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Given any constant C > 0, we show that there exists smooth bounded nonstarshaped domains U in ℝ N (N ≧ 5), such that the problem has no solution u , whose energy, ∫ U | ∇ u | 2 is less than C. [ABSTRACT FROM AUTHOR]

This study focused on the extraction and physicochemical characterization of proteins from larvae and larvae meal of Tenebrio molitor . The larvae were subjected to a protein extraction process which involved a thermo-mechanical pre-treatment to produce the larvae meal. Soluble proteins from larvae and from larvae meal were subsequently extracted by solubilisation at an alkaline pH. The products obtained were then characterized and compared. The larvae and larvae meal were rich in protein (65.6% and 71.6% respectively) and displayed good essential amino acid (EAA) profiles. They contained all EAA and in sufficient quantities to meet the dietary requirements of both humans and salmon, except for a deficiency in methionine. The EAA profile of the larvae meal was also comparable to those of fish and soya meals used for feed. At pH 10 and 45 °C, the protein extraction yield of larvae (59.9%) was two-fold that of larvae meal (26.4%). The soluble proteins had protein contents on dry matter of 84% and 80% from larvae and larvae meal respectively. Molecular weights ranged from ≤ 14 to 100 kDa but the two soluble proteins differed. The soluble proteins had a solubility which was highly pH-dependent, with a low solubility at pH 3 to 5. Their surface charge depended on both the pH (in particular) and the NaCl concentration. The surface hydrophobicity at pH 7 of soluble proteins from larvae (670.3) was higher than that of soluble proteins from larvae meal (102.5). These soluble proteins lowered the water surface tension to 42 mN/m and 32 mN/m for the soluble proteins from larvae and from larvae meal respectively. Chemical compounds used in this work. Glycine (PubChem CID: 750); Glycerol (PubChem CID: 753); Tris-(hydroxymethyl)aminomethane (PubChem CID: 4468930); Sodium chloride (PubChem CID: 5234); Ethanol (PubChem CID: 702); Monosodium phosphate (PubChem CID: 23672064); Disodium hydrogen phosphate (PubChem CID: 24203); 2-mercaptoethanol (PubChem CID: 1567); Hydrochloric acid (PubChem CID: 313); Bromophenol blue (PubChem CID: 8272); Sodium hydroxide (PubChem CID: 14798); Sodium dodecyl sulphate (PubChem CID: 3423265). [ABSTRACT FROM AUTHOR]

The article discusses changes to child mental health research since 1996, particularly noting the tendency of treatment and services research to focus on outcomes most relevant to public health and a broad group of stakeholders. It addresses the increased interest in parent symptomology and health-related outcomes over time, as well as comments on research's impact on mental health services.

Abstract: We consider four turbulent models for simulating the boundary mixing layer of the ocean. We show the existence of solutions to these models in the steady state case and then we study the mathematical linear stability of these solutions. [Copyright &y& Elsevier]

This study reports the development of a micromultiplane 8.2-mm transesophageal echocardiographic probe. The probe is applicable to newborn infants and can deliver diagnostic images in adults. [ABSTRACT FROM AUTHOR]

Background: Climate change has adverse effects on youth mental health and wellbeing, but limited large-scale data exist globally or in the USA. Understanding the patterns and consequences of climate-related distress among US youth can inform necessary responses at the individual, community, and policy level., Methods: A cross-sectional descriptive online survey was done of US youth aged 16-25 years from all 50 states and Washington, DC, between July 20 and Nov 7, 2023, via the Cint digital survey marketplace. The survey assessed: climate-related emotions and thoughts, including indicators of mental health; relational aspects of climate-related emotions; beliefs about who or what has responsibility for causing and responding to climate change; desired and planned actions in response to climate change; and emotions and thoughts about the US Government response to climate change. Respondents were asked whether they had been affected by various severe weather events linked to climate change and for their political party identification. Sample percentages were weighted according to 2022 US census age, sex, and race estimates. To test the effects of political party identification and self-reported exposure to severe weather events on climate-related thoughts and beliefs we used linear and logistic regression models, which included terms for political party identification, the number of self-reported severe weather event types in respondents' area of residence in the past year, and demographic control variables., Findings: We evaluated survey responses from 15 793 individuals (weighted proportions: 80·5% aged 18-25 years and 19·5% aged 16-17 years; 48·8% female and 51·2% male). Overall, 85·0% of respondents endorsed being at least moderately worried, and 57·9% very or extremely worried, about climate change and its impacts on people and the planet. 42·8% indicated an impact of climate change on self-reported mental health, and 38·3% indicated that their feelings about climate change negatively affect their daily life. Respondents reported negative thoughts about the future due to climate change and actions planned in response, including being likely to vote for political candidates who support aggressive climate policy (72·8%). In regression models, self-reported exposure to more types of severe weather events was significantly associated with stronger endorsement of climate-related distress and desire and plans for action. Political party identification as Democrat or as Independent or Other (vs Republican) was also significantly associated with stronger endorsement of distress and desire and plans for action, although a majority of self-identified Republicans reported at least moderate distress. For all survey outcomes assessed in the models, the effect of experiencing more types of severe weather events did not significantly differ by political party identification., Interpretation: Climate change is causing widespread distress among US youth and affecting their beliefs and plans for the future. These effects may intensify, across the political spectrum, as exposure to climate-related severe weather events increases., Funding: Avaaz Foundation., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Purpose: To determine 6-month interim safety, effectiveness, and multimodal imageability of imageable glass microsphere yttrium-90 ( 90 Y) radioembolization for unresectable hepatocellular carcinoma (HCC) in a first-in-human trial., Materials and Methods: Imageable microspheres (Eye90 Microspheres; ABK Biomedical, Halifax, Nova Scotia, Canada), a U.S. Food and Drug Administration (FDA) Breakthrough-Designated Device consisting of glass radiopaque 90 Y microspheres visible on computed tomography (CT) and single photon emission CT (SPECT), were used to treat 6 subjects with unresectable HCC. Patients underwent selective (≤2 segments) treatment in a prospective open-label pilot trial. Key inclusion criteria included liver-only HCC, performance status ≤1, total lesion diameter ≤9 cm, and Child-Pugh A status. Prospective partition dosimetry was utilized. Safety (measured by Common Terminology Criteria for Adverse Events [CTCAE] v5), multimodal imageability on CT and SPECT, and 3- and 6-month imaging response by modified Response Evaluation Criteria in Solid Tumors on magnetic resonance (MR) imaging were evaluated., Results: Seven tumors in 6 subjects were treated and followed to 180 days. Administration success was 100%. Microsphere distribution measured by radiopacity on CT correlated with SPECT. Ninety-day target lesion complete response (CR) was observed in 3 of 6 subjects (50%) and partial response (PR) in 2 (33.3%). At 180 days, target lesion CR was maintained in 3 subjects (50%) and PR in 1 (16.7%). Two subjects could not be reassessed, having undergone intervening chemoembolization. All subjects reported adverse events (AEs), and 5 reported AEs related to treatment. There were no treatment-related Grade ≥3 AEs., Conclusions: Radioembolization using imageable microspheres was safe and effective in 6 subjects with unresectable HCC at 6-month interim analysis. Microsphere distribution by radiopacity on CT correlated with radioactivity distribution by SPECT, providing previously unavailable CT-based tumor targeting information., (Copyright © 2024 SIR. Published by Elsevier Inc. All rights reserved.)

Yttrium-90 transarterial radioembolization (TARE) has progressed from a salvage or palliative lobar or sequential bilobar regional liver therapy for patients with advanced disease to a versatile, potentially curative, and often highly selective local treatment for patients across Barcelona Clinic Liver Cancer stages. With this shift, radiation dosimetry has evolved to become more tailored to patients and target lesion(s), with treatment dose and distributions adapted for specific clinical goals (ie, palliation, bridging or downstaging to liver transplantation, converting to surgical resection candidacy, or ablative/curative intent). Data have confirmed that "personalizing" dosimetry yields real-world improvements in tumor response and overall survival while maintaining a favorable adverse event profile. In this review, imaging techniques used before, during, and after TARE have been reviewed. Historical algorithms and contemporary image-based dosimetry methods have been reviewed and compared. Finally, recent and upcoming developments in TARE methodologies and tools have been discussed., (Copyright © 2023 SIR. Published by Elsevier Inc. All rights reserved.)

Background: A textbook outcome (TO) is a composite indicator covering the entire intervention process in order to reflect the "ideal" intervention and be a surrogate for patient important outcomes. Selective internal radiation therapy (SIRT) is a complex multidisciplinary and multistep intervention facing the challenge of standardization. This expert opinion-based study aimed to define a TO for SIRT of hepatocellular carcinoma., Methods: This study involved two steps: (1) the steering committee (4 interventional radiologists) first developed an extensive list of possible relevant items reflecting an optimal SIRT intervention based on a literature review and (2) then conducted an international and multidisciplinary survey which resulted in the final TO. This survey was online, from February to July 2021, and consisted three consecutive rounds with predefined settings. Experts were identified by contacting senior authors of randomized trials, large observational studies, or studies on quality improvement in SIRT. This study was strictly academic., Results: A total of 50 items were included in the first round of the survey. A total of 29/40 experts (73%) responded, including 23 interventional radiologists (79%), three nuclear medicine physicians (10%), two hepatologists, and one oncologist, from 11 countries spanning three continents. The final TO consisted 11 parameters across six domains ("pre-intervention workup," "tumor targeting and dosimetry," "intervention," "post- 90 Y imaging," "length of hospital stay," and "complications"). Of these, all but one were applied in the institutions of > 80% of experts., Conclusions: This multidimensional indicator is a comprehensive standardization tool, suitable for routine care, clinical round, and research., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: The availability of new immuno-oncology therapeutics markedly impacts oncology clinicians' treatment decision-making. To effectively support healthcare professionals (HCPs) in their practice, it is important to better understand the challenges and barriers that can accompany the introduction of these agents. This study aimed to establish the types and causes of clinical challenges posed by the introduction of new immuno-oncology agents., Methods: The mixed-methods design included qualitative in-depth interviews and group discussions with HCPs, in which participants discussed clinical challenges and potential underlying reasons for these challenges. Qualitative findings informed a quantitative survey. This survey investigated the extent and distribution of challenges using HCPs' self-rating of knowledge, skill, confidence, and exposure to system-level effects. These two phases were conducted sequentially with distinctly stratified samples of oncologists, nurse practitioners (NPs), physician assistants (PAs), pathologists, clinical pharmacists, interventional radiologists, rheumatologists, pulmonologists, and emergency department physicians. Participants were from the United States and had various levels of clinical experience and represented both academic and community-based settings., Results: The final sample included 107 HCPs in the qualitative phase and 554 in the quantitative phase. Analyses revealed clinical challenges related to the use of pharmacodiagnostics. For example, 47% of pathologists and 42% of oncologists reported skill gaps in identifying the appropriate marker and 46% of oncologists, 61% of PAs, 66% of NPs, 74% of pulmonologists and 81% of clinical pharmacists reported skill gaps in selecting treatment based on test results. Challenges also emerged regarding the integration of immuno-oncology agents, as oncologists, rheumatologists, pulmonologists, clinical pharmacists, PAs, and NPs reported knowledge gaps (74-81%) of the safety profiles of recently approved agents. In addition, 90% of clinical pharmacists reported skill gaps weighing the risks and benefits of treating patients with immuno-oncology agents while affected by lupus. Finally, patient communication challenges were identified: HCPs reported difficulties discussing essential aspects of immunotherapy to patients as well as how they might compare to other types of therapies., Conclusion: The challenges highlighted in this study reveal substantial educational gaps related to the integration of immuno-oncology agents into practice for various groups of HCPs. These findings provide a strong base of evidence for future educational initiatives., (© 2022. The Author(s).)

Patients with acute and chronic liver disease present with a wide range of disease states and severity that may require liver transplantation (LT). Physiologic alterations occur that are dynamic throughout all phases of perioperative care, creating complex management scenarios that necessitate multidisciplinary clinical care. Specifically, alterations in hemostasis in liver disease can be pronounced and evolve with disease progression over time. Recent studies and society guidance address this emerging paradigm and offer recommendations to assist with hemostatic management in patients with liver disease. However, patients undergoing LT are unique and diverse, often with unstable disease that requires specialized approaches. Our aim is to provide a focused review of hemostatic management of the LT patient, distinguish unique aspects of the three main phases of care (before LT, perioperative, and after LT), and identify knowledge gaps and critical areas of future research., (© 2022 The Authors. Liver Transplantation published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Aim: To report the technical success of image and endoscopy-guided retrograde trans-urostomy urinary drainage as a primary catheter placement method performed by interventional radiology (IR)., Materials and Methods: Nine patients (15 attempted drain placements) with ureteric obstruction following radical cystectomy and urostomy creation were included. The patients were referred to IR for urinary drainage. All patients underwent primary image and endoscopy-guided retrograde trans-urostomy urinary drainage., Results: Primary image and endoscopy-guided retrograde trans-urostomy urinary drainage was successful in 13/15 (86.6%) attempts. The proposed technique had a limited complication rate omitting the percutaneous nephrostomy access step., Conclusion: Primary image and endoscopy guided retrograde trans-urostomy urinary drainage should be considered before percutaneous nephrostomy in all patients with a urostomy., (Copyright © 2022 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Background: Climate change has important implications for the health and futures of children and young people, yet they have little power to limit its harm, making them vulnerable to climate anxiety. This is the first large-scale investigation of climate anxiety in children and young people globally and its relationship with perceived government response., Methods: We surveyed 10 000 children and young people (aged 16-25 years) in ten countries (Australia, Brazil, Finland, France, India, Nigeria, Philippines, Portugal, the UK, and the USA; 1000 participants per country). Invitations to complete the survey were sent via the platform Kantar between May 18 and June 7, 2021. Data were collected on participants' thoughts and feelings about climate change, and government responses to climate change. Descriptive statistics were calculated for each aspect of climate anxiety, and Pearson's correlation analysis was done to evaluate whether climate-related distress, functioning, and negative beliefs about climate change were linked to thoughts and feelings about government response., Findings: Respondents across all countries were worried about climate change (59% were very or extremely worried and 84% were at least moderately worried). More than 50% reported each of the following emotions: sad, anxious, angry, powerless, helpless, and guilty. More than 45% of respondents said their feelings about climate change negatively affected their daily life and functioning, and many reported a high number of negative thoughts about climate change (eg, 75% said that they think the future is frightening and 83% said that they think people have failed to take care of the planet). Respondents rated governmental responses to climate change negatively and reported greater feelings of betrayal than of reassurance. Climate anxiety and distress were correlated with perceived inadequate government response and associated feelings of betrayal., Interpretation: Climate anxiety and dissatisfaction with government responses are widespread in children and young people in countries across the world and impact their daily functioning. A perceived failure by governments to respond to the climate crisis is associated with increased distress. There is an urgent need for further research into the emotional impact of climate change on children and young people and for governments to validate their distress by taking urgent action on climate change., Funding: AVAAZ., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background and Aims: Extrahepatic portal vein occlusion (EHPVO) from portal vein thrombosis is a rare condition associated with substantial morbidity and mortality. The purpose of this study is to investigate the efficacy of transjugular intrahepatic portosystemic shunts (TIPS) for the treatment of chronic EHPVO, cavernomatosis, and mesenteric venous thrombosis in adults without cirrhosis who are refractory to standard-of-care therapy., Approach and Results: Thirty-nine patients with chronic EHPVO received TIPS. Laboratory parameters and follow-up were assessed at 1, 3, 6, 12, and 24 months, and every 6 months thereafter. Two hepatologists adjudicated symptom improvement attributable to mesenteric thrombosis and EHPVO before/after TIPS. Kaplan-Meier was used to assess primary and overall TIPS patency, assessing procedural success. Adverse events, radiation exposure, hospital length-of-stay and patency were recorded. Cavernoma was present in 100%, with TIPS being successful in all cases using splenic, mesenteric, and transhepatic approaches. Symptom improvement was noted in 26 of 30 (87%) at 6-month follow-up. Twelve patients (31%) experienced TIPS thrombosis. There were no significant long-term laboratory adverse events or deaths. At 36 months, freedom from primary TIPS thrombosis was 63%; following secondary interventions, overall patency was increased to 81%., Conclusions: TIPS in chronic, noncirrhotic EHPVO with cavernomas and mesenteric venous thrombosis is technically feasible and does not adversely affect liver function. Most patients demonstrate subjective and objective benefit from TIPS. Improvement in patency rates are needed with proper timing of adjuvant anticoagulation., (© 2021 by the American Association for the Study of Liver Diseases.)

Background and Aims: Locoregional therapies, including yttrium-90 radioembolization, play an important role in the treatment of unresectable HCC. The aim of the LEGACY (Local radioEmbolization using Glass Microspheres for the Assessment of Tumor Control with Y-90) study was to evaluate objective response rate (ORR) and duration of response (DoR) in patients with solitary unresectable HCC treated with yttrium-90 glass microspheres., Approach and Results: LEGACY is a multicenter, single-arm, retrospective study conducted at three sites that included all eligible, consecutive patients with HCC treated with radioembolization between 2014 and 2017. Eligibility criteria included solitary HCC ≤ 8 cm, Child-Pugh A cirrhosis, and Eastern Cooperative Oncology Group performance status 0-1. Primary endpoints were ORR and DoR based on modified Response Evaluation Criteria in Solid Tumors in the treated area (localized), as evaluated by blinded, independent, central review. Radioembolization was performed with intent of ablative-level dosimetry in a selective fashion when possible. Overall survival was evaluated using Kaplan-Meier and multivariate Cox proportional hazards. Among the 162 patients included, 60.5% were Eastern Cooperative Oncology Group 0, and the median tumor size was 2.7 cm (range: 1-8) according to blinded, independent, central review. Radioembolization served as neoadjuvant therapy for transplantation or resection in 21.0% (34 of 162) and 6.8% (11 of 162) of patients, respectively, and as primary treatment for all others. Median follow-up time was 29.9 months by reverse Kaplan-Meier. ORR (best response) was 88.3% (CI: 82.4-92.4), with 62.2% (CI: 54.1-69.8) exhibiting a DoR ≥ 6 months. Three-year overall survival was 86.6% for all patients and 92.8% for those neoadjuvant patients with resected or transplanted liver., Conclusions: In this multicenter study of radioembolization, clinical meaningful response rates and prolonged DoR were observed in the treatment of unresectable, solitary HCC ≤ 8 cm., (© 2021 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Background: This study empirically evaluates the influence of medical information on patient trust at the physician level, the medical profession, hospitals, and with the payer. Restoring patient trust in a medical setting in Poland appears to be significantly affected due to the COVID-19 pandemic. Patient trust improves results from medical treatment, raises perception of healthcare performance, and smoothens the overall functionality of healthcare systems., Methods: In order to study trust volatility, patients took part in a three-stage experiment designed via: (1) measured level of trust, (2) randomly dividing participants into two groups-control (i.e., re-examination of level of trust) and experimental (i.e., being exposed to a piece of certain manipulative information), and (3) checking whether observational changes were permanent., Results: Results indicate that in the experimental group the increase of trust was noticed in the payer (27.7%, p < 0.001), hospitals (10.9%, p = 0.011), and physicians (decrease of 9.2%, p = 0.036)., Conclusion: The study indicated that in Poland medical information is likely to influence patient trust in healthcare while interpersonal and social trust levels may be related to increases of trust in hospitals and in the payer versus decreases in physicians., (© 2021. The Author(s).)

Background: Increasing healthcare costs need to be contained in order to maintain equality of access to care for all EU citizens. A cross-disciplinary consortium of experts was supported by the EU FP7 research programme, to produce a roadmap on cost containment, while maintaining or improving the quality of healthcare. The roadmap comprises two drivers: person-centred care and health promotion; five critical enablers also need to be addressed: information technology, quality measures, infrastructure, incentive systems, and contracting strategies., Method: In order to develop and test the roadmap, a COST Action project was initiated: COST-CARES, with 28 participating countries. This paper provides an overview of evidence about the effects of each of the identified enablers. Intersections between the drivers and the enablers are identified as critical for the success of future cost containment, in tandem with maintained or improved quality in healthcare. This will require further exploration through testing., Conclusion: Cost containment of future healthcare, with maintained or improved quality, needs to be addressed through a concerted approach of testing key factors. We propose a framework for test lab design based on these drivers and enablers in different European countries., Competing Interests: None declared., (© 2021 The Authors. Health Science Reports published by Wiley Periodicals LLC.)

Basal cell carcinoma (BCC) is the most common skin malignancy afflicting modern Australian society. The most influential response to rising BCC incidence rates has been through public health primary prevention campaigns (PPC) which have persevered since the 1980s. These campaigns are widely heralded a success but clinical data quantifying these benefits are limited due to an absence of legislation around BCC reporting. A non-systematic search of the literature was conducted identifying articles investigating the incidence and clinical characteristics of BCC over the past 40 years, as well as the economic viability of the PPC. There is robust evidence supporting stabilizing rates of BCC incidence in Australia. Similarly, multiple studies have shown the economic benefits of PPC through cost analysis. Anatomical and histological data are reported inconsistently, consequently limiting analysis of changes in BCC clinical characteristics. The consensus throughout the literature is that BCC is a significant public health issue that requires legislative reform. This narrative literature review serves to highlight the need for statutory changes around non-melanocytic skin cancer data collection to enable appropriate analysis and evaluation of current management strategies., (© 2020 Royal Australasian College of Surgeons.)

Introduction: This article examines different motivators for medical staff in countries with a high gap in healthcare efficiency by comparing them in two healthcare systems-Polish (ie efficient) and Ukrainian (ie inefficient)., Method: This survey-based study applies a six-stage conceptual framework to two Polish and two Ukrainian hospitals as well as medical faculties of one university from each country. Following ethical approval, data were collected in the first quarter of 2019, using the 'Evaluation of motivators questionnaire for medical staff'., Findings: Medical staff perceived their working conditions in the inefficient healthcare system much worse than in the efficient system; however, they generally had a more optimistic outlook. Medical staff in efficient and inefficient healthcare systems has different motivational targets, including sizable differences from profession, gender, and age. These factors play an important role in developing a high-performance healthcare system. Results are illustrated in terms of motivators for medical staff., Conclusion: Optimising a healthcare system requires useful reform of enablers, especially in countries with inefficient systems, including policymaking and regulatory action. Best practices must incorporate all stakeholders interested in high healthcare performance-usage of suitable practices from abroad can act as an important resource., (© 2020 John Wiley & Sons Ltd.)

This article was migrated. The article was marked as recommended. The Australian College of Rural and Remote Medicine (ACRRM) has developed a flexible 'tele-assessment' approach to the delivery of its assessment modalities. Candidates can sit their examination remotely, close to their place of practice, which reduces the need for rural doctors - both candidates and examiners - to leave their communities for the purpose of assessment. A major component of the assessment process is the Structured Assessment using Multiple Patient Scenarios (StAMPS) examination, which blends the formats of an Objective Structured Clinical Examination (OSCE) and a traditional viva vocè examination. It is a high-stakes assessment, that was designed to be academically rigorous, flexible, valid, reliable, and fair. Since 2008 ACRRM has provided a videoconferencing option to candidates for their StAMPS examination allowing them to remain in or near their home location, while the examiners meet a central location. Travel restrictions due to the SARS-CoV-2 pandemic meant for the first time both candidates AND examiners participated in StAMPS via videoconference. ACRRM conducted an online StAMPS assessment using videoconferencing technology for 65 candidates in mid-May 2020, with all candidates, examiners and support staff remaining in or near their home communities. These Twelve Tips outline some of the experience gained in providing tele-assessment over the past twelve years., (Copyright: © 2020 Lewandowski R et al.)

Purpose: Somatic variants in tumor necrosis factor receptor-associated factor 7 (TRAF7) cause meningioma, while germline variants have recently been identified in seven patients with developmental delay and cardiac, facial, and digital anomalies. We aimed to define the clinical and mutational spectrum associated with TRAF7 germline variants in a large series of patients, and to determine the molecular effects of the variants through transcriptomic analysis of patient fibroblasts., Methods: We performed exome, targeted capture, and Sanger sequencing of patients with undiagnosed developmental disorders, in multiple independent diagnostic or research centers. Phenotypic and mutational comparisons were facilitated through data exchange platforms. Whole-transcriptome sequencing was performed on RNA from patient- and control-derived fibroblasts., Results: We identified heterozygous missense variants in TRAF7 as the cause of a developmental delay-malformation syndrome in 45 patients. Major features include a recognizable facial gestalt (characterized in particular by blepharophimosis), short neck, pectus carinatum, digital deviations, and patent ductus arteriosus. Almost all variants occur in the WD40 repeats and most are recurrent. Several differentially expressed genes were identified in patient fibroblasts., Conclusion: We provide the first large-scale analysis of the clinical and mutational spectrum associated with the TRAF7 developmental syndrome, and we shed light on its molecular etiology through transcriptome studies.

Background: Commercial uranium mining on the Navajo Nation has subjected communities on tribal lands in the Southwestern United States to exposures from residual environmental contamination. Vascular health effects from these ongoing exposures are an active area of study. There is an association between residential mine-site proximity and circulating biomarkers in residents, however, the contribution of mine-site derived wind-blown dusts on vascular and other health outcomes is unknown. To assess neurovascular effects of mine-site derived dusts, we exposed mice using a novel exposure paradigm, the AirCARE1 mobile inhalation laboratory, located 2 km from an abandoned uranium mine, Claim 28 in Blue Gap Tachee, AZ. Mice were exposed to filtered air (FA) (n = 6) or concentrated ambient particulate matter (CAPs) (n = 5) for 2 wks for 4 h per day., Results: To assess miRNA differential expression in cultured mouse cerebrovascular cells following particulate matter (PM) exposure (average: 96.6 ± 60.4 μg/m 3 for all 4 h exposures), the serum cumulative inflammatory potential (SCIP) assay was employed. MiRNA sequencing was then performed in cultured mouse cerebrovascular endothelial cells (mCECs) to evaluate transcriptional changes. Results indicated 27 highly differentially expressed (p < 0.01) murine miRNAs, as measured in the SCIP assay. Gene ontology (GO) pathway analysis revealed notable alterations in GO enrichment related to the cytoplasm, protein binding and the cytosol, while significant KEGG pathways involved pathways in cancer, axon guidance and Wnt signaling. Expression of these 27 identified, differentially expressed murine miRNAs were then evaluated in the serum. Nine of these miRNAs (~ 30%) were significantly altered in the serum and 8 of those miRNAs demonstrated the same directional change (either upregulation or downregulation) as cellular miRNAs, as measured in the SCIP assay. Significantly upregulated miRNAs in the CAPs exposure group included miRNAs in the let-7a family. Overexpression of mmu-let-7a via transfection experiments, suggested that this miRNA may mediate mCEC barrier integrity following dust exposure., Conclusions: Our data suggest that mCEC miRNAs as measured in the SCIP assay show similarity to serum-borne miRNAs, as approximately 30% of highly differentially expressed cellular miRNAs in the SCIP assay were also found in the serum. While translocation of miRNAs via exosomes or an alternative mechanism is certainly possible, other yet-to-be-identified factors in the serum may be responsible for significant miRNA differential expression in endothelium following inhaled exposures. Additionally, the most highly upregulated murine miRNAs in the CAPs exposure group were in the let-7a family. These miRNAs play a prominent role in cell growth and differentiation and based on our transfection experiments, mmu-let-7a may contribute to cerebrovascular mCEC alterations following inhaled dust exposure.

Pathogenic variants in HNRNPH1 were first reported in 2018. The reported individual, a 13 year old boy with a c.616C>T (p.R206W) variant in the HNRNPH1 gene, was noted to have overlapping symptoms with those observed in HNRNPH2-related X-linked intellectual disability, Bain type (MRXSB), specifically intellectual disability and dysmorphic features. While HNRNPH1 variants were initially proposed to represent an autosomal cause of MRXSB, we report an additional seven cases which identify phenotypic differences from MRXSB. Patients with HNRNPH1 pathogenic variants diagnosed via WES were identified using clinical networks and GeneMatcher. Features unique to individuals with HNRNPH1 variants include distinctive dysmorphic facial features; an increased incidence of congenital anomalies including cranial and brain abnormalities, genitourinary malformations, and palate abnormalities; increased incidence of ophthalmologic abnormalities; and a decreased incidence of epilepsy and cardiac defects compared to those with MRXSB. This suggests that pathogenic variants in HNRNPH1 result in a related, but distinct syndromic cause of intellectual disability from MRXSB, which we refer to as HNRNPH1-related syndromic intellectual disability., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Person-centred care is known as a novel approach which contributes to wellbeing, prevention, care and support of patients. There is little evidence about practising PCC in stroke rehabilitation. In this paper, we develop a novel framework for creation of person-centred services for stroke rehabilitation which supports service configuration adapted to the requirements of each patient. The framework is elaborated over evidence from neurology department of Clinical Centre in Montenegro.

In hereditary cancer, multigene panel testing is currently replacing older single-gene approaches. Patients whose tests were previously uninformative could benefit from updated testing. Research suggests that patients desire to be recontacted about updated genetic testing, but few studies have tested the efficacy of recontact efforts. This study investigated the outcomes of a recontact effort in a hereditary cancer clinic and explored the impact of four different recontact letters, randomized in a 2X2 factorial design. Patients who had negative genetic testing for single genes or conditions were mailed letters inviting them to schedule an appointment to discuss updated testing. Patients were randomized to receive one of four letters and each letter emphasized different implications of updated multigene genetic testing: (a) personal medical management implications, (b) implications for family members, (c) both personal and family implications or (d) a control letter. The proportion of patients who arrived for appointments was assessed approximately 7 months after mailing along with associations with patient demographics and type of letter received. Letters were mailed to 586 patients who had initial testing between 2001 and 2015. Most patients were white (78%) and female (97%) with private insurance (65%). At 7 months, 25 patients (4.3%, 95% CI: 2.6% to 5.9%) had arrived for an appointment. Older age was significantly associated with response rate (p = .01), while type of recontact letter was not (p = .54). This study suggests that recontacting patients about updated genetic testing by mail does not yield a large response. It also suggests that personal and/or familial implications do not seem to be significant factors that determine response rate. Nevertheless, results provide meaningful information for cancer clinics about the outcomes of recontact efforts via informational letter., (© 2019 National Society of Genetic Counselors.)

Actinic Keratosis (AK), Intraepidermal Carcinoma (IEC), and Squamous Cell Carcinoma (SCC) are generally considered to be advancing stages of the same disease spectrum. However, while AK often regress spontaneously, and IEC often regress in response to immune-activating treatments, SCC typically do not regress. Therefore, it is vital to define whether fundamental immunological changes occur during progression to SCC. Here we show that proinflammatory cytokine expression, chemokine expression, and immune cell infiltration density change during progression to SCC. Our findings suggest a switch from predominantly proinflammatory cytokine production to chemokine production is a key feature of progression from precancer to cancer. Together, these observations propose a model that can underpin current research and open new avenues of exploration into the clinical significance of these profiles with respect to immunotherapeutic or other treatment outcomes.

Background: Single institution reports demonstrate variable safety profiles when liver-directed therapy with Yttrium-90 (Y-90) is followed by hepatectomy. We hypothesized that in well-selected patients, hepatectomy after Y90 is feasible and safe., Methods: Nine institutions contributed data for patients undergoing Y90 followed by hepatectomy (2008-2017). Clinicopathologic and perioperative data were analyzed, with 90-day morbidity and mortality as primary endpoints., Results: Forty-seven patients were included. Median age was 59 (20-75) and 62% were male. Malignancies treated included hepatocellular cancer (n = 14; 30%), colorectal cancer (n = 11; 23%), cholangiocarcinoma (n = 8; 17%), neuroendocrine (n = 8; 17%) and other tumors (n = 6). The distribution of Y-90 treatment was: right (n = 30; 64%), bilobar (n = 14; 30%), and left (n = 3; 6%). Median future liver remnant (FLR) following Y90 was 44% (30-78). Resections were primarily right (n = 16; 34%) and extended right (n = 14; 30%) hepatectomies. The median time to resection from Y90 was 196 days (13-947). The 90-day complication rate was 43% and mortality was 2%. Risk factors for Clavien-Dindo Grade>3 complications included: number of Y-90-treated lobes (OR 4.5; 95% CI1.14-17.7; p = 0.03), extent of surgery (p = 0.04) and operative time (p = 0.009)., Conclusions: These data demonstrate that hepatectomy following Y-90 is safe in well-selected populations. This multi-disciplinary treatment paradigm should be more widely studied, and potentially adopted, for patients with inadequate FLR., (Copyright © 2019 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: Connected health (CH), as a new paradigm, manages individual and community health in a holistic manner by leveraging a variety of technologies and has the potential for the incorporation of telehealth and integrated care services, covering the whole spectrum of health-related services addressing healthy subjects and chronic patients. The reorganization of services around the person or citizen has been expected to bring high impact in the health care domain. There are a series of concerns (eg, contextual factors influencing the impact of care models, the cost savings associated with CH solutions, and the sustainability of the CH ecosystem) that should be better addressed for CH technologies to reach stakeholders more successfully. Overall, there is a need to effectively establish an understanding of the concepts of CH impact. As services based on CH technologies go beyond standard clinical interventions and assessments of medical devices or medical treatments, the need for standardization and for new ways of measurements and assessments emerges when studying CH impact., Objective: This study aimed to introduce the CH impact framework (CHIF) that serves as an approach to assess the impact of CH services., Methods: This study focused on the subset of CH comprising services that directly address patients and citizens on the management of disease or health and wellness. The CHIF was developed through a multistep procedure and various activities. These included, as initial steps, a literature review and workshop focusing on knowledge elicitation around CH concepts. Then followed the development of the initial version of the framework, refining of the framework with the experts as a result of the second workshop, and, finally, composition and deployment of a questionnaire for preliminary feedback from early-stage researchers in the relevant domains., Results: The framework contributes to a better understanding of what is CH impact and analyzes the factors toward achieving it. CHIF elaborates on how to assess impact in CH services. These aspects can contribute to an impact-aware design of CH services. It can also contribute to a comparison of CH services and further knowledge of the domain. The CHIF is based on 4 concepts, including CH system and service outline, CH system end users, CH outcomes, and factors toward achieving CH impact. The framework is visualized as an ontological model., Conclusions: The CHIF is an initial step toward identifying methodologies to objectively measure CH impact while recognizing its multiple dimensions and scales., (©Ioanna Chouvarda, Christos Maramis, Kristina Livitckaia, Vladimir Trajkovik, Serhat Burmaoglu, Hrvoje Belani, Jan Kool, Roman Lewandowski, The ENJECT Working Group 1 Network. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 03.09.2019.)

There is no satisfactory model to explain the mean velocity profile of the whole turbulent layer in canonical wall-bounded flows. In this paper, a mean velocity profile expression is proposed for wall-bounded turbulent flows based on a recently proposed stochastic representation of fluid flows dynamics. This original approach, called modeling under location uncertainty, introduces in a rigorous way a subgrid term generalizing the eddy-viscosity assumption and an eddy-induced advection term resulting from turbulence inhomogeneity. This latter term gives rise to a theoretically well-grounded model for the transitional zone between the viscous sublayer and the turbulent sublayer. An expression of the small-scale velocity component is also provided in the viscous zone. Numerical assessments of the results are provided for turbulent boundary layer flows, pipe flows and channel flows at various Reynolds numbers.

Objective: To describe the case of a patient who developed a serotonin syndrome due to a 3,4-methylenedioxymethamphetamine ingestion with electrical storm and refractory cardiac arrest., Design: Case report., Study Selection: ICU of a university hospital., Patient: A 22-year-old man transferred to the emergency room with hyperthermia, tremors, and mydriasis presented a cardiac arrest due to ventricular fibrillation., Interventions: We implemented extra-corporeal life support combined with vasoactive drugs. Later, he also benefited from renal replacement therapy and mechanical ventilation., Measurements and Main Results: We were able to rapidly regulate our patient's temperature and we weaned all hemodynamic support in the first week of hospitalisation., Conclusion: Extracorporeal life support has several advantages as part of the management of hemodynamic instability induced by serotonin syndrome.

The original version of this Article contained an error in the spelling of the author Laurence Faivre, which was incorrectly given as Laurence Faive. This has now been corrected in both the PDF and HTML versions of the Article.

Background: Colorectal cancer (CRC) is usually diagnosed in the metastatic stage, when chemotherapy and molecularly-targeted therapies, instead of surgery, play the most important therapeutic role. Application of anti-epidermal growth factor receptor (EGFR) therapy requires the analysis of RAS mutation status and only RAS wild-type (wt) patients are qualified for the therapy., Objectives: The objective of this study was to analyze driver mutations in KRAS, NRAS, BRAF, and PIK3CA genes in CRC patients., Material and Methods: We assessed the KRAS, NRAS, BRAF, and PIK3CA genes in 102 inoperable, locally advanced and advanced CRC patients. Real-time polymerase chain reaction (RT-PCR) and high resolution melt PCR (HRM-PCR) techniques with DNA intercalating dye were applied in the study., Results: Forty-six patients demonstrated the presence of examined mutations (45.1%). No significant differences in driver mutation occurrence between men and women, as well as between younger (<65 years) and older (≥65 years) patients were found. The mutations were present significantly more frequently in metastatic than in primary tumors (p = 0.039) due to the high incidence of KRAS gene mutations in metastatic tissue. BRAF and PIK3CA mutations were found only in primary tumors. The incidence of PIK3CA mutations was significantly higher (11.77%) in early than in advanced stages of the disease (1.96%; p = 0.05); NRAS mutations were found only in metastatic cancer (7.85%; p = 0.041). Only a single mutation of the PIK3CA and no mutations of NRAS were found in rectal cancer., Conclusions: Our results have shown low occurrence of driver mutations in Polish CRC patients, involving also mutations in rarely tested genes. The extent of the research panel of additional mutations could contribute to creating a better method of qualifying patients for molecularly targeted therapies and obtaining a better outcome for these therapeutic strategies.

Chromatin remodeling is of crucial importance during brain development. Pathogenic alterations of several chromatin remodeling ATPases have been implicated in neurodevelopmental disorders. We describe an index case with a de novo missense mutation in CHD3, identified during whole genome sequencing of a cohort of children with rare speech disorders. To gain a comprehensive view of features associated with disruption of this gene, we use a genotype-driven approach, collecting and characterizing 35 individuals with de novo CHD3 mutations and overlapping phenotypes. Most mutations cluster within the ATPase/helicase domain of the encoded protein. Modeling their impact on the three-dimensional structure demonstrates disturbance of critical binding and interaction motifs. Experimental assays with six of the identified mutations show that a subset directly affects ATPase activity, and all but one yield alterations in chromatin remodeling. We implicate de novo CHD3 mutations in a syndrome characterized by intellectual disability, macrocephaly, and impaired speech and language.

Surgical resection or liver transplantation offers the best chance of cure for patients with hepatocellular carcinoma (HCC). Unfortunately, most patients are not good candidates for liver resection due to locally advanced disease or compromised liver function. Moreover, liver transplantation waiting lists are long. For those cases not amenable for resection, a variety of local treatment modalities are available, such as image-guided ablative procedures, transarterial chemoembolization, and radioembolization, as well as external beam radiation. HCC presentation can vary considerably in size, number, and location of lesions. The management of inoperable HCC is, therefore, quite complex, and there is a lack of consensus on the best local treatment modality for each type tumor presentation. Here, we present 4 clinical case scenarios representative of commonly seen cases in the clinical setting, with different therapeutic perspectives from institutions with high expertise in the management of HCC., (Copyright © 2018. Published by Elsevier Inc.)

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice. A 68-year-old man with a remote history of alcohol abuse presented with vague abdominal pain. A review of systems suggested the patient had an Eastern Cooperative Oncology Group performance status 1 (restriction of strenuous physical activity). There were no physical examination findings of note. Laboratory studies disclosed Child-Pugh A liver status (no ascites; no encephalopathy; total bilirubin, 1 mg/dL; albumin, 3.5 g/dL; and international normalized rato, 1.2). The alpha-fetoprotein was mildly elevated (19.5 ng/mL). Magnetic resonance imaging with contrast disclosed an infiltrative mass with extensive malignant right and left portal vein thrombosis ( Fig 1A ) with cavernous transformation of the portal vein. The infiltrative mass ( Fig 2A ) was biopsied, revealing hepatocellular carcinoma. No distant metastases were found on a bone scintigraphy or computerized tomography scan. Given these features, this patient was classified as Barcelona Clinic for Liver Cancer stage C. The patient was referred for management of advanced hepatocellular carcinoma.

Purpose: Radiopaque microspheres may provide intraprocedural and postprocedural feedback during transarterial radioembolization (TARE). Furthermore, the potential to use higher resolution x-ray imaging techniques as opposed to nuclear medicine imaging suggests that significant improvements in the accuracy and precision of radiation dosimetry calculations could be realized for this type of therapy. This study investigates the absorbed dose kernel for novel radiopaque microspheres including contributions of both short and long-lived contaminant radionuclides while concurrently quantifying the self-shielding of the glass network., Methods: Monte Carlo simulations using EGSnrc were performed to determine the dose kernels for all monoenergetic electron emissions and all beta spectra for radionuclides reported in a neutron activation study of the microspheres. Simulations were benchmarked against an accepted 90 Y dose point kernel. Self-shielding was quantified for the microspheres by simulating an isotropically emitting, uniformly distributed source, in glass and in water. The ratio of the absorbed doses was scored as a function of distance from a microsphere. The absorbed dose kernel for the microspheres was calculated for (a) two bead formulations following (b) two different durations of neutron activation, at (c) various time points following activation., Results: Self-shielding varies with time postremoval from the reactor. At early time points, it is less pronounced due to the higher energies of the emissions. It is on the order of 0.4-2.8% at a radial distance of 5.43 mm with increased size from 10 to 50 μm in diameter during the time that the microspheres would be administered to a patient. At long time points, self-shielding is more pronounced and can reach values in excess of 20% near the end of the range of the emissions. Absorbed dose kernels for 90 Y, 90m Y, 85m Sr, 85 Sr, 87m Sr, 89 Sr, 70 Ga, 72 Ga, and 31 Si are presented and used to determine an overall kernel for the microspheres based on weighted activities. The shapes of the absorbed dose kernels are dominated at short times postactivation by the contributions of 70 Ga and 72 Ga. Following decay of the short-lived contaminants, the absorbed dose kernel is effectively that of 90 Y. After approximately 1000 h postactivation, the contributions of 85 Sr and 89 Sr become increasingly dominant, though the absorbed dose-rate around the beads drops by roughly four orders of magnitude., Conclusions: The introduction of high atomic number elements for the purpose of increasing radiopacity necessarily leads to the production of radionuclides other than 90 Y in the microspheres. Most of the radionuclides in this study are short-lived and are likely not of any significant concern for this therapeutic agent. The presence of small quantities of longer lived radionuclides will change the shape of the absorbed dose kernel around a microsphere at long time points postadministration when activity levels are significantly reduced., (© 2017 American Association of Physicists in Medicine.)

Bromodomain PHD finger transcription factor (BPTF) is the largest subunit of nucleosome remodeling factor (NURF), a member of the ISWI chromatin-remodeling complex. However, the clinical consequences of disruption of this complex remain largely uncharacterized. BPTF is required for anterior-posterior axis formation of the mouse embryo and was shown to promote posterior neuroectodermal fate by enhancing Smad2-activated wnt8 expression in zebrafish. Here, we report eight loss-of-function and two missense variants (eight de novo and two of unknown origin) in BPTF on 17q24.2. The BPTF variants were found in unrelated individuals aged between 2.1 and 13 years, who manifest variable degrees of developmental delay/intellectual disability (10/10), speech delay (10/10), postnatal microcephaly (7/9), and dysmorphic features (9/10). Using CRISPR-Cas9 genome editing of bptf in zebrafish to induce a loss of gene function, we observed a significant reduction in head size of F0 mutants compared to control larvae. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and phospho-histone H3 (PH3) staining to assess apoptosis and cell proliferation, respectively, showed a significant increase in cell death in F0 mutants compared to controls. Additionally, we observed a substantial increase of the ceratohyal angle of the craniofacial skeleton in bptf F0 mutants, indicating abnormal craniofacial patterning. Taken together, our data demonstrate the pathogenic role of BPTF haploinsufficiency in syndromic neurodevelopmental anomalies and extend the clinical spectrum of human disorders caused by ablation of chromatin remodeling complexes., (Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)