Relationships of gut microbiota, short-chain fatty acids, inflammation, and the gut barrier in Parkinson's disease

Background Previous studies have reported that gut microbiota, permeability, short-chain fatty acids (SCFAs), and inflammation are altered in Parkinson's disease (PD), but how these factors are linked and how they contribute to disease processes and symptoms remains uncertain. This study sought to compare and identify associations among these factors in PD patients and controls to elucidate their interrelations and links to clinical manifestations of PD. Methods Stool and plasma samples and clinical data were collected from 55 PD patients and 56 controls. Levels of stool SCFAs and stool and plasma inflammatory and permeability markers were compared between patients and controls and related to one another and to the gut microbiota. Results Calprotectin was increased and SCFAs decreased in stool in PD in a sex-dependent manner. Inflammatory markers in plasma and stool were neither intercorrelated nor strongly associated with SCFA levels. Age at PD onset was positively correlated with SCFAs and negatively correlated with CXCL8 and IL-1 beta in stool. Fecal zonulin correlated positively with fecal NGAL and negatively with PD motor and non-motor symptoms. Microbiota diversity and composition were linked to levels of SCFAs, inflammatory factors, and zonulin in stool. Certain relationships differed between patients and controls and by sex. Conclusions Intestinal inflammatory responses and reductions in fecal SCFAs occur in PD, are related to the microbiota and to disease onset, and are not reflected in plasma inflammatory profiles. Some of these relationships are distinct in PD and are sex-dependent. This study revealed potential alterations in microbiota-host interactions and links between earlier PD onset and intestinal inflammatory responses and reduced SCFA levels, highlighting candidate molecules and pathways which may contribute to PD pathogenesis and clinical presentation and which warrant further investigation.Peer reviewe

Bacterial Butyrate in Parkinson's Disease Is Linked to Epigenetic Changes and Depressive Symptoms

Background The gut microbiome and its metabolites can impact brain health and are altered in Parkinson's disease (PD) patients. It has been recently demonstrated that PD patients have reduced fecal levels of the potent epigenetic modulator butyrate and its bacterial producers. Objectives Here, we investigate whether the changes in the gut microbiome and associated metabolites are related to PD symptoms and epigenetic markers in leucocytes and neurons. Methods Stool, whole blood samples, and clinical data were collected from 55 PD patients and 55 controls. We performed DNA methylation analysis on whole blood samples and analyzed the results in relation to fecal short-chain fatty acid concentrations and microbiota composition. In another cohort, prefrontal cortex neurons were isolated from control and PD brains. We identified genome-wide DNA methylation by targeted bisulfite sequencing. Results We show that lower fecal butyrate and reduced counts of genera Roseburia, Romboutsia, and Prevotella are related to depressive symptoms in PD patients. Genes containing butyrate-associated methylation sites include PD risk genes and significantly overlap with sites epigenetically altered in PD blood leucocytes, predominantly neutrophils, and in brain neurons, relative to controls. Moreover, butyrate-associated methylated-DNA regions in PD overlap with those altered in gastrointestinal (GI), autoimmune, and psychiatric diseases. Conclusions Decreased levels of bacterially produced butyrate are related to epigenetic changes in leucocytes and neurons from PD patients and to the severity of their depressive symptoms. PD shares common butyrate-dependent epigenetic changes with certain GI and psychiatric disorders, which could be relevant for their epidemiological relation. (c) 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder SocietyPeer reviewe

QUBIC: The QU Bolometric Interferometer for Cosmology

One of the major challenges of modern cosmology is the detection of B-mode polarization anisotropies in the CMB. These originate from tensor fluctuations of the metric produced during the inflationary phase. Their detection would therefore constitute a major step towards understanding the primordial Universe. The expected level of these anisotropies is however so small that it requires a new generation of instruments with high sensitivity and extremely good control of systematic effects. We propose the QUBIC instrument based on the novel concept of bolometric interferometry, bringing together the sensitivity advantages of bolometric detectors with the systematics effects advantages of interferometry. Methods: The instrument will directly observe the sky through an array of entry horns whose signals will be combined together using an optical combiner. The whole set-up is located inside a cryostat. Polarization modulation will be achieved using a rotating half-wave plate and interference fringes will be imaged on two focal planes (separated by a polarizing grid) tiled with bolometers. We show that QUBIC can be considered as a synthetic imager, exactly similar to a usual imager but with a synthesized beam formed by the array of entry horns. Scanning the sky provides an additional modulation of the signal and improve the sky coverage shape. The usual techniques of map-making and power spectrum estimation can then be applied. We show that the sensitivity of such an instrument is comparable with that of an imager with the same number of horns. We anticipate a low level of beam-related systematics thanks to the fact that the synthesized beam is determined by the location of the primary horns. Other systematics should be under good control thanks to an autocalibration technique, specific to our concept, that will permit the accurate determination of most of the systematics parameters.Comment: 12 pages, 10 figures, submitted to Astronomy and Astrophysic

Oral fexinidazole for stage 1 or early stage 2 African Trypanosoma brucei gambiense trypanosomiasis: a prospective, multicentre, open-label, cohort study

BACKGROUND: Staging and treatment of human African trypanosomiasis caused by Trypanosoma brucei gambiense (g-HAT) required lumbar puncture to assess cerebrospinal fluid (CSF) and intravenous drugs that cross the blood-brain barrier for late-stage infection. These procedures are inconvenient in rural health systems of disease-endemic countries. A pivotal study established fexinidazole as the first oral monotherapy to be effective against non-severe stage 2 g-HAT. We aimed to assess the safety and efficacy of fexinidazole in early g-HAT. METHODS: In this prospective, multicentre, open-label, single-arm cohort study, patients with stage 1 or early stage 2 g-HAT were recruited from eight treatment centres in the Democratic Republic of the Congo. Primary inclusion criteria included being older than 15 years, being able to ingest at least one complete meal per day (or at least one sachet of Plumpy'Nut®), a Karnofsky score higher than 50, evidence of trypanosomes in the blood or lymph but no evidence of trypanosomes in the CSF, willingness to be admitted to hospital to receive treatment, having a permanent address, and being able to comply with the follow-up visit schedule. Exclusion criteria included severe malnutrition, inability to take medication orally, pregnant or breastfeeding women, any clinically important medical condition that could jeopardise patient safety or participation in the study, severely deteriorated general status, any contraindication to imidazole drugs, HAT treatment in the past 2 years, previous enrolment in the study or previous intake of fexinidazole, abnormalities on electrocardiogram that did not return to normal in pretreatment repeated assessments or were considered clinically important, QT interval corrected using Fridericia's formula of at least 450 ms, and patients not tested for malaria or not having received appropriate treatment for malaria or for soil-transmitted helminthiasis. Patients were classified into stage 1 or early stage 2 g-HAT groups following evidence of trypanosomes in the blood, lymph, and absence in CSF, and using white-blood-cell count in CSF. Patients received 1800 mg fexinidazole once per day on days 1-4 then 1200 mg fexinidazole on days 5-10. Patients were observed for approximately 19 months in total. Study participants were followed up on day 5 and day 8 during treatment, at end of treatment on day 11, at end of hospitalisation on days 11-18, at week 9 for a subset of patients, and after 6 months, 12 months, and 18 months. The primary endpoint was treatment success at 12 months. Safety was assessed through routine monitoring. Analyses were done in the intention-to-treat population. The acceptable success rate was defined as treatment efficacy in more than 80% of patients. This study is completed and registered with ClinicalTrials.gov (NCT02169557). FINDINGS: Patients were enrolled between April 30, 2014, and April 25, 2017. 238 patients were recruited: 195 (82%) patients with stage 1 g-HAT and 43 (18%) with early stage 2 g-HAT. 189 (97%) of 195 patients with stage 1 g-HAT and 41 (95%) of 43 patients with early stage 2 g-HAT were finally included and completed the 10 day treatment period. Three patients with stage 1 g-HAT died after the 10 day treatment period and before the 12 month primary follow-up visit, considered as treatment failure and were withdrawn from the study. Treatment was effective at 12 months for 227 (99%) of 230 patients (95% CI 96·2-99·7): 186 (98%) of 189 patients (95·4-99·7) with stage 1 and 41 (100%) of 41 patients (91·4-100·0) with early stage 2, indicating that the primary study endpoint was met. No new safety issues were observed. The most frequent adverse events were headache and vomiting. In total, 214 (93%) of 230 patients had treatment-emergent adverse events, mainly common-terminology criteria for adverse events grades 1 to 3. None led to treatment discontinuation. INTERPRETATION: Fexinidazole is a valuable first-line treatment option in the early stages of g-HAT. FUNDING: Through the Drugs for Neglected Diseases initiative: the Bill & Melinda Gates Foundation, the Republic and Canton of Geneva (Switzerland), the Dutch Ministry of Foreign Affairs (also known as DGIS; Netherlands), the Norwegian Agency for Development Cooperation (also known as Norad; Norway), the Federal Ministry of Education and Research (also known as BMBF) through KfW (Germany), the Brian Mercer Charitable Trust (UK), and other private foundations and individuals from the HAT campaign

New Non-Intravenous Routes for Benzodiazepines in Epilepsy: A Clinician Perspective.

Benzodiazepines represent the first-line treatment for the acute management of epileptic seizures and status epilepticus. The emergency use of benzodiazepines must be timely, and because most seizures occur outside of the hospital environment, there is a significant need for delivery methods that are easy for nonclinical caregivers to use and administer quickly and safely. In addition, the ideal route of administration should be reliable in terms of absorption. Rectal diazepam is the only licensed formulation in the USA, whereas rectal diazepam and buccal midazolam are currently licensed in the EU. However, the sometimes unpredictable absorption with rectal and buccal administration means they are not ideal routes. Several alternative routes are currently being explored. This is a narrative review of data about delivery methods for benzodiazepines alternative to the intravenous and oral routes for the acute treatment of seizures. Unconventional delivery options such as direct delivery to the central nervous system or inhalers are reported. Data show that intranasal diazepam or midazolam and the intramuscular auto-injector for midazolam are as effective as rectal or intravenous diazepam. Head-to-head comparisons with buccal midazolam are urgently needed. In addition, the majority of trials focused on children and adolescents, and further trials in adults are warranted

QUBIC: The QU Bolometric Interferometer for Cosmology

Context. One of the major challenges of modern cosmology is the detection of B-mode polarization anisotropies in the Cosmic Microwave Background. These originate from tensor fluctuations of the metric produced during the inflationary phase. Their detection would therefore constitute a major step towards understanding the primordial Universe. The expected level of these anisotropies is however so small that it requires a new generation of instruments with high sensitivity and extremely good control of systematic eects. Aims. We propose the QUBIC instrument based on the novel concept of bolometric interferometry, bringing together the sensitivity advantages of bolometric detectors with the systematics eects advantages of interferometry. Methods. The instrument will directly observe the sky through an array of entry horns whose signals will be combined together using an optical combiner. The whole set-up is located inside a cryostat. Polarization modulation will be achieved using a rotating half-wave plate and the images of the interference fringes will be formed on two focal planes (separated by a polarizing grid) tiled with bolometers. Results.We show that QUBIC can be considered as a synthetic imager, exactly similar to a usual imager but with a synthesized beam formed by the array of entry horns. Scanning the sky provides an additional modulation of the signal and improve the sky coverage shape. The usual techniques of map-making and power spectrum estimation can then be applied. We show that the sensitivity of such an instrument is comparable with that of an imager with the same number of horns. We anticipate a low level of beam-related systematics thanks to the fact that the synthesized beam is determined by the location of the primary horns. Other systematics should be under good control thanks to an autocalibration technique, specific to our concept, that will permit the accurate determination of most of the systematics parameters

QUBIC: the Q&U Bolometric Interferometer for Cosmology

The primordial B-mode polarisation of the Cosmic Microwave Background is the imprints of the gravitational wave background generated by inflation. Observing the B-mode is up to now the most direct way to constrain the physics of the primordial Universe, especially inflation. To detect these B-modes, high sensitivity is required as well as an exquisite control of systematics effects. To comply with these requirements, we propose a new instrument called QUBIC (Q and U Bolometric Interferometer for Cosmology) based on bolometric interferometry. The control of systematics is obtained with a close-packed interferometer while bolometers cooled to very low temperature allow for high sensitivity. We present the architecture of this new instrument, the status of the project and the self-calibration technique which allows accurate measurement of the instrumental systematic effects

Data from an International Multi-Centre Study of Statistics and Mathematics Anxieties and Related Variables in University Students (the SMARVUS Dataset)

This large, international dataset contains survey responses from N = 12,570 students from 100 universities in 35 countries, collected in 21 languages. We measured anxieties (statistics, mathematics, test, trait, social interaction, performance, creativity, intolerance of uncertainty, and fear of negative evaluation), self-efficacy, persistence, and the cognitive reflection test, and collected demographics, previous mathematics grades, self-reported and official statistics grades, and statistics module details. Data reuse potential is broad, including testing links between anxieties and statistics/mathematics education factors, and examining instruments’ psychometric properties across different languages and contexts. Data and metadata are stored on the Open Science Framework website [https://osf.io/mhg94/]

Invisible interpretations: reflections on the digital humanities and intellectual history

Much has been made of the digital humanities, yet it remains an underexplored field in relation to intellectual history. This paper aims to add to the little literature which does exist by offering a survey of the ideas and issues facing would-be practitioners. This includes: an overview of what the digital humanities are; reflections on what they offer intellectual history and how they may be problematic in regard to, first, accessing texts, and second, analysing source material; a conclusion with three reflections on future best practices – to be sceptical of digital sources, to be reflective of methodologies and how they may need to be modified when engaging with the digital humanities, and to embrace more directly the methodological, statistical, and technical aspects behind digital humanities. The aim is not to provide all the answers – at this stage that is impossible – but to be part of an emerging and ongoing discussion