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Dietary fibre supplementation enhances radiotherapy tumour control and alleviates intestinal radiation toxicity.
BACKGROUND: Non-toxic approaches to enhance radiotherapy outcomes are beneficial, particularly in ageing populations. Based on preclinical findings showing that high-fibre diets sensitised bladder tumours to irradiation by modifying the gut microbiota, along with clinical evidence of prebiotics enhancing anti-cancer immunity, we hypothesised that dietary fibre and its gut microbiota modification can radiosensitise tumours via secretion of metabolites and/or immunomodulation. We investigated the efficacy of high-fibre diets combined with irradiation in immunoproficient C57BL/6 mice bearing bladder cancer flank allografts. RESULT: Psyllium plus inulin significantly decreased tumour size and delayed tumour growth following irradiation compared to 0.2% cellulose and raised intratumoural CD8+ cells. Post-irradiation, tumour control positively correlated with Lachnospiraceae family abundance. Psyllium plus resistant starch radiosensitised the tumours, positively correlating with Bacteroides genus abundance and increased caecal isoferulic acid levels, associated with a favourable response in terms of tumour control. Psyllium plus inulin mitigated the acute radiation injury caused by 14 Gy. Psyllium plus inulin increased caecal acetate, butyrate and propionate levels, and psyllium alone and psyllium plus resistant starch increased acetate levels. Human gut microbiota profiles at the phylum level were generally more like mouse 0.2% cellulose profiles than high fibre profiles. CONCLUSION: These supplements may be useful in combination with radiotherapy in patients with pelvic malignancy. Video Abstract.
The future of psychological treatments: The Marburg Declaration.
Although psychological treatments are broadly recognized as evidence-based interventions for various mental disorders, challenges remain. For example, a substantial proportion of patients receiving such treatments do not fully recover, and many obstacles hinder the dissemination, implementation, and training of psychological treatments. These problems require those in our field to rethink some of our basic models of mental disorders and their treatments, and question how research and practice in clinical psychology should progress. To answer these questions, a group of experts of clinical psychology convened at a Think-Tank in Marburg, Germany, in August 2022 to review the evidence and analyze barriers for current and future developments. After this event, an overview of the current state-of-the-art was drafted and suggestions for improvements and specific recommendations for research and practice were integrated. Recommendations arising from our meeting cover further improving psychological interventions through translational approaches, improving clinical research methodology, bridging the gap between more nomothetic (group-oriented) studies and idiographic (person-centered) decisions, using network approaches in addition to selecting single mechanisms to embrace the complexity of clinical reality, making use of scalable digital options for assessments and interventions, improving the training and education of future psychotherapists, and accepting the societal responsibilities that clinical psychology has in improving national and global health care. The objective of the Marburg Declaration is to stimulate a significant change regarding our understanding of mental disorders and their treatments, with the aim to trigger a new era of evidence-based psychological interventions.
Assessment of Visual Function with Cotoretigene Toliparvovec in X-Linked Retinitis Pigmentosa in the Randomized XIRIUS Phase 2/3 Study.
PURPOSE: Cotoretigene toliparvovec (BIIB112/AAV8-RPGR) is an investigational vector-based gene therapy designed to provide a full-length, codon-optimized retinitis pigmentosa GTPase regulator (RPGR) protein to individuals with RPGR-associated X-linked retinitis pigmentosa (XLRP). We assessed efficacy and tolerability of cotoretigene toliparvovec subretinal gene therapy. DESIGN: Part 2 of the XIRIUS trial (ClinicalTrials.gov identifier, NCT03116113) was a phase 2/3, 12-month, randomized (1:1:1) dose-expansion study. PARTICIPANTS: Male patients ≥10 years of age with RPGR-associated XLRP were included. METHODS: Participants were randomized 1:1:1 to receive low-dose subretinal cotoretigene toliparvovec (5 × 1010 vector genomes/eye), high-dose cotoretigene toliparvovec (2.5 × 1011 vector genomes/eye) or to be an untreated control participant. MAIN OUTCOME MEASURES: The primary end point was the percentage of participants meeting microperimetry responder criteria (≥ 7-dB improvement at ≥ 5 of 16 central loci). Secondary end points included change from baseline in retinal sensitivity at the central 16 loci and the entire 68 loci at 12 months and change from baseline in low-luminance visual acuity (LLVA) at 12 months, as well as the proportion of eyes with a ≥ 15-Early Treatment Diabetic Retinopathy Study ETDRS letter LLVA and ≥ 10-ETDRS letter LLVA change from baseline at month 12. RESULTS: Because of the impact of the COVID-19 pandemic, enrollment ended before reaching the initial target, leaving the trial underpowered. Twenty-nine participants were included (low-dose group, n = 10; high-dose group, n = 10; control group, n = 9). At month 12, the percentage of participants meeting microperimetry responder criteria was not significantly different between either cotoretigene toliparvovec group (low dose, 37.5% [P = 0.3181]; high dose, 25.0% [P = 0.5177]) and the control group (22.2%). However, the mean change from baseline in microperimetry sensitivity improved significantly with the low-dose group versus the control group at month 12 (P = 0.0350). Significant improvement in LLVA occurred in the low-dose group versus the control group at month 12 (33.3% difference [80% confidence interval, 14.7%-55.2%]; P = 0.0498). Three ocular-related serious adverse events (SAEs) occurred in the low-dose group versus 7 SAEs in the high-dose group. CONCLUSIONS: The primary microperimetry end point was not met. Significant improvements in LLVA and mean microperimetry were observed compared with controls and fewer SAEs occured with low-dose compared with high dose cotoretigene toliparvovec. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
Signatures of kin selection in a natural population of the bacteria Bacillus subtilis.
Laboratory experiments have suggested that bacteria perform a range of cooperative behaviors, which are favored because they are directed toward relatives (kin selection). However, there is a lack of evidence for cooperation and kin selection in natural bacterial populations. Molecular population genetics offers a promising method to study natural populations because the theory predicts that kin selection will lead to relaxed selection, which will result in increased polymorphism and divergence at cooperative genes. Examining a natural population of Bacillus subtilis, we found consistent evidence that putatively cooperative traits have higher polymorphism and greater divergence than putatively private traits expressed at the same rate. In addition, we were able to eliminate alternative explanations for these patterns and found more deleterious mutations in genes controlling putatively cooperative traits. Overall, our results suggest that cooperation is favored by kin selection, with an average relatedness of r = .79 between interacting individuals.
Differentially biased sampling strategies reveal the non-stationarity of species distribution models for Indian small felids
Species Distribution Models (SDMs) have been used extensively to understand species-habitat relationships and design conservation strategies. The ability to train these models using a wide variety of datasets and modelling algorithms has led to their wide applicability across systems. However, the ease of modelling also leads to their use as off-the-shelf models without a detailed investigation of the data and their suitable end-use application. The effect of various modelling parameters on inferences has been explored, however, their interaction with training data type is limited. We used country-wide data for four sympatric Indian small cat species to understand the sensitivity of SDMs to data types, sampling extents and their interaction. Our results reveal the non-stationarity of models with varying modelling parameters. The extent of the training dataset had major implications on the inferences and interacted strongly with the type of dataset used. The divergent distribution of the target species revealed that the effect of sampling extent was more pronounced for species that have limited distribution within the predictive extent. Lastly, our results highlight the significance of sampled environmental space in explaining the non-stationarity of the model outputs.
Biochemical and molecular biomarkers and their association with anthropogenic chemicals in wintering Manx shearwaters (Puffinus puffinus).
Anthropogenic pollution poses a threat to marine conservation by causing chronic toxic effects. Seabirds have contact throughout their lives with pollutants like plastic, metals, polychlorinated biphenyls (PCBs), and organochlorine pesticides such as hexachlorocyclohexanes (HCHs). We assessed 155 Manx shearwaters (Puffinus puffinus) stranded along the Brazilian coast, analyzing associations between organic pollutants, plastic ingestion, biomarkers (transcript levels of aryl hydrocarbon receptor, cytochrome P450-1A-5 [CYP1A5], UDP-glucuronosyl-transferase [UGT1], estrogen receptor alpha-1 [ESR1], and heat shock protein-70 genes) and enzymes activity (ethoxy-resorufin O-deethylase and glutathione S-transferase [GST]). Plastic debris was found in 29 % of the birds. The transcription of UGT1 and CYP1A5 was significantly associated with hexachlorobenzene (HCB) and PCBs levels. ESR1 was associated with HCB and Mirex, and GST was associated with Drins and Mirex. While organic pollutants affected shearwaters more than plastic ingestion, reducing plastic availability remains relevant as xenobiotics are also potentially adsorbed onto plastics.
Factors associated with posttraumatic stress and anxiety among the parents of babies admitted to neonatal care: a systematic review.
BACKGROUND: Posttraumatic stress (PTS) and anxiety are common mental health problems among parents of babies admitted to a neonatal unit (NNU). This review aimed to identify sociodemographic, pregnancy and birth, and psychological factors associated with PTS and anxiety in this population. METHOD: Studies published up to December 2022 were retrieved by searching Medline, Embase, PsychoINFO, Cumulative Index to Nursing and Allied Health electronic databases. The modified Newcastle-Ottawa Scale for cohort and cross-sectional studies was used to assess the methodological quality of included studies. This review was pre-registered in PROSPERO (CRD42021270526). RESULTS: Forty-nine studies involving 8,447 parents were included; 18 studies examined factors for PTS, 24 for anxiety and 7 for both. Only one study of anxiety factors was deemed to be of good quality. Studies generally included a small sample size and were methodologically heterogeneous. Pooling of data was not feasible. Previous history of mental health problems (four studies) and parental perception of more severe infant illness (five studies) were associated with increased risk of PTS, and had the strongest evidence. Shorter gestational age (≤ 33 weeks) was associated with an increased risk of anxiety (three studies) and very low birth weight (
Inhaled pentamidine and prevention of pneumocystis pneumonia
To the Editor: In the report of the recent European controlled trial of inhaled pentamidine for prophylaxis against Pneumocystis carinii pneumonia (PCP), Hirschel and colleagues (April 18 issue)1 state that it appears that prophylaxis against PCP may be less expensive than treating this disease. On the basis of data from the United States, there are several reasons why inhaled pentamidine is unlikely to reduce costs in this country. First, its cost is $100 to $129 per 300-mg vial (the lowest wholesale cost to the hospital), four times the cost in Europe.2,3 In addition, according to data from the Multi-center AIDS. © 1991, Massachusetts Medical Society. All rights reserved.
Compliance Committees and Recent Multilateral Environmental Agreements: The Canadian Experience with Their Negotiation and Operation
In order to enhance and encourage compliance with obligations in multilateral environmental agreements (MEAs), states have agreed to the creation of compliance committees for all of the recent MEAs. Canada has been a strong supporter of the compliance committee experiment and an active participant in the negotiation and operation of numerous MEA compliance committees. This article does three things. First, it examines the international legal nature of the MEA compliance committees. Second, the key issues of the structure of the committees are explored. Finally, the article look at the development and operation of compliance committees pursuant to: the Montreal Protocol; the LRTAP Convention; the Espoo Convention; the Basel Convention; the Cartagena Protocol; the Rotterdam Convention; the Stockholm Convention; and the Protocol to the London Dumping Convention.
Reframing pain: the power of individual and societal factors to enhance pain treatment.
The effectiveness of analgesics can be increased if synergistic behavioural, psychological, and pharmacological interventions are provided within a supportive environment.
General practitioners' perspectives on diagnostic tests for children: a qualitative interview study.
Background Most healthcare contacts for children in the UK occur in general practice. Diagnostic tests can be beneficial in narrowing differential diagnoses, however, there is substantial variation in the use of tests for children in general practice. Unwarranted variation in testing can lead to variation in quality of care and exacerbate health inequities. No prior study has tried to understand why variation in testing exists for children in general practice. Aim To explore GP perspectives on using diagnostic tests for children in primary care and the underlying drivers of variation. Design and setting Semi-structured interviews were conducted with GPs and trainee GPs in England. Methods We conducted interviews with 18 GPs and 2 trainees between April and June 2023. The interviews were transcribed and analysed thematically. Results GPs reflected that their approach to testing in children differed from adults; their threshold to test was higher, but the threshold to refer to specialists was lower. GPs' perceptions of test utility varied, including objective testing for asthma. Perceived drivers of variation in testing included: 1) intrinsic (clinician) factors relating to their risk tolerance and experience, and 2) extrinsic factors, including disease prevalence, parental concern and expectations of healthcare, workforce changes leading to fragmentation in care, time constraints and differences in guidelines. Conclusions The findings of this study identify actionable issues for clinicians, researchers, and policymakers to address gaps in education, evidence, and guidance, reduce unwarranted differences in test use and improve the quality of health care delivered to children in general practice.
Acute to long-term characteristics of impedance recordings during neurostimulation in humans.
Objective.This study aims to characterize the time course of impedance, a crucial electrophysiological property of brain tissue, in the human thalamus (THL), amygdala-hippocampus, and posterior hippocampus over an extended period.Approach.Impedance was periodically sampled every 5-15 min over several months in five subjects with drug-resistant epilepsy using an investigational neuromodulation device. Initially, we employed descriptive piecewise and continuous mathematical models to characterize the impedance response for approximately three weeks post-electrode implantation. We then explored the temporal dynamics of impedance during periods when electrical stimulation was temporarily halted, observing a monotonic increase (rebound) in impedance before it stabilized at a higher value. Lastly, we assessed the stability of amplitude and phase over the 24 h impedance cycle throughout the multi-month recording.Main results.Immediately post-implantation, the impedance decreased, reaching a minimum value in all brain regions within approximately two days, and then increased monotonically over about 14 d to a stable value. The models accounted for the variance in short-term impedance changes. Notably, the minimum impedance of the THL in the most epileptogenic hemisphere was significantly lower than in other regions. During the gaps in electrical stimulation, the impedance rebound decreased over time and stabilized around 200 days post-implant, likely indicative of the foreign body response and fibrous tissue encapsulation around the electrodes. The amplitude and phase of the 24 h impedance oscillation remained stable throughout the multi-month recording, with circadian variation in impedance dominating the long-term measures.Significance.Our findings illustrate the complex temporal dynamics of impedance in implanted electrodes and the impact of electrical stimulation. We discuss these dynamics in the context of the known biological foreign body response of the brain to implanted electrodes. The data suggest that the temporal dynamics of impedance are dependent on the anatomical location and tissue epileptogenicity. These insights may offer additional guidance for the delivery of therapeutic stimulation at various time points post-implantation for neuromodulation therapy.
Comparing the Oxford Digital Multiple Errands Test (OxMET) to a real-life version: Convergence, feasibility, and acceptability.
We aimed to assess the convergence, feasibility, and acceptability of the Oxford Digital Multiple Errands Test (OxMET) and the in-person Multiple Errands Test-Home version (MET-Home). Participants completed OxMET, MET-Home, Montreal Cognitive Assessment (MoCA), and questionnaires on activities of daily living, depression, technology usage, mobility, and disability. Forty-eight stroke survivors (mean age 69.61, 41.67% female, and average 16.5 months post-stroke) and 50 controls (mean age 71.46, 56.00% female) took part. No performance differences were found for healthy and stroke participants for MET-Home, and only found below p = .05 for OxMET but not below the corrected p = .006. Convergent validity was found between MET-Home and OxMET metrics (most r ≥ .30, p
The GATAD2B-NuRD complex drives DNA:RNA hybrid-dependent chromatin boundary formation upon DNA damage.
Double-strand breaks (DSBs) are the most lethal form of DNA damage. Transcriptional activity at DSBs, as well as transcriptional repression around DSBs, are both required for efficient DNA repair. The chromatin landscape defines and coordinates these two opposing events. However, how the open and condensed chromatin architecture is regulated remains unclear. Here, we show that the GATAD2B-NuRD complex associates with DSBs in a transcription- and DNA:RNA hybrid-dependent manner, to promote histone deacetylation and chromatin condensation. This activity establishes a spatio-temporal boundary between open and closed chromatin, which is necessary for the correct termination of DNA end resection. The lack of the GATAD2B-NuRD complex leads to chromatin hyperrelaxation and extended DNA end resection, resulting in homologous recombination (HR) repair failure. Our results suggest that the GATAD2B-NuRD complex is a key coordinator of the dynamic interplay between transcription and the chromatin landscape, underscoring its biological significance in the RNA-dependent DNA damage response.