RESUMO
The insulin-linked polymorphic region is a variable number of tandem repeats region of DNA in the promoter of the insulin gene that regulates transcription of insulin. This region is known to form the alternative DNA structures, i-motifs and G-quadruplexes. Individuals have different sequence variants of tandem repeats and although previous work investigated the effects of some variants on G-quadruplex formation, there is not a clear picture of the relationship between the sequence diversity, the DNA structures formed, and the functional effects on insulin gene expression. Here we show that different sequence variants of the insulin linked polymorphic region form different DNA structures in vitro. Additionally, reporter genes in cellulo indicate that insulin expression may change depending on which DNA structures form. We report the crystal structure and dynamics of an intramolecular i-motif, which reveal sequences within the loop regions forming additional stabilising interactions that are critical to formation of stable i-motif structures. The outcomes of this work reveal the detail in formation of stable i-motif DNA structures, with potential for rational based drug design for compounds to target i-motif DNA.
Assuntos
DNA , Quadruplex G , Insulina , Regiões Promotoras Genéticas , Insulina/química , Insulina/genética , DNA/química , DNA/genética , Humanos , Conformação de Ácido Nucleico , Motivos de Nucleotídeos , Cristalografia por Raios X , Polimorfismo Genético , Sequências de Repetição em Tandem/genética , Sequência de Bases , Modelos Moleculares , Animais , Genes ReporterRESUMO
BACKGROUND: Many studies highlight poor health-related quality of life (HRQoL) in children treated for brain tumours and their parents. However, little is known about the extent to which their informational, healthcare and communication needs regarding HRQoL are met during medical outpatient consultations. AIM: To explore the experiences of families regarding communication with physicians about HRQoL issues during consultations after treatment for childhood brain tumours. METHODS: Interviews were conducted with 18 families of children and adolescents aged 8-17 years after completion of brain tumour treatment. Participants had completed treatment within the last 5 years and were receiving regular outpatient follow-up care. Thematic analysis was undertaken using the Framework Method. RESULTS: Five main themes were identified: (i) unmet emotional and mental health needs; (ii) double protection; (iii) unmet information needs; (iv) communication barriers within consultations; and (v) finding a new normal. CONCLUSION: There was a need to improve communication between clinicians and these families, improve information provision, and overcome barriers to conversing with children within these outpatient consultations. Children and their parents should be supported to voice their current needs and concerns regarding their HRQoL. These findings will inform further development of the UK version of the 'KLIK' patient- and parent-reported outcome (PROM) portal.
RESUMO
Thermoplastic composite organosheets (OSs) are increasingly recognized as a viable solution for automotive and aerospace structures, offering a range of benefits including cost-effectiveness through high-rate production, lightweight design, impact resistance, formability, and recyclability. This study examines the impact response, post-impact strength evaluation, and hot-pressing repair effectiveness of woven glass fiber nylon composite OSs across varying impact energy levels. Experimental investigations involved subjecting composite specimens to impact at varying energy levels using a drop-tower test rig, followed by compression-after-impact (CAI) tests. The results underscore the exceptional damage tolerance and improved residual compressive strength of the OSs compared to traditional thermoset composites. This enhancement was primarily attributed to the matrix's ductility, which mitigated transverse crack propagation and significantly increased the amount of absorbed energy. To mitigate impact-induced damage, a localized hot-pressing repair approach was developed. This allowed to restore the post-impact strength of the OSs to pristine levels for impact energies below 40 J and by 83.6% for higher impact energies, when OS perforation was observed. The measured levels of post-repair strength demonstrate a successful restoration of OS strength over a wide range of impact energies, and despite limitations in achieving complete strength recovery above 40 J, hot-pressing repair emerges as a promising strategy for ensuring the longevity of thermoplastic composites through repairability.
RESUMO
Neuromelanin-pigmented neurons of the substantia nigra are selectively lost during the progression of Parkinson's disease. These neurons accumulate iron in the disease state, and iron-mediated neuron damage is implicated in cell death. Animal models of Parkinson's have evidenced iron loading inside the nucleoli of nigral neurons, however the nature of intranuclear iron deposition in the melanised neurons of the human substantia nigra is not understood. Here, scanning transmission x-ray microscopy (STXM) is used to probe iron foci in relation to the surrounding ultrastructure in melanised neurons of human substantia nigra from a confirmed Parkinson's case. In addition to the expected neuromelanin-bound iron, iron deposits are also associated with the edge of the cell nucleolus. Speciation analysis confirms these deposits to be ferric (Fe3+) iron. The function of intranuclear iron in these cells remains unresolved, although both damaging and protective mechanisms are considered. This finding shows that STXM is a powerful label-free tool for the in situ, nanoscale chemical characterisation of both organic and inorganic intracellular components. Future applications are likely to shed new light on incompletely understood biochemical mechanisms, such as metal dysregulation and morphological changes to cell nucleoli, that are important in understanding the pathogenesis of Parkinson's.
Assuntos
Ferro , Melaninas , Neurônios , Doença de Parkinson , Substância Negra , Síncrotrons , Substância Negra/metabolismo , Substância Negra/patologia , Humanos , Ferro/metabolismo , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Melaninas/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Núcleo Celular/metabolismoRESUMO
BACKGROUND: Children and young people (CYP) with complex neurodisability experience multiple physical, communication, educational and social challenges, which require complex packages of multidisciplinary care. Part of the holistic care required includes supporting the families and parents/caregivers. The aim of the wider study was to introduce a new programme ('Ubuntu') to parents/caregivers and healthcare professionals (HCPs) in order to test the feasibility and acceptability of the concept and content, with the goal of potential adaptation for the UK in mind. Data collection and analysis uncovered rich data on caregiving journeys, navigation of health services, and perceived service gaps. This paper focuses solely on these topics. Further papers will report on the feasibility and adaptation data. METHODS: Two rounds of semi-structured interviews were conducted with 12 caregivers of CYP with complex neurodisability and six HCPs from a variety of disciplines, recruited from a community child health service in London Borough of Newham, UK in 2020. The interviews included open-ended questions to explore caregiving journeys, experiences of navigating health services and perceived service gaps. Transcripts were analysed using a data-driven inductive thematic analysis. RESULTS: Three themes were identified that related to the aim of understanding caregivers' experiences and unmet needs relating to current service provision. These were (1) Caregiver Mental Health, (2) The Information Gap and (3) The Need for Holistic Support. Mental health difficulties were reported, particularly around the period of diagnosis. Priority needs included the provision of clear information about the diagnosis and services offered, opportunities to forge peer support networks and for services across the community to collaborate. CONCLUSIONS: The delivery of health services for CYP with neurodisability should encompass the broad needs of the family as well as meeting the clinical needs of the CYP.
Assuntos
Cuidadores , Necessidades e Demandas de Serviços de Saúde , Pesquisa Qualitativa , Humanos , Cuidadores/psicologia , Criança , Masculino , Feminino , Adolescente , Reino Unido , Acessibilidade aos Serviços de Saúde , Pré-Escolar , Avaliação das Necessidades , Adulto , Serviços de Saúde da Criança/organização & administração , Crianças com Deficiência/reabilitação , Pais/psicologia , Pessoal de Saúde/psicologia , Adulto JovemRESUMO
An experimental investigation of interlaminar toughness for post-cured through-thickness reinforcement (PTTR) skin-stringer sub-element is presented. The improvement in the crack resistance capability of skin-stringer samples was shown through experimental testing and finite element analysis (FEA) modeling. The performance of PTTR was evaluated on a pristine and initial-disbond of the skin-stringer specimen. A macro-scale pin-spring modeling approach was employed in FEA using a non-linear spring to capture the pin failure under the mixed-mode load. The experimental results showed a 15.5% and 20.9% increase in strength for the pristine-PTTR and initial-disbond PTTR specimens, respectively. The modeling approach accurately represents the overall structural response of PTTR laminate, including stiffness, adhesive strength, crack extension scenarios and progressive pin failure modes. This modeling approach can be beneficial for designing damage-tolerant structures by exploring various PTTR arrangements for achieving improved structural responses.
RESUMO
The skin is a multifunctional organ, forming a barrier between the external and internal environment, thereby functioning as a safeguard against extrinsic factors. Autophagy has been implicated in epidermal differentiation and in preserving skin homeostasis. LC3-associated phagocytosis (LAP) uses some but not all components of autophagy. The Atg16l1 (Δ WD) mouse model lacks the WD40 domain required for LAP and has been widely used to study the effects of LAP deficiency and autophagy on tissue homeostasis and response to infection. In this study, the Δ WD model was used to study the relationship between LAP and skin homeostasis by determining whether LAP-deficient mice display a cutaneous phenotype. Skin histology of wild-type and Δ WD mice aged 1 year revealed minor morphological differences in the tail skin dermal layer. RT-qPCR and western blot analysis showed no differences in key keratin expression between genotypes. Skin barrier formation, assessed by dye permeation assays, demonstrated full and proper formation of the skin barrier at embryonic day 18.5 in both genotypes. Biomechanical analysis of the skin showed decreased skin elasticity in aged Δ WD but not wild-type mice. In summary, the LAP-deficient Δ WD mice displayed subtle alterations in dermal histology and age-related biomechanical changes.
RESUMO
INTRODUCTION: Parent carers of children with special educational needs or disabilities are at risk of poorer health and wellbeing outcomes because of the distinct and challenging circumstances they face. Evaluations of interventions promoting the health of parent carers should focus on measuring the aspects of health and wellbeing which are most relevant to this group. As part of a programme of research on parent carer-focused interventions, this study aimed to understand which aspects of health and wellbeing are perceived by parent carers as most meaningful and important. METHODS: A qualitative study using semistructured online interviews was conducted. A purposive sample of parent carers was interviewed about relevant health and wellbeing outcomes. Transcripts were analysed thematically. RESULTS: Thirty parent carers were interviewed, 19 of whom had experienced a health-promoting intervention, either as participants (n = 14) or facilitators (n = 5). Three main themes were identified: 'self, identity and beliefs'; 'social connections and support' and 'health-promoting practices and outcomes.' Each theme encompassed the challenges participants faced, and the changes that helped them overcome these challenges. 'Self-identity' challenges focused on the overwhelming nature of the parental care role and the emotional impact of this. Changes were brought about by developing a positive mindset, increasing confidence, and reconnecting with aspects of their identity which were important to them before they became parent carers. Challenges related to 'social connections' reflected parent carers' isolation. Change was brought about through increased peer support and peer interactions. Parent carers experienced challenges in terms of 'health-promoting activities' because they lacked free time and experienced poor physical health. Changes were brought about by engagement in health-promoting activities of various kinds. CONCLUSION: Parent carers view health and wellbeing in terms of overcoming the common challenges they face as a group. These challenges reflect the ways in which their physiological and psychological needs are often unmet. Researchers interested in measuring parent carer health and wellbeing should consider the specific challenges this group face, as well as theoretical frameworks which can make sense of these challenges, such as self-determination theory. PATIENT OR PUBLIC CONTRIBUTION: Our team carries out patient and public involvement (PPI) through a Family Faculty group facilitated by a Family Involvement Co-ordinator (A. McD.) who is herself a parent carer. A study-specific PPI working group was established which included members of the Family Faculty. The PPI group advised on various aspects of the research as reported in the paper. The manuscript was co-authored by the team's Family Involvement Co-ordinator (A. McD.).
Assuntos
Cuidadores , Crianças com Deficiência , Pais , Pesquisa Qualitativa , Humanos , Cuidadores/psicologia , Feminino , Masculino , Pais/psicologia , Criança , Adulto , Apoio Social , Pessoa de Meia-Idade , Entrevistas como Assunto , Adolescente , Nível de SaúdeRESUMO
BACKGROUND/PURPOSE: Radiation is a key component in the treatment of central nervous system pure germinoma (PG) in children and adolescents. Proton therapy (PT) improves normal tissue sparing and potentially reduces adverse effects (AE). The aim of this study was to present the largest single institution experience utilizing PT for the management of PG. MATERIALS METHODS: We enrolled 35 non-metastatic patients with PG that were treated with PT at our institution between July 2007 - September 2021. Most received induction chemotherapy (n = 31, 89 %) and whole ventricular irradiation with an involved field boost (n = 29, 83 %). The most common total dose was 30 CGE (n = 18, 51.4 %). We utilized the cumulative incidence method to estimate local control (LC), freedom from distant metastases (FFDM), freedom from progression (FFP), and overall survival (OS). Treatment related toxicity was assessed per CTCAE version 5. RESULTS: Median follow-up was 6.2 years (range, 0.9---15.2). The 10-year Kaplan-Meier estimates for LC, FFDM, FFP, and OS were 100 %, 100 %, 100 %, and 94 % respectively. The most common AE were hearing impairment requiring hearing aids (n = 3), transient hypersomnia requiring medication (n = 3), and new onset endocrinopathy (n = 1). Of the 23 evaluable patients ≥ 18 years old at last follow-up, 8 were high school graduates/in college, 8 college graduates, and 7 others gainfully employed. CONCLUSIONS: When utilized in modern multimodality treatment of non-metastatic PG, the precise dosimetry of PT does not compromise disease control. Although serious radiation side effects are rare, the 100% cure rate supports further investigation into selective radiation dose and volume de-escalation.
Assuntos
Germinoma , Terapia com Prótons , Humanos , Terapia com Prótons/efeitos adversos , Terapia com Prótons/métodos , Adolescente , Criança , Masculino , Germinoma/radioterapia , Germinoma/patologia , Feminino , Pré-Escolar , Resultado do Tratamento , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/mortalidade , Dosagem Radioterapêutica , Neoplasias do Sistema Nervoso Central/radioterapia , Neoplasias do Sistema Nervoso Central/mortalidade , Estudos Retrospectivos , Adulto JovemRESUMO
OBJECTIVES: Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) is considered a rare inflammatory rheumatologic disorder that is seen primarily in older adult men. Patients present with arthralgias of large joints accompanied by painful pitting edema of the hands and feet. Few studies have reported the prevalence of metabolic syndromes, including diabetes mellitus and hyperlipidemia in these patients. METHODS: This case series reviewed 25 patients who were diagnosed as having RS3PE in a private outpatient clinic. RESULTS: Nearly half of the patients (48%) had diabetes mellitus, predominantly type 2, and more than half of the patients (60%) had hyperlipidemia. CONCLUSIONS: We believe that future case studies on RS3PE should include an assessment of various comorbidities that can be seen in patients with this autoinflammatory disorder. The increased availability of musculoskeletal ultrasound provides a potential area of study to differentiate this disorder from other inflammatory arthritis and improve reaching the correct diagnosis.
Assuntos
Edema , Sinovite , Humanos , Masculino , Sinovite/diagnóstico , Sinovite/epidemiologia , Sinovite/complicações , Edema/epidemiologia , Edema/diagnóstico , Edema/etiologia , Pessoa de Meia-Idade , Feminino , Idoso , Adulto , Hiperlipidemias/epidemiologia , Hiperlipidemias/complicações , Comorbidade , Estudos Retrospectivos , Idoso de 80 Anos ou mais , Diabetes Mellitus Tipo 2/complicaçõesRESUMO
Purpose: Adenoid cystic carcinoma (ACC) is a rare malignancy accounting for 1% of all head and neck cancers. Treatment for ACC has its challenges and risks, yet few outcomes studies exist. We present long-term outcomes of patients with ACC of the head and neck treated with proton therapy (PT). Materials and Methods: Under an institutional review board-approved, single-institutional prospective outcomes registry, we reviewed the records of 56 patients with de novo, nonmetastatic ACC of the head and neck treated with PT with definitive (n = 9) or adjuvant PT (n = 47) from June 2007 to December 2021. The median dose to the primary site was 72.6 gray relative biological equivalent (range, 64-74.4) delivered as either once (n = 19) or twice (n = 37) daily treatments. Thirty patients received concurrent chemotherapy. Thirty-one patients received nodal radiation, 30 electively and 1 for nodal involvement. Results: With a median follow-up of 6.2 years (range, 0.9-14.7), the 5-year local-regional control (LRC), disease-free survival, cause-specific survival, and overall survival rates were 88%, 85%, 89%, and 89%, respectively. Intracranial extension (P = .003) and gross residual tumor (P = .0388) were factors associated with LRC rates. While the LRC rate for those with a gross total resection was 96%, those with subtotal resection or biopsy alone were 81% and 76%, respectively. The 5-year cumulative incidence of clinically significant grade ≥3 toxicity was 15%, and the crude incidence at the most recent follow-up was 23% (n = 13). Conclusion: This is the largest sample size with the longest median follow-up to date of patients with ACC treated with PT. PT can provide excellent disease control for ACC of the head and neck with acceptable toxicity. T4 disease, intracranial involvement, and gross residual disease at the time of PT following either biopsy or subtotal resection were significant prognostic features for worse outcomes.
RESUMO
BACKGROUND: Medication harm affects between 5 and 15% of hospitalised patients, with approximately half of the harm events considered preventable through timely intervention. The Adverse Inpatient Medication Event (AIME) risk prediction model was previously developed to guide a systematic approach to patient prioritisation for targeted clinician review, but frailty was not tested as a candidate predictor variable. AIM: To evaluate the predictive performance of an updated AIME model, incorporating a measure of frailty, when applied to a new multisite cohort of hospitalised adult inpatients. METHODS: A retrospective cohort study was conducted at two tertiary Australian hospitals on patients discharged between 1st January and April 31, 2020. Data were extracted from electronic medical records (EMRs) and clinical coding databases. Medication harm was identified using ICD-10 Y-codes and confirmed by senior pharmacist review of medical records. The Hospital Frailty Risk Score (HFRS) was calculated for each patient. Logistic regression analysis was used to construct a modified AIME model. Candidate variables of the original AIME model, together with new variables including HFRS were tested. Performance of the final model was reported using area under the curve (AUC) and decision curve analysis (DCA). RESULTS: A total of 4089 patient admissions were included, with a mean age ± standard deviation (SD) of 64 years (±19 years), 2050 patients (50%) were males, and mean HFRS was 6.2 (±5.9). 184 patients (4.5%) experienced one or more medication harm events during hospitalisation. The new AIME-Frail risk model incorporated 5 of the original variables: length of stay (LOS), anti-psychotics, antiarrhythmics, immunosuppressants, and INR greater than 3, as well as 5 new variables: HFRS, anticoagulants, antibiotics, insulin, and opioid use. The AUC was 0.79 (95% CI: 0.76-0.83) which was superior to the original model (AUC = 0.70, 95% CI: 0.65-0.74) with a sensitivity of 69%, specificity of 81%, positive predictive value of 0.14 (95% CI: 0.10-0.17) and negative predictive value of 0.98 (95% CI: 0.97-0.99). The DCA identified the model as having potential clinical utility between the probability thresholds of 0.05-0.4. CONCLUSION: The inclusion of a frailty measure improved the predictive performance of the AIME model. Screening inpatients using the AIME-Frail tool could identify more patients at high-risk of medication harm who warrant timely clinician review.
Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Fragilidade , Pacientes Internados , Humanos , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Austrália , Hospitalização/estatística & dados numéricos , Estudos Retrospectivos , Medição de Risco , Adulto , Registros Eletrônicos de Saúde , Estudos de CoortesRESUMO
This cohort study using pooled data from 2 randomized clinical trials examines whether removing more lymph nodes with axillary lymph node dissection improved outcomes over sentinel lymph node biopsy when most patients received adjuvant radiation therapy or regional nodal irradiation.
Assuntos
Axila , Neoplasias da Mama , Humanos , Neoplasias da Mama/cirurgia , Neoplasias da Mama/patologia , Feminino , Excisão de Linfonodo/métodos , Metástase Linfática , Linfonodos/patologia , Linfonodos/cirurgiaRESUMO
OBJECTIVES: To evaluate whether computed tomography (CT)-derived psoas major muscle measurements could predict preoperative cardiopulmonary exercise testing (CPET) performance and long-term mortality in patients undergoing major colorectal surgery and to compare predictive performance of psoas muscle measurements using 2D approach and 3D approach. METHODS: A retrospective cohort study compliant with STROCSS standards was conducted. Consecutive patients undergoing major colorectal surgery between January 2011 and January 2017 following CPET as part of their preoperative assessment were included. Regression analyses were modelled to investigate association between the CT-derived psoas major muscle mass variables [total psoas muscle area (TPMA), total psoas muscle volume (TPMV) and psoas muscle index (PMI)] and CPET performance and mortality (1-year and 5-year). Discriminative performances of the variables were evaluated using Receiver Operating Characteristic (ROC) curve analysis. RESULTS: A total of 457 eligible patients were included. The median TPMA and TPMV were 21 âcm2 (IQR: 15-27) and 274 âcm3 (IQR: 201-362), respectively. The median PMI measured via 2D and 3D approaches were 7 âcm2/m2 (IQR: 6-9) and 99 âcm3/m2 (IQR: 76-120), respectively. The risks of 1-year and 5-year mortality were 7.4% and 27.1%, respectively. Regression analyses showed TPMA, TPMV, and PMI can predict preoperative CPET performance and long-term mortality. However, ROC curve analyses showed no significant difference in predictive performance amongst TPMA, TPMV, and PMI. CONCLUSION: Radiologically-measured psoas muscle mass variables may predict preoperative CPET performance and may be helpful with informing more objective selection of patients for preoperative CPET and prehabilitation.
Assuntos
Músculos Psoas , Tomografia Computadorizada por Raios X , Humanos , Músculos Psoas/diagnóstico por imagem , Músculos Psoas/anatomia & histologia , Masculino , Estudos Retrospectivos , Feminino , Idoso , Pessoa de Meia-Idade , Teste de Esforço , Taxa de SobrevidaRESUMO
BACKGROUND: Pick's disease is a rare and predominantly sporadic form of frontotemporal dementia that is classified as a primary tauopathy. Pick's disease is pathologically defined by the presence in the frontal and temporal lobes of Pick bodies, composed of hyperphosphorylated, three-repeat tau protein, encoded by the MAPT gene. MAPT has two distinct haplotypes, H1 and H2; the MAPT H1 haplotype is the major genetic risk factor for four-repeat tauopathies (eg, progressive supranuclear palsy and corticobasal degeneration), and the MAPT H2 haplotype is protective for these disorders. The primary aim of this study was to evaluate the association of MAPT H2 with Pick's disease risk, age at onset, and disease duration. METHODS: In this genetic association study, we used data from the Pick's disease International Consortium, which we established to enable collection of data from individuals with pathologically confirmed Pick's disease worldwide. For this analysis, we collected brain samples from individuals with pathologically confirmed Pick's disease from 35 sites (brainbanks and hospitals) in North America, Europe, and Australia between Jan 1, 2020, and Jan 31, 2023. Neurologically healthy controls were recruited from the Mayo Clinic (FL, USA, or MN, USA between March 1, 1998, and Sept 1, 2019). For the primary analysis, individuals were directly genotyped for the MAPT H1-H2 haplotype-defining variant rs8070723. In a secondary analysis, we genotyped and constructed the six-variant-defined (rs1467967-rs242557-rs3785883-rs2471738-rs8070723-rs7521) MAPT H1 subhaplotypes. Associations of MAPT variants and MAPT haplotypes with Pick's disease risk, age at onset, and disease duration were examined using logistic and linear regression models; odds ratios (ORs) and ß coefficients were estimated and correspond to each additional minor allele or each additional copy of the given haplotype. FINDINGS: We obtained brain samples from 338 people with pathologically confirmed Pick's disease (205 [61%] male and 133 [39%] female; 338 [100%] White) and 1312 neurologically healthy controls (611 [47%] male and 701 [53%] female; 1312 [100%] White). The MAPT H2 haplotype was associated with increased risk of Pick's disease compared with the H1 haplotype (OR 1·35 [95% CI 1·12 to 1·64], p=0·0021). MAPT H2 was not associated with age at onset (ß -0·54 [95% CI -1·94 to 0·87], p=0·45) or disease duration (ß 0·05 [-0·06 to 0·16], p=0·35). Although not significant after correcting for multiple testing, associations were observed at p less than 0·05: with risk of Pick's disease for the H1f subhaplotype (OR 0·11 [0·01 to 0·99], p=0·049); with age at onset for H1b (ß 2·66 [0·63 to 4·70], p=0·011), H1i (ß -3·66 [-6·83 to -0·48], p=0·025), and H1u (ß -5·25 [-10·42 to -0·07], p=0·048); and with disease duration for H1x (ß -0·57 [-1·07 to -0·07], p=0·026). INTERPRETATION: The Pick's disease International Consortium provides an opportunity to do large studies to enhance our understanding of the pathobiology of Pick's disease. This study shows that, in contrast to the decreased risk of four-repeat tauopathies, the MAPT H2 haplotype is associated with an increased risk of Pick's disease in people of European ancestry. This finding could inform development of isoform-related therapeutics for tauopathies. FUNDING: Wellcome Trust, Rotha Abraham Trust, Brain Research UK, the Dolby Fund, Dementia Research Institute (Medical Research Council), US National Institutes of Health, and the Mayo Clinic Foundation.
Assuntos
Doença de Pick , Tauopatias , Feminino , Humanos , Masculino , Estudos de Associação Genética , Haplótipos , Doença de Pick/genética , Proteínas tau/genéticaRESUMO
Removal of fuel debris is planned to start at Unit 2 of the Fukushima Daiichi Nuclear Power Plant. During the removal, it is desirable to distinguish fuel debris from radioactive wastes and to sort the fuel debris accordingly to the amounts of nuclear material contained. Muon scattering tomography invented at Los Alamos in the early 2000s is highly sensitivity to high-atomic-number materials such as uranium. A muon scanner to sort the debris is designed and currently in production. One of the challenges is to operate the muon scanner in the presence of high γ-ray radiations from the debris: muon-event-identification electronics and a muon-tracking algorithm in the presence of high γ-ray radiations were developed.
RESUMO
OBJECTIVE: Describe families' experiences of interventions to improve continence in children and young people with neurodisability, and health professionals' and school and social care staff's perspectives regarding factors affecting intervention use. DESIGN: Four online surveys were developed and advertised to parent carers, young people with neurodisability, health professionals and school and social care staff, via societies, charities, professional contacts, schools, local authorities, and national parent carer and family forums, who shared invitations with their networks. Survey questions explored: difficulties helping children and young people use interventions; acceptability of interventions and waiting times; ease of use and availability of interventions, and facilitators and barriers to improving continence. RESULTS: 1028 parent carers, 26 young people, 352 health professionals and 202 school and social care staff registered to participate. Completed surveys were received from 579 (56.3%) parent carers, 20 (77%) young people, 193 (54.8%) health professionals, and 119 (58.9%) school and social care staff. Common parent carer-reported difficulties in using interventions to help their children and young people to learn to use the toilet included their child's lack of understanding about what was required (reported by 337 of 556 (60.6%) parent carers who completed question) and their child's lack of willingness (343 of 556, 61.7%). Almost all (142 of 156, 91%) health professionals reported lack of funding and resources as barriers to provision of continence services. Many young people (14 of 19, 74%) were unhappy using toilet facilities while out and about. CONCLUSIONS: Perceptions that children lack understanding and willingness, and inadequate facilities impact the implementation of toileting interventions for children and young people with neurodisability. Greater understanding is needed for children to learn developmentally appropriate toileting skills. Further research is recommended around availability and acceptability of interventions to ensure quality of life is unaffected.
Assuntos
Pais , Qualidade de Vida , Criança , Humanos , Adolescente , Pessoal de Saúde , Apoio Social , CuidadoresRESUMO
BACKGROUND: Pediatric esthesioneuroblastoma (EN) can infiltrate skull base anatomy, presenting challenges due to high radiation doses and pediatric tissue sensitivity. This study reports outcomes of pediatric EN treated with proton radiotherapy (PT). PROCEDURE: Using an IRB-approved prospective outcomes registry, we evaluated patient, tumor, and treatment-related variables impacting disease control and toxicity in pediatric nonmetastatic EN treated with modern multimodality therapy, including PT. RESULTS: Fifteen consecutive patients (median age 16) comprising Kadish stage B (n = 2), C (n = 9), and D (n = 4) tumors were assessed, including six with intracranial involvement, four with cranial nerve deficits, and four with cervical lymphadenopathy. Before radiation, two had subtotal and 13 had gross total resections (endoscopic or craniofacial). Two underwent neck dissection. Eleven received chemotherapy before radiation (n = 5), concurrent with radiation (n = 4), or both (n = 2). Median total radiation dose (primary site) was 66 Gy/CGE for gross disease and 54 Gy/CGE (cobalt Gray equivalent) for microscopic disease. Median follow-up was 4.8 years. No patients were lost to follow-up. Five-year disease-free and overall survival rates were 86% (no local or regional recurrences). Two patients developed vertebral metastases and died. Two required a temporary feeding tube for oral mucositis/dysphagia. Late toxicities included symptomatic retinopathy, major reconstructive surgery, cataracts, chronic otitis media, chronic keratoconjunctivitis, hypothyroidism, and in-field basal cell skin cancer. CONCLUSIONS: A multimodality approach for pediatric EN results in excellent local control. Despite the moderate-dose PT, serious radiation toxicity was observed; further dose and target volume reductions may benefit select patients. Longer follow-up and comparative data from modern photon series are necessary to fully characterize any relative PT advantage.
Assuntos
Estesioneuroblastoma Olfatório , Neoplasias Nasais , Terapia com Prótons , Humanos , Criança , Adolescente , Terapia com Prótons/métodos , Estesioneuroblastoma Olfatório/radioterapia , Estudos Prospectivos , Neoplasias Nasais/radioterapia , Cavidade Nasal , Dosagem RadioterapêuticaRESUMO
OBJECTIVE: The safety of single-treatment stereotactic radiosurgery (SRS) for vestibular schwannoma (VS) with radiographic evidence of brainstem compression but without motor deficit is controversial. Data on linear accelerator (linac)-based SRS in this setting are scarce. We address this with an outcomes report from an unselected series of patients with VS with radiographic brainstem compression treated with linac SRS. METHODS: We included 139 patients with unilateral VS (any size) with radiographic brainstem compression (all without serious brainstem neurological deficits). The SRS prescription dose was 12.5 Gy (single fraction) using 6MV linac-produced photon beams, delivered with a multiple arc technique. Inclusion criteria required at least 1 year of radiographic follow-up with magnetic resonance imaging. The primary endpoint was freedom from serious brainstem toxicity (≥grade 3 Common Terminology Criteria for Adverse Events v5); the secondary was freedom from enlargement (tumor progression or any requiring intervention). We assessed serious cranial nerve complications, excluding hearing loss, defined as Common Terminology Criteria for Adverse Events v5 grade 3 toxicity. RESULTS: Median magnetic resonance imaging follow-up time was 5 years, and median tumor size was 2.5 cm in greatest axial dimension and 5 ml in volume. The median brainstem D0.03 ml=12.6 Gy and median brainstem V10 Gy=0.4 ml. At 5 years, the actuarial freedom from serious brainstem toxicity was 100%, and freedom from tumor enlargement (requiring surgery and/or due to progression) was 90%. Severe facial nerve damage in patients without tumor enlargement was 0.9%. CONCLUSION: Linac-based SRS, as delivered in our series for VS with radiographic brainstem compression, is safe and effective.