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Mindfulness-Based Stress Reduction (MBSR) programs are offered worldwide. To date, there has been little discussion about for whom participation may not be appropriate. We reviewed the literature pertaining to attrition and adverse effects following participation in MBSR; relatively little was learned in this search. A few clinical trials from Mindfulness-Based Cognitive Therapy (MBCT) provide ideas concerning who may not benefit from this program and who is likely to drop out. There are some case studies of individuals who manifested various mental health issues following experiences with various forms of meditation, but often specifics are missing such that it is not known what type of meditation was practiced or if the individuals in question had previous psychiatric disorders or preexisting conditions that could predispose them to negative outcomes. While we could not provide an empirically based answer to our question, we open the discussion and offer recommendations, especially with regard to preprogram screening, to guide instructors when they form a new group for an MBSR course so that the risk of harm is reduced. We trust that this paper will prompt our colleagues to examine the issue of risk and report adverse events should they occur.

People with long-term conditions must complete many healthcare tasks such as take medications, attend appointments, and change their lifestyle. This treatment burden and ability to manage it (capacity) is not well-researched in Parkinson's disease. To explore and identify potentially modifiable factors contributing to treatment burden and capacity in people with Parkinson's disease and caregivers. Semi-structured interviews with nine people with Parkinson's disease and eight caregivers recruited from Parkinson's disease clinics in England (ages 59-84 years, duration of Parkinson's disease diagnosis 1-17 years, Hoehn and Yahr (severity of Parkinson's disease) stages 1-4) were conducted. Interviews were recorded and analyzed thematically. Four themes of treatment burden with modifiable factors were identified: 1) Challenges with appointments and healthcare access: organizing appointments, seeking help and advice, interactions with healthcare professionals, and caregiver role during appointments; 2) Issues obtaining satisfactory information: sourcing and understanding information, and satisfaction with information provision; 3) Managing medications: getting prescriptions right, organizing polypharmacy, and autonomy to adjust treatments; and 4) Lifestyle changes: exercise, dietary changes, and financial expenses. Aspects of capacity included access to car and technology, health literacy, financial capacity, physical and mental ability, personal attributes and life circumstances, and support from social networks. There are potentially modifiable factors of treatment burden including addressing the frequency of appointments, improving healthcare interactions and continuity of care, improving health literacy and information provision, and reducing polypharmacy. Some changes could be implemented at individual and system levels to reduce treatment burden for people with Parkinson's and their caregivers. Recognition of these by healthcare professionals and adopting a patient-centered approach may improve health outcomes in Parkinson's disease.

People with Parkinson's (PwP) and their caregivers have to manage multiple daily healthcare tasks (treatment burden). This can be challenging and may lead to poor health outcomes. To assess the extent of treatment burden in Parkinson's disease(PD), identify key modifiable factors, and develop recommendations to improve treatment burden. A mixed-methods study was conducted consisting of: 1) a UK-wide cross-sectional survey for PwP and caregivers using the Multimorbidity Treatment Burden Questionnaire (MTBQ) to measure treatment burden levels and associated factors and 2) focus groups with key stakeholders to discuss survey findings and develop recommendations. 160 PwP (mean age = 68 years) and 30 caregivers (mean age = 69 years) completed the surveys. High treatment burden was reported by 21% (N = 34) of PwP and 50% (N = 15) of caregivers using the MTBQ. Amongst PwP, higher treatment burden was significantly associated with advancing PD severity, frailty, a higher number of non-motor symptoms, and more frequent medication timings (>3 times/day). Caregivers reporting higher treatment burden were more likely to care for someone with memory issues, had lower mental well-being scores and higher caregiver burden. Three online focus groups involved 11 participants (3 PwP, 1 caregiver and 7 healthcare professionals) recruited from the South of England. Recommendations to reduce treatment burden that were discussed in the focus groups include improving communication. clear expectation setting, and better signposting from healthcare professionals, increasing education and awareness of PD complexity, flexibility of appointment structures, increasing access to healthcare professionals, and embracing the supportive role of technology. Treatment burden is common amongst PwP and caregivers and could be identified in clinical practice using the MTBQ. There is a need for change at individual provider and system levels to recognise and minimise treatment burden to improve health outcomes in PD.

In 2012, an international consensus paper reported that medulloblastoma comprises four molecular subgroups (WNT, SHH, Group 3, and Group 4), each associated with distinct genomic features and clinical behavior. Independently, multiple recent reports have defined further intra-subgroup heterogeneity in the form of biologically and clinically relevant subtypes. However, owing to differences in patient cohorts and analytical methods, estimates of subtype number and definition have been inconsistent, especially within Group 3 and Group 4. Herein, we aimed to reconcile the definition of Group 3/Group 4 MB subtypes through the analysis of a series of 1501 medulloblastomas with DNA-methylation profiling data, including 852 with matched transcriptome data. Using multiple complementary bioinformatic approaches, we compared the concordance of subtype calls between published cohorts and analytical methods, including assessments of class-definition confidence and reproducibility. While the lowest complexity solutions continued to support the original consensus subgroups of Group 3 and Group 4, our analysis most strongly supported a definition comprising eight robust Group 3/Group 4 subtypes (types I–VIII). Subtype II was consistently identified across all component studies, while all others were supported by multiple class-definition methods. Regardless of analytical technique, increasing cohort size did not further increase the number of identified Group 3/Group 4 subtypes. Summarizing the molecular and clinico-pathological features of these eight subtypes indicated enrichment of specific driver gene alterations and cytogenetic events amongst subtypes, and identified highly disparate survival outcomes, further supporting their biological and clinical relevance. Collectively, this study provides continued support for consensus Groups 3 and 4 while enabling robust derivation of, and categorical accounting for, the extensive intertumoral heterogeneity within Groups 3 and 4, revealed by recent high-resolution subclassification approaches. Furthermore, these findings provide a basis for application of emerging methods (e.g., proteomics/single-cell approaches) which may additionally inform medulloblastoma subclassification. Outputs from this study will help shape definition of the next generation of medulloblastoma clinical protocols and facilitate the application of enhanced molecularly guided risk stratification to improve outcomes and quality of life for patients and their families.

Historical risk stratification criteria for medulloblastoma rely primarily on clinicopathological variables pertaining to age, presence of metastases, extent of resection, histological subtypes and in some instances individual genetic aberrations such as MYC and MYCN amplification. In 2010, an international panel of experts established consensus defining four main subgroups of medulloblastoma (WNT, SHH, Group 3 and Group 4) delineated by transcriptional profiling. This has led to the current generation of biomarker-driven clinical trials assigning WNT tumors to a favorable prognosis group in addition to clinicopathological criteria including MYC and MYCN gene amplifications. However, outcome prediction of non-WNT subgroups is a challenge due to inconsistent survival reports. In 2015, a consensus conference was convened in Heidelberg with the objective to further refine the risk stratification in the context of subgroups and agree on a definition of risk groups of non-infant, childhood medulloblastoma (ages 3–17). Published and unpublished data over the past 5 years were reviewed, and a consensus was reached regarding the level of evidence for currently available biomarkers. The following risk groups were defined based on current survival rates: low risk (>90 % survival), average (standard) risk (75–90 % survival), high risk (50–75 % survival) and very high risk (<50 % survival) disease. The WNT subgroup and non-metastatic Group 4 tumors with whole chromosome 11 loss or whole chromosome 17 gain were recognized as low-risk tumors that may qualify for reduced therapy. High-risk strata were defined as patients with metastatic SHH or Group 4 tumors, or MYCN -amplified SHH medulloblastomas. Very high-risk patients are Group 3 with metastases or SHH with TP53 mutation. In addition, a number of consensus points were reached that should be standardized across future clinical trials. Although we anticipate new data will emerge from currently ongoing and recently completed clinical trials, this consensus can serve as an outline for prioritization of certain molecular subsets of tumors to define and validate risk groups as a basis for future clinical trials.

Approximately 50% of cancer patients receive radiation treatment, either alone or in combination with other therapies. Tumor hypoxia has long been associated with resistance to radiation therapy. Moreover, the expression of hypoxia inducible factors HIF1α and/or HIF2α correlates with poor prognosis in many tumors. Recent evidence indicates that HIF1α expression can enhance radiation-induced apoptosis in cancer cells. We demonstrate here that HIF2α inhibition promotes tumor cell death and, in contrast to HIF1α, enhances the response to radiation treatment. Specifically, inhibiting HIF2α expression augments p53 activity, increases apoptosis, and reduces clonogenic survival of irradiated and non-irradiated cells. Moreover, HIF2α inhibition promotes p53-mediated responses by disrupting cellular redox homeostasis, thereby permitting reactive oxygen species (ROS) accumulation and DNA damage. These results correlate with altered p53 phosphorylation and target gene expression in untreated human tumor samples and show that HIF2α likely contributes to tumor cell survival including during radiation therapy.

Primary aldosteronism (PA) diagnosis is a multistep process that begins with screening based on the plasma aldosterone-to-renin ratio (ARR). As cut-off values depend on the methods used, the aim of this study was 1) to validate the performances of new aldosterone and renin chemiluminescent immuno-assays using the Lumipulse® analyzer (Fujirebio®) and then 2) to define the criteria to distinguish PA patients from those with essential hypertension (EH). This monocentric retrospective study included 297 patients admitted to Georges Pompidou European Hospital, France, between January 2021 and December 2022 for the assessment of hypertension etiology. We evaluated analytical performances and compared Lumipulse® results for plasma renin (PRC) and plasma aldosterone (PAC) concentrations (n = 196) as well as 24-hour urine aldosterone excretion (24UA) (n = 201) to the reference methods (PRC: Liaison XL® Diasorin®; PAC and 24UA: LC-MS/MS). Receiver operating characteristic curve analysis was used to define the cut-off values for ARR, PAC, and 24UA to distinguish between PA and EH patients. Analytical characteristics were in accordance with requested performances. Our results showed excellent correlations between Lumipulse® and our reference methods. We propose cut-off values of 35 pmol/mIU as the ARR, 260 pmol/L for PAC, and 49 nmol/24h for 24UA for predicting PA diagnosis. Lumipulse® (Fujirebio®) is a reliable alternative for measuring PRC, PAC, and 24UA for predicting PA diagnosis with the use of corresponding cut-off values for each criterion.

Enhanced drought modeling is crucial for realistic prediction and effective management of water resources, especially with climate change anticipated to exacerbate drought frequency and severity. Global water models (GWMs) simulate historical and future terrestrial water storage (TWS) with continuous spatial and temporal coverage. However, a global evaluation of TWS simulations by GWMs focused on drought is lacking. Here we evaluate, for the first time, GWMs' capability to represent TWS droughts by comparing simulations with Gravity Recovery and Climate Experiment satellite data. We find notable underestimation of drought severity and coverage by GWMs, across diverse regions, including North America, South America, Africa, and Northern Asia. When examined without trend removal, the underestimation of TWS droughts is more pronounced in recent years (2016–2019) compared to 2002–2015, especially in northern latitudes. This underrepresentation highlights the necessity to improve GWMs to simulate TWS droughts. Our results imply that previously reported future TWS projections could have underestimated droughts.

Hepatocellular carcinoma is a primary liver cancer, characterised by diverse etiology, late diagnoses, and poor prognosis. Hepatocellular carcinoma is mostly resistant to current treatment options, therefore, identification of more effective druggable therapeutic targets is needed. We found microRNA miR-20a-5p is upregulated during mouse liver tumor progression and in human hepatocellular carcinoma patients. In this study, we elucidated the therapeutic potential of targeting oncogenic miR-20a-5p, in vivo, in a xenograft model and in two transgenic hepatocellular carcinoma mouse models via adeno-associated virus-mediated miR-20a-Tough-Decoy treatment. In vivo knockdown of miR-20a-5p attenuates tumor burden and prolongs survival in the two independent hepatocellular carcinoma mouse models. We identified and validated cytochrome c as a novel target of miR-20a-5p. Cytochrome c plays a key role in initiation of the apoptotic cascade and in the electron transport chain. We show for the first time, that miR-20a modulation affects both these key functions of cytochrome c during HCC development. Our study thus demonstrates the promising ‘two birds with one stone’ approach of therapeutic in vivo targeting of an oncogenic miRNA, whereby more than one key deregulated cellular process is affected, and unequivocally leads to more effective attenuation of HCC progression and significantly longer overall survival.