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\"When Harry Colebourn saw a baby bear at a train station, he knew he could care for it. Harry was a veterinarian. But he was also a soldier in training during World War I. Harry named the bear Winnie, short for Winnipeg, his company's home town, and he brought her along to the military camp in England. Winnie followed Harry everywhere and slept under his cot every night. Before long, she became the regiment's much-loved mascot. But who could care for the bear when Harry went to battle? Harry found just the right place for Winnie--the London Zoo. There a boy named Christopher Robin played with Winnie--he could care for this bear too!\"-- Provided by publisher.

I will point out the important role of a thorough planning process in which all stakeholders work together starting in early phases of the design process („phase 0“) and engage in a truly interdisciplinary and iterative process throughout the entire planning phase as well as the building phase (where often ad hoc decisions have to be made in order to adjust to unforeseen circumstances).I will examine the terms \"Consensus Design\" and \"Evidence-Based Design\" and relate them to lived reality by giving a number of examples from own experience. Here I will contrast different approaches in carrying out the planning process and demonstrate how only a truly interdisciplinary and iterative process can result in individualised and optimised therapeutic environments, strengthen identity and reduce stigmatisation.As a support to future projects which workshop participants may be involved in, I will share some of the basic methods and tools which I have seen or used to help build and maintain this type of collaborative conversations throughout project phases.Disclosure of InterestNone Declared

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause cystic fibrosis (CF), and the CFTR-W1282X nonsense mutation causes a severe form of CF. Although Trikafta and other CFTR-modulation therapies benefit most CF patients, targeted therapy for patients with the W1282X mutation is lacking. The CFTR-W1282X protein has residual activity but is expressed at a very low level due to nonsense-mediated messenger RNA (mRNA) decay (NMD). NMD-suppression therapy and read-through therapy are actively being researched for CFTR nonsense mutants. NMD suppression could increase the mutant CFTR mRNA, and readthrough therapies may increase the levels of full-length CFTR protein. However, these approaches have limitations and potential side effects: because the NMD machinery also regulates the expression of many normal mRNAs, broad inhibition of the pathway is not desirable, and read-through drugs are inefficient partly because the mutant mRNA template is subject to NMD. To bypass these issues, we pursued an exon-skipping antisense oligonucleotide (ASO) strategy to achieve gene-specific NMD evasion. A cock-tail of two splice-site–targeting ASOs induced the expression of CFTR mRNA without the premature-termination-codon–containing exon 23 (CFTR-Δex23), which is an in-frame exon. Treatment of human bronchial epithelial cells with this cocktail of ASOs that target the splice sites flanking exon 23 results in efficient skipping of exon 23 and an increase in CFTR-Δex23 protein. The splice-switching ASO cocktail increases the CFTR-mediated chloride current in human bronchial epithelial cells. Our results set the stage for developing an allele-specific therapy for CF caused by the W1282X mutation.

Slipped capital femoral epiphysis (SCFE) is the most common hip disorder in adolescents, occurring in 10.8 per 100,000 children. SCFE usually occurs in those eight to 15 years of age and is one of the most commonly missed diagnoses in children. SCFE is classified as stable or unstable based on the stability of the physis. It is associated with obesity, growth spurts, and (occasionally) endocrine abnormalities such as hypothyroidism, growth hormone supplementation, hypogonadism, and panhypopituitarism. Patients with SCFE usually present with limping and poorly localized pain in the hip, groin, thigh, or knee. Diagnosis is confirmed by bilateral hip radiography, which should include anteroposterior and frog-leg views in patients with stable SCFE, and anteroposterior and cross-table lateral views in unstable SCFE. The goals of treatment are to prevent slip progression and avoid complications such as avascular necrosis, chondrolysis, and femoroacetabular impingement. Stable SCFE is usually treated using in situ screw fixation. Treatment of unstable SCFE also usually involves in situ fixation, but there is controversy about timing of surgery and the value of reduction. Postoperative rehabilitation of patients with SCFE may follow a five-phase protocol.

Background Microphthalmia Transcription Factor (MITF)family translocation renal cell carcinoma (tRCC) is a rare RCC subtype harboring TFE3/TFEB translocations. The prognosis in the metastatic (m) setting is poor. Programmed death ligand-1 expression was reported in 90% of cases, prompting us to analyze the benefit of immune checkpoint inhibitors (ICI) in this population.Patients and methodsThis multicenter retrospective study identified patients with MITF family mtRCC who had received an ICI in any of 12 referral centers in France or the USA. Response rate according to RECIST criteria, progression-free survival (PFS), and overall survival (OS) were analyzed. Genomic alterations associated with response were determined for 8 patients.ResultsOverall, 24 patients with metastatic disease who received an ICI as second or later line of treatment were identified. Nineteen (82.6%) of these patients had received a VEGFR inhibitor as first-line treatment, with a median PFS of 3 months (range, 1–22 months). The median PFS for patients during first ICI treatment was 2.5 months (range, 1–40 months); 4 patients experienced partial response (16,7%) and 3 (12,5%) had stable disease. Of the patients whose genomic alterations were analyzed, two patients with mutations in bromodomain-containing genes (PBRM1 and BRD8) had a clinical benefit. Resistant clones in a patient with exceptional response to ipilimumab showed loss of BRD8 mutations and increased mutational load driven by parallel evolution affecting 17 genes (median mutations per gene, 3), which were enriched mainly for O-glycan processing (29.4%, FDR = 9.7 × 10− 6).Conclusions MITF family tRCC is an aggressive disease with similar responses to ICIs as clear-cell RCC. Mutations in bromodomain-containing genes might be associated with clinical benefit. The unexpected observation about parallel evolution of genes involved in O-glycosylation as a mechanism of resistance to ICI warrants exploration.

DDX3 is a DEAD box RNA helicase with oncogenic properties. RK-33 is developed as a small-molecule inhibitor of DDX3 and showed potent radiosensitizing activity in preclinical tumor models. This study aimed to assess DDX3 as a target in breast cancer and to elucidate how RK-33 exerts its anti-neoplastic effects. High DDX3 expression was present in 35% of breast cancer patient samples and correlated with markers of aggressiveness and shorter survival. With a quantitative proteomics approach, we identified proteins involved in the mitochondrial translation and respiratory electron transport pathways to be significantly downregulated after RK-33 or DDX3 knockdown. DDX3 localized to the mitochondria and DDX3 inhibition with RK-33 reduced mitochondrial translation. As a consequence, oxygen consumption rates and intracellular ATP concentrations decreased and reactive oxygen species (ROS) increased. RK-33 antagonized the increase in oxygen consumption and ATP production observed after exposure to ionizing radiation and reduced DNA repair. Overall, we conclude that DDX3 inhibition with RK-33 causes radiosensitization in breast cancer through inhibition of mitochondrial translation, which results in reduced oxidative phosphorylation capacity and increased ROS levels, culminating in a bioenergetic catastrophe.

Aromatic compounds constitute the second most abundant class of organic substrates and environmental pollutants, a substantial part of which (e.g., phenylalanine or styrene) is metabolized by bacteria via phenylacetate. Surprisingly, the bacterial catabolism of phenylalanine and phenylacetate remained an unsolved problem. Although a phenylacetate metabolic gene cluster had been identified, the underlying biochemistry remained largely unknown. Here we elucidate the catabolic pathway functioning in 16% of all bacteria whose genome has been sequenced, including Escherichia coli and Pseudomonas putida. This strategy is exceptional in several aspects. Intermediates are processed as CoA thioesters, and the aromatic ring of phenylacetyl-CoA becomes activated to a ring 1,2-epoxide by a distinct multicomponent oxygenase. The reactive nonaromatic epoxide is isomerized to a seven-member O-heterocyclic enol ether, an oxepin. This isomerization is followed by hydrolytic ring cleavage and β-oxidation steps, leading to acetyl-CoA and succinyl-CoA. This widespread paradigm differs significantly from the established chemistry of aerobic aromatic catabolism, thus widening our view of how organisms exploit such inert substrates. It provides insight into the natural remediation of man-made environmental contaminants such as styrene. Furthermore, this pathway occurs in various pathogens, where its reactive early intermediates may contribute to virulence.

Norm entrepreneurs have made significant strides in advancing sexual orientation and gender identity (SOGI) resolutions at the UN Human Rights Council. However, these advancements are being fiercely contested. This paper examines the development of SOGI at the Council including how states advocate for and contest SOGI and the extent to which their positions are mutable. Resolution 32/2 of 2016, which created an independent expert, is the central focus of the paper. Participant interviews and content analysis of documents and statements are used to provide an in-depth analysis of how states advocate their positions on SOGI. The paper finds that framing is the primary tool used by states. Both proponents and opponents of SOGI believe their own positions are universal and adhere to prior international law, while their opponents’ positions are relativist and revisionist. The paper further finds that deadlock on SOGI resolutions is imminent until Member States’ domestic legislation changes.

Increasing quantities of atmospheric anthropogenic fixed nitrogen entering the open ocean could account for up to about a third of the ocean's external (nonrecycled) nitrogen supply and up to ∼30% of the annual new marine biological production, ∼0.3 petagram of carbon per year. This input could account for the production of up to ∼1.6 teragrams of nitrous oxide ($\\text{N}_{2}\\text{O}$) per year. Although ∼10% of the ocean's drawdown of atmospheric anthropogenic carbon dioxide may result from this atmospheric nitrogen fertilization, leading to a decrease in radiative forcing, up to about two-thirds of this amount may be offset by the increase in$\\text{N}_{2}\\text{O}$emissions. The effects of increasing atmospheric nitrogen deposition are expected to continue to grow in the future.

The COVID-19 pandemic has had adverse impacts on mental health and substance use worldwide. Systematic reviews suggest eHealth interventions can be effective at addressing these problems. However, strong positive eHealth outcomes are often tied to the intensity of web-based therapist guidance, which has time and cost implications that can make the population scale-up of more effective interventions difficult. A way to offset cost while maintaining the intensity of therapist guidance is to offer eHealth programs to groups rather than more standard one-on-one formats. This systematic review aims to assess experimental evidence for the effectiveness of live health professional-led group eHealth interventions on mental health, substance use, or bereavement among community-dwelling adults. Within the articles selected for our primary aim, we also seek to examine the impact of interventions that encourage physical activity compared with those that do not. Overall, 4 databases (MEDLINE, CINAHL, PsycINFO, and the Cochrane Library) were searched in July 2020. Eligible studies were randomized controlled trials (RCTs) of eHealth interventions led by health professionals and delivered entirely to adult groups by videoconference, teleconference, or webchat. Eligible studies reported mental health, substance use, or bereavement as primary outcomes. The results were examined by outcome, eHealth platform, and intervention length. Postintervention data were used to calculate effect size by study. The findings were summarized using the Synthesis Without Meta-Analysis guidelines. Risk of bias was assessed using the Cochrane Collaboration Tool. Of the 4099 identified studies, 21 (0.51%) RCTs representing 20 interventions met the inclusion criteria. These studies examined mental health outcomes among 2438 participants (sample size range: 47-361 participants per study) across 7 countries. When effect sizes were pooled, live health professional-led group eHealth interventions had a medium effect on reducing anxiety compared with inactive (Cohen d=0.57) or active control (Cohen d=0.48), a medium to small effect on reducing depression compared with inactive (Cohen d=0.61) or active control (Cohen d=0.21), and mixed effects on mental distress and coping. Interventions led by videoconference, and those that provided 8-12 hours of live health professional-led group contact had more robust effects on adult mental health. Risk of bias was high in 91% (19/21) of the studies. Heterogeneity across interventions was significant, resulting in low to very low quality of evidence. No eligible RCT was found that examined substance use, bereavement, or physical activity. Live eHealth group interventions led by health professionals can foster moderate improvements in anxiety and moderate to small improvements in depression among community-based adults, particularly those delivered by videoconference and those providing 8-12 hours of synchronous engagement. PROSPERO CRD42020187551; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=187551. RR2-10.1186/s13643-020-01479-3.