredom, social isolation, stress, or sleep deprivation. Anxiety, post-traumatic stress disorder, depression, suicidal or addictive behaviours, domestic violence are described effects of confinement, but the mechanisms of emergence of these disorders and their interrelationships remain to be studied. For example, what are the mechanisms of emergence of post-traumatic stress disorders in the context of confinement? We also remind the reader of points of vigilance to be kept in mind with regard to eating disorders and hallucinations. Hallucinations are curiously ignored in the literature on confinement, whereas a vast literature links social isolation and hallucinations. Due to the broad psychopathological consequences, we have to look for these various symptoms to manage them. We quickly summarize the diagnostic and therapeutic approaches already in place, such as telemedicine, which is undergoing rapid development during the COVID-19 crisis.

Racing and crowded thoughts in mood disorders: A data-oriented theoretical reappraisal.

OBJECTIVES: Speed of thought is a central phenomenon in mood disorders. We aimed to provide an update on the topic ten years after a first narrative review published on racing and crowded thoughts in mood disorders. This update is based on recent publications, including recent works of our group. METHODS: Narrative review based on publications from the last ten years including publications of our group and a systematic research of references on PubMed. RESULTS: The traditional dichotomist view of racing versus crowded thoughts is not refuted but appears to be more complex, as revealed by validation studies of the Racing and Crowded Thoughts Questionnaire. Moreover, this dualistic view can no longer be conceptualized in a simple bijective concordance with the distinction of hypomania versus mixed depression. We also show that racing/crowded thoughts are strongly associated with mixed depression and not with non-mixed depression, that they tend to be more associated in hypomania to irritability than to the typical symptoms of energy and activity increase and that they are clearly distinguishable from ruminations. Yet, although tightly linked to mood disorders, racing/crowded thoughts appear to be associated to anxiety as well as attention deficit/hyperactivity disorder and insomnia. CONCLUSIONS: Racing and crowded thoughts should be studied in a dimensional perspective as an important facet of mind activity within and beyond the field of mood disorders.

Low time resolution in schizophrenia Lengthened windows of simultaneity for visual, auditory and bimodal stimuli.

The guarantee of perceptual coherence for events through everyday life situations depends upon the capacity to correctly integrate series of multi-sensory experiences. Patients with schizophrenia have been shown to reveal a deficit in integrating, i.e., "binding", perceptual information together. However, results in the literature have also suggested the reverse effect. Indeed, in certain paradigms patients have revealed more binding phenomenon than healthy controls and reported experiencing two distinct events as occurring "together". This finding suggests that patients may require longer time intervals between two distinct events before being able to perceive them as "one-after-the-other". The question here was to test whether this perceptual binding abnormality in schizophrenia is confined to events within the same modality or whether it is also present across sensory modalities. Thirty patients with schizophrenia were compared with 33 normal controls using a simultaneity judgement paradigm. There were two uni-modal conditions in which stimuli were presented in the same modality (visual or auditory) and one bimodal condition (audio-visual). Participants were presented with stimuli varying across a range of inter-stimulus intervals (ISI). They were required to judge whether they experienced two stimuli as occurring "together" or "one-after-the-other". Compared to controls and in all conditions, patients needed larger ISI to experience two stimuli as "one-after-the-other" (all ISI x Group interactions p<5 x 10(-5)). These abnormalities correlated with the disorganization dimension but not with the dosage of chlorpromazine equivalent. The increase of the time interval needed to perceive two stimuli as "one-after-the-other", reflect an abnormally low time resolution in patients with schizophrenia. We discuss the possible involvement of anatomical disconnectivity in schizophrenia which would specifically affect the time integration properties of neural assemblies.

A two-stage account of computing and binding occluded and visible contours: Evidence from visual agnosia and effects of lorazepam.

Previous work has shown that HJA, a patient suffering from visual agnosia, can complete occluded contours whilst being impaired at assigning contours to foreground and background figures (Giersch, Humphreys, Boucart, & Kovacs, 2000). Here we tested whether completed contours are automatically bound with visible contours, after being derived from them. HJA, lorazepam-treated and nontreated healthy participants were asked to match a first reference line with an equal or longer line of identical orientation included in one of two lateral figures. The target line was in the foreground or the background of the figures. The distractor picture included two short collinear line-segments belonging to two different figures, so that participants had to process the occluded parts to discriminate the target from the distractor line. When the target line was in the background, both HJA and lorazepam-treated participants were faster when the length of the reference line corresponded to the length of the occluded part of the target line, relative to when it corresponded to the length of the occluded part plus a visible contour. In contrast, control participants tended to show an advantage for matching a reference line whose length was the same as the visible contours plus the occluded part. However, when the stimuli were displayed for 50 ms only and then masked, controls showed the same results as HJA. These results suggest that responses in the matching tasks are biased by the existence of an early completed occluded line that remains isolated from real contours.

Novel ATP6V1B1 and ATP6V0A4 mutations in autosomal recessive distal renal tubular acidosis with new evidence for hearing loss.

Autosomal recessive distal renal tubular acidosis (rdRTA) is characterised by severe hyperchloraemic metabolic acidosis in childhood, hypokalaemia, decreased urinary calcium solubility, and impaired bone physiology and growth. Two types of rdRTA have been differentiated by the presence or absence of sensorineural hearing loss, but appear otherwise clinically similar. Recently, we identified mutations in genes encoding two different subunits of the renal alpha-intercalated cell's apical H(+)-ATPase that cause rdRTA. Defects in the B1 subunit gene ATP6V1B1, and the a4 subunit gene ATP6V0A4, cause rdRTA with deafness and with preserved hearing, respectively. We have investigated 26 new rdRTA kindreds, of which 23 are consanguineous. Linkage analysis of seven novel SNPs and five polymorphic markers in, and tightly linked to, ATP6V1B1 and ATP6V0A4 suggested that four families do not link to either locus, providing strong evidence for additional genetic heterogeneity. In ATP6V1B1, one novel and five previously reported mutations were found in 10 kindreds. In 12 ATP6V0A4 kindreds, seven of 10 mutations were novel. A further nine novel ATP6V0A4 mutations were found in "sporadic" cases. The previously reported association between ATP6V1B1 defects and severe hearing loss in childhood was maintained. However, several patients with ATP6V0A4 mutations have developed hearing loss, usually in young adulthood. We show here that ATP6V0A4 is expressed within the human inner ear. These findings provide further evidence for genetic heterogeneity in rdRTA, extend the spectrum of disease causing mutations in ATP6V1B1 and ATP6V0A4, and show ATP6V0A4 expression within the cochlea for the first time.

Lorazepam, sedation, and conscious recollection: a dose-response study with healthy volunteers.

The role of sedation in the benzodiazepine-induced impairment of conscious recollection is still subject to debate. The aim of this study was to investigate further the role of sedation using the Remember-Know procedure and a physiological measure of sedation based on pupillography in addition to standard measures of sedation and attention (digit-symbol substitution task, symbol cancellation task, self-rated sedation). Twelve subjects were tested after the intake of placebo, lorazepam 0.026 mg/kg and lorazepam 0.038 mg/kg, administered in a randomized order, with a minimum interval of 8 days between each administration. On a recognition memory task, they were asked to give 'Remember', 'Know' or 'Guess' responses to items that were recognized on the basis of conscious recollection, familiarity, or guessing, respectively. Lorazepam selectively impaired recognition based on 'Remember' responses. This impairment was greater in the lorazepam 0.038 mg/kg than in the lorazepam 0.026 mg/kg groups. Measures of sedation were not correlated with the proportion of 'Remember' responses. These results suggest that sedation alone cannot account for the impairment of conscious recollection induced by lorazepam.

Different effects of lorazepam and diazepam on perceptual integration.

Recent research has established the detrimental effect of lorazepam, a benzodiazepine, on both implicit and explicit memory. Furthermore, lorazepam is known to affect perceptual integration. Diazepam, on the other hand, though being a benzodiazepine too, only impairs explicit memory, leaving implicit memory fairly intact. Little is known about the effect of diazepam on perceptual integration. The present study aimed at filling in this gap, by comparing the effects of lorazepam and diazepam on the detection of discontinuities in random-shaped outlines. In line with previous findings, the results in a lorazepam-treated group were quite different from the results in a placebo-treated group. The results in a diazepam-treated group were analogous to the results in the placebo-treated group and different from the results in the lorazepam-treated group. This shows that lorazepam and diazepam differ, not only with respect to their effect on implicit memory, but also with respect to their effect on perceptual integration. It is argued that this bears important consequences for memory research that makes use of a pharmacological dissociation rationale.

Effects of lorazepam on vision and oculomotor balance.

BACKGROUND: Previous studies have shown an effect of the tranquilizer lorazepam on visual perception. We explored the effects of the drug on binocular vision, visual acuity and accommodation. SUBJECTS AND METHODS: Twenty-four paid healthy volunteers (13 women, 11 men) were recruited from the University of Strasbourg (mean age: 23.6 years, mean weight: 66.8 Kg). They were randomly assigned to one of two parallel groups of 12 subjects each (a placebo group and a lorazepam 0.038 mg/kg group). Visual acuity was measured for each eye separately (Snellen chart and Parinaud scale). Binocular vision was studied using the cover tests, measurement of the fusional amplitudes (with Berens prisms), and the Duane Scale Test (near point rule) measuring convergence and/or accommodation in centimeters or diopters as a function of age. RESULTS: Regarding vision, there was no lorazepam effect, at either 33 cm or 5 m. An esophoria was observed after the intake of lorazepam (0Delta before intake and 2.8Delta after intake, p=0.001). Both fusional convergence and fusional divergence amplitudes decreased by lorazepam, (p=0.008, and p=0.002). Lorazepam also impaired the near point of convergence but did not affect accommodation. CONCLUSION: A single dose of lorazepam induces an esophoric oculomotor imbalance and impaired fusional convergence and divergence amplitudes without impairing visual acuity or accommodation.

The computation of occluded contours in visual agnosia: Evidence for early computation prior to shape binding and figure-ground coding.

We examined whether an agnosic patient with a deficit in early visual processing, HJA, completed occluded contours. We used matching tasks with stimuli composed of three superimposed or occluded shapes. Experiments 2 and 6 required superimposed or occluded shapes to be discriminated from distractors in which the position of one shape was changed. HJA was selectively impaired with occluded relative to superimposed shapes. His performance was affected by the spatial separation of the occluded contours rather than the area of the occluded surface. Experiments 3 and 5 required HJA to discriminate the central shape. Making occluded contours easier to compute (by reducing their spatial separation) facilitated discrimination of a central occluded shape (in the background), although it impaired discrimination of a central occluding shape (in the foreground). Free-choice shape judgements made to the central shape (Experiment 2) showed that HJA used both real and completed contours to segment foreground shapes inappropriately. When asked to copy overlapping shapes (Experiment 4), HJA drew in the occluded parts as if real contours were present, at least on some occasions. These drawings and a task requiring discrimination between real and occluded contours (Experiment 7), showed a tendency to continue contours inappropriately, an insensitiviy to junctions, and impaired integration of contours into more global shapes. The results suggest that occluded contours can be computed early on in visual processing, probably at the level where long-range mechanisms group collinear contour segments together. Our control experiment shows that HJA is not impaired in collinear contour grouping. These mechanisms are prior to processes in which contours are bound to shapes and in which foregroundbackground relationships between shapes are resolved. In visual agnosia, occluded contours can be computed even when there is impairment of both binding of contours to shapes and the computation of foreground-background relations in overlapping shapes.

Genetic causes of nonsyndromic hearing loss.

Explosive progress is being made in genetic studies of hearing and deafness from the clinical and basic research perspectives. Greater than half of hearing loss is estimated to have a genetic basis. Recent studies of hearing and deafness have identified a dozen genes that cause nonsyndromic hearing disorders. Deafness can be inherited in an autosomal recessive, autosomal dominant, X-linked, or mitochondrial manner. Mutations in one gene, connexin 26 (encoding the gap junction protein beta 2), may be responsible for half of all autosomal recessive nonsyndromic deafness. With new mandates for hearing screening programs for newborns in many states, for the first time, the new information on the genetics of hearing loss can be used to diagnose the cause of hearing loss in some children and to understand better the molecular biology of hearing.

Effects of a benzodiazepine, lorazepam, on motion integration and segmentation: an effect on the processing of line-ends?

Previous studies have shown that the perceptual integration of component motions distributed across space is inhibited whenever segmentation cues, such as line-ends, are salient. Herein, we investigate to what extent enhanced inhibition induced by lorazepam, a benzodiazepine facilitating the fixation of GABA on GABAA receptors, modifies the balance between motion integration and motion segmentation at the behavioural level. Motion integration was tested in 16 healthy volunteers taking a single and oral dose of either placebo or lorazepam (0.038 mg kg-1). The stimulus consisted of an outlined diamond presented behind four, otherwise invisible, apertures and translating along a circular trajectory (Lorenceau & Shiffrar (1992). Vision Research, 32, 263-273). Under these conditions, recovering the global diamond direction requires the integration of the component motions available within each aperture. The observers were asked to discriminate the global, clockwise or counter-clockwise, diamond direction under difficult--at high luminance contrasts--or easy--at low luminance contrasts--conditions. Overall, reaction times and error rates increased in the lorazepam group as compared to the placebo group, suggesting strong non-specific effects. However, the changes in performance in the lorazepam group are not homogeneous across conditions, suggesting that lorazepam also induces specific effects that modulate the integration/segmentation balance. Additional experiments performed with visible apertures or visible diamond vertices indicate that the effects of lorazepam are unlikely to reflect a deficit of motion processing or motion integration mechanisms since performance is only slightly impaired in the lorazepam as compared to the placebo group under these conditions. These results suggest that lorazepam might specifically modulate the saliency of line-ends, presumably because processing these features involves inhibitory mechanisms using GABA as a neuromediator, and in turn modify the balance between motion integration and segmentation.

Lorazepam impairs perceptual integration of visual forms: a central effect.

Previous studies have shown a lorazepam effect on visual perception. We tested whether this impairment resulted from a peripheral effect induced by benzodiazepines. A first experiment showed that a single dose of lorazepam induces an oculomotor imbalance without impairing visual acuity or accommodation. In a second experiment, we tested whether the impairment induced by lorazepam on visual perception still occurred in monocular vision. Subjects matched incomplete forms controlled on the spacing and alignment of their local contour elements. A reference object was first displayed and followed by two laterally displayed objects, a target and a distractor. The distractor was the mirror-reversed version of the target. Performance was impaired in the lorazepam group when the reference was an incomplete form with a spacing of 10.8' or 22.2' of arc. These results were not correlated with sedation. They confirm that lorazepam has a central deleterious effect on visual perception. A post-hoc analysis also suggested that lorazepam-treated subjects used asymmetry in the stimuli as a compensatory strategy. This result is discussed in relation to previous hypotheses about the physiological mechanisms that determine the effects of lorazepam on visual perception.

Effects of lorazepam on perceptual integration of visual forms in healthy volunteers.

We tested whether lorazepam (a benzodiazepine) affects perceptual processes involved in the computation of contour information. Subjects matched incomplete forms whose contour was composed of line segments varying in their spacing and in their alignment. An initial centrally displayed object (a reference) was followed by two laterally displayed pictures, a target and a distractor. The distractor was the mirror-reversed version of the target. In one condition, the reference was always an outline drawing of an object. In another condition, the reference was either an outline drawing or an incomplete form. All subjects were run in both conditions. Lorazepam 0.038 mg/kg induced a larger increase in RTs than the placebo and lorazepam 0.026 mg/kg when the spacing between local contour elements was larger than 10.8' arc and when the line segments were not aligned. Performance was improved in the 0.038 mg/kg lorazepam group when subjects started with the condition in which the reference was always an outline drawing. Performance was not correlated with sedation. These results show that lorazepam impairs visual perception. They are interpreted in terms of impaired binding processes, which can be compensated for by the use of stored object representations. This effect is consistent with electrophysiological studies showing that the neuromediator GABA is involved in perceptual processes.

Time course of the effects of diazepam and lorazepam on perceptual priming and explicit memory.

The effects of diazepam and lorazepam on explicit memory and perceptual priming were studied 50, 130 and 300 min after drug administration. Sixty healthy volunteers were randomly assigned to one of five parallel groups (placebo, diazepam 0.2 or 0.3 mg/kg, lorazepam 0.026 or 0.038 mg/kg). The corresponding doses of benzodiazepines exerted a similar negative effect on explicit performance. Lorazepam markedly impaired priming performance, whereas the effect of diazepam was intermediate between that of placebo and that of lorazepam 0.038 mg/kg. The impairment was maximal at the theoretical peak plasma concentration. Contamination by explicit memory could account for the decrease in priming performance observed in the diazepam groups.

Lorazepam and diazepam effects on memory acquisition in priming tasks.

Unlike diazepam, lorazepam has repeatedly been shown to impair perceptual priming as well as explicit memory. To determine whether this deleterious effect was due to an impairment in acquisition of information, 60 healthy volunteers were randomly assigned to five treatment groups (placebo, lorazepam 0.026 or 0.038 mg/kg, diazepam 0.2 or 0.3 mg/kg) and successively performed perceptual priming tasks and a free-recall task. Priming performance on information learned before or 2 h after drug administration, i.e. at the peak concentration of lorazepam, was assessed under the influence of the drugs, using a picture-fragment and a word-stem completion task. Free-recall performance was altered by both drugs. Lorazepam decreased priming performance when information was acquired after, but not before, drug administration, indicating that the drug alters the acquisition of information. Lorazepam also impaired the ability to identify fragmented pictures, but there was no evidence that this perceptual effect accounts for the priming impairment. Surprisingly, diazepam also decreased priming when information was acquired after drug administration, suggesting that, at least in certain circumstances, the two benzodiazepines may exert similar effects on priming measures.

The computation of contour information in complex objects.

Perceptual organisation, and especially the computation of contour information, has been the object of considerable interest in the last few years. In the first part of the paper we review recent accounts on the mechanisms involved in the processing of contour. In the second part we report an experiment designed to examine (1) how physical parameters such as spatial proximity and collinearity of elements affect the integration of global contour in objects and (2) whether the activation of stored representations of objects facilitates the computation of contour. Incomplete forms varying in the spacing and the alignment of line segments on their contour were used as stimuli in a matching task. Subjects were asked to decide which of two laterally displayed figures matched a reference form presented previously. The matching target and the distractor were physically identical but differed in their orientation. In one condition the reference object was always an outline drawing of an object. In a second condition the reference object was either a complete object or a more or less identifiable incomplete form. Little variation in performance was found for forms having continuous and discontinuous contour up to a spacing of 5 pixels (10.8 min) between elements. Response times and errors increased abruptly beyond this limit. This effect occurred in the two conditions of reference stimulus, suggesting that the computation of contour information is more affected by physical constraints at early processes than by high-level processes involving activation of stored structural representations of objects.