Developmental Dysregulation of Childhood Cancer.

Most childhood cancers possess distinct clinicopathological profiles from those seen in adulthood, reflecting their divergent mechanisms of carcinogenesis. Rather than depending on the decades-long, stepwise accumulation of changes within a mature cell that defines adult carcinomas, many pediatric malignancies emerge rapidly as the consequence of random errors during development. These errors-whether they be genetic, epigenetic, or microenvironmental-characteristically block maturation, resulting in phenotypically primitive neoplasms. Only an event that falls within a narrow set of spatiotemporal parameters will forge a malignant clone; if it occurs too soon then the event might be lethal, or negatively selected against, while if it is too late or in an incorrectly primed precursor cell then the necessary intracellular conditions for transformation will not be met. The precise characterization of these changes, through the study of normal tissues and tumors from patients and model systems, will be essential if we are to develop new strategies to diagnose, treat, and perhaps even prevent childhood cancer.

Unraveling the Photoionization Dynamics of Indole in Aqueous and Ethanol Solutions.

The photoionization dynamics of indole, the ultraviolet-B chromophore of tryptophan, were explored in water and ethanol using ultrafast transient absorption spectroscopy with 292, 268, and 200 nm excitation. By studying the femtosecond-to-nanosecond dynamics of indole in two different solvents, a new photophysical model has been generated that explains many previously unsolved facets of indole's complex solution phase photochemistry. Photoionization is only an active pathway for indole in aqueous solution, leading to a reduction in the fluorescence quantum yield in water-rich environments, which is frequently used in biophysical experiments as a key signature of the protein-folded state. Photoionization of indole in aqueous solution was observed for all three pump wavelengths but via two different mechanisms. For 200 nm excitation, electrons are ballistically ejected directly into the bulk solvent. Conversely, 292 and 268 nm excitation populates an admixture of two 1ππ* states, which form a dynamic equilibrium with a tightly bound indole cation and electron-ion pair. The ion pair dissociates on a nanosecond time scale, generating separated solvated electrons and indole cations. The charged species serve as important precursors to triplet indole production and greatly enhance the overall intersystem crossing rate. Our proposed photophysical model for indole in aqueous solution is the most appropriate for describing photoinduced dynamics of tryptophan in polypeptide sequences; tryptophan in aqueous pH 7 solution is zwitterionic, unlike in peptides, and resultantly has a competitive excited state proton transfer pathway that quenches the tryptophan fluorescence.

Biomarker Predictors of Clinical Efficacy of the Anti-IgE Biologic, Omalizumab, in Severe Asthma in Adults: Results of the SoMOSA Study.

BACKGROUND: The anti-IgE monoclonal, omalizumab, is widely used for severe asthma. This study aimed to identify biomarkers that predict clinical improvement during one year of omalizumab treatment. METHODS: 1-year, open-label, Study of Mechanisms of action of Omalizumab in Severe Asthma (SoMOSA) involving 216 severe (GINA step 4/5) uncontrolled atopic asthmatics (≥2 severe exacerbations in previous year) on high-dose inhaled corticosteroids, long-acting ß-agonists, ± mOCS. It had two phases: 0-16 weeks, to assess early clinical improvement by Global Evaluation of Therapeutic Effectiveness (GETE), and 16-52 weeks, to assess late responses by ≥50% reduction in exacerbations or dose of maintenance oral corticosteroids (mOCS). All participants provided samples (exhaled breath, blood, sputum, urine) before and after 16 weeks of omalizumab treatment. RESULTS: 191 patients completed phase 1; 63% had early improvement. Of 173 who completed phase 2, 69% had reduced exacerbations by ≥50%, while 57% (37/65) on mOCS reduced their dose by ≥50%. The primary outcome 2, 3-dinor-11-ß-PGF2α, GETE and standard clinical biomarkers (blood and sputum eosinophils, exhaled nitric oxide, serum IgE) did not predict either clinical response. Five breathomics (GC-MS) and 5 plasma lipid biomarkers strongly predicted the ≥50% reduction in exacerbations (receiver operating characteristic area under the curve (AUC): 0.780 and 0.922, respectively) and early responses (AUC:0.835 and 0.949, respectively). In independent cohorts, the GC-MS biomarkers differentiated between severe and mild asthma. Conclusions This is the first discovery of omics biomarkers that predict improvement to a biologic for asthma. Their prospective validation and development for clinical use is justified. This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).

Understanding the impact of children's and young people's self-harm on parental well-being: a systematic literature review of qualitative and quantitative findings.

BACKGROUND: Self-harm in children and young people is increasing. Parents are vital in supporting young people; however, parents may experience distress linked to the self-harm. Previous reviews have highlighted the emotional impact and need for information and support, however, have not elucidated the relationships between these themes, nor examined the quantitative data examining parents' well-being. METHODS: We conducted a mixed methods review, with qualitative meta-synthesis focusing on links between themes and quantitative synthesis of parental well-being findings, including pooled means. PsycInfo, Medline, EMBASE, AMED, CINHAL and Web of Science were searched to identify relevant records. References of included studies were also searched. Every abstract was screened by two authors. Data were extracted by one author and checked by another. RESULTS: We identified 39 reports of 32 studies: 16 with qualitative data and 17 with quantitative data (one had both). Qualitative findings showed how parents' emotions were associated to their knowledge and beliefs about self-harm. Parents' emotions often evidenced the need to self-care, but emotions of guilt reduced engagement in self-care. How parents supported their young person was linked to their knowledge, and the management of their own emotions, and influenced if they could engage in self-care. Quantitative findings were mixed, however suggested poor general mental health amongst these parents. CONCLUSIONS: Further good quality quantitative studies are needed, with measurement of psychological mechanisms that may underpin parental distress. Current evidence supports peer-support and interventions that go beyond information provision to address the connected factors of knowledge, emotion, self-care, and parenting behaviours.

Oxygenic Photosynthesis in Far-Red Light: Strategies and Mechanisms.

Oxygenic photosynthesis, the process that converts light energy into chemical energy, is traditionally associated with the absorption of visible light by chlorophyll molecules. However, recent studies have revealed a growing number of organisms capable of using far-red light (700-800 nm) to drive oxygenic photosynthesis. This phenomenon challenges the conventional understanding of the limits of this process. In this review, we briefly introduce the organisms that exhibit far-red photosynthesis and explore the different strategies they employ to harvest far-red light. We discuss the modifications of photosynthetic complexes and their impact on the delivery of excitation energy to photochemical centers and on overall photochemical efficiency. Finally, we examine the solutions employed to drive electron transport and water oxidation using relatively low-energy photons. The findings discussed here not only expand our knowledge of the remarkable adaptation capacities of photosynthetic organisms but also offer insights into the potential for enhancing light capture in crops. Expected final online publication date for the Annual Review of Physical Chemistry, Volume 75 is April 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Drug Shortages in Oncology: ASCO Clinical Guidance for Alternative Treatments.

PURPOSE: To increase awareness, outline strategies, and offer clinical guidance on navigating the complexities of treatment planning amid antineoplastic drug shortages. METHODS: A multidisciplinary panel of oncologists, ethicists, and patient advocates was assembled to provide rapid clinical guidance to help providers navigate appropriate patient care in cases where rationing or alternative therapies must be considered. The groups of content experts developed general principles for resource allocation during shortages and clinical guidance on alternative therapies for specific disease sites. The recommendations are supported by evidence when available. RESULTS: A total of 44 volunteers with content expertise formed the Advisory Group that developed general guidance on the prioritization of antineoplastic agents in limited supply. Disease site-specific clinical guidance was then produced by subgroups on the basis of members' specialties and expertise. The majority of alternative treatment options were developed in consideration of cisplatin and carboplatin shortages. All guidance is posted on ASCO's website. RECOMMENDATIONS: The prioritization of antineoplastic agents in limited supply should be based on specific goals of the therapy where evidence-based medicine has shown survival outcome and life-extending benefit in both early and advanced stages. Recommendations for specific disease sites are presented. While management options vary according to the disease site, alternatives are presented. For settings in which there are no alternatives with comparable efficacy and safety, it is recommended that patients are referred to an area where the necessary drug is available or can be obtained.Additional information is available at asco.org/drug-shortages.

Transforming healthcare documentation: harnessing the potential of AI to generate discharge summaries.

BACKGROUND: Hospital discharge summaries play an essential role in informing GPs of recent admissions to ensure excellent continuity of care and prevent adverse events; however, they are notoriously poorly written, time-consuming, and can result in delayed discharge. AIM: To evaluate the potential of artificial intelligence (AI) to produce high-quality discharge summaries equivalent to the level of a doctor who has completed the UK Foundation Programme. DESIGN & SETTING: Feasibility study using 25 mock patient vignettes. METHOD: Twenty-five mock patient vignettes were written by the authors. Five junior doctors wrote discharge summaries from the case vignettes (five each). The same case vignettes were input into ChatGPT. In total, 50 discharge summaries were generated; 25 by Al and 25 by junior doctors. Quality and suitability were determined through both independent GP evaluators and adherence to a minimum dataset. RESULTS: Of the 25 AI-written discharge summaries 100% were deemed by GPs to be of an acceptable quality compared with 92% of the junior doctor summaries. They both showed a mean compliance of 97% with the minimum dataset. In addition, the ability of GPs to determine if the summary was written by ChatGPT was poor, with only a 60% accuracy of detection. Similarly, when run through an AI-detection tool all were recognised as being very unlikely to be written by AI. CONCLUSION: AI has proven to produce discharge summaries of equivalent quality to a junior doctor who has completed the UK Foundation Programme; however, larger studies with real-world patient data with NHS-approved AI tools will need to be conducted.

Targetable NOTCH1 rearrangements in reninoma.

Reninomas are exceedingly rare renin-secreting kidney tumours that derive from juxtaglomerular cells, specialised smooth muscle cells that reside at the vascular inlet of glomeruli. They are the central component of the juxtaglomerular apparatus which controls systemic blood pressure through the secretion of renin. We assess somatic changes in reninoma and find structural variants that generate canonical activating rearrangements of, NOTCH1 whilst removing its negative regulator, NRARP. Accordingly, in single reninoma nuclei we observe excessive renin and NOTCH1 signalling mRNAs, with a concomitant non-excess of NRARP expression. Re-analysis of previously published reninoma bulk transcriptomes further corroborates our observation of dysregulated Notch pathway signalling in reninoma. Our findings reveal NOTCH1 rearrangements in reninoma, therapeutically targetable through existing NOTCH1 inhibitors, and indicate that unscheduled Notch signalling may be a disease-defining feature of reninoma.

Feasibility of home administration of nebulised interferon ß-1a (SNG001) for COVID-19: a remote study.

BACKGROUND: Effective therapeutics given early to high-risk ambulatory patients with coronavirus disease 2019 (COVID-19) could improve outcomes and reduce overall healthcare burden. However, conducting site visits in non-hospitalised patients, who should remain isolated, is problematic. AIM: To evaluate the feasibility of a purely remote (virtual) study in non-hospitalised patients with COVID-19; and the efficacy and safety of nebulised recombinant interferon-ß1a (SNG001) in this setting. DESIGN & SETTING: Randomised, double-blind, parallel-group study, which was conducted remotely. METHOD: Eligible patients aged ≥65 years (or ≥50 years with risk factors) with COVID-19 and not requiring hospital admission were recruited remotely. They were randomised to SNG001 or placebo once-daily via nebuliser for 14 days. The main outcomes were assessments of feasibility and safety, which were all conducted remotely. RESULTS: Of 114 patients treated, 111 (97.4%) completed 28 days of follow-up. Overall compliance to study medication was high, with ≥13 doses taken by 89.7% and 92.9% of treated patients in the placebo and SNG001 groups, respectively. Over the course of the study, only two patients were hospitalised, both in the placebo group; otherwise there were no notable differences between treatments for the efficacy parameters. No patients withdrew owing to an adverse event, and a similar proportion of patients experienced on-treatment adverse events in the two treatment groups (64.3% and 67.2% with SNG001 and placebo, respectively); most were mild or moderate and not treatment-related. CONCLUSION: This study demonstrated that it is feasible to conduct a purely virtual study in community-based patients with COVID-19, when the study included detailed daily assessments and with medication administered via nebuliser.

Multicolor Photoluminescent Carbon Dots à La Carte for Biomedical Applications.

Dual-emission fluorescence probes that provide high sensitivity are key for biomedical diagnostic applications. Nontoxic carbon dots (CDs) are an emerging alternative to traditional fluorescent probes; however, robust and reproducible synthetic strategies are still needed to access materials with controlled emission profiles and improved fluorescence quantum yields (FQYs). Herein, we report a practical and general synthetic strategy to access dual-emission CDs with FQYs as high as 0.67 and green/blue, yellow/blue, or red/blue excitation-dependent emission profiles using common starting materials such as citric acid, cysteine, and co-dopants to bias the synthetic pathway. Structural and physicochemical analysis using nuclear magnetic resonance, absorbance and fluorescence spectroscopy, Fourier-transform infrared spectroscopy, and X-ray photoelectron spectroscopy in addition to transmission electron and atomic force microscopy (TEM and AFM) is used to elucidate the material's composition which is responsible for the unique observed photoluminescence properties. Moreover, the utility of the probes is demonstrated in the clinical setting by the synthesis of green/blue emitting antibody-CD conjugates which are used for the immunohistochemical staining of human brain tissues of glioblastoma patients, showing detection under two different emission channels.

The Solvent-Dependent Photophysics of Diphenyloctatetraene.

Despite many decades of study, the excited state photophysics of polyenes remains controversial. In diphenylpolyenes with conjugated backbones that contain between 2 and 4 double carbon-carbon bonds, the first two excited electronic states are nearly degenerate but of entirely different character, and their energy splitting is strongly dependent on solvent polarizability. To examine the interplay between these different states, steady-state and time-resolved fluorescence spectroscopies were used to undertake a comprehensive investigation of diphenylocatetraene's (DPO) excited state dynamics in 10 solvents of different polarizabilities and polarities, ranging from weakly interacting alkanes to polar hydrogen-bonding alcohols. These data revealed that photopreparation of the optically bright 1Bu state resulted in fast (<170 ps) internal conversion to the lower-lying optically dark 2Ag state. The 2Ag state is responsible for almost all the observed DPO fluorescence and gains oscillator strength via vibronic intensity stealing with the near-degenerate 1Bu state. The fluorescence lifetime associated with the 2Ag state decayed monoexponentially (4.2-7.2 ns) in contrast to prior biexponential decay kinetics reported for similar polyenes, diphenylbutadiene and diphenylhexatriene. An analysis combining the measured fluorescence lifetimes and fluorescence quantum yields (the latter varying between 7 and 21%) allowed for a 190 cm-1 Herzberg-Teller vibronic coupling constant between the 1Bu and 2Ag states to be determined. The analysis also revealed that the ordering of electronic states remains constant in all the solvents studied, with the 2Ag state minimum always lower in energy than that of the 1Bu state, thus making it a relatively simple polyene compared to structurally similar diphenylhexatriene.

Sense of community and mental health: a cross-sectional analysis from a household survey in Wisconsin.

BACKGROUND: In the USA, one in five adults live with a mental illness, and researchers have estimated that nearly half of the population will have a mental illness over the course of their lifetime. Research has shown significant associations between social relationships and mental health outcomes at the individual and population levels. This study aims to examine whether sense of community, a type of social capital, is associated with mental health. METHODS: In a cross-sectional analysis, multiple logistic regression models were used to examine whether sense of community was associated with symptoms of depression, anxiety and stress reported over the last week. The analysis used data from the Survey of the Health of Wisconsin collected between 2014 and 2016. A total of 1647 observations are included in the analyses. RESULTS: Compared with those who report a positive sense of community, those with a negative sense of community had a significantly higher odds of reporting depression, anxiety and stress symptoms. Socioeconomic status is negatively associated with depression and anxiety, but not with stress. Women were more likely to experience moderate, severe, or extremely severe anxiety and stress, compared with men. CONCLUSION: This study extends current understanding of health benefits of social capital and found that individuals' sense of community is associated with reduced symptoms of depression, anxiety and stress. Further research examining mechanisms to support improved sense of community and other types of social capital could benefit health equity research.

An expandable, modular de novo protein platform for precision redox engineering.

The electron-conducting circuitry of life represents an as-yet untapped resource of exquisite, nanoscale biomolecular engineering. Here, we report the characterization and structure of a de novo diheme "maquette" protein, 4D2, which we subsequently use to create an expanded, modular platform for heme protein design. A well-folded monoheme variant was created by computational redesign, which was then utilized for the experimental validation of continuum electrostatic redox potential calculations. This demonstrates how fundamental biophysical properties can be predicted and fine-tuned. 4D2 was then extended into a tetraheme helical bundle, representing a 7 nm molecular wire. Despite a molecular weight of only 24 kDa, electron cryomicroscopy illustrated a remarkable level of detail, indicating the positioning of the secondary structure and the heme cofactors. This robust, expressible, highly thermostable and readily designable modular platform presents a valuable resource for redox protein design and the future construction of artificial electron-conducting circuitry.

Human contact in internet-based interventions for depression: A pre-registered replication and meta-analysis of randomized trials.

Introduction: Internet-based self-help interventions have shown to be effective in the treatment of depression. Several meta-analyses indicated that human contact has a crucial impact on adherence and outcome. While most research focused on the role of guidance during interventions, a review by Andersson and Johansson (2012) suggested that contact before the intervention too may play an important role. Objective: We investigated the impact of the degree of contact in internet-based interventions (IBIs) for depression on outcome in adults suffering from elevated symptoms of depression. Methods: We conducted a preregistered meta-analysis (www.osf.io/4mzyd) and included trials comparing IBIs for depression against control conditions (treatment as usual [TAU] or waiting list [WL]) in patients with symptoms of unipolar depression searching the databases PsycINFO and Cochrane's Central Register of Controlled Trials (CENTRAL) limited to entries from EMBASE and PubMed. Following Andersson and Johansson (2012), contact before an intervention was defined as having had a diagnostic interview before the IBI, and contact during intervention was defined as having received guidance during the IBI. IBIs were grouped as providing (0) no contact, (1) contact before the IBI, (2) contact during the IBI, or (3) contact both before and during the IBI. The primary outcome was standardized mean difference (SMD) of the IBI and control in depressive symptoms at treatment termination. Secondary outcomes were study dropout and adherence to the IBI. Results: We included 56 eligible trials that randomized 13,335 patients to 75 internet-based intervention conditions and control groups (TAU in 23 trials, WL in 33 trials). In total, 44 trials (78.57 %) were judged to show some concerns or a high risk of bias. Overall heterogeneity was high regarding the primary outcome (I2s < 66 %) and even higher for secondary outcomes (I2s < 91 %). Degree of contact was a robust predictor of outcome and adherence in all pre-registered and exploratory analyses. We found the effect of the IBI to increase with higher degree of contact. However, in pair-wise contrasts, only IBIs offering both contact before and during the intervention (SMD = 0.573, 95 % CI: 0.437, 0.709) significantly outperformed interventions offering no contact (SMD = 0.224, 95 % CI: 0.090, 0.340). Conclusions: The results suggest that contact before and during an intervention increases the effects of IBIs. The combination of contact before and during the intervention seems to a pivotal role regarding adherence as well as treatment outcome for patients suffering from depression.

The Evolution and Evolvability of Photosystem II.

Photosystem II is the water-oxidizing and O2-evolving enzyme of photosynthesis. How and when this remarkable enzyme arose are fundamental questions in the history of life that have remained difficult to answer. Here, recent advances in our understanding of the origin and evolution of photosystem II are reviewed and discussed in detail. The evolution of photosystem II indicates that water oxidation originated early in the history of life, long before the diversification of cyanobacteria and other major groups of prokaryotes, challenging and transforming current paradigms on the evolution of photosynthesis. We show that photosystem II has remained virtually unchanged for billions of years, and yet the nonstop duplication process of the D1 subunit of photosystem II, which controls photochemistry and catalysis, has enabled the enzyme to become adaptable to variable environmental conditions and even to innovate enzymatic functions beyond water oxidation. We suggest that this evolvability can be harnessed to develop novel light-powered enzymes with the capacity to carry out complex multistep oxidative transformations for sustainable biocatalysis.

Trade-offs across values in cesspool management highlight challenges to policy making.

On-site Sewage Disposal Systems (OSDS) are globally common, and in Hawai'i they present a risk of contamination to drinking water sources and nearshore waters. State legislation has commanded that all cesspools are to be banned by 2050, thus requiring tens of thousands of systems to be converted in the coming decades. This project followed a participatory structured decision-making (SDM) approach to collaboratively design cost-effective and equitable solutions for thousands of cesspools in the high elevation areas of north Maui, Hawai'i. Participatory workshops with a diverse group of stakeholders set ten objectives and brainstormed 33 alternatives, for which the technical team then modeled groundwater nutrients, costs, and equity. All alternatives posed trade-offs, though composting toilets performed best across most objectives, albeit with high maintenance burden. Discounting innovative toilets, the multi-objective analysis suggests that the state should invest in cluster sewering of high-density communities, followed by incentivizing septic tank solutions in properties with the highest effluent flow first, then expanding across the area. The total project cost (installation and operation/maintenance) would be $183-258 million, depending upon the sewer-septic combination. An efficiency frontier reveals sub-par combinations, including aerobic treatment units and passive absorption systems, which cost much more and deliver lower mass flux reduction than more cost-effective alternatives. This study contributes a novel case of rural sanitation to the literature in which decision support tools are used to facilitate evidence-based, collaborative decision-making for sanitation planning. The state could use a similar participatory SDM process when approaching other communities to discuss their cesspool upgrade strategies. Broadening the use of decision analytic techniques can have wider ecological, economic, and social benefits for the state and contexts beyond Hawai'i, as SDM provides a transparent and rigorous, evidence-based decision-theoretic framework to explore multiple values and strategies to address difficult resource management problems.

Working alliance and adherence mediate the effect of guidance in a web-based program for participants with mild to moderate depressive symptoms: A secondary mediation analysis.

Guided web-based self-help programs for individuals with depressive symptoms have shown to be more efficacious than unguided programs. However, research has paid little attention to why guided interventions are superior. The present study investigated whether working alliance and adherence to the program mediated the effect of guidance on depressive symptom outcome. The study is a secondary analysis of a randomized factorial trial. In the trial, 302 adults with mild to moderate depressive symptoms (Patient Health Questionnaire-9 score: 5-14) were randomized to either a guided or an unguided group. All participants received access to a web-based self-help program based on problem-solving therapy. Working alliance with the treatment providers was assessed using an adapted version of the Working Alliance Inventory for Guided Internet Interventions two weeks (early-treatment) and eight weeks (post-treatment) after pre-treatment. The primary outcome was depressive symptoms at post-treatment. The total working alliance score was significantly higher for guided participants compared to unguided participants (at early-treatment: t 248.6 = -3.36, p < .001, d = 0.42, at post-treatment: t 194.9 = -4.77, p < .001, d = 0.66). The total working alliance score correlated significantly with the change in depressive symptoms for guided (rs = 0.16, 0.34) and unguided participants (rs = 0.26, 0.23). The WAI-I total score statistically mediated the relationship between guidance and outcome (at early-treatment: B = -0.028, at post-treatment: B = -0.053). Furthermore, the subscale tasks (at post-treatment: B = -0.051), the subscale goals (at early-treatment: B = -0.031 and at post-treatment: B = -0.052), and adherence to the program (B = -0.034) mediated the relationship between guidance and outcome. Finally, in a multiple mediation model both early-treatment working alliance and adherence to the program (B = -0.050) mediated the relationship between guidance and outcome. These findings indicate that guidance increases working alliance to treatment providers as early as two weeks after treatment beginning. The alliance predicts outcome and mediates the relationship between guidance and outcome. Participants' agreement with tasks and goals of a program seems to be more important than the bond with treatment providers. Treatment providers might therefore attune web-based programs to the preferences and expectations of participants. In addition to the working alliance, adherence to the program co-mediates the relationship between guidance and outcome.