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The NeNa and the MgAl cycles play a fundamental role in the nucleosynthesis of asymptotic giant branch stars undergoing hot bottom burning. The Na23(p,γ)24Mg reaction links these two cycles and a precise determination of its rate is required to correctly estimate the contribution of these stars to the chemical evolution of various isotopes of Na, Mg and Al. At temperatures of 50≲T≲110MK, narrow resonances at Ep=140 and 251keV are the main contributors to the reaction rate, in addition to the direct capture that dominates in the lower part of the temperature range. We present new measurements of the strengths of these resonances at the Laboratory for Underground Nuclear Astrophysics (LUNA). We have used two complementary detection approaches: high efficiency with a 4π BGO detector for the 140keV resonance, and high resolution with a HPGe detector for the 251keV resonance. Thanks to the reduced cosmic ray background of LUNA, we were able to determine the resonance strength of the 251keV resonance as ωγ=482(82)μeV and observed new gamma ray transitions for the decay of the corresponding state in Mg24 at Ex=11931keV. With the highly efficient BGO detector, we observed a signal for the 140keV resonance for the first time in a direct measurement, resulting in a strength of ωγ140=1.46−0.53+0.58neV (68% CL). Our measurement reduces the uncertainty of the Na23(p,γ)24Mg reaction rate in the temperature range from 0.05 to 0.1GK to at most −35%+50% at 0.07GK. Accordingly, our results imply a significant reduction of the uncertainties in the nucleosynthesis calculations. Keywords: Experimental nuclear astrophysics, Underground nuclear physics, Hydrogen burning, Stellar evolution

The 18O(p,α)15N reaction affects the synthesis of 15N, 18O and 19F isotopes, whose abundances can be used to probe the nucleosynthesis and mixing processes occurring deep inside asymptotic giant branch (AGB) stars. We performed a low-background direct measurement of the 18O(p,α)15N reaction cross-section at the Laboratory for Underground Nuclear Astrophysics (LUNA) from center of mass energy Ec.m.=340 keV down to Ec.m.=55 keV, the lowest energy measured to date corresponding to a cross-section of less than 1 picobarn/sr. The strength of a key resonance at center of mass energy Er=90 keV was found to be a factor of 10 higher than previously reported. A multi-channel R-matrix analysis of our and other data available in the literature was performed. Over a wide temperature range, T=0.01–1.00 GK, our new astrophysical rate is both more accurate and precise than recent evaluations. Stronger constraints can now be placed on the physical processes controlling nucleosynthesis in AGB stars with interesting consequences on the abundance of 18O in these stars and in stardust grains, specifically on the production sites of oxygen-rich Group II grains. Keywords: Stellar hydrogen burning, Hydrostatic stellar nucleosynthesis

Hyperpolarization techniques significantly enhance the sensitivity of magnetic resonance (MR) and thus present fascinating new directions for research and applications with in vivo MR imaging and spectroscopy (MRI/S). Hyperpolarized 13C MRI/S, in particular, enables real-time non-invasive assessment of metabolic processes and holds great promise for a diverse range of clinical applications spanning fields like oncology, neurology, and cardiology, with a potential for improving early diagnosis of disease, patient stratification, and therapy response assessment. Despite its potential, technical challenges remain for achieving clinical translation. This paper provides an overview of the discussions that took place at the international workshop "New Horizons in Hyperpolarized 13C MRI," in March 2023 at the Bavarian Academy of Sciences and Humanities, Munich, Germany. The workshop covered new developments, as well as future directions, in topics including polarization techniques (particularly focusing on parahydrogen-based methods), novel probes, considerations related to data acquisition and analysis, and emerging clinical applications in oncology and other fields.

The observation of oxygen isotopes in giant stars sheds light on mixing processes operating in their interiors. Due to the very strong correlation between nuclear burning and mixing processes it is very important to reduce the uncertainty on the cross sections of the nuclear reactions that are involved. In this paper we focus our attention on the reaction O18(p,γ)19F. While the O18(p,α)15N channel is thought to be dominant, the (p,γ) channel can still be an important component in stellar burning in giants, depending on the low energy cross section. So far only extrapolations from higher-energy measurements exist and recent estimates vary by orders of magnitude. These large uncertainties call for an experimental reinvestigation of this reaction. We present a direct measurement of the O18(p,γ)19F cross section using a high-efficiency 4π BGO summing detector at the Laboratory for Underground Nuclear Astrophysics (LUNA). The reaction cross section has been directly determined for the first time from 140 keV down to 85 keV and the different cross section components have been obtained individually. The previously highly uncertain strength of the 90 keV resonance was found to be 0.53 ± 0.07 neV, three orders of magnitude lower than an indirect estimate based on nuclear properties of the resonant state and a factor of 20 lower than a recently established upper limit, excluding the possibility that the 90 keV resonance can contribute significantly to the stellar reaction rate. Keywords: Experimental nuclear astrophysics, Underground nuclear physics, Hydrogen burning, Stellar evolution

Brown and brown-like adipose tissues have attracted significant attention for their role in metabolism and therapeutic potential in diabetes and obesity. Despite compelling evidence of an interplay between adipocytes and lymphocytes, the involvement of these tissues in immune responses remains largely unexplored. This study explicates a newfound connection between neuroinflammation and brown- and bone marrow adipose tissue. Leveraging the use of [18F]F-AraG, a mitochondrial metabolic tracer capable of tracking activated lymphocytes and adipocytes simultaneously, we demonstrate, in models of glioblastoma and multiple sclerosis, the correlation between intracerebral immune infiltration and changes in brown- and bone marrow adipose tissue. Significantly, we show initial evidence that a neuroinflammation-adipose tissue link may also exist in humans. This study proposes the concept of an intricate immuno-neuro-adipose circuit, and highlights brown- and bone marrow adipose tissue as an intermediary in the communication between the immune and nervous systems. Understanding the interconnectedness within this circuitry may lead to advancements in the treatment and management of various conditions, including cancer, neurodegenerative diseases and metabolic disorders.

BACKGROUND: The value, speed of completion and robustness of the evidence generated by TB treatment trials could be improved by implementing standards for best practice.METHODS: A global panel of experts participated in a Delphi process, using a 7-point Likert scale to score and revise draft standards until consensus was reached.RESULTS: Eleven standards were defined: Standard 1, high quality data on TB regimens are essential to inform clinical and programmatic management; Standard 2, the research questions addressed by TB trials should be relevant to affected communities, who should be included in all trial stages; Standard 3, trials should make every effort to be as inclusive as possible; Standard 4, the most efficient trial designs should be considered to improve the evidence base as quickly and cost effectively as possible, without compromising quality; Standard 5, trial governance should be in line with accepted good clinical practice; Standard 6, trials should investigate and report strategies that promote optimal engagement in care; Standard 7, where possible, TB trials should include pharmacokinetic and pharmacodynamic components; Standard 8, outcomes should include frequency of disease recurrence and post-treatment sequelae; Standard 9, TB trials should aim to harmonise key outcomes and data structures across studies; Standard 10, TB trials should include biobanking; Standard 11, treatment trials should invest in capacity strengthening of local trial and TB programme staff.CONCLUSION: These standards should improve the efficiency and effectiveness of evidence generation, as well as the translation of research into policy and practice.

Abstract Gut microbiota changes and brain-gut-axis (BGA) dysregulation are common in people with Parkinson’s Disease (PD). Probiotics and prebiotics are emerging as a potential therapeutic approach for PD patients. The aim of this paper was to assess the neurological and gastroenterological effects in PD patients with constipation after the administration of a synbiotic product, with a focus on behavioral and cognitive symptoms. We enrolled patients with stable PD who met diagnostic criteria for functional constipation and/or irritable bowel syndrome with constipation according to Rome IV Criteria. Patients received a synbiotic treatment (Enterolactis Duo, containing the probiotic strain Lacticaseibacillus paracasei DG and the prebiotic fiber inulin) for 12 weeks. A neurological and a gastroenterological evaluation were collected before and after the treatment. In addition, 16S rRNA gene profiling and short chain fatty acid quantification were performed to characterize the microbial ecosystem of fecal samples collected before (n = 22) and after (n = 9) the synbiotic administration. 30 patients were consecutively enrolled. After treatment, patients performed better in MDS-UPDRS part 1 (p = 0.000), SCOPA-AUT (p = 0.001), TAS-20 (p = 0.014), HAM-D (p = 0.026), DIFt (p = 0.003), PAS-A (p = 0.048). Gastroenterological evaluations showed improvements in PAC-SYM score (p

Abstract Malnutrition is linked to 45% of global childhood mortality, however, the impact of maternal malnutrition on the child’s health remains elusive. Previous studies suggested that maternal malnutrition does not affect breast milk composition. Yet, malnourished children often develop a so-called environmental enteropathy, assumed to be triggered by frequent pathogen uptake and unfavorable gut colonization. Here, we show in a murine model that maternal malnutrition induces a persistent inflammatory gut dysfunction in the offspring that establishes during nursing and does not recover after weaning onto standard diet. Early intestinal influx of neutrophils, impaired postnatal development of gut-regulatory functions, and expansion of Enterobacteriaceae were hallmarks of this enteropathy. This gut phenotype resembled those developing under deficient S100a8/a9-supply via breast milk, which is a known key factor for the postnatal development of gut homeostasis. We could confirm that S100a8/a9 is lacking in the breast milk of malnourished mothers and the offspring’s intestine. Nutritional supply of S100a8 to neonates of malnourished mothers abrogated the aberrant development of gut mucosal immunity and microbiota colonization and protected them lifelong against severe enteric infections and non-infectious bowel diseases. S100a8 supplementation after birth might be a promising measure to counteract deleterious imprinting of gut immunity by maternal malnutrition.

In Chile, the arrival of immigrant students has had significant consequences for teachers, who have had to adapt quickly and with few resources to a new school reality. This makes it relevant to study variables affecting their attitudes towards immigrant students. This work aimed to determine the role of outgroup anxiety and intercultural sensitivity in the relationship between cultural threat and attitudes toward multiculturalism at school in a sample of 190 primary and secondary education teachers. A sequential mediation model was carried out. Outcomes show the direct effect of cultural threat on teachers’ attitudes towards multiculturalism at school, as well as its indirect effects through outgroup anxiety and intercultural sensitivity. The model explains 55% of the variability of the dependent variable. Results stress the importance of attending to the socio cognitive and emotional processes affecting teachers’ beliefs and attitudes regarding immigrant students to facilitate teaching work and school relationships.

BACKGROUND: Treatment for fluoroquinolone-resistant multidrug-resistant/rifampicin-resistant tuberculosis (pre-XDR TB) often lasts longer than treatment for less resistant strains, yields worse efficacy results, and causes substantial toxicity. The newer anti-tuberculosis drugs, bedaquiline and delamanid, and repurposed drugs clofazimine and linezolid, show great promise for combination in shorter, less-toxic, and effective regimens. To date, there has been no randomized, internally and concurrently controlled trial of a shorter, all-oral regimen comprising these newer and repurposed drugs sufficiently powered to produce results for pre-XDR TB patients. METHODS: endTB-Q is a phase III, multi-country, randomized, controlled, parallel, open-label clinical trial evaluating the efficacy and safety of a treatment strategy for patients with pre-XDR TB. Study participants are randomized 2:1 to experimental or control arms, respectively. The experimental arm contains bedaquiline, linezolid, clofazimine, and delamanid. The control comprises the contemporaneous WHO standard of care for pre-XDR TB. Experimental arm duration is determined by a composite of smear microscopy and chest radiographic imaging at baseline and re-evaluated at 6 months using sputum culture results: participants with less extensive disease receive 6 months and participants with more extensive disease receive 9 months of treatment. Randomization is stratified by country and by participant extent-of-TB-disease phenotype defined according to screening/baseline characteristics. Study participation lasts up to 104 weeks post randomization. The primary objective is to assess whether the efficacy of experimental regimens at 73 weeks is non-inferior to that of the control. A sample size of 324 participants across 2 arms affords at least 80% power to show the non-inferiority, with a one-sided alpha of 0.025 and a non-inferiority margin of 12%, against the control in both modified intention-to-treat and per-protocol populations. DISCUSSION: This internally controlled study of shortened treatment for pre-XDR TB will provide urgently needed data and evidence for clinical and policy decision-making around the treatment of pre-XDR TB with a four-drug, all-oral, shortened regimen. TRIAL REGISTRATION: ClinicalTrials.Gov NCT03896685. Registered on 1 April 2018; the record was last updated for study protocol version 4.3 on 17 March 2023.

Abstract Background Older subjects are at risk of elevated intestinal permeability (IP) which can lead to immune system activation and low-grade systemic inflammation. Dietary changes are a potential strategy to reduce IP. The MaPLE project evaluated the hypothesis that increasing (poly)phenol intake would beneficially impact on several important markers and pathways related to IP. The objective of the present study was to assess the effects of the MaPLE (poly)phenol-rich diet (PR-diet) on additional IP-related biomarkers and any relationships between biomarker responses. Methods A randomised, controlled, crossover study was performed involving 51 participants (≥ 60 y) with increased IP, as determined by serum zonulin levels. Participants were randomly assigned to one of two intervention groups: a control diet (C-diet) or a PR-diet. Each intervention lasted 8 weeks and was separated by an 8-week washout period. For the present study, serum and faecal samples were used to measure zonula occludens-1 (ZO-1), occludin, adiponectin, calprotectin, faecal calprotectin, soluble cluster of differentiation 14 (sCD14), interleukin-6 receptor (IL-6R), and vascular endothelial-cadherin (VEC) levels using quantitative ELISA assays. Data were analysed using ANOVA, and Spearman and network correlation analysis were performed to identify the relationship among biomarkers at baseline. Results Among the different markers analysed, a significant reduction was observed for faecal and serum calprotectin (p = 0.0378 and p = 0.0186, respectively) following the PR-diet, while a significant increase in ZO-1 was found (p = 0.001) after both the intervention periods (PR-diet and C-diet). In addition, a time effect was observed for VEC levels showing a reduction (p = 0.038) following the PR-diet. Based on network correlation analysis, two clusters of correlations were identified: one cluster with high levels of serum calprotectin, faecal calprotectin, sCD14, interleukin (IL)-6, tumor necrosis factor (TNF)-α, C-reactive protein (CRP) and bacterial DNAemia (16 S rRNA gene copies), with potential inflammatory-induced intestinal permeability. Differently, the other cluster had high levels of serum occludin, IL-6R, soluble intercellular adhesion molecule-1 (sICAM-1) and VEC, with potential inflammatory-induced endothelial dysfunction. Conclusions Overall, this study provides further support to the hypothesis that a (poly)phenol-rich diet may help to ameliorate intestinal permeability-associated conditions. In this regard, calprotectin might represent a promising biomarker since it is a protein that typically increases with age and it is considered indicative of intestinal and systemic inflammation. Further research is needed to develop targeted (poly)phenol-rich diets against age-related gut dysfunction and inflammation. Trial registration 28/04/2017; ISRCTN10214981; https://doi.org/10.1186/ISRCTN10214981 .

Abstract Brown and brown-like adipose tissues have attracted significant attention for their role in metabolism and therapeutic potential in diabetes and obesity. Despite compelling evidence of an interplay between adipocytes and lymphocytes, the involvement of these tissues in immune responses remains largely unexplored. This study explicates a newfound connection between neuroinflammation and brown- and bone marrow adipose tissue. Leveraging the use of [18F]F-AraG, a mitochondrial metabolic tracer capable of tracking activated lymphocytes and adipocytes simultaneously, we demonstrate, in models of glioblastoma and multiple sclerosis, the correlation between intracerebral immune infiltration and changes in brown- and bone marrow adipose tissue. Significantly, we show initial evidence that a neuroinflammation-adipose tissue link may also exist in humans. This study proposes the concept of an intricate immuno-neuro-adipose circuit, and highlights brown- and bone marrow adipose tissue as an intermediary in the communication between the immune and nervous systems. Understanding the interconnectedness within this circuitry may lead to advancements in the treatment and management of various conditions, including cancer, neurodegenerative diseases and metabolic disorders.

Neurons require large amounts of energy, but whether they can perform glycolysis or require glycolysis to maintain energy remains unclear. Using metabolomics, we show that human neurons do metabolize glucose through glycolysis and can rely on glycolysis to supply tricarboxylic acid (TCA) cycle metabolites. To investigate the requirement for glycolysis, we generated mice with postnatal deletion of either the dominant neuronal glucose transporter (GLUT3cKO) or the neuronal-enriched pyruvate kinase isoform (PKM1cKO) in CA1 and other hippocampal neurons. GLUT3cKO and PKM1cKO mice show age-dependent learning and memory deficits. Hyperpolarized magnetic resonance spectroscopic (MRS) imaging shows that female PKM1cKO mice have increased pyruvate-to-lactate conversion, whereas female GLUT3cKO mice have decreased conversion, body weight, and brain volume. GLUT3KO neurons also have decreased cytosolic glucose and ATP at nerve terminals, with spatial genomics and metabolomics revealing compensatory changes in mitochondrial bioenergetics and galactose metabolism. Therefore, neurons metabolize glucose through glycolysis in vivo and require glycolysis for normal function.

Abstract Bromodomain and extra-terminal domain (BET) proteins are therapeutic targets in several cancers including the most common malignant adult brain tumor glioblastoma (GBM). Multiple small molecule inhibitors of BET proteins have been utilized in preclinical and clinical studies. Unfortunately, BET inhibitors have not shown efficacy in clinical trials enrolling GBM patients. One possible reason for this may stem from resistance mechanisms that arise after prolonged treatment within a clinical setting. However, the mechanisms and timeframe of resistance to BET inhibitors in GBM is not known. To identify the temporal order of resistance mechanisms in GBM we performed quantitative proteomics using multiplex-inhibitor bead mass spectrometry and demonstrated that intrinsic resistance to BET inhibitors in GBM treatment occurs rapidly within hours and involves the fibroblast growth factor receptor 1 (FGFR1) protein. Additionally, small molecule inhibition of BET proteins and FGFR1 simultaneously induces synergy in reducing GBM tumor growth in vitro and in vivo. Further, FGFR1 knockdown synergizes with BET inhibitor mediated reduction of GBM cell proliferation. Collectively, our studies suggest that co-targeting BET and FGFR1 may dampen resistance mechanisms to yield a clinical response in GBM.

ABSTRACTProbiotics are exploited for adjuvant treatment in IBS, but reliable guidance for selecting the appropriate probiotic to adopt for different forms of IBS is lacking. We aimed to identify markers for recognizing non-constipated (NC) IBS patients that may show significant clinical improvements upon treatment with the probiotic strain Lacticaseibacillus paracasei DG (LDG). To this purpose, we performed a post-hoc analysis of samples collected during a multicenter, double-blind, parallel-group, placebo-controlled trial in which NC-IBS patients were randomized to receive at least 24 billion CFU LDG or placebo capsules b.i.d. for 12 weeks. The primary clinical endpoint was the composite response based on improved abdominal pain and fecal type. The fecal microbiome and serum markers of intestinal (PV1 and zonulin), liver, and kidney functions were investigated. We found that responders (R) in the probiotic arm (25%) differed from non-responders (NR) based on the abundance of 18 bacterial taxa, including the families Coriobacteriaceae, Dorea spp. and Collinsella aerofaciens, which were overrepresented in R patients. These taxa also distinguished R (but not NR) patients from healthy controls. Probiotic intervention significantly reduced the abundance of these bacteria in R, but not in NR. Analogous results emerged for C. aerofaciens from the analysis of data from a previous trial on IBS with the same probiotic. Finally, C. aerofaciens was positively correlated with the plasmalemmal vesicle associated protein-1 (PV-1) and the markers of liver function. In conclusion, LDG is effective on NC-IBS patients with NC-IBS with a greater abundance of potential pathobionts. Among these, C. aerofaciens has emerged as a potential predictor of probiotic efficacy.

The G protein-coupled receptor melanocortin-4 receptor (MC4R) and its associated protein melanocortin receptor-associated protein 2 (MRAP2) are essential for the regulation of food intake and body weight in humans. MC4R localizes and functions at the neuronal primary cilium, a microtubule-based organelle that senses and relays extracellular signals. Here, we demonstrate that MRAP2 is critical for the weight-regulating function of MC4R neurons and the ciliary localization of MC4R. More generally, our study also reveals that GPCR localization to primary cilia can require specific accessory proteins that may not be present in heterologous cell culture systems. Our findings further demonstrate that targeting of MC4R to neuronal primary cilia is essential for the control of long-term energy homeostasis and suggest that genetic disruption of MC4R ciliary localization may frequently underlie inherited forms of obesity.

BackgroundIn recent years, the ability of conventional magnetic resonance imaging (MRI), including T1 contrast-enhanced (CE) MRI, to monitor high-efficacy therapies and predict long-term disability in multiple sclerosis (MS) has been challenged. Therefore, non-invasive methods to improve MS lesions detection and monitor therapy response are needed.MethodsWe studied the combined cuprizone and experimental autoimmune encephalomyelitis (CPZ-EAE) mouse model of MS, which presents inflammatory-mediated demyelinated lesions in the central nervous system as commonly seen in MS patients. Using hyperpolarized 13C MR spectroscopy (MRS) metabolic imaging, we measured cerebral metabolic fluxes in control, CPZ-EAE and CPZ-EAE mice treated with two clinically-relevant therapies, namely fingolimod and dimethyl fumarate. We also acquired conventional T1 CE MRI to detect active lesions, and performed ex vivo measurements of enzyme activities and immunofluorescence analyses of brain tissue. Last, we evaluated associations between imaging and ex vivo parameters.ResultsWe show that hyperpolarized [1-13C]pyruvate conversion to lactate is increased in the brain of untreated CPZ-EAE mice when compared to the control, reflecting immune cell activation. We further demonstrate that this metabolic conversion is significantly decreased in response to the two treatments. This reduction can be explained by increased pyruvate dehydrogenase activity and a decrease in immune cells. Importantly, we show that hyperpolarized 13C MRS detects dimethyl fumarate therapy, whereas conventional T1 CE MRI cannot.ConclusionsIn conclusion, hyperpolarized MRS metabolic imaging of [1-13C]pyruvate detects immunological responses to disease-modifying therapies in MS. This technique is complementary to conventional MRI and provides unique information on neuroinflammation and its modulation.

Introduction: Melanoma early detection and optimal referral to the specialist, starts in primary care. The medical formation is usually deficient in training general physicians in early detection and risk management for most skin malignancies. A three-point dermoscopy checklist is used as a screening tool for differentiating malignant and benign pigmented lesions in non-expert clinicians using dermoscopy. Objectives: To evaluate the impact of brief medical training on the three-point dermoscopy algorithm in third-year medical students, new to dermatology, and determine the levels of sensitivity and specificity to differentiate malignant and benign pigmented lesions. Methods: Optional dermoscopic lecture for third-year medical students, new to dermatology, in the context of general medical semiology courses, with posterior case discussion and evaluation of 50 dermoscopy cases, 25 benign and 25 malignant. Students were asked to classify malignant versus benign pathology, based on the three-point dermoscopy algorithm discussed. Sensitivity, specificity, and predictive values were calculated according to the student’s responses. Results: 3250 responses from 65 students. Malignant pathology was misclassified as being in 154 responses, while benign pathology was misclassified as malignant in 668 responses. Sensitivity and specificity for differentiating malignant lesions were 89.70% and 61.99% respectively. Moderate interobserver agreement was found (Kappa Value 0.50 [CI 0.47-0.54]). Conclusion: When evaluating melanocytic lesions, the focus of the primary healthcare and general medical formation should emphasize the correct determination of malignant or benign pathology. Teaching the three-point dermoscopy rule to medical students, new to dermatology, yields satisfactory levels of sensitivity and specificity, comparable to general physicians.

Many biomarkers in clinical neuroscience lack pathological certification. This issue is potentially a significant contributor to the limited success of neuroprotective and neurorestorative therapies for human neurological disease-and is evident even in areas with therapeutic promise such as myelin repair. Despite the identification of promising remyelinating candidates, biologically validated methods to demonstrate therapeutic efficacy or provide robust preclinical evidence of remyelination in the CNS are lacking. Therapies with potential to remyelinate the CNS constitute one of the most promising and highly anticipated therapeutic developments in the pipeline to treat multiple sclerosis and other demyelinating diseases. The optic nerve has been proposed as an informative pathway to monitor remyelination in animals and human subjects. Recent clinical trials using visual evoked potential have had promising results, but without unequivocal evidence about the cellular and molecular basis for signal changes on visual evoked potential, the interpretation of these trials is constrained. The visual evoked potential was originally developed and used in the clinic as a diagnostic tool but its use as a quantitative method for assessing therapeutic response requires certification of its biological specificity. Here, using the tools of experimental pathology we demonstrate that quantitative measurements of myelination using both histopathological measures of nodal structure and ultrastructural assessments correspond to visual evoked potential latency in both inflammatory and chemical models of demyelination. Visual evoked potential latency improves after treatment with a tool remyelinating compound (clemastine), mirroring both quantitative and qualitative myelin assessment. Furthermore, clemastine does not improve visual evoked potential latency following demyelinating injury when administered to a transgenic animal incapable of forming new myelin. Therefore, using the capacity for therapeutic enhancement and biological loss of function we demonstrate conclusively that visual evoked potential measures myelin status and is thereby a validated tool for preclinical verification of remyelination.

Introduction: European mistletoe (Viscum album L.) has been gaining increasing interest in the field of oncology as a clinically relevant adjunctive treatment in many forms of cancer. In the field of phytopharmacology, harvesting time is pivotal. In the last century, a form of metabolomic fingerprinting based on pattern formation was proposed as a way to determine optimal harvesting times to ensure high quality of mistletoe as raw material for pharmaceutical use. In order to further evaluate the information obtained with this metabolomic fingerprinting method, we analysed a large time series of previously undigitised daily mistletoe chromatograms dating back to the 1950s.Methods: These chromatograms were scanned and evaluated using computerized image analysis, resulting in 12 descriptors for each individual chromatogram. We performed a statistical analysis of the data obtained, investigating statistical distributions, cross-correlations and time self-correlations.Results: The analysed dataset spanning about 27 years, contains 19,037 evaluable chromatograms in daily resolution. Based on the distribution and cross-correlation analyses, the 12 descriptors could be clustered into six independent groups describing different aspects of the chromatograms. One descriptor was found to mirror the annual rhythm being well correlated with temperature and a phase shift of 10 days. The time self-correlation analysis showed that most other descriptors had a characteristic self-correlation of ∼50 days, which points to further infradian rhythms (i.e., more than 24 h).Discussion: To our knowledge, this dataset is the largest of its type. The combination of this form of metabolomic fingerprinting with the proposed computer analysis seems to be a promising tool to characterise biological variations of mistletoe. Additional research is underway to further analyse the different rhythms present in this dataset.

Obesity is a chronic, complex, and multifactorial disease resulting from the interaction of genetic, environmental, and behavioral factors. It is characterized by excessive fat accumulation in adipose tissue, which damages health and deteriorates the quality of life. Although dietary treatment can significantly improve health, high attrition is a common problem in weight loss interventions with serious consequences for weight loss management and frustration. The strategy used to improve compliance has been combining dietary prescriptions and recommendations for physical activity with cognitive behavioral treatment (CBT) for weight management. This systematic review determined the dropout rate and predictive factors associated with dropout from CBT for adults with overweight and obesity. The data from the 37 articles selected shows an overall dropout rate between 5 and 62%. The predictive factors associated with attrition can be distinguished by demographics (younger age, educational status, unemployed status, and ethnicity) and psychological variables (greater expected 1-year Body Mass Index loss, previous weight loss attempts, perceiving more stress with dieting, weight and shape concerns, body image dissatisfaction, higher stress, anxiety, and depression). Common reasons for dropping out were objective (i.e., long-term sickness, acute illness, and pregnancy), logistical, poor job conditions or job difficulties, low level of organization, dissatisfaction with the initial results, lack of motivation, and lack of adherence. According to the Mixed Methods Appraisal quality analysis, 13.5% of articles were classified as five stars, and none received the lowest quality grade (1 star). The majority of articles were classified as 4 stars (46%). At least 50% of the selected articles exhibited a high risk of bias. The domain characterized by a higher level of bias was that of randomization, with more than 60% of the articles having a high risk of bias. The high risk of bias in these articles can probably depend on the type of study design, which, in most cases, was observational and non-randomized. These findings demonstrate that CBT could be a promising approach for obesity treatment, achieving, in most cases, lower dropout rates than other non-behavioral interventions. However, more studies should be conducted to compare obesity treatment strategies, as there is heterogeneity in the dropout assessment and the population studied. Ultimately, gaining a deeper understanding of the comparative effectiveness of these treatment strategies is of great value to patients, clinicians, and healthcare policymakers.Systematic review registration: PROSPERO 2022 CRD42022369995 Available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022369995.

Abstract Background Treatment for fluoroquinolone-resistant multidrug-resistant/rifampicin-resistant tuberculosis (pre-XDR TB) often lasts longer than treatment for less resistant strains, yields worse efficacy results, and causes substantial toxicity. The newer anti-tuberculosis drugs, bedaquiline and delamanid, and repurposed drugs clofazimine and linezolid, show great promise for combination in shorter, less-toxic, and effective regimens. To date, there has been no randomized, internally and concurrently controlled trial of a shorter, all-oral regimen comprising these newer and repurposed drugs sufficiently powered to produce results for pre-XDR TB patients. Methods endTB-Q is a phase III, multi-country, randomized, controlled, parallel, open-label clinical trial evaluating the efficacy and safety of a treatment strategy for patients with pre-XDR TB. Study participants are randomized 2:1 to experimental or control arms, respectively. The experimental arm contains bedaquiline, linezolid, clofazimine, and delamanid. The control comprises the contemporaneous WHO standard of care for pre-XDR TB. Experimental arm duration is determined by a composite of smear microscopy and chest radiographic imaging at baseline and re-evaluated at 6 months using sputum culture results: participants with less extensive disease receive 6 months and participants with more extensive disease receive 9 months of treatment. Randomization is stratified by country and by participant extent-of-TB-disease phenotype defined according to screening/baseline characteristics. Study participation lasts up to 104 weeks post randomization. The primary objective is to assess whether the efficacy of experimental regimens at 73 weeks is non-inferior to that of the control. A sample size of 324 participants across 2 arms affords at least 80% power to show the non-inferiority, with a one-sided alpha of 0.025 and a non-inferiority margin of 12%, against the control in both modified intention-to-treat and per-protocol populations. Discussion This internally controlled study of shortened treatment for pre-XDR TB will provide urgently needed data and evidence for clinical and policy decision-making around the treatment of pre-XDR TB with a four-drug, all-oral, shortened regimen. Trial registration ClinicalTrials.Gov NCT03896685. Registered on 1 April 2018; the record was last updated for study protocol version 4.3 on 17 March 2023.

Lymphocytes and innate immune cells are key drivers of multiple sclerosis (MS) and are the main target of MS disease-modifying therapies (DMT). Ex vivo analyses of MS lesions have revealed cellular heterogeneity and variable T cell levels, which may have important implications for patient stratification and choice of DMT. Although MRI has proven valuable to monitor DMT efficacy, its lack of specificity for cellular subtypes highlights the need for complementary methods to improve lesion characterization. Here, we evaluated the potential of 2'-deoxy-2'-18F-fluoro-9-β-d-arabinofuranosylguanine (18F-FAraG) PET imaging to noninvasively assess infiltrating T cells and to provide, in combination with MRI, a novel tool to determine lesion types. Methods: We used a novel MS mouse model that combines cuprizone and experimental autoimmune encephalomyelitis to reproducibly induce 2 brain inflammatory lesion types, differentiated by their T cell content. 18F-FAraG PET imaging, T2-weighted MRI, and T1-weighted contrast-enhanced MRI were performed before disease induction, during demyelination with high levels of innate immune cells, and after T cell infiltration. Fingolimod immunotherapy was used to evaluate the ability of PET and MRI to detect therapy response. Ex vivo immunofluorescence analyses for T cells, microglia/macrophages, myelin, and blood-brain barrier (BBB) integrity were performed to validate the in vivo findings. Results: 18F-FAraG signal was significantly increased in the brain and spinal cord at the time point of T cell infiltration. 18F-FAraG signal from white matter (corpus callosum) and gray matter (cortex, hippocampus) further correlated with T cell density. T2-weighted MRI detected white matter lesions independently of T cells. T1-weighted contrast-enhanced MRI indicated BBB disruption at the time point of T cell infiltration. Fingolimod treatment prevented motor deficits and decreased T cell and microglia/macrophage levels. In agreement, 18F-FAraG signal was decreased in the brain and spinal cord of fingolimod-treated mice; T1-weighted contrast-enhanced MRI revealed intact BBB, whereas T2-weighted MRI findings remained unchanged. Conclusion: The combination of MRI and 18F-FAraG PET enables detection of inflammatory demyelination and T cell infiltration in an MS mouse model, providing a new way to evaluate lesion heterogeneity during disease progression and after DMT. On clinical translation, these methods hold great potential for stratifying patients, monitoring MS progression, and determining therapy responses.

Traumatic brain injury (TBI) is a major public health problem. Despite considerable research deciphering injury pathophysiology, precision therapies remain elusive. Here, we present large-scale data sharing and machine intelligence approaches to leverage TBI complexity. The Open Data Commons for TBI (ODC-TBI) is a community-centered repository emphasizing Findable, Accessible, Interoperable, and Reusable data sharing and publication with persistent identifiers. Importantly, the ODC-TBI implements data sharing of individual subject data, enabling pooling for high-sample-size, feature-rich data sets for machine learning analytics. We demonstrate pooled ODC-TBI data analyses, starting with descriptive analytics of subject-level data from 11 previously published articles (N = 1250 subjects) representing six distinct pre-clinical TBI models. Second, we perform unsupervised machine learning on multi-cohort data to identify persistent inflammatory patterns across different studies, improving experimental sensitivity for pro- versus anti-inflammation effects. As funders and journals increasingly mandate open data practices, ODC-TBI will create new scientific opportunities for researchers and facilitate multi-data-set, multi-dimensional analytics toward effective translation.

BackgroundTreatment of multidrug- and rifampin-resistant tuberculosis (MDR/RR-TB) is expensive, labour-intensive, and associated with substantial adverse events and poor outcomes. While most MDR/RR-TB patients do not receive treatment, many who do are treated for 18 months or more. A shorter all-oral regimen is currently recommended for only a sub-set of MDR/RR-TB. Its use is only conditionally recommended because of very low-quality evidence underpinning the recommendation. Novel combinations of newer and repurposed drugs bring hope in the fight against MDR/RR-TB, but their use has not been optimized in all-oral, shorter regimens. This has greatly limited their impact on the burden of disease. There is, therefore, dire need for high-quality evidence on the performance of new, shortened, injectable-sparing regimens for MDR-TB which can be adapted to individual patients and different settings.MethodsendTB is a phase III, pragmatic, multi-country, adaptive, randomized, controlled, parallel, open-label clinical trial evaluating the efficacy and safety of shorter treatment regimens containing new drugs for patients with fluoroquinolone-susceptible, rifampin-resistant tuberculosis. Study participants are randomized to either the control arm, based on the current standard of care for MDR/RR-TB, or to one of five 39-week multi-drug regimens containing newly approved and repurposed drugs. Study participation in all arms lasts at least 73 and up to 104 weeks post-randomization. Randomization is response-adapted using interim Bayesian analysis of efficacy endpoints. The primary objective is to assess whether the efficacy of experimental regimens at 73 weeks is non-inferior to that of the control. A sample size of 750 patients across 6 arms affords at least 80% power to detect the non-inferiority of at least 1 (and up to 3) experimental regimens, with a one-sided alpha of 0.025 and a non-inferiority margin of 12%, against the control in both modified intention-to-treat and per protocol populations.DiscussionThe lack of a safe and effective regimen that can be used in all patients is a major obstacle to delivering appropriate treatment to all patients with active MDR/RR-TB. Identifying multiple shorter, safe, and effective regimens has the potential to greatly reduce the burden of this deadly disease worldwide.Trial registrationClinicalTrials.gov Identifier NCT02754765. Registered on 28 April 2016; the record was last updated for study protocol version 3.3, on 27 August 2019.

Background: Mobile technology is increasingly prevalent in healthcare, serving various purposes, including remote health monitoring and patient self-management, which could prove beneficial to early hospital discharges. Aims: This study investigates the transitional care program experience facilitating early discharges in a pediatric setting through the use of an easy-to-use mobile medical device (TytoCare™, TytoCare Ltd., Natanya, Israel). Outcomes: This study aims to assess the effectiveness of telehomecare in achieving complete resolution of diseases without readmission, compare the length of stay between intervention and standard care groups, and gather user and professional experiences. Methods: A randomized open-label, controlled pilot study enrolled 102 children, randomly assigned to the telehomecare (TELE) group (n = 51, adopting early hospital discharge with continued home monitoring) or the standard-of-care (STAND) group (n = 51). Primary outcomes include complete disease resolution without readmission. Secondary objectives include recording a shorter length of stay in the intervention group. Surveys on user and professional experiences were conducted. A group of 51 children declining telemedicine services (NO-TELE) was also included. Results: In the TELE group, 100% of children achieved complete disease resolution without readmission, with a median duration of stay of 4 days, significantly shorter than the 7 days in the STAND group (p = 0.01). The telemedicine system demonstrated efficient performance and high satisfaction levels. The NO-TELE group showed no significant differences in demographics or digital technology competence. Perceived benefits of telemedicine included time and cost savings, reduced hospital stays, and technology utility and usability. Conclusions: This study demonstrates that user-friendly mobile medical devices effectively facilitate early hospital discharges in a pediatric setting. These devices serve as a bridge between home and hospital, optimizing care pathways.

Healthy eating habits are the basis for good health status, especially for children and adolescents, when growth and development are still ongoing. Nutrition educational programs are essential to prevent and treat chronic diseases. Nutritional counseling (NC), as a collaborative process between the counselor and the client process, could help to achieve better outcomes. This review aims to collect information about the utilization of NC during childhood and adolescence and to highlight its possible impact on adherence/compliance rates, nutrition knowledge, status and dietary intake. The methods applied in this systematic review followed the instruction of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The search in PubMed/Medline, Scopus, Web of Science, LILACS, and Science Direct included observational or randomized studies. RoB 2.0 and Robins-I tools was used for the risk of bias assessment in randomized and non-randomized studies, respectively. The quality of evidence was checked by the Mixed Methods Appraisal Tool system. A total of 21 articles were selected, computing 4,345 individuals. 11 achieved at least 4 stars quality level. The highest risk of bias for randomized studies was related to the randomization process. 42.9% of non-randomized studies had some concerns of bias, mainly because of a lack of control of all confounding factors. Different strategies of NC were used in children and adolescents with positive results for health or diseases. NC strategies can be effectively used in children and adolescents. In general, NC showed benefits in pediatrics age for anthropometric or body composition parameters, dietary intake, nutrition knowledge and physical activity improvement. Performing NC in pediatrics is challenging due to the counseling strategies that must be adapted in their contents to the cognitive ability of each age. More structured research must be done focused on this population. Investments in healthy eating behaviors in pediatrics can lead to better health outcomes in the future population with substantial benefits to society.Systematic review registration[https://www.crd.york.ac.uk/prospero/#recordDetails], identifier [CRD42022374177].

We determined the impact of the COVID-19 pandemic on mycobacterial diagnostic services. 40 laboratories from 22 countries completed an online questionnaire covering the redeployment of the laboratory infrastructure and/or staff for SARS-CoV-2 testing, staff shortages and supply chain disruptions. 28 laboratories reported monthly numbers of samples processed for mycobacterial investigations and monthly numbers of M. tuberculosis complex (MTBC) PCRs performed between October 1st 2018 and October 31st 2020. More than half (23/40) of the participating TB laboratories reported having performed COVID-19 diagnostics in the early phase of the pandemic, in part with negative impact on the mycobacterial service activities. All participating laboratories reported shortages of consumables and laboratory equipment due to supply chain issues. Average monthly sample numbers decreased by 24% between January 2020 and October 2020 compared to pre-pandemic averages. At the end of the study period, most participating laboratories had not returned to pre-pandemic average MTBC PCR throughput.

BackgroundTreatment of multidrug-resistant tuberculosis requires long-term therapy with a combination of multiple second-line drugs. These drugs are associated with numerous adverse events that can cause severe morbidity, such as deafness, and in some instances can lead to death. Our aim was to estimate the absolute and relative frequency of adverse events associated with different tuberculosis drugs to provide useful information for clinicians and tuberculosis programmes in selecting optimal treatment regimens.MethodsWe did a meta-analysis using individual-level patient data that were obtained from studies that reported adverse events that resulted in permanent discontinuation of anti-tuberculosis medications. We used a database created for our previous meta-analysis of multidrug-resistant tuberculosis treatment and outcomes, for which we did a systematic review of literature published between Jan 1, 2009, and Aug 31, 2015 (updated April 15, 2016), and requested individual patient-level information from authors. We also considered for this analysis studies contributing patient-level data in response to a public call made by WHO in 2018. Meta-analysis for proportions and arm-based network meta-analysis were done to estimate the incidence of adverse events for each tuberculosis drug.Findings58 studies were identified, including 50 studies from the updated individual patient data meta-analysis for multidrug-resistant tuberculosis treatment. 35 of these studies, with 9178 patients, were included in our analysis. Using meta-analysis of proportions, drugs with low risks of adverse event occurrence leading to permanent discontinuation included levofloxacin (1·3% [95% CI 0·3-5·0]), moxifloxacin (2·9% [1·6-5·0]), bedaquiline (1·7% [0·7-4·2]), and clofazimine (1·6% [0·5-5·3]). Relatively high incidence of adverse events leading to permanent discontinuation was seen with three second-line injectable drugs (amikacin: 10·2% [6·3-16·0]; kanamycin: 7·5% [4·6-11·9]; capreomycin: 8·2% [6·3-10·7]), aminosalicylic acid (11·6% [7·1-18·3]), and linezolid (14·1% [9·9-19·6]). Risk of bias in selection of studies was judged to be low because there were no important differences between included and excluded studies. Variability between studies was significant for most outcomes analysed.InterpretationFluoroquinolones, clofazimine, and bedaquiline had the lowest incidence of adverse events leading to permanent drug discontinuation, whereas second-line injectable drugs, aminosalicylic acid, and linezolid had the highest incidence. These results suggest that close monitoring of adverse events is important for patients being treated for multidrug-resistant tuberculosis. Our results also underscore the urgent need for safer and better-tolerated drugs to reduce morbidity from treatment itself for patients with multidrug-resistant tuberculosis.FundingCanadian Institutes of Health Research, Centers for Disease Control and Prevention (USA), American Thoracic Society, European Respiratory Society, and Infectious Diseases Society of America.