[Digital twins in healthcare: State of the art and potential use cases in a hospital setting]. / Le jumeau numérique en santé - État des lieux et perspectives d'application à l'hôpital.

The field of modeling and simulation including digital twins (DT) is getting a lot of traction in the health sector, with various benefits being outlined. Indeed, DT are designed to support the transformation of healthcare, ranging from the medical act itself to the organization of healthcare systems and hospitals, also including medical research. However, the technology is still in its infancy and needs to be evaluated according to medical standards. First and foremost, their clinical value remains to be assessed, taking into account the limits associated with AI tools. The aim of this review is to provide an overview of the use cases being tested in hospital settings. We go back to the definition of the DT concept and provide a summary of current studies. Finally, we outline the challenges to be taken into account in order to provide a framework for the deployment of DT tools, guaranteeing the trust and safety of those involved, especially of patients.

Title: Le jumeau numérique en santé - État des lieux et perspectives d'application à l'hôpital. Abstract: La recherche et développement en santé est très dynamique dans le champ de la simulation, et de nombreux projets se réclament du jumeau numérique (JN). Les JN sont voués à accompagner la transformation du soin, qu'il s'agisse de l'acte médical, du parcours de soins ou de leur organisation. Toutefois, cette technologie est naissante et nécessite d'être évaluée. L'objectif de cette synthèse est de dresser un état des lieux des cas d'usages du JN à l'hôpital. Nous revenons sur la définition du concept de JN et proposons un condensé des études en cours. Enfin, nous rappelons l'importance de créer un cadre propice au déploiement de ces outils, garantissant la confiance et la sécurité des acteurs et des patients.

Transdifferentiation of Human Circulating Monocytes Into Neuronal-Like Cells in 20 Days and Without Reprograming.

Despite progress, our understanding of psychiatric and neurological illnesses remains poor, at least in part due to the inability to access neurons directly from patients. Currently, there are in vitro models available but significant work remains, including the search for a less invasive, inexpensive and rapid method to obtain neuronal-like cells with the capacity to deliver reproducible results. Here, we present a new protocol to transdifferentiate human circulating monocytes into neuronal-like cells in 20 days and without the need for viral insertion or reprograming. We have thoroughly characterized these monocyte-derived-neuronal-like cells (MDNCs) through various approaches including immunofluorescence (IF), flow cytometry, qRT-PCR, single cell mRNA sequencing, electrophysiology and pharmacological techniques. These MDNCs resembled human neurons early in development, expressed a variety of neuroprogenitor and neuronal genes as well as several neuroprogenitor and neuronal proteins and also presented electrical activity. In addition, when these neuronal-like cells were exposed to either dopamine or colchicine, they responded similarly to neurons by retracting their neuronal arborizations. More importantly, MDNCs exhibited reproducible differentiation rates, arborizations and expression of dopamine 1 receptors (DR1) on separate sequential samples from the same individual. Differentiation efficiency measured by cell morphology was on average 11.9 ± 1.4% (mean, SEM, n = 38,819 cells from 15 donors). To provide context and help researchers decide which in vitro model of neuronal development is best suited to address their scientific question,we compared our results with those of other in vitro models currently available and exposed advantages and disadvantages of each paradigm.

Comparative effects of α2δ-1 ligands in mouse models of colonic hypersensitivity.

AIM: To investigate anti-hypersensitive effects of α2δ-1 ligands in non-inflammatory and inflammation-associated colonic hypersensitivity (CHS) mouse models. METHODS: To induce an inflammation-associated CHS, 1% dextran sulfate sodium (DSS) was administered to C57Bl/6J male mice, in drinking water, for 14 d. Regarding the non-inflammatory neonatal maternal separation (NMS) -induced CHS model, wild-type C57BI/6J pups were isolated from their mother from day 2 to day 14 (P2 to P14), three hours per day (from 9:00 a.m. to 12:00 p.m.). Colorectal distension was performed by inflating distension probe from 20 µL to 100 µL by 20 µL increment step every 10 s. After a first colorectal distension (CRD), drugs were administered subcutaneously, in a cumulative manner, (Gabapentin at 30 mg/kg and 100 mg/kg; Pregabalin at 10 mg/kg and 30 mg/kg; Carbamazepine at 10 mg/kg and 30 mg/kg) and a second CRD was performed one hour after each injection. RESULTS: The visceromotor response (VMR) to CRD was increased by our NMS paradigm protocol in comparison to non-handled (NH) mice, considering the highest distension volumes (80 µL: 0.783 ± 0.056 mV/s vs 0.531 ± 0.034 mV/s, P < 0.05 and 100 µL: 1.087 ± 0.056 mV/s vs 0.634 ± 0.038 mV/s, P < 0.05 for NMS and NH mice, respectively). In the inflammation-associated CHS, DSS-treated mice showed a dramatic and significant increase in VMR at 60 and 80 µL distension volumes when compared to control mice (60 µL: 0.920 ± 0.079 mV/s vs 0.426 ± 0.100 mV/s P < 0.05 and 80 µL: 1.193 ± 0.097 mV/s vs 0.681 ± 0.094 mV/s P < 0.05 for DSS- and Water-treated mice, respectively). Carbamazepine failed to significantly reduce CHS in both models. Gabapentin significantly reduced CHS in the DSS-induced model for both subcutaneous injections at 30 or 100 mg/kg. Pregabalin significantly reduced VMR to CRD in the non-inflammatory NMS-induced CHS model for the acute subcutaneous administration of the highest cumulative dose (30 mg/kg) and significantly reduced CHS in low-dose DSS-treated mice in a dose-dependent manner. Finally, the percent decrease of AUC induced by acute GBP or Pregabalin treatment were higher in the inflammatory DSS-induced CHS model in comparison to the non-inflammatory NMS-induced CHS model. CONCLUSION: This preclinical study demonstrates α2δ-1 ligands efficacy on inflammation-associated CHS, highlighting their potential clinical interest in patients with chronic abdominal pain and moderate intestinal inflammation.

Distinct neuronal activation patterns are associated with PCP-induced social withdrawal and its reversal by the endocannabinoid-enhancing drug URB597.

The fatty acid amide hydrolase inhibitor, URB597, an endocannabinoid enhancing drug, reverses social withdrawal in the sub-chronic PCP rat model of schizophrenia, but reduces social interaction (SI) in controls. To identify the anatomical substrates associated with PCP-induced social withdrawal and the contrasting effects of URB597 on SI in PCP- versus saline-treated rats, we analyzed SI-induced c-Fos expression in 28 brain areas relevant to schizophrenia and/or social behavior following vehicle or URB597 administration. In saline-treated rats, SI was accompanied by changes in c-Fos expression in the infralimbic and orbitofrontal cortices, dorsomedial caudate putamen, ventrolateral nucleus of the septum, dorsolateral periaqueductal gray (dlPAG) and central amygdala. Except for the dlPAG, these changes were not observed in PCP-treated rats or in saline-treated rats receiving URB597. In the dorsomedial part of the bed nucleus of the stria terminalis (dmBNST), SI-induced c-Fos expression was observed only in PCP-treated rats. Interestingly, URB597 in PCP-treated rats restored a similar c-Fos expression pattern as observed in saline-treated rats: activation of the orbitofrontal cortex, inhibition of the central amygdala and suppression of activation of the dmBNST. These data suggest that orbitofrontal cortex, central amygdala and dmBNST play a critical role in the reversal of PCP-induced social withdrawal by URB597.

Gender-related differences in irritable bowel syndrome: potential mechanisms of sex hormones.

According to epidemiological studies, twice as many women as men are affected by irritable bowel syndrome (IBS) in western countries, suggesting a role for sex hormones in IBS pathophysiology. Despite growing evidence about the implications of sex hormones in IBS symptom modulation, data on mechanisms by which they influence disease development are sparse. This review aims to determine the state of knowledge about the role of sex hormones in sensorimotor dysfunctions and to address the possible interplay of sex hormones with common risk factors associated with IBS. The scientific bibliography was searched using the following keywords: irritable bowel syndrome, sex, gender, ovarian hormone, estradiol, progesterone, testosterone, symptoms, pain, sensitivity, motility, permeability, stress, immune system, brain activity, spinal, supraspinal, imaging. Ovarian hormones variations along the menstrual cycle affect sensorimotor gastrointestinal function in both healthy and IBS populations. They can modulate pain processing by interacting with neuromodulator systems and the emotional system responsible for visceral pain perception. These hormones can also modulate the susceptibility to stress, which is a pivotal factor in IBS occurrence and symptom severity. For instance, estrogen-dependent hyper-responsiveness to stress can promote immune activation or impairments of gut barrier function. In conclusion, whereas it is important to keep in mind that ovarian hormones cannot be considered as a causal factor of IBS, they arguably modulate IBS onset and symptomatology. However, our understanding of the underlying mechanisms remains limited and studies assessing the link between IBS symptoms and ovarian hormone levels are needed to improve our knowledge of the disease evolution with regard to gender. Further studies assessing the role of male hormones are also needed to understand fully the role of sex hormones in IBS. Finally, investigation of brain-gut interactions is critical to decipher how stress, ovarian hormones, and female brain processing of pain can translate into gut dysfunctions.

T-type calcium channels contribute to colonic hypersensitivity in a rat model of irritable bowel syndrome.

The symptoms of irritable bowel syndrome (IBS) include significant abdominal pain and bloating. Current treatments are empirical and often poorly efficacious, and there is a need for the development of new and efficient analgesics aimed at IBS patients. T-type calcium channels have previously been validated as a potential target to treat certain neuropathic pain pathologies. Here we report that T-type calcium channels encoded by the Ca(V)3.2 isoform are expressed in colonic nociceptive primary afferent neurons and that they contribute to the exaggerated pain perception in a butyrate-mediated rodent model of IBS. Both the selective genetic inhibition of Ca(V)3.2 channels and pharmacological blockade with calcium channel antagonists attenuates IBS-like painful symptoms. Mechanistically, butyrate acts to promote the increased insertion of Ca(V)3.2 channels into primary sensory neuron membranes, likely via a posttranslational effect. The butyrate-mediated regulation can be recapitulated with recombinant Ca(V)3.2 channels expressed in HEK cells and may provide a convenient in vitro screening system for the identification of T-type channel blockers relevant to visceral pain. These results implicate T-type calcium channels in the pathophysiology of chronic visceral pain and suggest Ca(V)3.2 as a promising target for the development of efficient analgesics for the visceral discomfort and pain associated with IBS.

Spinal cord plasticity and acid-sensing ion channels involvement in a rodent model of irritable bowel syndrome.

Irritable bowel syndrome (IBS) is a common functional gastro-intestinal disorder characterized by intractable chronic abdominal pain. In this study, we examined the possible spinal mechanisms underlying colonic hypersensitivity (CHS) using a non-inflammatory rat model of IBS induced by rectal enemas of butyrate, a short-chain fatty acid. We hypothesized that spinal plasticity could be responsible for CHS and that ASIC channels, which are known to support pain-elicited currents in the spinal cord, could contribute to central sensitization in our model of IBS. First, in order to determine if visceral pain relies on changes in spinal activity, we analyzed Fos expression in the spinal cord of rats treated with butyrate following a challenge with repetitive noxious colorectal distension. We found that Fos immunoreactivity was increased in thoracic T10-11-12, lumbar L1-2-6 and sacral S1 spinal segments. In control rats treated with saline, noxious repetitive colorectal distensions evoked Fos expression only in L1-2-6 and S1 spinal segments. Secondly, intrathecal injection of PcTx1, a specific ASIC1A antagonist, in the lumbar spinal cord completely prevented the development of CHS induced by butyrate. ASIC1 and 2 mRNAs, especially ASIC1A, were upregulated in the lumbar spinal cord. ASIC1A could thus contribute to spinal sensitization in our model of IBS, as it is supported by spinal colocalization of ASIC1A and Fos proteins. The whole data pinpoint a potential critical role of thoracic spinal cord in non-inflammatory pain states such as IBS and suggest that ASIC channels are part of the molecular effectors of central sensitization leading to visceral pain.

[Immunopathogenesis of inflammatory bowel disease]. / Immuno- pathogenèse des maladies inflammatoires chroniques de l'intestin.

Inflammatory bowel diseases (IBD) are idiopathic, chronic and relapsing inflammatory conditions of the gastrointestinal tract. New insights into the pathogenesis of IBD have been provided by three lines of research: (1) studying susceptibility genes involved in the detection of bacterial components and in the regulation of the host immune response, (2) highlighting the disruption of tolerance towards the commensal microbiota and (3) unravelling the critical role of environmental factors such as sanitation and hygiene. This review presents current etiological hypothesis of IBD which argue that pathogenic intestinal bacteria and/or infectious agents initiate and perpetuate the inflammation of the gut in an individual with genetic vulnerability leading to impaired epithelial barrier function and abnormal mucosal immune responses.

Neuropathological and Reelin deficiencies in the hippocampal formation of rats exposed to MAM; differences and similarities with schizophrenia.

BACKGROUND: Adult rats exposed to methylazoxymethanol (MAM) at embryonic day 17 (E17) consistently display behavioral characteristics similar to that observed in patients with schizophrenia and replicate neuropathological findings from the prefrontal cortex of psychotic individuals. However, a systematic neuropathological analysis of the hippocampal formation and the thalamus in these rats is lacking. It is also unclear if reelin, a protein consistently associated with schizophrenia and potentially involved in the mechanism of action of MAM, participates in the neuropathological effects of this compound. Therefore, a thorough assessment including cytoarchitectural and neuromorphometric measurements of eleven brain regions was conducted. Numbers of reelin positive cells and reelin expression and methylation levels were also studied. PRINCIPAL FINDINGS: Compared to untreated rats, MAM-exposed animals showed a reduction in the volume of entorhinal cortex, hippocampus and mediodorsal thalamus associated with decreased neuronal soma. The entorhinal cortex also showed laminar disorganization and neuronal clusters. Reelin methylation in the hippocampus was decreased whereas reelin positive neurons and reelin expression were unchanged. CONCLUSIONS: Our results indicate that E17-MAM exposure reproduces findings from the hippocampal formation and the mediodorsal thalamus of patients with schizophrenia while providing little support for reelin's involvement. Moreover, these results strongly suggest MAM-treated animals have a diminished neuropil, which likely arises from abnormal neurite formation; this supports a recently proposed pathophysiological hypothesis for schizophrenia.

Immunopathogenesis of inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a group of idiopathic, chronic and relapsing inflammatory conditions of the gastrointestinal tract. Familial and epidemiological studies have stressed the involvement of genetic factors and have also shown the critical role of environmental factors such as sanitation and hygiene in the development of IBD. However, the molecular mechanisms of intestinal inflammation in IBD have long remained unknown. In recent years, the study of susceptibility genes involved in the detection of bacterial components and in the regulation of the host immune response has shed light onto the potential role of intestinal pathogens and gut flora in IBD immunobiology. This review presents current knowledge on intestinal epithelial barrier alterations and on dysfunction of mucosal innate and acquired immune responses in IBD. The data support the etiological hypothesis which argues that pathogenic intestinal bacteria and/or infectious agents initiate and perpetuate the inflammation of the gut through disruption of tolerance towards the commensal microbiota in an individual with genetic vulnerability.

Potential application as screening and drug designing tools of cytoarchitectural deficiencies present in three animal models of schizophrenia.

BACKGROUND: The development of new treatment alternatives for schizophrenia has been prevented by the unknown etiology of the illness and the divergence of results in the field. However, consistent neuropathological findings are emerging from anatomical areas known to be at the core of schizophrenia. If these deficiencies are replicated in animal models then such anomalies could become the target for a new generation of drugs. OBJECTIVE: To determine if the methylazoxymethanol acetate (MAM) model, the heterozygote reeler mouse (HRM) and NMDA-antagonists treated rats replicate neuropathological deficits encountered in patients with schizophrenia and to establish if such changes could lead the search for developing novel treatment alternatives. METHODS: Databases including MEDLINE, Cochrane and Ovid were searched; search terms included neuropathology, schizophrenia and animal models. RESULTS/CONCLUSIONS: NMDA-antagonist treated animals partially replicate schizophrenia anomalies in parvalbumin positive interneurons. In contrast, neuroanatomical deficiencies replicated by the MAM model and the HRM in the hippocampus and the prefrontal cortex seem promising targets for future pharmacological research in schizophrenia. Such neuroanatomical findings along with evidence from molecules and genes associated with schizophrenia suggest new drugs should aim to correct deficits in the formation of dendrites and axons that seems to be implicated in this illness pathophysiology.