Publications by authors named "Michael Schumacher"

175 Publications

Selpercatinib in RET fusion-positive non-small-cell lung cancer (SIREN): a retrospective analysis of patients treated through an access program.

Ther Adv Med Oncol 2021 11;13:17588359211019675. Epub 2021 Jun 11.

R.S. McLaughlin Durham Regional Cancer Center at Lakeridge Health, Adjunct Assistant Professor Queen's University, Ontario, Canada.

Introduction: Rearranged during transfection (RET) gene fusions are rare genetic drivers in non-small cell lung cancer (NSCLC). Selective RET-inhibitors such as selpercatinib have shown therapeutic activity in early clinical trials; however, their efficacy in the real-world setting is unknown.

Methods: A retrospective efficacy and safety analysis was performed on data from RET fusion-positive NSCLC patients who participated in a selpercatinib access program (named patient protocol) between August 2019 and January 2021.

Results: Data from 50 patients with RET fusion-positive advanced NSCLC treated with selpercatinib at 27 centers in 12 countries was analyzed. Most patients were Non-Asian (90%), female (60%), never-smokers (74%), with a median age of 65 years (range, 38-89). 32% of the patients had known brain metastasis at the time of selpercatinib treatment. Overall, 13 patients were treatment-naïve, while 37 were pretreated with a median of three lines of therapy (range, 1-8). The objective response rate (ORR) was 68% [95% confidence interval (CI), 53-81] in the overall population. The disease control rate was 92%. The median progression-free survival was 15.6 months (95% CI, 8.8-22.4) after a median follow-up of 9 months. In patients with measurable brain metastases ( = 8) intracranial ORR reached 100%. In total, 88% of patients experienced treatment-related adverse events (TRAEs), a large majority of them being grade 1 or 2. The most common grade ⩾ 3 TRAEs were increased liver enzyme levels (in 10% of patients), prolonged QTc time (4%), abdominal pain (4%), hypertension (4%), and fatigue/asthenia (4%). None of patients discontinued selpercatinib treatment for safety reasons. No new safety concerns were observed, nor where there any treatment-related death.

Conclusions: In this real-world setting, the selective RET-inhibitor selpercatinib demonstrated durable systemic and intracranial antitumor activity in RET fusion-positive NSCLC and was well tolerated.
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http://dx.doi.org/10.1177/17588359211019675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8202258PMC
June 2021

Progesterone and Allopregnanolone Neuroprotective Effects in the Wobbler Mouse Model of Amyotrophic Lateral Sclerosis.

Cell Mol Neurobiol 2021 Jun 17. Epub 2021 Jun 17.

Laboratory of Neuroendocrine Biochemistry, Instituto de Biología y Medicina Experimental-CONICET, Vuelta de Obligado 2490, 1428, Buenos Aires, Argentina.

Progesterone regulates a number of processes in neurons and glial cells not directly involved in reproduction or sex behavior. Several neuroprotective effects are better observed under pathological conditions, as shown in the Wobbler mouse model of amyotrophic laterals sclerosis (ALS). Wobbler mice are characterized by forelimb atrophy due to motoneuron degeneration in the spinal cord, and include microgliosis and astrogliosis. Here we summarized current evidence on progesterone reversal of Wobbler neuropathology. We demonstrated that progesterone decreased motoneuron vacuolization with preservation of mitochondrial respiratory complex I activity, decreased mitochondrial expression and activity of nitric oxide synthase, increased Mn-dependent superoxide dismutase, stimulated brain-derived neurotrophic factor, increased the cholinergic phenotype of motoneurons, and enhanced survival with a concomitant decrease of death-related pathways. Progesterone also showed differential effects on glial cells, including increased oligodendrocyte density and downregulation of astrogliosis and microgliosis. These changes associate with reduced anti-inflammatory markers. The enhanced neurochemical parameters were accompanied by longer survival and increased muscle strength in tests of motor behavior. Because progesterone is locally metabolized to allopregnanolone (ALLO) in nervous tissues, we also studied neuroprotection by this derivative. Treatment of Wobbler mice with ALLO decreased oxidative stress and glial pathology, increased motoneuron viability and clinical outcome in a progesterone-like manner, suggesting that ALLO could mediate some progesterone effects in the spinal cord. In conclusion, the beneficial effects observed in different parameters support the versatile properties of progesterone and ALLO in a mouse model of motoneuron degeneration. The studies foresee future therapeutic opportunities with neuroactive steroids for deadly diseases like ALS.
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http://dx.doi.org/10.1007/s10571-021-01118-yDOI Listing
June 2021

NRG4-ErbB4 signaling represses proinflammatory macrophage activity.

Am J Physiol Gastrointest Liver Physiol 2021 06 7;320(6):G990-G1001. Epub 2021 Apr 7.

The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California.

Proinflammatory macrophages are essential drivers of colitis and express the growth factor receptor ErbB4. This study tested the role of ErbB4 and its specific ligand, NRG4, in regulating macrophage function. We show that endogenous NRG4-ErbB4 signaling limits macrophage production of proinflammatory cytokines in vitro and limits colitis severity in vivo and thus is a potential target for therapeutic intervention.
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http://dx.doi.org/10.1152/ajpgi.00296.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285586PMC
June 2021

Squalenoyl siRNA PMP22 nanoparticles are effective in treating mouse models of Charcot-Marie-Tooth disease type 1 A.

Commun Biol 2021 03 9;4(1):317. Epub 2021 Mar 9.

U1195 Diseases and Hormones of the Nervous System, Inserm and University Paris-Saclay, 94276, Le Kremlin-Bicêtre, France.

Charcot-Marie-Tooth disease type 1 A (CMT1A) lacks an effective treatment. We provide a therapy for CMT1A, based on siRNA conjugated to squalene nanoparticles (siRNA PMP22-SQ NPs). Their administration resulted in normalization of Pmp22 protein levels, restored locomotor activity and electrophysiological parameters in two transgenic CMT1A mouse models with different severity of the disease. Pathological studies demonstrated the regeneration of myelinated axons and myelin compaction, one major step in restoring function of myelin sheaths. The normalization of sciatic nerve Krox20, Sox10 and neurofilament levels reflected the regeneration of both myelin and axons. Importantly, the positive effects of siRNA PMP22-SQ NPs lasted for three weeks, and their renewed administration resulted in full functional recovery. Beyond CMT1A, our findings can be considered as a potent therapeutic strategy for inherited peripheral neuropathies. They provide the proof of concept for a new precision medicine based on the normalization of disease gene expression by siRNA.
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http://dx.doi.org/10.1038/s42003-021-01839-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943818PMC
March 2021

Sprouty2 limits intestinal tuft and goblet cell numbers through GSK3β-mediated restriction of epithelial IL-33.

Nat Commun 2021 02 5;12(1):836. Epub 2021 Feb 5.

The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA, USA.

Dynamic regulation of intestinal cell differentiation is crucial for both homeostasis and the response to injury or inflammation. Sprouty2, an intracellular signaling regulator, controls pathways including PI3K and MAPKs that are implicated in differentiation and are dysregulated in inflammatory bowel disease. Here, we ask whether Sprouty2 controls secretory cell differentiation and the response to colitis. We report that colonic epithelial Sprouty2 deletion leads to expanded tuft and goblet cell populations. Sprouty2 loss induces PI3K/Akt signaling, leading to GSK3β inhibition and epithelial interleukin (IL)-33 expression. In vivo, this results in increased stromal IL-13+ cells. IL-13 in turn induces tuft and goblet cell expansion in vitro and in vivo. Sprouty2 is downregulated by acute inflammation; this appears to be a protective response, as VillinCre;Sprouty2 mice are resistant to DSS colitis. In contrast, Sprouty2 is elevated in chronic colitis and in colons of inflammatory bowel disease patients, suggesting that this protective epithelial-stromal signaling mechanism is lost in disease.
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http://dx.doi.org/10.1038/s41467-021-21113-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864916PMC
February 2021

Functional cooperation of the hedgehog and androgen signaling pathways during developmental and repairing myelination.

Glia 2021 Jun 23;69(6):1369-1392. Epub 2021 Jan 23.

U1195 Inserm, University Paris-Saclay, Kremlin-Bicêtre, France.

Hedgehog morphogens control fundamental cellular processes during tissue development and regeneration. In the central nervous system (CNS), Hedgehog signaling has been implicated in oligodendrocyte and myelin production, where it functions in a concerted manner with other pathways. Since androgen receptor (AR) plays a key role in establishing the sexual phenotype of myelin during development and is required for spontaneous myelin regeneration in the adult CNS, we hypothesized the existence of a possible coordination between Hedgehog and androgen signals in oligodendrocyte and myelin production. Here, we report complementary activities of both pathways during early postnatal oligodendrogenesis further revealing that persistent Hedgehog signaling activation impedes myelin production. The data also uncover prominent pro-myelinating activity of testosterone and involvement of AR in the control of neural stem cell commitment toward the oligodendroglial lineage. In the context of CNS demyelination, we provide evidence for the functional cooperation of the pathways leading to acceleration of myelin regeneration that might be related to their respective role on microglial and astroglial responses, higher preservation of axonal integrity, lower neuroinflammation, and functional improvement of animals in an immune model of CNS demyelination. Strong decreases of deleterious cytokines in the CNS (GM-CSF, TNF-α, IL-17A) and spleen (IL-2, IFN-γ) stand as unique features of the combined drugs while the potent therapeutic activity of testosterone on peripheral immune cells contributes to increase tolerogenic CD11c dendritic cells, reduce the clonal expansion of conventional CD4 T cells and increase CD4 Foxp3 regulatory T cells. Altogether, these data might open promising perspectives for demyelinating diseases.
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http://dx.doi.org/10.1002/glia.23967DOI Listing
June 2021

Developmental expression of genes involved in progesterone synthesis, metabolism and action during the post-natal cerebellar myelination.

J Steroid Biochem Mol Biol 2021 03 16;207:105820. Epub 2021 Jan 16.

Laboratory of Neuroendocrine Biochemistry, Instituto de Biologia y Medicina Experimental-CONICET, Obligado 2490, 1428 Buenos Aires, Argentina; Department of Human Biochemistry, University of Buenos Aires, Paraguay 2155, 1121 Buenos Aires, Argentina. Electronic address:

Progesterone is involved in dendritogenesis, synaptogenesis and maturation of cerebellar Purkinge cells, major sites of steroid synthesis in the brain. To study a possible time-relationship between myelination, neurosteroidogenesis and steroid receptors during development of the postnatal mouse cerebellum, we determined at postnatal days 5 (P5),18 (P18) and 35 (P35) the expression of myelin basic protein (MBP), components of the steroidogenic pathway, levels of endogenous steroids and progesterone's classical and non-classical receptors. In parallel with myelin increased expression during development, P18 and P35 mice showed higher levels of cerebellar progesterone and its reduced derivatives, higher expression of steroidogenic acute regulatory protein (StAR) mRNA, cholesterol side chain cleavage enzyme (P450scc) and 5α-reductase mRNA vs. P5 mice. Other steroids such as corticosterone and its reduced derivatives and 3β-androstanodiol (ADIOL) showed a peak increase at P18 compared to P5. Progesterone membrane receptors and binding proteins (PGRMC1, mPRα, mPRβ, mPRγ, and Sigma1 receptors) mRNAs levels increased during development while that of classical progesterone receptors (PR) remained invariable. PRKO mice showed similar MBP levels than wild type. Thus, these data suggests that progesterone and its neuroactive metabolites may play a role in postnatal cerebellar myelination.
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http://dx.doi.org/10.1016/j.jsbmb.2021.105820DOI Listing
March 2021

Neuroprotective Effects of Testosterone in Male Wobbler Mouse, a Model of Amyotrophic Lateral Sclerosis.

Mol Neurobiol 2021 May 7;58(5):2088-2106. Epub 2021 Jan 7.

Laboratory of Neuroendocrine Biochemistry, Instituto de Biologia y Medicina Experimental-CONICET, Obligado 2490, 1428, Buenos Aires, Argentina.

Patients suffering of amyotrophic lateral sclerosis (ALS) present motoneuron degeneration leading to muscle atrophy, dysphagia, and dysarthria. The Wobbler mouse, an animal model of ALS, shows a selective loss of motoneurons, astrocytosis, and microgliosis in the spinal cord. The incidence of ALS is greater in men; however, it increases in women after menopause, suggesting a role of sex steroids in ALS. Testosterone is a complex steroid that exerts its effects directly via androgen (AR) or Sigma-1 receptors and indirectly via estrogen receptors (ER) after aromatization into estradiol. Its reduced-metabolite 5α-dihydrotestosterone acts via AR. This study analyzed the effects of testosterone in male symptomatic Wobblers. Controls or Wobblers received empty or testosterone-filled silastic tubes for 2 months. The cervical spinal cord from testosterone-treated Wobblers showed (1) similar androgen levels to untreated control and (2) increased levels of testosterone, and its 5α-reduced metabolites, 5α- dihydrotestosterone, and 3β-androstanediol, but (3) undetectable levels of estradiol compared to untreated Wobblers. Testosterone-treated controls showed comparable steroid concentrations to its untreated counterpart. In testosterone- treated Wobblers a reduction of AR, ERα, and aromatase and high levels of Sigma-1 receptor mRNAs was demonstrated. Testosterone treatment increased ChAT immunoreactivity and the antiinflammatory mediator TGFβ, while it lessened vacuolated motoneurons, GFAP+ astrogliosis, the density of IBA1+ microgliosis, proinflammatory mediators, and oxidative/nitrosative stress. Clinically, testosterone treatment in Wobblers slowed the progression of paw atrophy and improved rotarod performance. Collectively, our findings indicate an antiinflammatory and protective effect of testosterone in the degenerating spinal cord. These results coincided with a high concentration of androgen-reduced derivatives after testosterone treatment suggesting that the steroid profile may have a beneficial role on disease progression.
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http://dx.doi.org/10.1007/s12035-020-02209-5DOI Listing
May 2021

Afatinib in EGFR TKI-naïve patients with locally advanced or metastatic EGFR mutation-positive non-small cell lung cancer: Interim analysis of a Phase 3b study.

Lung Cancer 2021 02 17;152:127-134. Epub 2020 Dec 17.

Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland.

Objectives: Randomized controlled trials have demonstrated that afatinib is a suitable treatment option for patients with epidermal growth factor receptor mutation-positive (EGFRm +) non-small cell lung cancer (NSCLC). However, such studies often exclude patients treated in routine clinical practice. We report interim results from a Phase 3b, open-label, multicenter, single-arm, exploratory trial, in which afatinib was investigated in a real-world setting.

Materials And Methods: Patients with EGFRm + tyrosine kinase inhibitor (TKI)-naïve NSCLC received afatinib 40 mg orally, once-daily, until disease progression, or voluntary withdrawal. Primary objective was safety.

Results: Overall, 479 patients received afatinib: median age 65 years, 8 % of patients had an ECOG performance status ≥ 2, 17 % had brain metastases, and 13 % had tumors containing uncommon mutations only. All but one patient (99.8 %) had an adverse event (AE). Treatment-related AEs (TRAEs; any/grade ≥ 3) occurred in 97 %/44 % of patients; most common were diarrhea (87 %/16 %) and rash (51 %/11 %). AEs leading to afatinib dose-reduction were reported in 258 patients (54 %), and 37 patients (8 %) discontinued treatment due to a TRAE. Objective response rate was 45.5 %, median duration of response was 14.1 months (95 % CI: 12.2-16.4). Overall median time to symptomatic progression and progression-free survival were 14.9 months (95 % CI: 13.8-17.6) and 13.4 months (95 % CI: 11.8-14.5), respectively, in the overall population and 19.3 months (95 % CI: 15.6-21.8) and 15.9 months (95 % CI: 13.9-19.1) in patients with EGFR exon 19 deletions.

Conclusions: Afatinib administration in routine clinical practice was well tolerated with no new safety signals and demonstrated promising efficacy in patients with EGFRm + NSCLC. TRAEs were generally manageable with tolerability-guided dose reductions. Overall, these data independently support findings from randomized controlled trials of afatinib in EGFRm + NSCLC.
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http://dx.doi.org/10.1016/j.lungcan.2020.12.011DOI Listing
February 2021

Nestorone , a 19nor-progesterone derivative boosts remyelination in an animal model of demyelination.

CNS Neurosci Ther 2021 Apr 24;27(4):464-469. Epub 2020 Dec 24.

Population Council and Rockefeller University, New York, NY, USA.

Introduction: We previously showed that Nestorone (NES), a synthetic progestin structurally related to progesterone, stimulated remyelination of the corpus callosum in a Cuprizone (CUP) mouse model of demyelination in intact females by promoting replenishment with mature oligodendrocytes (OL) (Glia. 2015;63:104-117). Here, we further investigated the underlying mechanisms of this promyelinating effect.

Methods: We explored whether NES, applied subcutaneously through Alzet mini-osmotic pumps, regulates specific transcription factors involved in oligodendrocyte progenitor cell (OPC) proliferation and their differentiation into mature OL, using RT-qPCR and Western Blot analysis.

Results: Our present data show that in comparison to controls, a one-week treatment with NES, through Alzet mini-osmotic pumps, enhanced the production of three relevant transcription factor mRNAs encoding Olig2, Myt1, and Sox17. After 3 weeks, NES treatment reversed the effect of CUP on the levels of corresponding Olig2, Myt1, and Sox17 proteins. Moreover, in mice receiving NES + Estradiol (E2) co-treatment, levels of Olig2, Myt1, and Sox17 proteins did not change as compared to NES alone.

Conclusion: NES alone or with E2 increased the levels of transcription factors, essential for myelin synthesis.
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http://dx.doi.org/10.1111/cns.13538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7941173PMC
April 2021

Progress in progestin-based therapies for neurological disorders.

Neurosci Biobehav Rev 2021 03 24;122:38-65. Epub 2020 Dec 24.

Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL, USA. Electronic address:

Hormone therapy, primarily progesterone and progestins, for central nervous system (CNS) disorders represents an emerging field of regenerative medicine. Following a failed clinical trial of progesterone for traumatic brain injury treatment, attention has shifted to the progestin Nestorone for its ability to potently and selectively transactivate progesterone receptors at relatively low doses, resulting in robust neurogenetic, remyelinating, and anti-inflammatory effects. That CNS disorders, including multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), spinal cord injury (SCI), and stroke, develop via demyelinating, cell death, and/or inflammatory pathological pathways advances Nestorone as an auspicious candidate for these disorders. Here, we assess the scientific and clinical progress over decades of research into progesterone, progestins, and Nestorone as neuroprotective agents in MS, ALS, SCI, and stroke. We also offer recommendations for optimizing timing, dosage, and route of the drug regimen, and identifying candidate patient populations, in advancing Nestorone to the clinic.
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http://dx.doi.org/10.1016/j.neubiorev.2020.12.007DOI Listing
March 2021

Later-Line Treatment with Lorlatinib in - and -Rearrangement-Positive NSCLC: A Retrospective, Multicenter Analysis.

Pharmaceuticals (Basel) 2020 Nov 7;13(11). Epub 2020 Nov 7.

Department of Respiratory and Critical Care Medicine, Karl Landsteiner Institute of Lung Research and Pulmonary Oncology, Klinik Floridsdorf, Brünner Strasse 68, 1210 Vienna, Austria.

In clinical practice, patients with -rearrangement-positive non-small-cell lung cancer commonly receive sequential treatment with ALK tyrosine kinase inhibitors. The third-generation agent lorlatinib has been shown to inhibit a wide range of resistance mutations and thus offers potential benefit in later lines, although real-world data are lacking. This multicenter study retrospectively investigated later-line, real-world use of lorlatinib in patients with advanced - or -positive lung cancer. Fifty-one patients registered in a compassionate use program in Austria, who received second- or later-line lorlatinib between January 2016 and May 2020, were included in this retrospective real-world data analysis. Median follow-up was 25.3 months. Median time of lorlatinib treatment was 4.4 months for -positive and 12.2 months for -positive patients. -positive patients showed a response rate of 43.2%, while 85.7% percent of the -positive patients were considered responders. Median overall survival from lorlatinib initiation was 10.2 and 20.0 months for the - and -positive groups, respectively. In the -positive group, lorlatinib proved efficacy after both brigatinib and alectinib. Lorlatinib treatment was well tolerated. Later-line lorlatinib treatment can induce sustained responses in patients with advanced - and -positive lung cancer.
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http://dx.doi.org/10.3390/ph13110371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694976PMC
November 2020

Progesterone and fetal-neonatal neuroprotection.

Best Pract Res Clin Obstet Gynaecol 2020 Nov 8;69:50-61. Epub 2020 Sep 8.

U1195 "Diseases and Hormones of the Nervous System", Inserm and University Paris-Saclay, 80, Rue Du Général Leclerc, 94276, Kremlin-Bicêtre, France.

The role of progesterone goes beyond the maintenance of pregnancy. The hormone, indeed, protects the developing fetal brain and influences its maturation. Metabolomes analyzed by mass spectrometric methods have revealed the great diversity of steroids in maternal plasma and fetal fluids, but their developmental significance remains to be investigated. Progesterone and its metabolites reach highest levels during the third trimester, when the brain growth spurt occurs: its volume triples, synaptogenesis is particularly active, and axons start to be myelinated. This developmental stage coincides with a period of great vulnerability. Studies in sheep have shown that progesterone and its metabolite allopregnanolone protect the vulnerable fetal brain. Work in rats and mice have demonstrated that progesterone plays an important role in myelin formation. These experimental studies are discussed in relation to preterm birth. Influences of progesterone on very early stages of neural development at the beginning of pregnancy are yet to be explored.
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http://dx.doi.org/10.1016/j.bpobgyn.2020.09.001DOI Listing
November 2020

Homeopathic Treatment as an Add-On Therapy May Improve Quality of Life and Prolong Survival in Patients with Non-Small Cell Lung Cancer: A Prospective, Randomized, Placebo-Controlled, Double-Blind, Three-Arm, Multicenter Study.

Oncologist 2020 12 7;25(12):e1930-e1955. Epub 2020 Nov 7.

Department of Respiratory and Critical Care Medicine and Ludwig Boltzmann Institute for Lung Health, Otto Wagner Hospital and Sigmund Freud University, Medical School, Vienna, Austria.

Lessons Learned: Conventional medicine and homeopathy work well together. Quality of life improves with additive homeopathy in patients with non-small cell lung cancer (NSCLC). Survival improves with additive homeopathy in patients with NSCLC.

Background: Patients with advanced non-small cell lung cancer (NSCLC) have limited treatment options. Alongside conventional anticancer treatment, additive homeopathy might help to alleviate side effects of conventional therapy. The aim of the present study was to investigate whether additive homeopathy might influence quality of life (QoL) and survival in patients with NSCLC.

Methods: In this prospective, randomized, placebo-controlled, double-blind, three-arm, multicenter, phase III study, we evaluated the possible effects of additive homeopathic treatment compared with placebo in patients with stage IV NSCLC, with respect to QoL in the two randomized groups and survival time in all three groups. Treated patients visited the outpatients' centers every 9 weeks: 150 patients with stage IV NSCLC were included in the study; 98 received either individualized homeopathic remedies (n = 51) or placebo (n = 47) in a double-blinded fashion; and 52 control patients without any homeopathic treatment were observed for survival only. The constituents of the different homeopathic remedies were mainly of plant, mineral, or animal origin. The remedies were manufactured by stepwise dilution and succussion, thereby preparing stable Good Manufacturing Practice grade formulations.

Results: QoL as well as functional and symptom scales showed significant improvement in the homeopathy group when compared with placebo after 9 and 18 weeks of homeopathic treatment (p < .001). Median survival time was significantly longer in the homeopathy group (435 days) versus placebo (257 days; p = .010) as well as versus control (228 days; p < .001). Survival rate in the homeopathy group differed significantly from placebo (p = .020) and from control (p < .001).

Conclusion: QoL improved significantly in the homeopathy group compared with placebo. In addition, survival was significantly longer in the homeopathy group versus placebo and control. A higher QoL might have contributed to the prolonged survival. The study suggests that homeopathy positively influences not only QoL but also survival. Further studies including other tumor entities are warranted.
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http://dx.doi.org/10.1002/onco.13548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8108047PMC
December 2020

ACTION-EHR: Patient-Centric Blockchain-Based Electronic Health Record Data Management for Cancer Care.

J Med Internet Res 2020 08 21;22(8):e13598. Epub 2020 Aug 21.

Department of Computer Science, Stony Brook University, Stony Brook, NY, United States.

Background: With increased specialization of health care services and high levels of patient mobility, accessing health care services across multiple hospitals or clinics has become very common for diagnosis and treatment, particularly for patients with chronic diseases such as cancer. With informed knowledge of a patient's history, physicians can make prompt clinical decisions for smarter, safer, and more efficient care. However, due to the privacy and high sensitivity of electronic health records (EHR), most EHR data sharing still happens through fax or mail due to the lack of systematic infrastructure support for secure, trustable health data sharing, which can also cause major delays in patient care.

Objective: Our goal was to develop a system that will facilitate secure, trustable management, sharing, and aggregation of EHR data. Our patient-centric system allows patients to manage their own health records across multiple hospitals. The system will ensure patient privacy protection and guarantee security with respect to the requirements for health care data management, including the access control policy specified by the patient.

Methods: We propose a permissioned blockchain-based system for EHR data sharing and integration. Each hospital will provide a blockchain node integrated with its own EHR system to form the blockchain network. A web-based interface will be used for patients and doctors to initiate EHR sharing transactions. We take a hybrid data management approach, where only management metadata will be stored on the chain. Actual EHR data, on the other hand, will be encrypted and stored off-chain in Health Insurance Portability and Accountability Act-compliant cloud-based storage. The system uses public key infrastructure-based asymmetric encryption and digital signatures to secure shared EHR data.

Results: In collaboration with Stony Brook University Hospital, we developed ACTION-EHR, a system for patient-centric, blockchain-based EHR data sharing and management for patient care, in particular radiation treatment for cancer. The prototype was built on Hyperledger Fabric, an open-source, permissioned blockchain framework. Data sharing transactions were implemented using chaincode and exposed as representational state transfer application programming interfaces used for the web portal for patients and users. The HL7 Fast Healthcare Interoperability Resources standard was adopted to represent shared EHR data, making it easy to interface with hospital EHR systems and integrate a patient's EHR data. We tested the system in a distributed environment at Stony Brook University using deidentified patient data.

Conclusions: We studied and developed the critical technology components to enable patient-centric, blockchain-based EHR sharing to support cancer care. The prototype demonstrated the feasibility of our approach as well as some of the major challenges. The next step will be a pilot study with health care providers in both the United States and Switzerland. Our work provides an exemplar testbed to build next-generation EHR sharing infrastructures.
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http://dx.doi.org/10.2196/13598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7474412PMC
August 2020

Agent-based Modeling for Ontology-driven Analysis of Patient Trajectories.

J Med Syst 2020 Aug 2;44(9):158. Epub 2020 Aug 2.

University of Applied Sciences and Arts Western Switzerland, HES-SO Valais-Wallis, TechnoPole 3, CH-3960, Sierre, Switzerland.

Patients are often required to follow a medical treatment after discharge, e.g., for a chronic condition, rehabilitation after surgery, or for cancer survivor therapies. The need to adapt to new lifestyles, medication, and treatment routines, can produce an individual burden to the patient, who is often at home without the full support of healthcare professionals. Although technological solutions -in the form of mobile apps and wearables- have been proposed to mitigate these issues, it is essential to consider individual characteristics, preferences, and the context of a patient in order to offer personalized and effective support. The specific events and circumstances linked to an individual profile can be abstracted as a patient trajectory, which can contribute to a better understanding of the patient, her needs, and the most appropriate personalized support. Although patient trajectories have been studied for different illnesses and conditions, it remains challenging to effectively use them as the basis for data analytics methodologies in decentralized eHealth systems. In this work, we present a novel approach based on the multi-agent paradigm, considering patient trajectories as the cornerstone of a methodology for modelling eHealth support systems. In this design, semantic representations of individual treatment pathways are used in order to exchange patient-relevant information, potentially fed to AI systems for prediction and classification tasks. This paper describes the major challenges in this scope, as well as the design principles of the proposed agent-based architecture, including an example of its use through a case scenario for cancer survivors support.
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http://dx.doi.org/10.1007/s10916-020-01620-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396405PMC
August 2020

Treating PMP22 gene duplication-related Charcot-Marie-Tooth disease: the past, the present and the future.

Transl Res 2021 01 18;227:100-111. Epub 2020 Jul 18.

U 1195, INSERM and Paris-Saclay University, Le Kremlin-Bicêtre, France. Electronic address:

Charcot-Marie-Tooth (CMT) disease is the most frequent inherited neuropathy, affecting 1/1500 to 1/10000. CMT1A represents 60%-70% of all CMT and is caused by a duplication on chromosome 17p11.2 leading to an overexpression of the Peripheral Myelin Protein 22 (PMP22). PMP22 gene is under tight regulation and small changes in its expression influences myelination and affect motor and sensory functions. To date, CMT1A treatment is symptomatic and classic pharmacological options have been disappointing. Here, we review the past, present, and future treatment options for CMT1A, with a special emphasis on the highly promising potential of PMP22-targeted small interfering RNA and antisense oligonucleotides.
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http://dx.doi.org/10.1016/j.trsl.2020.07.006DOI Listing
January 2021

Guest Editorial: Healthcare Intelligent Multi Agent Systems.

J Med Syst 2020 Jul 9;44(8):138. Epub 2020 Jul 9.

University of Applied Sciences Western Switzerland, Sierre, Switzerland.

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http://dx.doi.org/10.1007/s10916-020-01601-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346579PMC
July 2020

Effects of the Remaining and/or Spontaneously Regenerated Facial Axons After Hypoglossal-Facial Nerve Neurorrhaphy for Facial Paralysis.

Front Neurol 2020 29;11:413. Epub 2020 May 29.

Department of Injury and Repair, Beijing Neurosurgical Institute, Beijing, China.

The incidence of incomplete facial paralysis is now relatively higher in clinical practice, and surgical intervention is still desirable for patients with significant facial paralysis. However, the importance and usefulness of the remaining and/or spontaneously regenerated facial axons for regaining facial function when using hypoglossal-facial nerve (HN-FN) neurorrhaphy or other nerve-transferring methods to treat facial paralysis remain controversial. We designed a rat FN injury model with preservation of the anatomical structure followed by HN-FN side-to-side neurorrhaphy to investigate the effects of the remaining and/or spontaneously regenerated FN axons on restoration of facial function. After the evident return of facial function in 3 months following FN injury and HN-FN side-to-side neurorrhaphy, the FN was cross-sectioned again according to different ratios (0, 30, 70, and 100%) at the site rostral to the initial FN injury to retain, partially abolish, or completely abolish the spontaneously regenerated FN axons that had successfully reinnervated the paralyzed facial muscles. Then, FN function was assessed using clinical evaluation methods and electrophysiological examinations, as well as retrograde labeling and axonal counting assessments of the reconstructed nerve pathways. The evaluations show that the remaining facial axons not only influenced the extent of regained function, such as facial symmetry, eye blinking activity, and vibrissae motion, but also had an impact on regeneration and innervation of hypoglossal motoneurons. Participation of remaining or spontaneously regenerated facial axons plays an important role in innervating paralyzed facial muscles by both facial and hypoglossal motoneurons, thus, reestablishing facial function.
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http://dx.doi.org/10.3389/fneur.2020.00413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272673PMC
May 2020

Roles of Progesterone, Testosterone and Their Nuclear Receptors in Central Nervous System Myelination and Remyelination.

Int J Mol Sci 2020 Apr 30;21(9). Epub 2020 Apr 30.

U1195 Inserm and University Paris Sud / Paris-Saclay, 80 rue du Général Leclerc, 94276 Kremlin-Bicêtre, France.

Progesterone and testosterone, beyond their roles as sex hormones, are neuroactive steroids, playing crucial regulatory functions within the nervous system. Among these, neuroprotection and myelin regeneration are important ones. The present review aims to discuss the stimulatory effects of progesterone and testosterone on the process of myelination and remyelination. These effects have been demonstrated in vitro (i.e., organotypic cultures) and in vivo (cuprizone- or lysolecithin-induced demyelination and experimental autoimmune encephalomyelitis (EAE)). Both steroids stimulate myelin formation and regeneration by acting through their respective intracellular receptors: progesterone receptors (PR) and androgen receptors (AR). Activation of these receptors results in multiple events involving direct transcription and translation, regulating general homeostasis, cell proliferation, differentiation, growth and myelination. It also ameliorates immune response as seen in the EAE model, resulting in a significant decrease in inflammation leading to a fast recovery. Although natural progesterone and testosterone have a therapeutic potential, their synthetic derivatives-the 19-norprogesterone (nestorone) and 7α-methyl-nortestosterone (MENT), already used as hormonal contraception or in postmenopausal hormone replacement therapies, may offer enhanced benefits for myelin repair. We summarize here a recent advancement in the field of myelin biology, to treat demyelinating disorders using the natural as well as synthetic analogs of progesterone and testosterone.
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http://dx.doi.org/10.3390/ijms21093163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246940PMC
April 2020

Pregnane steroidogenesis is altered by HIV-1 Tat and morphine: Physiological allopregnanolone is protective against neurotoxic and psychomotor effects.

Neurobiol Stress 2020 May 29;12:100211. Epub 2020 Jan 29.

Department of Anatomy and Neurobiology, Virginia Commonwealth University, School of Medicine, Richmond, VA, 23298, USA.

Pregnane steroids, particularly allopregnanolone (AlloP), are neuroprotective in response to central insult. While unexplored , AlloP may confer protection against the neurological dysfunction associated with human immunodeficiency virus type 1 (HIV-1). The HIV-1 regulatory protein, trans-activator of transcription (Tat), is neurotoxic and its expression in mice increases anxiety-like behavior; an effect that can be ameliorated by progesterone, but not when 5α-reduction is blocked. Given that Tat's neurotoxic effects involve mitochondrial dysfunction and can be worsened with opioid exposure, we hypothesized that Tat and/or combined morphine would perturb steroidogenesis in mice, promoting neuronal death, and that exogenous AlloP would rescue these effects. Like other models of neural injury, conditionally inducing HIV-1 Tat in transgenic mice significantly increased the central synthesis of pregnenolone and progesterone's 5α-reduced metabolites, including AlloP, while decreasing central deoxycorticosterone (independent of changes in plasma). Morphine significantly increased brain and plasma concentrations of several steroids (including progesterone, deoxycorticosterone, corticosterone, and their metabolites) likely via activation of the hypothalamic-pituitary-adrenal stress axis. Tat, but not morphine, caused glucocorticoid resistance in primary splenocytes. In neurons, Tat depolarized mitochondrial membrane potential and increased cell death. Physiological concentrations of AlloP (0.1, 1, or 10 nM) reversed these effects. High-concentration AlloP (100 nM) was neurotoxic in combination with morphine. Tat induction in transgenic mice potentiated the psychomotor effects of acute morphine, while exogenous AlloP (1.0 mg/kg, but not 0.5 mg/kg) was ameliorative. Data demonstrate that steroidogenesis is altered by HIV-1 Tat or morphine and that physiological AlloP attenuates resulting neurotoxic and psychomotor effects.
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http://dx.doi.org/10.1016/j.ynstr.2020.100211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7109513PMC
May 2020

Insights into the Therapeutic Potential of Glucocorticoid Receptor Modulators for Neurodegenerative Diseases.

Int J Mol Sci 2020 Mar 20;21(6). Epub 2020 Mar 20.

Laboratory of Neuroendocrine Biochemistry, Instituto de Biologia y Medicina Experimental-CONICET, Obligado 2490, 1428 Buenos Aires, Argentina.

Glucocorticoids are crucial for stress-coping, resilience, and adaptation. However, if the stress hormones become dysregulated, the vulnerability to stress-related diseases is enhanced. In this brief review, we discuss the role of glucocorticoids in the pathogenesis of neurodegenerative disorders in both human and animal models, and focus in particular on amyotrophic lateral sclerosis (ALS). For this purpose, we used the Wobbler animal model, which mimics much of the pathology of ALS including a dysfunctional hypothalamic-pituitary-adrenal axis. We discuss recent studies that demonstrated that the pathological cascade characteristic for motoneuron degeneration of ALS is mimicked in the genetically selected Wobbler mouse and can be attenuated by treatment with the selective glucocorticoid receptor antagonist (GRA) CORT113176. In long-term treatment (3 weeks) GRA attenuated progression of the behavioral, inflammatory, excitatory, and cell-death-signaling pathways while increasing the survival signal of serine-threonine kinase (pAkt). The action mechanism of the GRA may be either by interfering with GR deactivation or by restoring the balance between pro- and anti-inflammatory signaling pathways driven by the complementary mineralocorticoid receptor (MR)- and GR-mediated actions of corticosterone. Accordingly, GR antagonism may have clinical relevance for the treatment of neurodegenerative diseases.
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http://dx.doi.org/10.3390/ijms21062137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139912PMC
March 2020

Dose-dependent and long-term cerebroprotective effects of intranasal delivery of progesterone after ischemic stroke in male mice.

Neuropharmacology 2020 06 6;170:108038. Epub 2020 Mar 6.

U1195 Inserm and University Paris-Sud and University Paris-Saclay, 80 rue du Général Leclerc, 94276 Kremlin-Bicêtre, France. Electronic address:

Intranasal administration is emerging as a very promising route to deliver therapeutics to the brain. We have recently shown that the intranasal delivery of progesterone at 8 mg/kg is neuroprotective after stroke in male mice. To explore the translational potential of intranasal progesterone treatment, we performed a dose-response study and analyzed outcomes at 48 h after middle cerebral artery occlusion (MCAO). The effects on functional outcomes at long-term were examined by using the optimal dose. In the first experiment, male C57BL/6JRj mice were treated with progesterone at 8, 16 or 24 mg/kg, or with placebo at 1, 6 and 24 h post-MCAO. Our results show that the dose of 8 mg/kg was optimal in counteracting the early histopathological impairments as well as in improving functional recovery. Steroid profiling in plasma showed that the dose of 8 mg/kg is the one that leads to sustained high levels of progesterone and its neuroactive metabolites. In the second experiment, the dose of 8 mg/kg was used and analyzes were performed at 2, 7 and 21 days post-MCAO. Progesterone increased survival, glycemia and body weight. Furthermore, progesterone decreased neurological deficits and improved performances of mice on the rotarod and pole as early as 2 days and up to 21 days post-MCAO. These findings show that intranasal administration of progesterone has a significant translational potential as a cerebroprotective treatment after stroke that can be effective to reduce mortality, to limit tissue and cell damage at the acute phase; and to confer a long-term functional recovery.
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http://dx.doi.org/10.1016/j.neuropharm.2020.108038DOI Listing
June 2020

Analysis of Preoperative Factors Influencing Hypoglossal-facial 'Side'-to-side Neurorrhaphy for Facial Paralysis after Excision of Acoustic Neuroma.

Biomed Environ Sci 2020 Jan;33(1):30-36

Beijing Neurosurgical Institute and Beijing Key Laboratory of Central Nervous System Injury, Capital Medical University, Beijing 100070, China;Department of Neurosurgery and China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China;U 1195, INSERM and University Paris-Sud and University Paris Saclay, 94276 Le Kremlin-Bicêtre, France.

Objective: Hypoglossal nerve-facial nerve 'side'-to-side neurorrhaphy is a new method for the treatment of potential incomplete facial paralysis after acoustic neuroma. However, there are differences in postoperative outcomes among patients. This study analysed preoperative factors that may influence the treatment outcomes of neurorrhaphy.

Methods: We performed a retrospective study of 53 patients who were treated by neurorrhaphy for facial paralysis after acoustic neuroma resection. After a one-year follow-up period, the patients were divided into two groups according to facial functional outcome: better recovery or ordinary recovery. We analysed the following factors: gender, age, tumour size, and characteristics, tumour adhesion to the facial nerve, the duration of facial paralysis (DFP) and F wave appearance prior to neurorrhaphy (F wave).

Results: Univariate analysis showed significant differences between the two groups in DFP ( = 0.0002), tumour adhesion to the facial nerve ( = 0.0079) and F waves ( = 0.0048). Logistic regression analysis of these factors also showed statistical significance with values of 0.042 for the DFP, 0.043 for F waves, and 0.031 for tumour adhesion to the facial nerve.

Conclusions: Tumour adhesion to the facial nerve, F waves appearance and DFP prior to neurorrhaphy are the predominant factors that influence treatment outcomes.
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http://dx.doi.org/10.3967/bes2020.004DOI Listing
January 2020

Autonomous agents and multi-agent systems applied in healthcare.

Artif Intell Med 2019 05 27;96:142-144. Epub 2019 Feb 27.

eHealth Unit - Eurecat, Centre Tecnològic de Catalunya, Spain. Electronic address:

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http://dx.doi.org/10.1016/j.artmed.2019.02.007DOI Listing
May 2019

Real-time multi-agent systems for telerehabilitation scenarios.

Artif Intell Med 2019 05 14;96:217-231. Epub 2019 Feb 14.

University of Applied Science Western Switzerland (HES-SO), Sierre, Switzerland.

Telerehabilitation in older adults is most needed in the patient environments, rather than in formal ambulatories or hospitals. Supporting such practices brings significant advantages to patients, their family, formal and informal caregivers, clinicians, and researchers. This paper presents a focus group with experts in physiotherapy and telerehabilitation, debating on the requirements, current techniques and technologies developed to facilitate and enhance the effectiveness of telerehabilitation, and the still open challenges. Particular emphasis is given to (i) the body-parts requiring the most rehabilitation, (ii) the typical environments, initial causes, and general conditions, (iii) the values and parameters to be observed, (iv) common errors and limitations of current practices and technological solutions, and (v) the envisioned and desired technological support. Consequently, it has been performed a systematic review of the state of the art, investigating what types of systems and support currently cope with telerehabilitation practices and possible matches with the outcomes of the focus group. Technological solutions based on video analysis, wearable devices, robotic support, distributed sensing, and gamified telerehabilitation are examined. Particular emphasis is given to solutions implementing agent-based approaches, analyzing and discussing strength, limitations, and future challenges. By doing so, it has been possible to relate functional requirements expressed by professional physiotherapists and researchers, with the need for extending multi-agent systems (MAS) peculiarities at the sensing level in wearable solutions establishing new research challenges. In particular, to be employed in safety-critical cyber-physical scenarios with user-sensor and sensor-sensor interactions, MAS are requested to handle timing constraints, scarcity of resources and new communication means, crucial to providing real-time feedback and coaching. Therefore, MAS pillars such as the negotiation protocol and the agent's internal scheduler have been investigated, proposing solutions to achieve the aforementioned real-time compliance.
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http://dx.doi.org/10.1016/j.artmed.2019.02.001DOI Listing
May 2019

Steroid profiles in quail brain and serum: Sex and regional differences and effects of castration with steroid replacement.

J Neuroendocrinol 2019 02 1;31(2):e12681. Epub 2019 Feb 1.

GIGA Neurosciences, University of Liège, Liège, Belgium.

Both systemic and local production contribute to the concentration of steroids measured in the brain. This idea was originally based on rodent studies and was later extended to other species, including humans and birds. In quail, a widely used model in behavioural neuroendocrinology, it was demonstrated that all enzymes needed to produce sex steroids from cholesterol are expressed and active in the brain, although the actual concentrations of steroids produced were never investigated. We carried out a steroid profiling in multiple brain regions and serum of sexually mature male and female quail by gas chromatography coupled with mass spectrometry. The concentrations of some steroids (eg, corticosterone, progesterone and testosterone) were in equilibrium between the brain and periphery, whereas other steroids (eg, pregnenolone (PREG), 5α/β-dihydroprogesterone and oestrogens) were more concentrated in the brain. In the brain regions investigated, PREG sulphate, progesterone and oestrogen concentrations were higher in the hypothalamus-preoptic area. Progesterone and its metabolites were more concentrated in the female than the male brain, whereas testosterone, its metabolites and dehydroepiandrosterone were more concentrated in males, suggesting that sex steroids present in quail brain mainly depend on their specific steroidogenic pathways in the ovaries and testes. However, the results of castration experiments suggested that sex steroids could also be produced in the brain independently of the peripheral source. Treatment with testosterone or oestradiol restored the concentrations of most androgens or oestrogens, respectively, although penetration of oestradiol in the brain appeared to be more limited. These studies illustrate the complex interaction between local brain synthesis and the supply from the periphery for the steroids present in the brain that are either directly active or represent the substrate of centrally located enzymes.
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http://dx.doi.org/10.1111/jne.12681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6412023PMC
February 2019

Hypoglossal-facial 'side'-to-side Neurorrhaphy Combined with Electrical Myostimulation for Facial Palsy in Rats.

Transl Neurosci 2018 4;9:167-174. Epub 2018 Dec 4.

Beijing Neurosurgical Institute, Capital Medical University, Beijing 100050, China.

Introduction This study investigated the effect of combining hypoglossal-facial nerve "side"-to-side neurorrhaphy and electrical myostimulation in a rat model of facial palsy. Methods Rats with facial nerve crush injury were subjected to control condition, monotherapy of either neurorrhaphy or electrical myostimulation, or bitherapy of the two treatments. After 1, 3, and 6 months, rats were performed the facial symmetry evaluation, electrophysiological examination and the retrograde labeling of motor neurons. Results As early as 3 months after injury, face symmetry significantly improved in rats of the bitherapy group. At 3 or 6 months after injury, either the parameters of electrophysiological examination or the number of labeled motor neurons were significantly increased in the bitherapy group than in any other group. Discussion The combination of neurorrhaphy and electrical myostimulation effectively promoted the functional recovery after facial nerve crush injury.
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http://dx.doi.org/10.1515/tnsci-2018-0025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6294042PMC
December 2018

Indexing the Event Calculus: Towards practical human-readable Personal Health Systems.

Artif Intell Med 2019 05 13;96:154-166. Epub 2018 Nov 13.

Open University of the Netherlands, Heerlen, The Netherlands; BISS Institute, Heerlen, The Netherlands. Electronic address:

Personal Health Systems (PHS) are mobile solutions tailored to monitoring patients affected by chronic non communicable diseases. In general, a patient affected by a chronic disease can generate large amounts of events: for example, in Type 1 Diabetic patients generate several glucose events per day, ranging from at least 6 events per day (under normal monitoring) to 288 per day when wearing a continuous glucose monitor (CGM) that samples the blood every 5 minutes for several days. Just by itself, without considering other physiological parameters, it would be impossible for medical doctors to individually and accurately follow every patient, highlighting the need of simple approaches towards querying physiological time series. Achieving this with current technology is not an easy task, as on one hand it cannot be expected that medical doctors have the technical knowledge to query databases and on the other hand these time series include thousands of events, which requires to re-think the way data is indexed. Anyhow, handling data streams efficiently is not enough. Domain experts' knowledge must be explicitly included into PHSs in a way that it can be easily readed and modified by medical staffs. Logic programming represents the perfect programming paradygm to accomplish this task. In this work, an Event Calculus-based reasoning framework to standardize and express domain-knowledge in the form of monitoring rules is suggested, and applied to three different use cases. However, if online monitoring has to be achieved, the reasoning performance must improve dramatically. For this reason, three promising mechanisms to index the Event Calculus Knowledge Base are proposed. All of them are based on different types of tree indexing structures: k-d trees, interval trees and red-black trees. The paper then compares and analyzes the performance of the three indexing techniques, by computing the time needed to check different type of rules (and eventually generating alerts), when the number of recorded events (e.g. values of physiological parameters) increases. The results show that customized jREC performs much better when the event average inter-arrival time is little compared to the checked rule time-window. Instead, where the events are more sparse, the use of k-d trees with standard EC is advisable. Finally, the Multi-Agent paradigm helps to wrap the various components of the system: the reasoning engines represent the agent minds, and the sensors are its body. The said agents have been developed in MAGPIE, a mobile event based Java agent platform.
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http://dx.doi.org/10.1016/j.artmed.2018.10.003DOI Listing
May 2019
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