Interleukin 21 Drives a Hypermetabolic State and CD4+ T-Cell-Associated Pathogenicity in Chronic Intestinal Inflammation.

BACKGROUND & AIMS: Incapacitated regulatory T cells (Tregs) contribute to immune-mediated diseases. Inflammatory Tregs are evident during human inflammatory bowel disease; however, mechanisms driving the development of these cells and their function are not well understood. Therefore, we investigated the role of cellular metabolism in Tregs relevant to gut homeostasis. METHODS: Using human Tregs, we performed mitochondrial ultrastructural studies via electron microscopy and confocal imaging, biochemical and protein analyses using proximity ligation assay, immunoblotting, mass cytometry and fluorescence-activated cell sorting, metabolomics, gene expression analysis, and real-time metabolic profiling utilizing the Seahorse XF analyzer. We used a Crohn's disease single-cell RNA sequencing dataset to infer the therapeutic relevance of targeting metabolic pathways in inflammatory Tregs. We examined the superior functionality of genetically modified Tregs in CD4+ T-cell-induced murine colitis models. RESULTS: Mitochondria-endoplasmic reticulum appositions, known to mediate pyruvate entry into mitochondria via voltage-dependent anion channel 1 (VDAC1), are abundant in Tregs. VDAC1 inhibition perturbed pyruvate metabolism, eliciting sensitization to other inflammatory signals reversible by membrane-permeable methyl pyruvate supplementation. Notably, interleukin (IL) 21 diminished mitochondria-endoplasmic reticulum appositions, resulting in enhanced enzymatic function of glycogen synthase kinase 3 ß, a putative negative regulator of VDAC1, and a hypermetabolic state that amplified Treg inflammatory response. Methyl pyruvate and glycogen synthase kinase 3 ß pharmacologic inhibitor (LY2090314) reversed IL21-induced metabolic rewiring and inflammatory state. Moreover, IL21-induced metabolic genes in Tregs in vitro were enriched in human Crohn's disease intestinal Tregs. Adoptively transferred Il21r-/- Tregs efficiently rescued murine colitis in contrast to wild-type Tregs. CONCLUSIONS: IL21 triggers metabolic dysfunction associated with Treg inflammatory response. Inhibiting IL21-induced metabolism in Tregs may mitigate CD4+ T-cell-driven chronic intestinal inflammation.

A Randomized Trial of Convalescent Plasma in Covid-19 Severe Pneumonia.

BACKGROUND: Convalescent plasma is frequently administered to patients with Covid-19 and has been reported, largely on the basis of observational data, to improve clinical outcomes. Minimal data are available from adequately powered randomized, controlled trials. METHODS: We randomly assigned hospitalized adult patients with severe Covid-19 pneumonia in a 2:1 ratio to receive convalescent plasma or placebo. The primary outcome was the patient's clinical status 30 days after the intervention, as measured on a six-point ordinal scale ranging from total recovery to death. RESULTS: A total of 228 patients were assigned to receive convalescent plasma and 105 to receive placebo. The median time from the onset of symptoms to enrollment in the trial was 8 days (interquartile range, 5 to 10), and hypoxemia was the most frequent severity criterion for enrollment. The infused convalescent plasma had a median titer of 1:3200 of total SARS-CoV-2 antibodies (interquartile range, 1:800 to 1:3200). No patients were lost to follow-up. At day 30 day, no significant difference was noted between the convalescent plasma group and the placebo group in the distribution of clinical outcomes according to the ordinal scale (odds ratio, 0.83; 95% confidence interval [CI], 0.52 to 1.35; P = 0.46). Overall mortality was 10.96% in the convalescent plasma group and 11.43% in the placebo group, for a risk difference of -0.46 percentage points (95% CI, -7.8 to 6.8). Total SARS-CoV-2 antibody titers tended to be higher in the convalescent plasma group at day 2 after the intervention. Adverse events and serious adverse events were similar in the two groups. CONCLUSIONS: No significant differences were observed in clinical status or overall mortality between patients treated with convalescent plasma and those who received placebo. (PlasmAr ClinicalTrials.gov number, NCT04383535.).

Development of a Six-Degree-of-Freedom Analog 3D Tactile Probe Based on Non-Contact 2D Sensors.

In this paper, a six-degree-of-freedom analog tactile probe with a new, simple, and robust mechanical design is presented. Its design is based on the use of one elastomeric ring that supports the stylus carrier and allows its movement inside a cubic measuring range of ±3 mm. The position of the probe tip is determined by three low-cost, noncontact, 2D PSD (position-sensitive detector) sensors, facilitating a wider application of this probe to different measuring systems compared to commercial ones. However, several software corrections, regarding the size and orientation of the three LED light beams, must be carried out when using these 2D sensors for this application due to the lack of additional focusing or collimating lenses and the very wide measuring range. The development process, simulation results, correction models, experimental tests, and calibration of this probe are presented. The results demonstrate high repeatability along the X-, Y-, and Z-axes (2.0 µm, 2.0 µm, and 2.1 µm, respectively) and overall accuracies of 6.7 µm, 7.0 µm, and 8.0 µm, respectively, which could be minimized by more complex correction models.

Alteration of Gut Microbiota Composition in the Progression of Liver Damage in Patients with Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD).

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a complex disorder whose prevalence is rapidly growing in South America. The disturbances in the microbiota-gut-liver axis impact the liver damaging processes toward fibrosis. Gut microbiota status is shaped by dietary and lifestyle factors, depending on geographic location. We aimed to identify microbial signatures in a group of Chilean MASLD patients. Forty subjects were recruited, including healthy controls (HCs), overweight/obese subjects (Ow/Ob), patients with MASLD without fibrosis (MASLD/F-), and MASLD with fibrosis (MASLD/F+). Both MASLD and fibrosis were detected through elastography and/or biopsy, and fecal microbiota were analyzed through deep sequencing. Despite no differences in α- and ß-diversity among all groups, a higher abundance of Bilophila and a lower presence of Defluviitaleaceae, Lachnospiraceae ND3007, and Coprobacter was found in MASLD/F- and MASLD/F+, compared to HC. Ruminococcaceae UCG-013 and Sellimonas were more abundant in MASLD/F+ than in Ow/Ob; both significantly differed between MASLD/F- and MASLD/F+, compared to HC. Significant positive correlations were observed between liver stiffness and Bifidobacterium, Prevotella, Sarcina, and Acidaminococcus abundance. Our results show that MASLD is associated with changes in bacterial taxa that are known to be involved in bile acid metabolism and SCFA production, with some of them being more specifically linked to fibrosis.

Three Adult Cases of STAT1 Gain-of-Function with Chronic Mucocutaneous Candidiasis Treated with JAK Inhibitors.

PURPOSE: The aim of this study was to characterize clinical effects and biomarkers in three patients with chronic mucocutaneous candidiasis (CMC) caused by gain-of-function (GOF) mutations in the STAT1 gene during treatment with Janus kinase (JAK) inhibitors. METHODS: Mass cytometry (CyTOF) was used to characterize mononuclear leukocyte populations and Olink assay to quantify 265 plasma proteins. Flow-cytometric Assay for Specific Cell-mediated Immune-response in Activated whole blood (FASCIA) was used to quantify the reactivity against Candida albicans. RESULTS: Overall, JAK inhibitors improved clinical symptoms of CMC, but caused side effects in two patients. Absolute numbers of neutrophils, T cells, B cells, and NK cells were sustained during baricitinib treatment. Detailed analysis of cellular subsets, using CyTOF, revealed increased expression of CD45, CD52, and CD99 in NK cells, reflecting a more functional phenotype. Conversely, monocytes and eosinophils downregulated CD16, consistent with reduced inflammation. Moreover, T and B cells showed increased expression of activation markers during treatment. In one patient with a remarkable clinical effect of baricitinib treatment, the immune response to C. albicans increased after 7 weeks of treatment. Alterations in plasma biomarkers involved downregulation of cellular markers CXCL10, annexin A1, granzyme B, granzyme H, and oncostatin M, whereas FGF21 was the only upregulated marker after 7 weeks. After 3 months, IFN-É£ and CXCL10 were downregulated. CONCLUSIONS: The clinical effect of JAK inhibitor treatment of CMC is promising. Several biological variables were altered during baricitinib treatment demonstrating that lymphocytes, NK cells, monocytes, and eosinophils were affected. In parallel, cellular reactivity against C. albicans was enhanced.

Long-term antibody titers variation in unvaccinated patients receiving convalescent plasma or placebo for severe SARS-CoV-2 pulmonary infection.

BACKGROUND: Convalescent plasma (CP) became a prominent treatment in the early stages of the SARS-CoV-2 pandemic. In Argentina, a randomized clinical trial was executed to compare the use of CP in inpatients with severe COVID-19 pneumonia versus placebo. No differences in clinical outcomes or overall mortality between groups were observed. We conducted a cohort study in outpatients enrolled in the trial to describe long-term antibody titer variations between CP and placebo recipients. METHODS: Patients' total SARS-CoV-2 IgG antibodies against spike protein were collected 3, 6 and 12 months after hospital discharge from August 2020 to December 2021. In addition, reinfections, deaths and vaccination status were retrieved. Statistical analysis was performed using antibody geometric mean titers (GMT). All estimations were made considering the date of the trial infusion (placebo or CP) as time 0. RESULTS: From the 93 patients included in the follow-up, 64 had received CP and 29 placebo. We excluded all 12-month measurements because they were collected after the patients' vaccination date. At 90 days post-infusion, patients had an antibody GMT of 8.1 (IQR 7.4-8.1) in the CP group and 8.8 (IQR 8.1-9.1) in the placebo group. At 180 days, both groups had a GMT of 8.1 (IQR 7.4-8.1). No statistical differences in GMT were found between CP and placebo groups at 90 days (p = 0.12) and 180 days (p = 0.25). No patients registered a new COVID-19 infection; one died in the CP group from an ischemic stroke. CONCLUSIONS: No differences were observed in long-term antibody titers in unvaccinated patients that received CP or placebo after severe COVID-19 pneumonia.

Diet and stomach characteristics of feral piglets (Sus scrofa): Implications for farmed piglets.

Evaluation of the diet of the pig (Sus scrofa) in natural settings may provide new views on diet optimization for growth and development of commercially raised piglets under farm conditions. A field study was conducted to gain insight in the diet and stomach characteristics of feral piglets. Forty animals (body weight: 4.6 ± 1.37 kg) were collected from the Bahía Samborombón (Buenos Aires, Argentina). Stomachs were weighed after storage in formalin and the particle size distribution of their contents was determined by wet sieving. Diet items present in their stomachs were classified and their proportional weight and relative abundance was calculated. Based on their dentition, 5, 16 and 19 piglets were approximately 1, 3-6 and 6-16 weeks of age respectively. Vegetable matter (mainly 'leaves and stems') was predominantly present in 39 animals. It represented on average 83 ± 36.4% of total stomach contents by weight. The stomachs of 12 piglets contained curd and represented on average 16 ± 35.1% by weight. Other diet items were less abundant or absent. The proportion of stomach particles retained were 24%, 13%, 22%, 13% and 28% for sieves with mesh sizes of 2000, 1000, 420, 210 and <210 µm respectively. For comparison, we used data of farmed piglets of similar age and fed a nutrient-dense, finely ground diet. Feral piglets' relative empty stomach weights increased with age (p < 0.050), whereas this was not the case for farmed piglets. Relative stomach contents weight increased significantly with age only for farmed piglets (p < 0.050). We infer from our data that feral suckling piglets consumed a variety of non-milk items, mainly consisting of vegetable material with a coarse particle size from their first week in life onwards. Their diet is associated with an enhanced stomach development compared to those of farmed piglets.

TYPE II ACHALASIA WITH SUBSEQUENT RECOVERY OF ESOPHAGEAL MOTILITY - POEM.

CASE REPORT: 54-year-old woman with acromegaly due to pituitary macroadenoma that consulted for dysphagia for solids. In gastroscopy, it is observed difficulty in passing in the esophagogastric junction (EGJ). Under the suspect of Achalasia, a high-resolution esophageal manometry (HRM) was performed, observing a complete absence of motility of the esophageal body, panesophageal pressurization in > 20% of swallows and IRP of 21mmHg, confirming the diagnosis of type II Achalasia. Peroral endoscopic myotomy (POEM) is performed. After the intervention, the patient presented clinical improvement. In the control HRM carried out one year after the POEM, in addition to a decrease in IRP, is remarkable a partial recovery of motility in the upper and middle third of the esophagus. DISCUSSION: Achalasia is an esophageal motor disorder characterized by incomplete relaxation of the lower esophageal sphincter and a complete absence of peristalsis in the esophageal body. The cause of the absence of motility is the loss of the inhibitory neurons of the myenteric plexus, but the accurate etiopathogenesis is still unknown. Therefore, there is no curative treatment and all therapeutic options are symptomatic, aimed to relieve the obstruction of the EGJ. POEM is the newest method. Absence of motility of the esophageal body in patients with achalasia was believed to be irreversible. Nevertheless, more and more studies describe a partial recovery of motility observed in manometry after POEM, especially in type II Achalasia. The exact pathophysiological mechanism of this recovery is still unknown. IMAGES DESCRIPTION: Figure 1 (Before POEM): High-resolution manometry with a diagnosis of type II Achalasia: Absence of motility, panesophageal pressurization and IRP 21mmHg Figure 2 (After POEM): High resolution manometry showing ineffective esophageal motility (partial recovery of motility) after POEM with IRP of 4mmHg.

Underlying etiology associated with the diagnosis of absent contractility on high resolution esophageal manometry.

BACKGROUND/AIMS: Absent contractility is considered a disorder of peristalsis. The literature about the etiology and clinical characteristics is scarce and the evidence on systemic diseases associated with this esophageal disorder is limited. Therefore, we aimed to determine the etiology of absent contractility in our population using the clinical algorithm recently described in the literature. METHODS: We conducted a retrospective, descriptive study at a single tertiary hospital of all patients diagnosed of absent contractility between May 2018 and February 2020. Data on demographic characteristics, medication, comorbidities, and laboratory and paraclinical tests were recorded from clinical records. RESULTS: A total of 72 patients with absent contractility were included for analysis. There was a predominance of female sex (n=43, 59.7%), with a mean age of 55.4 (±15.0) years. We identified a systemic disorder associated with absent contractility in 64 (88.9%) patients. From these, 31 (43.1%) patients were diagnosed with a systemic autoimmune disease, 26 (36.1%) patients were considered to have absent contractility secondary to pathological exposure to acid-reflux and 15 (20.8%) patients were diagnosed with other non-autoimmune systemic disorders. In the remaining eight (11.1%) patients, there were no underlying systemic disorders that could justify the diagnosis of absent contractility. CONCLUSIONS: A systematic approach to search for an underlying cause in patients diagnosed with absent contractility is warranted. Up to 90% of patients with absent contractility have a systemic disorder associated with this condition.

Multilevel interactions between native and ectopic isoprenoid pathways affect global metabolism in rice.

Isoprenoids are natural products derived from isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP). In plants, these precursors are synthesized via the cytosolic mevalonate (MVA) and plastidial methylerythritol phosphate (MEP) pathways. The regulation of these pathways must therefore be understood in detail to develop effective strategies for isoprenoid metabolic engineering. We hypothesized that the strict regulation of the native MVA pathway could be circumvented by expressing an ectopic plastidial MVA pathway that increases the accumulation of IPP and DMAPP in plastids. We therefore introduced genes encoding the plastid-targeted enzymes HMGS, tHMGR, MK, PMK and MVD and the nuclear-targeted transcription factor WR1 into rice and evaluated the impact of their endosperm-specific expression on (1) endogenous metabolism at the transcriptomic and metabolomic levels, (2) the synthesis of phytohormones, carbohydrates and fatty acids, and (3) the macroscopic phenotype including seed morphology. We found that the ectopic plastidial MVA pathway enhanced the expression of endogenous cytosolic MVA pathway genes while suppressing the native plastidial MEP pathway, increasing the production of certain sterols and tocopherols. Plants carrying the ectopic MVA pathway only survived if WR1 was also expressed to replenish the plastid acetyl-CoA pool. The transgenic plants produced higher levels of fatty acids, abscisic acid, gibberellins and lutein, reflecting crosstalk between phytohormones and secondary metabolism.

Sport and self-esteem in people living with HIV: a cross-sectional study.

BACKGROUND: In the general population, sport activity is associated with better health and better self-esteem. Among people living with HIV (PLHIV), sport activity could also be associated with better self-esteem. The main objective of our study was to assess the association between sport activity and self-esteem among people living with HIV. The secondary objectives were to evaluate the associations between sport activity with fatigue as well as with pain. METHODS: We performed a cross-sectional observational study among PLHIV in our region (Pays de la Loire in France). Each adult seen in routine HIV care was invited to participate in the study. Participants were invited to fill out self-questionnaires about sport activity, self-esteem, fatigue, and pain. The 2 groups of participants with and without sport activity were compared with a T Student test for self-esteem, fatigue, and pain scales. RESULTS: Among the 1160 people included in the study, 47% performed sport activity. The self-esteem score was better in the "sporting group" compared with the "non sporting group" (Rosenberg mean scale 32.7 ± 5.1/40 vs 31.9 ± 5 p = 0.01). The Functional Assessment of Chronic Illness Therapy Fatigue scale showed a lower fatigue in the sporting group than in the non-sporting group (mean total score 125 ± 22 vs 118 ± 24 p < 0.0001). The sporting group had a lower mean pain score (1.1 ± 1.8) than the non sporting group (1.4 ± 1.9 p = 0.004). CONCLUSIONS: Among PLHIV in our region, sport activity was associated with better self-esteem, lower fatigue and lower pain. Sport activity should be included in patient care for people living with HIV.

mRNA-1273 SARS-CoV-2 vaccine safety and COVID-19 risk perception in recently transplanted allogeneic hematopoietic stem cell transplant recipients.

PURPOSE: This study aims to describe the incidence and severity of adverse events (AEs) following the mRNA-1273 SARS-CoV-2 vaccine and explore the risk perception of COVID-19 in allogeneic hematopoietic stem cell transplant (HCT) recipients. METHODS: We performed a single-center prospective study including recently transplanted (< 2 years post-infusion) allogeneic HCT recipients. AEs were assessed through phone calls and graded from 0 to 4, while COVID-19 risk perception was measured using the Brief Illness Perception Questionnaire (BIP-Q5). RESULTS: Fifty-four HCT recipients were evaluated. Incidence and grades of AE (94.4% and 85.2% after the first and second dose, respectively) were similar to those described in the general population. The most common AE was pain at the site of injection. Three patients (5.6%) developed a grade ≥ 3 AE. Vaccine-related cytopenias and graft-versus-host disease flares were not observed. Female sex (OR 3.94, 95% CI 1.14-13.58, p = 0.03) and time since HCT (per month since HCT: OR 1.09, 95% CI 1.01-1.18, p = 0.04) were associated with the occurrence of any AE. The patients' risk perception level of COVID-19 decreased over time (p < 0.05). CONCLUSION: Our study confirms that the mRNA-1273 SARS-CoV-2 vaccine is safe in recent HCT recipients and suggests that the perceived risk of COVID-19 decreases over time.

Opioid-induced esophageal dysfunction - Prevalence and manometric findings.

BACKGROUND: prescription opioid use is on the rise. There has been an increasing recognition that chronic opioid consumption can result in esophageal motility disorders, and this association has been named opioid-induced esophageal dysfunction (OIED). AIMS: to analyze the prevalence of chronic opioid consumption in patients referred for esophageal motility testing in a European center; to describe the clinical characteristics and the association of opioid consumption with esophageal motility disorders. METHODS: a retrospective, descriptive study in patients who had undergone an HRM in a single center. The clinical history in the electronic medical records was reviewed. RESULTS: the prevalence of opioid prescription in patients referred to our institution was 10.1 %, and 4.8 % of them were chronic active opioid users. There was a 32 % prevalence of OIED. Comparing chronic active opioid users (CAOU) with OIED and CAOU patients without OIED, there was a higher prevalence of males (43.8 % vs 8.8 %; p-value = 0.007). Converting the different opioid medications to morphine milligram equivalent daily dose (MMED), CAOU patients with OIED had a higher MMED than CAOU patients without OIED (125.2 ± 31.3 vs 33.4 ± 5.7 MME; p = 0.041). Dysphagia was the most common indication for performing an HRM in 60.0 % of CAOU patients. Furthermore, dysphagia was more frequent in CAOU patients with OIED (87.5 % vs 47.0 %; p = 0.019). CONCLUSIONS: chronic opioid users with OIED complained mostly of dysphagia. There was an association of male sex and a higher dose of opioids in CAOU patients with esophageal motility disorders.

Classification of fold/hom and fold/Hopf spike-adding phenomena.

The Hindmarsh-Rose neural model is widely accepted as an important prototype for fold/hom and fold/Hopf burstings. In this paper, we are interested in the mechanisms for the production of extra spikes in a burst, and we show the whole parametric panorama in an unified way. In the fold/hom case, two types are distinguished: a continuous one, where the bursting periodic orbit goes through bifurcations but persists along the whole process and a discontinuous one, where the transition is abrupt and happens after a sequence of chaotic events. In the former case, we speak about canard-induced spike-adding and in the second one, about chaos-induced spike-adding. For fold/Hopf bursting, a single (and continuous) mechanism is distinguished. Separately, all these mechanisms are presented, to some extent, in the literature. However, our full perspective allows us to construct a spike-adding map and, more significantly, to understand the dynamics exhibited when borders are crossed, that is, transitions between types of processes, a crucial point not previously studied.

Optimized Liquid-Phase Exfoliation of Magnetic van der Waals Heterostructures: Towards the Single Layer and Deterministic Fabrication of Devices.

Van der Waals magnetic materials are promising candidates for spintronics and testbeds for exotic magnetic phenomena in low dimensions. The two-dimensional (2D) limit in these materials is typically reached by mechanically breaking the van der Waals interactions between layers. Alternative approaches to producing large amounts of flakes rely on wet methods such as liquid-phase exfoliation (LPE). Here, we report an optimized route for obtaining monolayers of magnetic cylindrite by LPE. We show that the selection of exfoliation times is the determining factor in producing a statistically significant amount of monolayers while keeping relatively big flake areas (~1 µm2). We show that the cylindrite lattice is preserved in the flakes after LPE. To study the electron transport properties, we have fabricated field-effect transistors based on LPE cylindrite. Flakes are deterministically positioned between nanoscale electrodes by dielectrophoresis. We show that dielectrophoresis can selectively move the larger flakes into the devices. Cylindrite nanoscale flakes present a p-doped semiconducting behaviour, in agreement with the mechanically exfoliated counterparts. Alternating current (AC) admittance spectroscopy sheds light on the role played by potential barriers between different flakes in terms of electron transport properties. The present large-scale exfoliation and device fabrication strategy can be extrapolated to other families of magnetic materials.

Comparison of original and biosimilar infliximab (CTP-13) in biologic-naïve patients with Crohn's disease and ulcerative colitis: a retrospective, multicenter real-life study in Spain.

PURPOSE: biosimilar infliximab (CTP-13) has been recently approved for the treatment of several immune-mediated inflammatory disorders, including inflammatory bowel disease (IBD). Comparative studies between this biosimilar and original infliximab in the real clinical practice are scarce. The objective of this study was to compare short and long-term safety and efficacy of original (O) and biosimilar infliximab (B-IFX) in biologic-naïve, IBD patients in the real life clinical practice. METHODS: a retrospective, multicentric study was performed in five Spanish hospitals. Consecutive IBD, biologic-naïve patients from an historic cohort who initiated O-IFX from January 2013 were compared with biologic-naïve patients, who started treatment with B-IFX since its approval in January 2015. The evaluation of efficacy was assessed after the induction phase, at week 14 and week 54 of treatment. Time to dose escalation or treatment persistence of both O-IFX and B-IFX was also considered. The appearance of serious adverse events was recorded. RESULTS: two hundred and thirty-nine IBD biologic-naïve patients who started with O-IFX or B-IFX were included: 153 patients were diagnosed with Crohn's disease (95 treated with O- and 58 treated with B-IFX) and 86 with ulcerative colitis (40 received O- and 46 received B-IFX). At weeks 14 and 54, both O-IFX and B-IFX groups reached a similar clinical response and remission rates. Time to dose escalation, treatment persistence and safety profile were comparable between both groups. CONCLUSIONS: this long-term real-life experience provides additional evidence of the similarity of O- and B-IFX CTP-13 in terms of efficacy and safety in IBD patients.

Homoclinic organization in the Hindmarsh-Rose model: A three parameter study.

Bursting phenomena are found in a wide variety of fast-slow systems. In this article, we consider the Hindmarsh-Rose neuron model, where, as it is known in the literature, there are homoclinic bifurcations involved in the bursting dynamics. However, the global homoclinic structure is far from being fully understood. Working in a three-parameter space, the results of our numerical analysis show a complex atlas of bifurcations, which extends from the singular limit to regions where a fast-slow perspective no longer applies. Based on this information, we propose a global theoretical description. Surfaces of codimension-one homoclinic bifurcations are exponentially close to each other in the fast-slow regime. Remarkably, explained by the specific properties of these surfaces, we show how the Hindmarsh-Rose model exhibits isolas of homoclinic bifurcations when appropriate two-dimensional slices are considered in the three-parameter space. On the other hand, these homoclinic bifurcation surfaces contain curves corresponding to parameter values where additional degeneracies are exhibited. These codimension-two bifurcation curves organize the bifurcations associated with the spike-adding process and they behave like the "spines-of-a-book," gathering "pages" of bifurcations of periodic orbits. Depending on how the parameter space is explored, homoclinic phenomena may be absent or far away, but their organizing role in the bursting dynamics is beyond doubt, since the involved bifurcations are generated in them. This is shown in the global analysis and in the proposed theoretical scheme.

A Comprehensive Framework for Uncovering Non-Linearity and Chaos in Financial Markets: Empirical Evidence for Four Major Stock Market Indices.

The presence of chaos in the financial markets has been the subject of a great number of studies, but the results have been contradictory and inconclusive. This research tests for the existence of nonlinear patterns and chaotic nature in four major stock market indices: namely Dow Jones Industrial Average, Ibex 35, Nasdaq-100 and Nikkei 225. To this end, a comprehensive framework has been adopted encompassing a wide range of techniques and the most suitable methods for the analysis of noisy time series. By using daily closing values from January 1992 to July 2013, this study employs twelve techniques and tools of which five are specific to detecting chaos. The findings show no clear evidence of chaos, suggesting that the behavior of financial markets is nonlinear and stochastic.

Concomitant Medications and Risk of Chemotherapy-Induced Peripheral Neuropathy.

BACKGROUND: Peripheral neuropathy is the dose-limiting toxicity of many oncology drugs, including paclitaxel. There is large interindividual variability in the neuropathy, and several risk factors have been proposed; however, many have not been replicated. Here we present a comprehensive study aimed at identifying treatment and physiopathology-related paclitaxel-induced neuropathy risk factors in a large cohort of well-characterized patients. PATIENTS AND METHODS: Analyses included 503 patients with breast or ovarian cancer who received paclitaxel treatment. Paclitaxel dose modifications caused by the neuropathy were extracted from medical records and patients self-reported neuropathy symptoms were collected. Multivariate logistic regression analyses were performed to identify concomitant medications and comorbidities associated with paclitaxel-induced neuropathy. RESULTS: Older patients had higher neuropathy: for each increase of 1 year of age, the risk of dose modifications and grade 3 neuropathy increased 4% and 5%, respectively. Cardiovascular drugs increased the risk of paclitaxel dose reductions (odds ratio [OR], 2.51; p = .006), with a stronger association for beta-adrenergic antagonists. The total number of concomitant medications also showed an association with dose modifications (OR, 1.25; p = .012 for each concomitant drug increase). A dose modification predictive model that included the new identified factors gave an area under the curve of 0.74 (p = 1.07 × 10-10). Preexisting nerve compression syndromes seemed to increase neuropathy risk. CONCLUSION: Baseline characteristics of the patients, including age and concomitant medications, could be used to identify individuals at high risk of neuropathy, personalizing chemotherapy treatment and reducing the risk of severe neuropathy. IMPLICATIONS FOR PRACTICE: Peripheral neuropathy is a common adverse effect of many cancer drugs, including chemotherapeutics, targeted therapies, and immune checkpoint inhibitors. About 40% of survivors of cancer have functional deficits caused by this toxicity, some of them irreversible. Currently, there are no effective treatments to prevent or treat this neuropathy. This study, performed in a large cohort of well-characterized patients homogenously treated with paclitaxel, identified concomitant medications, comorbidities, and demographic factors associated with peripheral neuropathy. These factors could serve to identify patients at high risk of severe neuropathy for whom alternative non-neurotoxic alternatives may be considered.

Tenofovir DF/emtricitabine/rilpivirine as HIV post-exposure prophylaxis: results from a multicentre prospective study.

OBJECTIVES: Since 2016, French guidelines have recommended the single-tablet regimen of tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC)/rilpivirine (RPV) as HIV post-exposure prophylaxis (PEP), but few data support this usage. We evaluated the tolerability, treatment completion and occurrence of HIV seroconversion associated with this combination in occupational and non-occupational PEP. PATIENTS AND METHODS: We conducted an observational, prospective, multicentre, open-label, non-randomized study in five French HIV centres. Adults requiring PEP according to national French guidelines were prescribed TDF/FTC/RPV one pill once a day for 28 days. Clinical and biological tolerability was assessed at week 4; occurrence of HIV seroconversion was evaluated after week 16. RESULTS: From March 2016 to March 2017, 163 courses of PEP were prescribed for 150 sexual exposures (44% heterosexual and 56% MSM) and 13 non-sexual exposures. Five participants stopped PEP after a few days because the source person was HIV uninfected. Of the remaining 158 individuals, 15 (9.5%) were lost to follow-up at week 4, 7 (4.4%) prematurely discontinued PEP [patient's decision/non-adherence (n = 3) or adverse events (gastrointestinal intolerance n = 3, fatigue n = 1)] and 136 (86.1%) completed the 28 day treatment. Overall, 69.6% of participants declared at least one adverse event, mostly of mild to moderate intensity and no serious adverse events or hepatic or renal toxicity occurred. No HIV seroconversion occurred at week 16. CONCLUSIONS: The low rate of premature treatment interruption, the good tolerability and the absence of documented HIV seroconversion support the current French guidelines of a 28 day course of TDF/FTC/RPV for sexual and non-sexual PEP.