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This experiment was designed to investigate the effect of cognitive problem-solving operations (termed contextual interference) and complexity of tasks on the acquisition retention and transfer of motor skills. Ninety-six children, ages 7.5-9.5 practiced the task of throwing beanbags under either low contextual interference (blocked practice), high contextual interference (random practice) or medium contextual interference (combined practice). Half of the participants acquired a complex task and the other half a simple task. All participants performed 30 acquisition trials, 9 retention trials and 4 transfer trials. Results indicated that participants who practiced in the blocked practice group did not differ in their performance whether they acquired complex or simple tasks. On the other hand, participants from the random and combined practice groups who acquired simple tasks performed better than those who acquired complex tasks. These findings support the hypothesis that there is a limit to the interference during practice that will benefit retention and transfer, thus creating the contextual interference effect. It seems that the complex-task condition combined with random or combined practice schedule increased the difficulty of acquisition, possibly impeding the cognitive processing during acquisition, thus impairing the learning process. [ABSTRACT FROM AUTHOR]

The P-glycoprotein efflux pump, encoded by the MDR1 gene, is an ATP-driven transporter capable of expelling a diverse array of compounds from cells. Overexpression of this protein is implicated in the multi-drug resistant phenotype observed in various cancers. Numerous studies have attempted to decipher the impact of genetic variants within MDR1 on P-glycoprotein expression, functional activity, and clinical outcomes in cancer patients. Among these, three specific single nucleotide polymorphisms-T1236C, T2677G, and T3435C - have been the focus of extensive research efforts, primarily through in vitro cell line models and clinical cohort analyses. However, the findings from these studies have been remarkably contradictory. In this study, we employ a computational, data-driven approach to systematically evaluate the effects of these three variants on principal stages of the gene expression process. Leveraging current knowledge of gene regulatory mechanisms, we elucidate potential mechanisms by which these variants could modulate P-glycoprotein levels and function. Our findings suggest that all three variants significantly change the mRNA folding in their vicinity. This change in mRNA structure is predicted to increase local translation elongation rates, but not to change the protein expression. Nonetheless, the increased translation rate near T3435C is predicted to affect the protein's co-translational folding trajectory in the region of the second ATP binding domain. This potentially impacts P-glycoprotein conformation and function. Our study demonstrates the value of computational approaches in elucidating the functional consequences of genetic variants. This framework provides new insights into the molecular mechanisms of MDR1 variants and their potential impact on cancer prognosis and treatment resistance. Furthermore, we introduce an approach which can be systematically applied to identify mutations potentially affecting mRNA folding in pathology. We demonstrate the utility of this approach on both ClinVar and TCGA and identify hundreds of disease related variants that modify mRNA folding at essential positions., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Gutman, Tuller. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Metastatic urothelial carcinoma (mUC) is a lethal cancer, with limited therapeutic options. Large-scale studies in early settings provided critical insights into the genomic and transcriptomic characteristics of non-metastatic UC. The genomic landscape of mUC remains however unclear. Using Whole Exome (WES) and mRNA sequencing (RNA-seq) performed on metastatic biopsies from 111 patients, we show that driver genomic alterations from mUC were comparable to primary UC (TCGA data). APOBEC, platin, and HRD mutational signatures are the most prevalent in mUC, identified in 56%, 14%, and 9% of mUC samples, respectively. Molecular subtyping using consensus transcriptomic classification in mUC shows enrichment in neuroendocrine subtype. Paired samples analysis reveals subtype heterogeneity and temporal evolution. We identify potential therapeutic targets in 73% of mUC patients, of which FGFR3 (26%), ERBB2 (7%), TSC1 (7%), and PIK3CA (13%) are the most common. NECTIN4 and TACSTD2 are highly expressed regardless of molecular subtypes, FGFR3 alterations and sites of metastases., (© 2024. The Author(s).)

The characterization of somatic genomic variation associated with the biology of tumors is fundamental for cancer research and personalized medicine, as it guides the reliability and impact of cancer studies and genomic-based decisions in clinical oncology. However, the quality and scope of tumor genome analysis across cancer research centers and hospitals are currently highly heterogeneous, limiting the consistency of tumor diagnoses across hospitals and the possibilities of data sharing and data integration across studies. With the aim of providing users with actionable and personalized recommendations for the overall enhancement and harmonization of somatic variant identification across research and clinical environments, we have developed ONCOLINER. Using specifically designed mosaic and tumorized genomes for the analysis of recall and precision across somatic SNVs, insertions or deletions (indels), and structural variants (SVs), we demonstrate that ONCOLINER is capable of improving and harmonizing genome analysis across three state-of-the-art variant discovery pipelines in genomic oncology., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: The involvement of consumers (people with lived experience of disease) in guidelines is widely advocated to improve their relevance and uptake. However, the approaches to consumer involvement in guidelines vary and are not well documented. We describe the consumer involvement framework of Caring for Australians and New ZealandeRs with kidney Impairment Guidelines., Study Design and Setting: We used a descriptive document analysis to collate all relevant policies, documents, e-mails, and presentations on consumer involvement in our organizations. We performed a narrative synthesis of collated data to summarize our evolving consumer involvement approach in guidelines., Results: We involve consumers at all levels of Caring for Australians and New ZealandeRs with kidney Impairment guideline development and dissemination according to their capacity, from conducting consumer workshops to inform the scope of guidelines, to including consumers as members of the guideline Working Groups and overseeing operations and governance as members of the Steering Committee and staff. Our approach has resulted in tangible outcomes including high-priority topics on patient education, psychosocial care, and clinical care pathways, and focusing the literature reviews to assess patient-important outcomes. The ongoing partnership with consumers led to the generation of consumer version guidelines to improve guideline dissemination and translation to support shared decision-making., Conclusion: Meaningful consumer involvement can be achieved through a comprehensive approach across the entire lifecycle of guidelines. However, it must be individualized by ensuring that the involvement of consumers is timely and flexible. Future work is needed to assess the impact of consumer involvement in guideline development., Competing Interests: Declaration of competing interest None relevant., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: High tumor mutational burden (TMB) was reported to predict the efficacy of immune checkpoint inhibitors (ICIs). Pembrolizumab, an anti-PD-1, received FDA-approval for the treatment of unresectable/metastatic tumors with high TMB as determined by the FoundationOne®CDx test. It remains to be determined how TMB can also be calculated using other tests., Results: FFPE/frozen tumor samples from various origins were sequenced in the frame of the Institut Curie (IC) Molecular Tumor Board using an in-house next-generation sequencing (NGS) panel. A TMB calculation method was developed at IC (IC algorithm) and compared to the FoundationOne® (FO) algorithm. Using IC algorithm, an optimal 10% variant allele frequency (VAF) cut-off was established for TMB evaluation on FFPE samples, compared to 5% on frozen samples. The median TMB score for MSS/POLE WT tumors was 8.8 mut/Mb versus 45 mut/Mb for MSI/POLE-mutated tumors. When focusing on MSS/POLE WT tumor samples, the highest median TMB scores were observed in lymphoma, lung, endometrial, and cervical cancers. After biological manual curation of these cases, 21% of them could be reclassified as MSI/POLE tumors and considered as "true TMB high." Higher TMB values were obtained using FO algorithm on FFPE samples compared to IC algorithm (40 mut/Mb [10-3927] versus 8.2 mut/Mb [2.5-897], p < 0.001)., Conclusions: We herein propose a TMB calculation method and a bioinformatics tool that is customizable to different NGS panels and sample types. We were not able to retrieve TMB values from FO algorithm using our own algorithm and NGS panel., (© 2024. The Author(s).)

Objective: This study aims to investigate the effectiveness of a combined Self-Determination Theory (SDT) and Acceptance and Commitment Therapy (ACT) intervention, the "Running Minds" program, in promoting physical activity (PA) among young adults., Methods: The intervention, consisting of eight sessions, targeted motivational and psychological barriers to PA. It intertwined SDT's core components (autonomy, competence, relatedness) with ACT's emphasis on mindfulness and value-driven actions. This study used a qualitative approach, collecting data through semi-structured interviews with twelve participants aged 20-35, conducted post-intervention., Results: Our reflexive thematic analysis of the interviews revealed five key themes: alignment with personal values, rewarding experience of the sessions, fulfillment of social connectedness, enhancement of both intrinsic and extrinsic motivation, and observable behavioral changes. These findings highlight the importance of aligning exercise with personal values and the role of supportive social environments in sustaining PA., Conclusions: The integration of SDT and ACT in the "Running Minds" program appears to be a viable approach for enhancing motivation and adherence to PA among young adults. This study offers valuable insights for future PA interventions, underscoring the need for strategies that consider psychological and social dimensions. Limitations and Future Research: Despite the promising results, limitations include potential recall bias and the short duration of the study. Further research, especially focusing on more diverse groups and employing longitudinal designs, is recommended to broaden and substantiate these findings.

Aims: The mutY DNA glycosylase encoded by the MUTYH gene prevents G:C → T:A transversions through the base excision repair DNA repair system. Germline biallelic pathogenic variants in MUTYH cause an adenomatous polyposis called MUTYH-associated polyposis (MAP), an autosomal recessive disease (OMIM: 608456), with an increased risk of colorectal cancer. Digestive lesions in this context show an excess of G:C → T:A transversions, individualising a specific mutational signature associated with MUTYH deficiency called signature SBS36. Predisposition to other tumours in patients with germline biallelic pathogenic variants in MUTYH is suspected but remains unclear. We report the first case of medulloblastoma in a patient with MAP, carrying the homozygous pathogenic variant c.1227&#95;1228dup, p.(Glu410Glyfs*43) in MUTYH., Methods: Whole exome sequencing was performed on the medulloblastoma to enlighten single nucleotide variants of interest, microsatellite status and mutational signature. The objective was to determine the involvement of MUTYH deficiency in the oncogenesis of this medulloblastoma., Results: The medulloblastoma has the mutational signature SBS36 and driver pathogenic variants in CTNNB1, PTCH1 and KDM6A corresponding to G:C → T:A transversions, suggesting a role of MUTYH deficiency in oncogenesis., Conclusions: Therefore, medulloblastoma could be a rare manifestation associated with germline biallelic pathogenic variants in MUTYH., (© 2023 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.)

Aim: Chronic kidney disease (CKD) and its treatment places a financial burden on healthcare systems and households worldwide, yet little is known of its financial impact, on those who reside in rural settings. We aimed to quantify the financial impacts and out-of-pocket expenditure experienced by adult rural patients with CKD in Australia., Methods: A web based structured survey was completed between November 2020 and January 2021. English speaking participants over 18 years of age, diagnosed with CKD stages 3-5, those receiving dialysis or with a kidney transplant, who lived in a rural location in Australia., Results: In total 77 (69% completion rate) participated. The mean out of pocket expenses were 5056 AUD annually (excluding private health insurance costs), 78% of households experienced financial hardship with 54% classified as experiencing financial catastrophe (out-of-pocket expenditure greater than 10% of household income). Mean distances to access health services for all rural and remote classifications was greater than 50 kilometres for specialist nephrology services and greater than 300 kilometres for transplanting centres. Relocation for a period greater than 3 months to access care was experienced by 24% of participants., Conclusion: Rural households experience considerable financial hardship due to out-of-pocket costs in accessing treatment for CKD and other health-related care, raising concerns about equity in Australia, a high-income country with universal healthcare., (© 2023 The Authors. Nephrology published by John Wiley & Sons Australia, Ltd on behalf of Asian Pacific Society of Nephrology.)

Objective: Chordomas are rare bone neoplasms characterized by a high recurrence rate and no benefit from any approved medical treatment to date. However, the investigation of molecular alterations in chordomas could be essential to prognosticate, guide clinical decision-making, and identify theranostic biomarkers. The aim of this study was to provide a detailed genomic landscape of a homogeneous series of 64 chordoma samples, revealing driver events, theranostic markers, and outcome-related genomic features., Methods: The authors conducted whole-exome sequencing (WES), targeted next-generation sequencing, and RNA sequencing of 64 skull base and spinal chordoma samples collected between December 2006 and September 2020. Clinical, histological, and radiological data were retrospectively analyzed and correlated to genetic findings., Results: The authors identified homozygous deletions of CDKN2A/2B, PIK3CA mutations, and alterations affecting genes of SWI/SNF chromatin remodeling complexes (PBRM1 and ARID1A) as potential theranostic biomarkers. Using matched germline WES, they observed a higher frequency of a common genetic variant (rs2305089; p.(Gly177Asp)) in TBXT (97.8%, p < 0.001) compared to its distribution in the general population. PIK3CA mutation was identified as an independent biomarker of short progression-free survival (HR 10.68, p = 0.0008). Loss of CDKN2A/2B was more frequently observed in spinal tumors and recurrent tumors., Conclusions: In the current study, the authors identified driver events such as PBRM1 and PIK3CA mutations, TBXT alterations, or homozygous deletions of CDKN2A/2B, which could, for some, be considered potential theranostic markers and could allow for identifying novel therapeutic approaches. With the aim of a future biomolecular prognostication classification, alterations affecting PIK3CA and CDKN2A/2B could be considered as poor prognostic biomarkers.

Background: Children with chronic kidney disease (CKD) generally have worse educational and psychosocial outcomes compared with their healthy peers. This can impair their ability to manage their treatment, which in turn can have long-term health consequences through to adulthood. We attempted to capture the experiences of children with CKD and to describe the perspectives of their parents and caregivers on access to educational and psychosocial support., Methods: Children with CKD (n = 34) and their caregivers (n = 62) were sampled via focus groups from pediatric hospitals in Australia, Canada, and the USA. Sixteen focus groups were convened and the transcripts were analyzed thematically., Results: We identified four themes: disruption to self-esteem and identity (emotional turmoil of adolescence, wrestling with the sick self, powerlessness to alleviate child's suffering, balancing normality and protection); disadvantaged by lack of empathy and acceptance (alienated by ignorance, bearing the burden alone); a hidden and inaccessible support system (excluded from formal psychological support, falling behind due to being denied special considerations); and building resilience (finding partners in the journey, moving towards acceptance of the illness, re-establishing childhood)., Conclusions: Children with CKD and their caregivers encountered many barriers in accessing psychosocial and educational support and felt extremely disempowered and isolated as a consequence. Improved availability and access to psychosocial and educational interventions are needed to improve the wellbeing and educational advancement of children with CKD. A higher resolution version of the Graphical abstract is available as Supplementary information., (© 2022. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Rationale & Objective: Caregivers of patients with chronic kidney disease from rural communities play a crucial role in access to dialysis and transplantation, but they face many challenges including geographical distance, financial hardship, and limited support. This study aimed to inform strategies to overcome these challenges by describing the experiences of caregivers of patients with kidney failure from rural Australian communities in accessing kidney replacement therapy., Study Design: Qualitative study., Setting & Participants: 18 adult caregivers of Australian rural patients with kidney failure treated with dialysis or kidney transplantation., Analytical Approach: Semistructured interviews were conducted. Interview transcripts were thematically analyzed., Results: The 18 participants were aged 20 to 78 years; 13 (72%) were female, and 13 (72%) were the spouse/partner of the patient. We identified 5 themes: devastating social isolation (difficult periods of separation, exclusion from peers, forced relocation); financial dependency and sacrifice (burgeoning out-of-pocket costs, disruption to work life, foregoing autonomy); ongoing psychological trauma (concern for neglect and stress on children, long-term emotional distress); overwhelmed by multifaceted roles and expectations (patient advocacy, uncertainty in navigating multiple health systems); and persistent burden of responsibility (loss of self-identity, ongoing travel requirements, scarcity of psychosocial support, unpreparedness for treatment regime)., Limitations: The study was conducted in a high-income, English-speaking country with universal health insurance, which may limit the transferability of the findings., Conclusions: Australian rural caregivers of people with kidney failure treated by maintenance dialysis or transplantation experience an exhausting physical, financial, and psychological burden. Strategies to address these profound challenges are needed., Plain-Language Summary: This interview-based study elicited the challenges faced by people and family members who care for patients from rural towns who are receiving dialysis or kidney transplantation. The barriers and difficulties reported included traveling long distances, needing to move to larger towns and leaving their homes, feeling concerned for the long-term effects on their children, physical exhaustion, and financial issues. Additional efforts are needed to identify the means by which caregivers and their families in rural towns can obtain support to care for those with kidney failure., (Copyright © 2022 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

The purpose of the present study was to evaluate the effectiveness of a physical activity (PA) intervention program designed to enhance levels of engagement in PA. Despite robust evidence supporting the beneficial effects of PA on overall health, only about 22% of individuals engage in the recommended minimum amount of PA. Recent surveys suggested that most individuals express intentions to be physically active, though the psychological state of amotivation dismissed these struggles. In the current study, we pilot-tested a new intervention program, aimed at enhancing engagement in PA among sedentary individuals. The intervention was based on two behavioral change and motivational psychological frameworks: Self-Determination Theory (SDT) and Acceptance and Commitment Therapy (ACT). During a 14-week intervention program, 94 sedentary Israeli college students (Mage = 24.4, SD = 1.42, Females = 89) were randomly assigned into one of three groups: SDT and ACT-based intervention, traditional intervention, and a non-treatment group. Prior to and following the intervention, participants completed the Behavioral Regulation in Exercise Questionnaire-3 (BREQ-3) to examine motivation to exercise and the International Physical Activity Measurement IPAQ to evaluate their training frequency. Results showed that the SDT and ACT-based intervention group exhibited a significant increase in motivation to exercise between time 1 and time 2, while the other two groups (i.e., the traditional intervention program and the non-treatment group) showed insignificant differences in motivation to exercise. Furthermore, neither of the groups showed significant differences in their training frequency per week. However, those in the SDT and ACT-based groups reported an increase in activity intensity from time 1 to time 2 compared to the two other groups. Further, exercise psychology consultants and scholars can use the intervention protocol and utilize these findings to improve PA behaviors and promote health in the general population. Limitations, future directions, and implications are discussed in detail., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lev Arey, Blatt and Gutman.)

Rationale & Objective: Clinical decision-making priorities may differ among children, their parents, and their clinicians. This study describes clinicians' perspectives on shared decision making in pediatric chronic kidney disease (CKD) and identifies opportunities to improve shared decision making and care for children with CKD and their families., Study Design: Semistructured interviews., Setting & Participants: Fifty clinicians participated, including pediatric nephrologists, nurses, social workers, surgeons, dietitians, and psychologists involved in providing care to children with CKD. They worked at 18 hospitals and 4 university research departments across 11 countries (United States of America, Canada, Australia, People's Republic of China, United Kingdom, Germany, France, Italy, Lithuania, New Zealand, and Singapore)., Analytical Approach: Interview transcripts were analyzed thematically., Results: We identified 4 themes: (1) striving to blend priorities (minimizing treatment burden, emphasizing clinical long-term risks, achieving common goals), (2) focusing on medical responsibilities (carrying decisional burden and pressure of expectations, working within system constraints, ensuring safety is foremost concern), (3) collaborating to achieve better long-term outcomes (individualizing care, creating partnerships, encouraging ownership and participation in shared decision making, sensitive to parental distress), and (4) forming cumulative knowledge (balancing reassurance and realistic expectations, building understanding around treatment, harnessing motivation for long-term goals)., Limitations: Most clinicians were from high-income countries, so the transferability of the findings to other settings is uncertain., Conclusions: Clinicians reported striving to minimize treatment burden and working with children and their families to manage their expectations and support their decision making. However, they are challenged with system constraints and sometimes felt the pressure of being responsible for the child's long-term outcomes. Further studies are needed to test whether support for shared decision making would promote strategies to establish and improve the quality of care for children with CKD., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: More than 50% of children with chronic kidney disease (CKD) have uncontrolled hypertension, increasing their long-term risk of cardiovascular disease and progression to kidney failure. Children receiving medications or dialysis may also experience acute blood pressure fluctuations accompanied by debilitating symptoms. We aimed to describe the perspectives of children with CKD and their parental caregivers on blood pressure to inform patient-centered care., Methods: Secondary thematic analysis was conducted on qualitative data from the Standardized Outcomes in Nephrology-Children and Adolescents initiative, encompassing 16 focus groups, an international Delphi survey and two consensus workshops. We analyzed responses from children with CKD (ages 8-21 years) and caregivers (of children ages 0-21 years) pertaining to blood pressure., Results: Overall, 120 patients and 250 caregivers from 22 countries participated. We identified five themes: invisibility and normalization (reassured by apparent normotension, absence of symptoms and expected links with CKD), confused by ambiguity (hypertension indistinguishable from cardiovascular disease, questioning the need for prophylactic intervention, frustrated by inconsistent messages and struggling with technical skills in measurement), enabling monitoring and maintaining health (gaging well-being and preventing vascular complications), debilitating and constraining daily living (provoking anxiety and agitation, helpless and powerless and limiting life activities) and burden of medications (overwhelmed by the quantity of tablets and distress from unexpected side effects)., Conclusions: For children with CKD and their caregivers, blood pressure was an important heath indicator, but uncertainty around its implications and treatment hampered management. Providing educational resources to track blood pressure and minimizing symptoms and treatment burden may improve outcomes in children with CKD., (© The Author(s) 2021. Published by Oxford University Press on behalf of ERA-EDTA.)

Objectives: People with chronic kidney disease requiring dialysis or kidney transplantation in rural areas have worse outcomes, including an increased risk of hospitalisation and mortality and encounter many barriers to accessing kidney replacement therapy. We aim to describe clinicians' perspectives of equity of access to dialysis and kidney transplantation in rural areas., Design: Qualitative study with semistructured interviews., Setting and Participants: Twenty eight nephrologists, nurses and social workers from 19 centres across seven states in Australia., Results: We identified five themes: the tyranny of distance (with subthemes of overwhelming burden of travel, minimising relocation distress, limited transportation options and concerns for patient safety on the roads); supporting navigation of health systems (reliance on local champions, variability of health literacy, providing flexible models of care and frustrated by gatekeepers); disrupted care (without continuity of care, scarcity of specialist services and fluctuating capacity for dialysis); pervasive financial distress (crippling out of pocket expenditure and widespread socioeconomic disadvantage) and understanding local variability (lacking availability of safe and sustainable resources for dialysis, sensitivity to local needs and dependence on social support)., Conclusions: Clinicians identified geographical barriers, dislocation from homes and financial hardship to be major challenges for patients in accessing kidney replacement therapy. Strategies such as telehealth, outreach services, increased service provision and patient navigators were suggested to improve access., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)