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Self-sufficiency, climate change and increasing geopolitical risks have driven energy policies to make renewable energy sources dominant in the power production portfolios. The initial boom in the mid-2000s of global photovoltaic installations demonstrated the feasibility of the ambitious renewable energy targets. However, this rapid scale-up has introduced challenges, including price volatility and system integration issues. This communication calls the attention to these emerging challenges and offers quantitative insights on how rapid adoption of a more diversified photovoltaics deployment strategies can mitigate price volatilities, reduce fossil fuel dependence and steer Europe towards a forward-thinking sustainable energy pathway. The analysis reveals that as innovative bifacial photovoltaic systems are incorporated on a large-scale disruptive scenario, four main patterns emerge: economic value of solar production increases, base-load electricity price decreases, sun-rich countries expand their solar contributions, whereas nations with ample grid interconnections enhance their energy imports from neighbouring countries. It also underscores the importance of maintaining photovoltaics an attractive option for energy investors and traders in the future. Establishing this groundwork is critical since a successful integration of large-scale solar systems contributing to decrease price volatilities in Europe and US will carry significant repercussions for global energy policy formulation., (© 2024. The Author(s).)

The sustainability of social-ecological systems within river deltas globally is in question as rapid development and environmental change trigger "negative" or "positive" tipping points depending on actors' perspectives, e.g. regime shift from abundant sediment deposition to sediment shortage, agricultural sustainability to agricultural collapse or shift from rural to urban land use. Using a systematic review of the literature, we show how cascading effects across anthropogenic, ecological, and geophysical processes have triggered numerous tipping points in the governance, hydrological, and land-use management of the world's river deltas. Crossing tipping points had both positive and negative effects that generally enhanced economic development to the detriment of the environment. Assessment of deltas that featured prominently in the review revealed how outcomes of tipping points can inform the long-term trajectory of deltas towards sustainability or collapse. Management of key drivers at the delta scale can trigger positive tipping points to place social-ecological systems on a pathway towards sustainable development., (© 2024. Crown.)

Objective: Weight loss following vertical sleeve gastrectomy (VSG) in youth can range from 10% to 50%. We examined whether there are differences in demographic or metabolic parameters before VSG in youth who achieve above-average weight loss (AAWL) versus below-average weight loss (BAWL) at 1 year post VSG and if youth with BAWL still achieve metabolic health improvements at 1 year post VSG., Methods: Demographic, anthropometric, and clinical lab data were collected before VSG and at 1, 3, 6, and 12 months after VSG., Results: Forty-three youth with a mean age of 16.9 (SD 1.7) years before VSG were studied; 70% were female, 19% non-Hispanic Black, 58% non-Hispanic White, and 23% mixed/other race. Mean baseline BMI was 51.1 (SD 10.5) kg/m 2 . Average weight loss was 25.8%. The AAWL group lost 18.6 kg/m 2 (35.3%) versus the BAWL group, who lost 8.8 kg/m 2 (17.5%). BMI, age, race, sex, and socioeconomic status at baseline were similar between AAWL and BAWL groups; however, the BAWL group had a higher frequency of pre-VSG dysglycemia, steatotic liver disease, and dyslipidemia. At 1 year post VSG, fewer youth in the BAWL group achieved ideal health parameters, and they had less resolution of comorbidities., Conclusions: The presence of comorbidities before VSG is associated with less weight loss and reduced resolution of metabolic conditions at 1 year post VSG., (© 2024 The Authors. Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society.)

In neurocritical care, the gold standard method is intracranial pressure (ICP) monitoring for the patient's lifesaving. Since it is an invasive method, it is desirable to use an alternative, noninvasive technique. The computerized real-time invasive cerebral blood flow (CBF) autoregulation (AR) monitoring calculates the status of CBF AR, called the pressure reactivity index (PRx). Studies documented that the electrical impedance of the head (Rheoencephalography - REG) can detect the status of CBF AR (REGx) and ICP noninvasively. We aimed to test REG to reflect ICP and CBF AR. For nineteen healthy subjects we recorded bipolar bifrontal and bitemporal REG derivations and arm bioimpedance pulses with a 200 Hz sampling rate. The challenges were a 30-second breath-holding and head-down-tilt (HDT - Trendelenburg) position. Data were stored and processed offline. REG pulse wave morphology and REGx were calculated. The most relevant finding was the significant morphological change of the REG pulse waveform (2 nd peak increase) during the HDT position. Breath-holding caused REG amplitude increase, but it was not significant. REGx in male and female group averages have similar trends during HDT by indicating the active status of CBF AR. The morphological change of REG pulse wave during HDT position was identical to ICP waveform change during increased ICP, reflecting decreased intracranial compliance. A correlation study between ICP and REG was initiated in neurocritical care patients. The noninvasive REG monitoring would also be useful in space research as well as in military medicine during the transport of wounded service members as well as for fighter pilots to indicate the loss of CBF and consciousness., Competing Interests: Conflict of interest The authors state there is no conflict of interest., (© 2024 Sandor Szabo et al., published by Sciendo.)

Plexiform neurofibromas (PNFs) are nerve tumors caused by loss of NF1 and dysregulation of RAS-MAPK signaling in Schwann cells. Most PNFs shrink in response to MEK inhibition, but targets with increased and durable effects are needed. We identified the anaphylatoxin C5a as increased in PNFs and expressed largely by PNF m acrophages. We defined pharmacokinetic and immunomodulatory properties of a C5aR1/2 antagonist and tested if peptide antagonists augment the effects of MEK inhibition. MEK inhibition recruited C5AR1 to the macrophage surface; short-term inhibition of C5aR elevated macrophage apoptosis and Schwann cell death, without affecting MEK-induced tumor shrinkage. PNF macrophages lacking C5aR1 increased the engulfment of dying Schwann cells, allowing their visualization. Halting combination therapy resulted in altered T-cell distribution, elevated Iba1+ and CD169+ immunoreactivity, and profoundly altered cytokine expression, but not sustained trumor shrinkage. Thus, C5aRA inhibition independently induces macrophage cell death and causes sustained and durable effects on the PNF microenvironment., (© 2024 Perrino et al.)

Stress is the nonspecific response of the body to any demand made upon it, as defined by Hans Selye more than 80 years ago, based on his animal experiments at McGill University in Montreal, Canada. By emphasizing 'nonspecificity' he tried to underline that stress response is elicited my several factors, like nowadays in COVID-19, e.g., fear of infection, social isolation, death in family, loss of employment, etc. Thus, COVID-19 has been the largest new human stressor in the twenty-first century. Selye's studies in rats also revealed 3 stages of stress response: the short initial "alarm reaction" is followed by a longer "stage of resistance", associated with increased levels of corticosterone that is often terminated by a "stage of exhaustion", referring to an exhausted adrenal cortex when the secretion of glucocorticoids drops. Fast forward, that is exactly what has been documented in severe cases of infections caused by the SARS-CoV-2 virus: in hospitalized COVID-19 patients initially the blood levels of cortisol not only have been elevated, but only those with high concentration of this natural anti-inflammatory corticosteroid survived vs. those who had low levels of cortisol, suggesting diminished adrenocortical functions. Furthermore, patients with very severe cases of COVID-19 who ended up in intensive care units had significantly low cortisol blood levels, compared to patients with equal severity of diseases due to other causes. Thus, these 'natural phenomena' in clinical medicine, unfortunately confirmed Selye's studies in experimental animals several decades ago. Still, the good news is that astute clinicians empirically recognized this and started to give potent synthetic glucocorticoids such as dexamethasone to severe COVD-19 patients and this beneficial effect of exogenous corticoids has been extensively confirmed in the scientific literature., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Influenza virus-induced respiratory pneumonia remains a major public health concern. Obesity, metabolic diseases, and female sex are viewed as independent risk factors for worsened influenza virus-induced lung disease severity. However, lack of experimental models of severe obesity in female mice limits discovery-based studies. Here, via utility of thermoneutral housing (30 °C) and high-fat diet (HFD) feeding, we induced severe obesity and metabolic disease in female C57BL/6 mice and compared their responses to severely obese male C57BL/6 counterparts during influenza virus infection. We show that lean male and female mice have similar lung edema, inflammation, and immune cell infiltration during influenza virus infection. At standard housing conditions, HFD-fed male, but not female, mice exhibit severe obesity, metabolic disease, and exacerbated influenza disease severity. However, combining thermoneutral housing and HFD feeding in female mice induces severe obesity and metabolic disease, which is sufficient to amplify influenza virus-driven disease severity to a level comparable to severely obese male counterparts. Lastly, increased total body weights of male and female mice at time of infection correlated with worsened influenza virus-driven disease severity metrics. Together, our findings confirm the impact of obesity and metabolic disease as key risk factors to influenza disease severity and present a novel mouse experimental model suitable for future mechanistic interrogation of sex, obesity, and metabolic disease traits in influenza virus-driven disease severity., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: This study evaluates the precision of a commercially available spine planning software in automatic spine labelling and screw-trajectory proposal., Methods: The software uses automatic segmentation and registration of the vertebra to generate screw proposals. 877 trajectories were compared. Four neurosurgeons assessed suggested trajectories, performed corrections, and manually planned pedicle screws. Additionally, automatic identification/labelling was evaluated., Results: Automatic labelling was correct in 89% of the cases. 92.9% of automatically planned trajectories were in accordance with G&R grade A + B. Automatic mode reduced the time spent planning screw trajectories by 7 s per screw to 20 s per vertebra. Manual mode yielded differences in screw-length between surgeons (largest distribution peak: 5 mm), automatic in contrast at 0 mm. The size of suggested pedicle screws was significantly smaller (largest peaks in difference between 0.5 and 3 mm) than the surgeon's choice., Conclusion: Automatic identification of vertebrae works in most cases and suggested pedicle screw trajectories are acceptable. So far, it does not substitute for an experienced surgeon's assessment., (© 2023 The Authors. The International Journal of Medical Robotics and Computer Assisted Surgery published by John Wiley & Sons Ltd.)

BCOR alterations are described in ultra-rare infantile soft tissue sarcomas including primitive myxoid mesenchymal tumor of infancy and undifferentiated round cell sarcoma (URCS). Previous reports often describe dismal outcomes. Thus, we undertook a retrospective, multi-institutional study of infants with BCOR -rearranged soft tissue sarcomas. Nine patients aged 6 weeks to 15 months were identified. One tumor carried a BCOR :: CCNB3 fusion, whereas 7 tumors harbored internal tandem duplication of BCOR , including 4 cases classified as primitive myxoid mesenchymal tumor of infancy, 1 case as URCS, and 2 cases characterized by a "hybrid morphology" in our evaluation. Four patients underwent upfront surgery with residual disease that progressed locally after a median of 2.5 months. Locoregional recurrences were observed in hybrid patients, and the URCS case recurred with brain metastases. Complete radiographic responses after chemotherapy were achieved in patients treated with vincristine/doxorubicin/cyclophosphamide alternating with ifosfamide/etoposide, vincristine/doxorubicin/cyclophosphamide alternating with cyclophosphamide/etoposide (regimen I), and ifosfamide/carboplatin/etoposide. Seven patients received radiotherapy. With a median of 23.5 months off therapy, 8 patients are with no evidence of disease. In our study, observation was inadequate for the management of untreated postsurgical residual disease. Tumors demonstrated chemosensitivity with anthracycline-based regimens and ifosfamide/carboplatin/etoposide. Radiotherapy was required to achieve durable response in most patients., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Asparaginase is a key component of chemotherapy protocols for the treatment of lymphoblastic malignancies among children. Adequate asparagine depletion is an important factor to achieve optimal therapeutic outcomes., Methods: Over a 3.5 year period, 106 patients were monitored for asparaginase activity (329 samples) in a single center of the Hungarian Pediatric Oncology-Hematology Group. In Hungary, three asparaginase products are available: native E. coli ASNase (Kidrolase), a pegylated form of this enzyme (Pegaspargase) and another native product from Erwinia chrysanthemi (Erwinase). A retrospective data analysis was performed., Results: In 81% (268/329) of our patients, AEA levels were in the optimal therapeutic range of over 100 IU/L. Of 106 patients, 13 (12%) were diagnosed with 'silent inactivation'., Conclusions: Monitoring of AEA can help to identify patients with 'silent inactivation' and their asparaginase therapy can thus be optimized.

Background: There are no consensus guidelines regarding the use of percutaneous needle biopsy for the diagnosis of soft tissue and bone tumors. The aim of this study was to understand the efficacy of image-guided percutaneous biopsy for pediatric patients with soft tissue and bony masses, the role of intraoperative image guidance, and diagnostic accuracy., Patients and Methods: A retrospective institutional chart review was performed on patients who underwent percutaneous biopsy of soft tissue or bone tumors between 2007 and 2017. Data collected included preoperative imaging, type of biopsy, demographics, insurance status, number of samples taken, and pathologic results., Results: One hundred forty-one children and young adults underwent 169 biopsies. Female patients received 48.2% of biopsies. The mean age was 14.3 ± 7.0 years. Core needle biopsies made up 89.4% of procedures, while 10.6% were fine needle aspirate. The mean number of samples per patient was 3.6 ± 2.5. All patients had imaging guidance, with computed tomography used in 44.7% of patients, 9.9% using fluoroscopy, 7.1% using ultrasound for guidance, and 53 (37.6%) patients had more than one modality. Diagnostic specimens were obtained in 97.9% of biopsies. The most common overall pathology was osteoid osteoma. The most common malignant tumors were osteosarcoma and Ewing's sarcoma., Conclusion: Image-guided percutaneous biopsy is a safe and effective method of obtaining accurate tissue samples in children and young adults with soft tissue or bone masses., Level of Evidence: Level 4-Study of diagnostic test., (© 2023. Society of Surgical Oncology.)

Clinically significant endemic mycoses (fungal infections) in the United States (U.S.) include Blastomyces dermatitidis, Histoplasma capsulatum, and Coccidioides immitis/posadasii. While the majority of infections go clinically unnoticed, symptomatic disease can occur in immunocompromised or hospitalized patients, and occasionally in immune-competent individuals. Clinical manifestations vary widely and their diagnosis may require fungal culture, making the rapid diagnosis a challenge. Imaging can be helpful in making a clinical diagnosis prior to laboratory confirmation, as well as assist in characterizing disease extent and severity. In this review, we discuss the three major endemic fungal infections that occur in the U.S., including mycology, epidemiology, clinical presentations, and typical imaging features with an emphasis on the pediatric population., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Recent developments in health technology assessment (HTA), including the promotion of a new and internationally accepted definition of HTA, have highlighted the need to go beyond clinical and cost-effectiveness to fully understand the potential value of health technologies. Multidisciplinary efforts to generate patient-focused evidence relevant to HTA, using both quantitative and qualitative approaches, are needed. Although it has been more than 20 years since opportunities for qualitative methods to inform HTA were first discussed, their use remains infrequent. The goal of this article is to resurrect the debate about the value of qualitative research in HTA. Drawing on examples from published literature, we propose five key areas where qualitative methods can contribute to HTA, complementary to studies of clinical and cost-effectiveness: (i) assessing acceptability and subjective value; (ii) understanding perspectives and providing context; (iii) reaching the groups other methods cannot reach; (iv) laying the groundwork for subsequent quantitative exercises; and (v) contributing to economic model development.

Activating non-inherited mutations in the guanine nucleotide-binding protein G(q) subunit alpha (GNAQ) gene family have been identified in childhood vascular tumors. Patients experience extensive disfigurement, chronic pain and severe complications including a potentially lethal coagulopathy termed Kasabach-Merritt phenomenon. Animal models for this class of vascular tumors do not exist. This has severely hindered the discovery of the molecular consequences of GNAQ mutations in the vasculature and, in turn, the preclinical development of effective targeted therapies. Here we report a mouse model expressing hyperactive mutant GNAQ in endothelial cells. Mutant mice develop vascular and coagulopathy phenotypes similar to those seen in patients. Mechanistically, by transcriptomic analysis we demonstrate increased mitogen activated protein kinase signaling in the mutant endothelial cells. Targeting of this pathway with Trametinib suppresses the tumor growth by reducing vascular cell proliferation and permeability. Trametinib also prevents the development of coagulopathy and improves mouse survival., (© 2023. The Author(s).)

The previous acute respiratory diseases caused by viruses originating from China or the middle east (e.g., SARS, MERS) remained fast developing short diseases without major sequalae or any long-lasting complications. The new COVID-19, on the other hand, not only that it rapidly spread over the world, but some patients never fully recovered or even if they did, a few weeks later started to complain not only of shortness of breath, if any, but general weakness, muscle pains and 'brain fog', i.e., fuzzy memories. Thus, these signs and symptoms were eventually labelled 'long COVID', for which the most widely used definition is 'new signs and symptoms occurring 4-8 weeks after recovering from acute stage of COVID-19'. The other most frequent manifestations associated with long COVID include headache, loss of memory, smell and of hair, nausea, and vomiting. Thus, long COVID is not a simple disease, but complex disorder of several organ systems malfunctioning; hence, it is probably more appropriate to call this a syndrome. The pathogenesis of long COVID syndrome is poorly understood, but initial and persistent vascular endothelial injury that often triggers the formation of microthrombi that if dislodged as emboli, damage several organs, especially in the brain, heart and kidney, by creating microinfarcts. The other major contributory mechanistic factor is the persistent cytokine storm that may last longer in long COVID patients than in others, probably triggered by aggregates of SARS-Co-2 discovered recently in the adrenal cortex, kidney and brain. The prevalence of long COVID is relatively high, e.g., initially varied 3-30%, and recent data indicate that 2.5% of UK population suffers from this syndrome, while in the US 14.7% of acute COVID-19 patients continued to have symptoms longer than 2 months. Thus, the long COVID syndrome deserves to be further investigated, both from clinical and basic research perspectives., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Neurofibromatosis type 1 (NF1) patients are predisposed to develop plexiform neurofibromas (PNFs). Three endoplasmic reticulum (ER) stress response pathways restore cellular homeostasis. The unfolded protein response (UPR) sensors contribute to tumor initiation in many cancers. We found that all three UPR pathways were activated in mouse and human PNFs, with protein kinase RNA [PKR]-like ER kinase (PERK) the most highly expressed. We tested if neurofibroma cells adapt to ER stress, leading to their growth. Pharmacological or genetic inhibition of PERK reduced mouse neurofibroma-sphere number, and genetic inhibition in PERK in Schwann cell precursors (SCPs) decreased tumor-like lesion numbers in a cell transplantation model. Further, in a PNF mouse model, deletion of PERK in Schwann cells (SCs) and SCPs reduced tumor size, number, and increased survival. Mechanistically, loss of Nf1 activated PERK-eIF2α-ATF4 signaling and increased ATF4 downstream target gene p21 translocation from nucleus to cytoplasm. This nucleus-cytoplasm translocation was mediated by exportin-1. Runx transcriptionally activated ribosome gene expression and increased protein synthesis to allow SCs to adapt to ER stress and tumor formation. We propose that targeting proteostasis might provide cytotoxic and/or potentially durable novel therapy for PNFs., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Introduction: Inflammation is a common unifying factor in experimental models of non-alcoholic fatty liver disease (NAFLD) progression. Recent evidence suggests that housing temperature-driven alterations in hepatic inflammation correlate with exacerbated hepatic steatosis, development of hepatic fibrosis, and hepatocellular damage in a model of high fat diet-driven NAFLD. However, the congruency of these findings across other, frequently employed, experimental mouse models of NAFLD has not been studied., Methods: Here, we examine the impact of housing temperature on steatosis, hepatocellular damage, hepatic inflammation, and fibrosis in NASH diet, methionine and choline deficient diet, and western diet + carbon tetrachloride experimental models of NAFLD in C57BL/6 mice., Results: We show that differences relevant to NAFLD pathology uncovered by thermoneutral housing include: (i) augmented NASH diet-driven hepatic immune cell accrual, exacerbated serum alanine transaminase levels and increased liver tissue damage as determined by NAFLD activity score; (ii) augmented methionine choline deficient diet-driven hepatic immune cell accrual and increased liver tissue damage as indicated by amplified hepatocellular ballooning, lobular inflammation, fibrosis and overall NAFLD activity score; and (iii) dampened western diet + carbon tetrachloride driven hepatic immune cell accrual and serum alanine aminotransferase levels but similar NAFLD activity score., Discussion: Collectively, our findings demonstrate that thermoneutral housing has broad but divergent effects on hepatic immune cell inflammation and hepatocellular damage across existing experimental NAFLD models in mice. These insights may serve as a foundation for future mechanistic interrogations focused on immune cell function in shaping NAFLD progression., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Oates, Sawada, Giles, Alarcon, Damen, Szabo, Stankiewicz, Moreno-Fernandez and Divanovic.)

Results from multiple electrode aggregometry (MEA) may vary according to pre-analytic factors. This study aimed to analyze the association of time from blood draw to MEA in patients undergoing percutaneous coronary intervention (PCI). In this observational single-center cohort study, platelet aggregation (aggregation units, U) was quantified by MEA (Multiplate Analyzer) after stimulation with adenosine diphosphate (ADP; final concentration [Fc] 6.4 μM), thrombin receptor activating peptide (TRAP; Fc 32 μM), or arachidonic acid (AA; Fc 0.5 mM) in patients treated with ASA and clopidogrel following PCI. High on-clopidogrel platelet reactivity (HPR) was defined as ADP-induced platelet aggregation ≥ 46 U. The manufacturer recommends performing the analysis within 30-180 min after blood draw. Patients were grouped according to the time from blood draw to MEA: 30-180 min, < 30 min, or > 180 min. Platelet function of 273 patients with coronary artery disease undergoing PCI with dual antiplatelet therapy was analyzed. The median age was 72 years (interquartile range, IQR 62-79) and 179 (66%) were male. Median ADP-, TRAP-, and AA-induced aggregation was 25 (IQR 18-36) U, 79 (IQR 63-96) U, and 12 (IQR 7-18) U, respectively. For those analyzed within 30-180 min from blood draw, no significant correlation of time from blood draw to MEA was observed 1) ADP (r = - 0.04, p = 0.51); 2) TRAP (r = - 0.06, p = 0.32); 3) AA (r = - 0.03, p = 0.67). In patients undergoing percutaneous coronary intervention and treated with dual antiplatelet therapy, the time from blood draw to multiple electrode aggregometry does not correlate with ADP- induced aggregation when the measurement occurred within the recommended time interval of 30-180 min after blood draw., (© 2022. The Author(s).)

Large publicly funded programmes of research continue to receive increased investment as interventions aiming to produce impact for the world's poorest and most marginalized populations. At this intersection of research and development, research is expected to contribute to complex processes of societal change. Embracing a co-produced view of impact as emerging along uncertain causal pathways often without predefined outcomes calls for innovation in the use of complexity-aware approaches to evaluation. The papers in this special issue present rich experiences of authors working across sectors and geographies, employing methodological innovation and navigating power as they reconcile tensions. They illustrate the challenges with (i) evaluating performance to meet accountability demands while fostering learning for adaptation; (ii) evaluating prospective theories of change while capturing emergent change; (iii) evaluating internal relational dimensions while measuring external development outcomes; (iv) evaluating across scales: from measuring local level end impact to understanding contributions to systems level change. Taken as a whole, the issue illustrates how the research for development evaluation field is maturing through the experiences of a growing and diverse group of researchers and evaluators as they shift from using narrow accountability instruments to appreciating emergent causal pathways within research for development., (© The Author(s) 2023.)

While evaluation of research-to-policy projects is a fundamental aspect of measuring the impact of new knowledge, limited studies have examined evaluation methods in such projects, as well as how the evaluation can generate learning to facilitate the progress towards the Sustainable Development Goals (SDGs). This study conducted a systematic literature review and found that the most commonly used methods for SDG contribution evaluation were Analytical Hierarchy Process (40.4%), Fuzzy TOPSIS (13.2%) and ELECTRE and SPADE Methodology (3.5% each). Ranking analysis was undertaken to determine priorities among the six "Big Wins" as defined for the UKRI-GCRF Trade Hub Project, as a case, where the ranking was exercised by the project partners across the globe. Results revealed that "nature and social factors" was better considered in international trade agreements as the priority (36.4%) among others. Moreover, among the four "mechanisms" of the project, "knowledge, networks, and connectivity" was ranked as the top priority (56.9%), followed by "capacity building" (28.5%), "metrics, tools and models" (7.2%), and "improving the knowledge base" (4.6%). Mapping and evaluation revealed that the Big Wins of the Trade Hub contributed to ten out of the 17 SDGs. The most fulfilled goals were SDG 12 (Sustainable Consumption and Production), SDG 15 (Life on Land), and SDG 2 (Zero Hunger) in descending order. Furthermore, interaction analysis of the core SDGs revealed both synergy and tradeoff between different outputs. The research articles reviewed for this paper showed no gold standard framework for assessing international development projects against the SDGs. Further research should develop a tool to capture holistic and synergistic contributions of the target outcomes of projects to sustainable development., (© The Author(s) 2023.)

Background: Radioiodine therapy for Graves disease can be achieved with dosing based on estimated thyroid gland mass. Thyroid mass can be estimated using linear ultrasound measurements, and conversion factors for volume and density. The choice of conversion factors could impact estimated thyroid mass and thus administered radioiodine dose., Objective: The objective of this study was to define the relationship between thyroid mass estimated by ultrasound and measured thyroid mass following thyroidectomy., Materials and Methods: This was a retrospective, exempt study that included patients < 18 years of age with < 6 months between thyroid ultrasound and thyroidectomy January 2010-June 2020. Thyroid dimensions by ultrasound, thyroid mass at thyroidectomy and histopathological diagnosis were collected. Published conversion factors were used to estimate thyroid volume with conversion to mass using a density of 1.05 g/cm 3 . Pearson correlations and Bland-Altman difference analyses were used to define the relationship between estimated mass and specimen weight. Linear regression was used to calculate an optimal conversion factor for estimating thyroid mass., Results: We included 86 patients, 67 female (78%), with a mean age of 14.5 ± 3.15 years. Mass estimated using all tested conversion factors had similar strong, positive correlation with specimen weight (r = 0.95). The mean difference between thyroid mass estimated by ultrasound and measured mass ranged from - 0.34 g (conversion factor = 0.523) to 1.69 g (conversion factor = 0.554). The optimal simplified factor for estimation of thyroid mass for the study sample was 0.537., Conclusion: All published conversion factors for estimating thyroid mass based on linear ultrasound measurements produce good estimates of thyroid mass. Errors in estimated mass are less than 2 g on average., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Prevalence is reflective of disease incidence and survival, and defined as the number of patients living with active disease. In diseases such as diffuse large B-cell lymphoma (DLBCL) with treatments with curative potential, a proportion of patients are cured, leading to a need for accurate, contemporary estimates of DLBCL prevalence to gauge the impact of the rapidly emerging treatment landscape., Methods: Data from Surveillance, Epidemiology, and End Results (SEER) from 2000-2018 were utilized to develop an epidemiological model of incidence, survival, and cure, to estimate the current prevalent DLBCL population requiring active management in the United States (US). A variety of estimates were explored regarding cure rate and timing, based on a companion analysis of MarketScan data for treatment patterns and survival in incident DLBCL patients, and conditional survival analysis of SEER data., Results: Across scenarios, with estimated cure ranging from 52.8% and 68.9%, and timing of cure ranging from 1 and 20 years post diagnosis, the estimated prevalence ranged from 63,883 to 142,889. With an assumption of no cure, estimated prevalence was 179,475., Discussion: Prevalence estimates of DLBCL varied almost 3-fold, depending on specific cure adjustments made. Further understanding of DLBCL prevalence, for newly diagnosed and relapsed and/or refractory disease, is important to characterize the impact of emerging treatment options and related health care burden., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: 177 Lu-DOTATATE, a radionuclide therapy that binds somatostatin type-2A receptors (SST2A), has demonstrated efficacy in neuroendocrine tumors and evidence of central nervous system (CNS) penetration, supporting potential expansion within pediatric neuro-oncology. Understanding the prevalence of SST2A expression across pediatric CNS tumors is essential to identify patients who may benefit from somatostatin receptor-targeted therapy and to further elucidate the oncogenic role of SST2A., Methods: SST2A immunohistochemistry (IHC) was performed on tumor specimens and interpreted by an experienced pathologist (blinded), utilizing semi-quantitative scoring of membranous expression within viable tumor. Immunoreactive cell percentage was visually scored as 0 (none), 1 (<10%), 2 (10-50%), 3 (51-80%), or 4 (>80%). Staining intensity was scored as 0 (none), 1 (weak), 2 (moderate), or 3 (strong). Combined scores for each specimen were calculated by multiplying percent immunoreactivity and staining intensity values (Range: 0-12)., Results: A total of 120 tumor samples from 114 patients were analyzed. Significant differences in SST2A IHC scores were observed across histopathologic diagnoses, with consistently high scores in medulloblastoma (mean ± SD: 7.5 ± 3.6 [n=38]) and meningioma (5.7 ± 3.4 [n=15]), compared to minimal or absent expression in ATRT (0.3 ± 0.6 [n=3]), ETMR (1.0 ± 0 [n=3]), ependymoma (grades I-III; 0.2 ± 0.7 [n=27]), and high-grade glioma (grades III-IV; 0.4 ± 0.7 [n=23]). Pineoblastoma (3.8 ± 1.5 [n=4]) and other embryonal tumors (2.0 ± 4.0 [n=7]) exhibited intermediate, variable expression. Among medulloblastomas, SST2A IHC scores were higher in non-SHH (8.5 ± 3.1) than SHH (5.0 ± 3.3) molecular subgroups (p=0.033). In a subset of paired primary and recurrent specimens from four patients, SST2A IHC scores remained largely unchanged., Discussion: High membranous SST2A expression was demonstrated in medulloblastoma, meningioma, and some rarer embryonal tumors with potential diagnostic, biologic, and therapeutic implications. Somatostatin receptor-targeted therapy such as 177 Lu-DOTATATE deserves further investigation in these highly SST2A-expressing pediatric CNS tumors., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lazow, Fuller, Trout, Stanek, Reuss, Turpin, Szabo and Salloum.)

Malignant peripheral nerve sheath tumor (MPNST), a highly aggressive Schwann cell (SC)-derived soft tissue sarcoma, arises from benign neurofibroma (NF); however, the identity, heterogeneity and origins of tumor populations remain elusive. Nestin + cells have been implicated as tumor stem cells in MPNST; unexpectedly, single-cell profiling of human NF and MPNST and their animal models reveal a broad range of nestin-expressing SC lineage cells and dynamic acquisition of discrete cancer states during malignant transformation. We uncover a nestin-negative mesenchymal neural crest-like subpopulation as a previously unknown malignant stem-like state common to murine and human MPNSTs, which correlates with clinical severity. Integrative multiomics profiling further identifies unique regulatory networks and druggable targets against the malignant subpopulations in MPNST. Targeting key epithelial-mesenchymal transition and stemness regulators including ZEB1 and ALDH1A1 impedes MPNST growth. Together, our studies reveal the underlying principles of tumor cell-state evolution and their regulatory circuitries during NF-to-MPNST transformation, highlighting a hitherto unrecognized mesenchymal stem-like subpopulation in MPNST disease progression.

Purpose: The primary objective of the REMEMBR Y90 study is to evaluate the efficacy of Yttrium-90 (Y90) radioembolization in patients with breast cancer metastases to the liver as a 2nd or 3rd line treatment option with systemic therapy by assessing liver-specific and overall progression-free survival. Secondary objectives include quality of life, overall survival benefit, and toxicity in relation to patients' tumor biology., Materials and Methods: This trial is a multi-center, prospective, Phase 2, open-label, IRB-approved, randomized control trial in the final phases of activation. Eligible patients include those over 18 years of age with metastatic breast cancer to the liver with liver-only or liver-dominant disease, and history of tumor progression on 1-2 lines of chemotherapy. 60 patients will be randomized to radioembolization with chemotherapy versus chemotherapy alone. Permissible regimens include capecitabine, eribulin, vinorelbine, and gemcitabine within 2 weeks of enrollment for every patient. Patients receiving radioembolization will receive lobar or segmental treatment within 1-6 weeks of enrollment depending on their lesion. After final radioembolization, patients will receive clinical and imaging follow-up every 12-16 weeks for two years, including contrast-enhanced computed tomography or magnetic resonance imaging of the abdomen and whole-body positron emission tomography/computed tomography., Discussion: This study seeks to elucidate the clinical benefit and toxicity of Y90 in patients with metastatic breast cancer to the liver who are receiving minimal chemotherapy. Given previous data, it is anticipated that the use of Y90 and chemotherapy earlier in the metastatic disease course would improve survival outcomes and reduce toxicity., Level of Evidence: Level 1b, Randomized Controlled Trial., Trial Registration Number: NCT05315687 on clinicaltrials.gov., (© 2022. Springer Science+Business Media, LLC, part of Springer Nature and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE).)

In this commentary, we make a case that the mechanism of COVID pathogenesis is related to virus-induced endothelial injury resulting in platelet activation and the formation of microthrombi both systemically and in cardiac and pulmnonary circulation which result in major causes of COVID morbidity and mortality. Aspirin by virtue of its irreversible inhibition of platelet COX-1, should reverse these platelet-induced pathogenic changes associated with COVID infection for the 6-9 day lifetime of the platelet. We also cite recent findings of a retrospective analysis that supports the use of low-dose (81 mg) aspirin to treat the symptoms associated with the early stages of COVID infection., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Transplant-associated thrombotic microangiopathy (TA-TMA) and atypical hemolytic uremic syndrome (aHUS) are complement-mediated TMAs. The central nervous system (CNS) is the most common extrarenal organ affected by aHUS, and, despite mechanistic overlap between aHUS and TA-TMA, CNS involvement is rarely reported in TA-TMA, suggesting that CNS involvement in TA-TMA may be underdiagnosed and that these patients may benefit from complement blockers. In addition, there are no widely used histologic or radiologic criteria for the diagnosis of TMA in the brain. Thirteen recipients of pediatric hematopoietic cell transplants (HCTs) who had TA-TMA and who underwent autopsy were studied. Seven of 13 brains had vascular injury, and 2 had severe vascular injury. Neurologic symptoms correlated with severe vascular injury. Classic TMA histology was present and most often observed in the cerebellum, brainstem, and cerebral white matter. Abnormalities in similar anatomic regions were seen on imaging. Brain imaging findings related to TMA included hemorrhages, siderosis, and posterior reversible encephalopathy syndrome. We then studied 100 consecutive HCT recipients to identify differences in neurologic complications between patients with and those without TA-TMA. Patients with TA-TMA were significantly more likely to have a clinical concern for seizure, have an electroencephalogram performed, and develop altered mental status. In summary, our study confirms that TA-TMA involves the brains of recipients of HCT and is associated with an increased incidence of neurologic symptoms. Based on these findings, we propose that patients with low- or moderate-risk TA-TMA who develop neurologic complications should be considered for TA-TMA-directed therapy., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Objective: To examine the association between remittances and food security in Bangladesh, controlling for other key factors., Design: The secondary data analysis was performed on the most recent (2016) nationally representative Household Income and Expenditure Survey. We used logistic regression models to measure the association between food security of the household and remittances received. The household food security was measured based on expenditure on food items and the energy intake of the household members. The key explanatory variables included the receipt of remittances by the household and household-level socio-economic characteristics., Setting: Bangladesh., Participants: Totally, 45 977 households across seven divisions of Bangladesh., Results: Findings suggested that remittances have a significant positive effect on food security. Further, the households with female heads were significantly more likely to be food insecure. The wealth status and geographical locations were significantly associated with food security status in Bangladesh., Conclusions: The findings highlight the importance of considering remittance as one of the key factors, while stakeholders implement nutritional interventions in Bangladesh and other low-income settings. Future research should consider this as an important determinant while further examining food security in such settings.

We investigate the climatic influence on COVID-19 transmission risks in 228 cities globally across three climatic zones. The results, based on the application of a Boosted Regression Tree algorithm method, show that average temperature and average relative humidity explain significant variations in COVID-19 transmission across temperate and subtropical regions, whereas in the tropical region, the average diurnal temperature range and temperature seasonality significantly predict the infection outbreak. The number of positive cases showed a decrease sharply above an average temperature of 10°C in the cities of France, Turkey, the US, the UK, and Germany. Among the tropical countries, COVID-19 in Indian cities is most affected by mean diurnal temperature, and those in Brazil by temperature seasonality. The findings have implications on public health interventions, and contribute to the ongoing scientific and policy discourse on the complex interplay of climatic factors determining the risks of COVID-19 transmission.

The study is the first attempt to assess the role of climatic predictors in the rise of COVID-19 intensity in the Russian climatic region. The study used the Random Forest algorithm to understand the underlying associations and monthly scenarios. The results show that temperature seasonality (29.2 ± 0.9%) has the highest contribution for COVID-19 transmission in the humid continental region. In comparison, the diurnal temperature range (26.8 ± 0.4%) and temperature seasonality (14.6 ± 0.8%) had the highest impacts in the sub-arctic region. Our results also show that September and October have favorable climatic conditions for the COVID-19 spread in the sub-arctic and humid continental regions, respectively. From June to August, the high favorable zone for the spread of the disease will shift towards the sub-arctic region from the humid continental region. The study suggests that the government should implement strict measures for these months to prevent the second wave of COVID-19 outbreak in Russia.

Nature-based solutions including rooftop-water storage ponds are increasingly adopted in cities as new eco-designs to address climate change issues, such as water scarcity and storm-water runoff. Macrophytes may be valuable additions for treating stored rooftop waters and provisioning other services, including aquaponics, esthetic and wildlife-conservation values. However, the efficacy of macrophyte treatments has not been tested with influxes of different labile carbon loadings such as those occurring in storms. Moreover, little is known about how macrophytes affect communities of metazoans and microbes, including protozoans, which are key players in the water-treatment process. Here, we experimentally investigated the effectiveness of two widely distributed macrophytes, Ceratophyllum demersum and Egeria densa, for treating drained rooftop water fed with two types of leaf litter, namely Quercus robur (high C lability) and Quercus rubra (low C lability). C. demersum was better than E. densa at reducing water conductivity (by 10 ̶ 40 µS/cm), TDS (by 10-18 mg/L), DOC (by 4-5 mg/L) and at increasing water transparency (by 4-9%), water O 2 levels (by 19-27%) and daylight pH (by 0.9-1.3) compared to leaf-litter only microcosms after 30 days. Each treatment developed a different community of algae, protozoa and metazoa. Greater plant mass and epiphytic chlorophyll-a suggested that C. demersum was better at providing supporting habitat than E. densa. The two macrophytes did not differ in detritus accumulation, but E. densa was more prone to develop filamentous bacteria, which cause sludge bulking in water-treatment systems. Our study highlights the superior capacity of C. demersum and the usefulness of whole-ecosystem experiments in choosing the most adequate macrophyte species for nature-based engineered solutions., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: The risks of excess sugar intake in addition to high-fat diet consumption on immunopathogenesis of obesity-associated metabolic diseases are poorly defined. Interleukin-4 (IL-4) and IL-13 signaling via IL-4Rα regulates adipose tissue lipolysis, insulin sensitivity, and liver fibrosis in obesity. However, the contribution of IL-4Rα to sugar rich diet-driven obesity and metabolic sequelae remains unknown., Methods: WT, IL-4Rα-deficient (IL-4Rα -/- ) and STAT6-deficient mice (STAT6 -/- ) male mice were fed low-fat chow, high fat (HF) or HF plus high carbohydrate (HC/fructose) diet (HF + HC). Analysis included quantification of: (i) body weight, adiposity, energy expenditure, fructose metabolism, fatty acid oxidation/synthesis, glucose dysmetabolism and hepatocellular damage; (ii) the contribution of the hematopoietic or non-hematopoietic IL-4Rα expression; and (iii) the relevance of IL-4Rα downstream canonical STAT6 signaling pathway in this setting., Results: We show that IL-4Rα regulated HF + HC diet-driven weight gain, whole body adiposity, adipose tissue inflammatory gene expression, energy expenditure, locomotor activity, glucose metabolism, hepatic steatosis, hepatic inflammatory gene expression and hepatocellular damage. These effects were potentially, and in part, dependent on non-hematopoietic IL-4Rα expression but were independent of direct STAT6 activation. Mechanistically, hepatic ketohexokinase-A and C expression was dependent on IL-4Rα, as it was reduced in IL-4Rα-deficient mice. KHK activity was also affected by HF + HC dietary challenge. Further, reduced expression/activity of KHK in IL-4Rα mice had a significant effect on fatty acid oxidation and fatty acid synthesis pathways., Conclusion: Our findings highlight potential contribution of non-hematopoietic IL-4Rα activation of a non-canonical signaling pathway that regulates the HF + HC diet-driven induction of obesity and severity of obesity-associated sequelae., (© 2021. The Author(s).)

Masses and masslike lesions of the pancreas are uncommon in the pediatric population. However, owing to overlapping clinical and imaging features, it can be challenging to differentiate the various causes of pediatric pancreatic masses at initial patient presentation. Clinical data such as patient age, signs and symptoms at presentation, laboratory test results, and potential underlying cancer predisposition syndrome can be helpful when formulating a differential diagnosis. US may be the first imaging study to depict a pancreatic mass in a child, as this examination is frequently performed in children with nonspecific abdominal signs and symptoms because of its wide availability and relatively low cost and the lack of a need for sedation or anesthesia. CT or MRI is typically required for more thorough characterization of the mass and surgical planning. Complete characterization of pancreatic masses includes assessment of vascular involvement, local invasion, and extrapancreatic spread of tumor. The authors provide an up-to-date comprehensive review of the clinical manifestations, histopathologic features, and imaging findings of primary and secondary tumors of the pancreas in children and young adults. Advances in imaging, current prognostic information, and treatment paradigms also are highlighted. Finally, nontumorous masslike lesions of the pediatric pancreas, including vascular malformations, cystic disorders (eg, von Hippel-Lindau syndrome, cystic fibrosis), intrapancreatic accessory spleen, and autoimmune pancreatitis, are discussed. Online supplemental material is available for this article. © RSNA, 2021.

The dynein axonemal heavy chain 5 gene codes for a subunit of axonemal dynein necessary for ciliary motor function. Though research has elucidated the consequences of some variants in this gene, it is still unclear whether many variants in the DNAH5 locus are benign or pathogenic due to the rarity of primary ciliary dyskinesia (PCD, of which Kartagener's syndrome is a subset). Here, we introduce the case of an infant boy presenting with the classical findings of PCD along with visceral heterotaxia and neonatal cholestasis. Genetic testing indicated that the patient is a compound heterozygote with a pathogenic c.8498G > A (known as pathogenic) on the maternally derived allele and two variants of uncertain significance, c.1206T > A and c.7800T > G, on the paternally derived allele. As PCD is autosomal recessive, we conclude that one, or both, of these paternally derived variants are pathogenic. To our knowledge, this is the first time that the clinical implications of c.1206T > A (p.Asn402Lys) and c.7800T > G (p.Ile2600Met) are documented. Furthermore, we use this case as an example to recommend clinicians to assess for PCD and laterality defects when presented with severe infantile cholestasis. While the association of cholestasis with PCD is relatively uncommon, PCD is a risk factor for increased prevalence of biliary atresia and infections, both of which are known causes of cholestasis in early infancy., Competing Interests: Conflict of Interest None declared., (Thieme. All rights reserved.)

Thrombotic microangiopathy (TMA) causes global endothelial damage and multiorgan injury. No study has described reproductive organ involvement in TMA. Our study aimed to characterize testicular involvement in TMA. We reviewed autopsies from four patients who underwent hematopoietic cell transplant (HCT) complicated by TMA. Three patients had striking histologic evidence of TMA, while the fourth had normal testicular histology. This suggests that TMA injures the testicles and may adversely affect fertility. There is now an urgent need for a larger analysis of reproductive organ involvement in TMA., (© 2021 Wiley Periodicals LLC.)

Emerging evidence suggests a key contribution to non-alcoholic fatty liver disease (NAFLD) pathogenesis by Th17 cells. The pathogenic characteristics and mechanisms of hepatic Th17 cells, however, remain unknown. Here, we uncover and characterize a distinct population of inflammatory hepatic CXCR3 + Th17 (ihTh17) cells sufficient to exacerbate NAFLD pathogenesis. Hepatic ihTh17 cell accrual was dependent on the liver microenvironment and CXCR3 axis activation. Mechanistically, the pathogenic potential of ihTh17 cells correlated with increased chromatin accessibility, glycolytic output, and concomitant production of IL-17A, IFNγ, and TNFα. Modulation of glycolysis using 2-DG or cell-specific PKM2 deletion was sufficient to reverse ihTh17-centric inflammatory vigor and NAFLD severity. Importantly, ihTh17 cell characteristics, CXCR3 axis activation, and hepatic expression of glycolytic genes were conserved in human NAFLD. Together, our data show that the steatotic liver microenvironment regulates Th17 cell accrual, metabolism, and competence toward an ihTh17 fate. Modulation of these pathways holds potential for development of novel therapeutic strategies for NAFLD., Competing Interests: Declaration of interests S.D. is a consultant for Janssen Research & Development., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction/background: The administration schedule of capecitabine for the treatment of metastatic colorectal cancer (mCRC) in clinical trials has been 14 days of drug with 7 days off in a 21 day cycle (14/7). In an effort to improve tolerability, an alternative every other week treatment (7/7) is often administered. The purpose of this study was to determine the safety and efficacy of administering 7/7 compared with 14/7 capecitabine dosing., Materials and Methods: In this retrospective study, mCRC patients received capecitabine on a 7/7 or 14/7 schedule. The primary objective was to determine the tolerability of the respective dosing schedules, defined according to frequency of dose reductions and treatment delays. Secondary objectives included comparisons of objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety of dosing strategies., Results: Of 175 included patients, 73 (41.7%) received the capecitabine 7/7 schedule and 102 (58.3%) received the 14/7 schedule. There was a statistically significant difference between the 7/7 and 14/7 groups with regard to dose reductions (4% vs. 29%; P < .001) and treatment delays (22% vs. 43%; P = .004). The incidence of any adverse effects (45% vs. 72%; P < .001) and specifically, palmar-plantar erythrodysesthesia (18% vs. 45%; P < .001), were significantly higher in the 14/7 group. No significant difference was seen with regard to ORR, PFS, or OS., Conclusion: Patients with mCRC who received the 7/7 schedule had significantly fewer dose reductions and treatment delays compared with patients who received the 14/7 schedule. Although no difference in efficacy outcomes were observed, prospective studies are needed to confirm these findings., (Copyright © 2020 Elsevier Inc. All rights reserved.)

EWSR1/FLI1 , the most common fusion gene in Ewing sarcoma, upregulates expression of the Eyes Absent 3 (EYA3) transactivator-phosphatase protein. The purpose of this study was to investigate molecular and cellular mechanisms through which EYA3 might promote Ewing sarcoma tumor growth and to determine whether the EYA3 tyrosine phosphatase activity represents a viable therapeutic target. We used genetic and pharmacologic modulation of EYA3 in cell line-based xenografts to examine how loss of EYA3 tyrosine phosphatase activity affects tumor growth and angiogenesis. Molecular mechanisms were evaluated in vivo and in vitro through analyses of tumor tissue and multicellular tumor spheroids. Our results show that both loss of EYA3 in Ewing sarcoma cells and pharmacologic inhibition of the EYA3 tyrosine phosphatase activity inhibit tumor growth and tumor angiogenesis. EYA3 regulates levels of VEGFA in Ewing tumors, as well as promoting DNA damage repair and survival of Ewing sarcoma tumor cells. Target engagement is demonstrated in tumor tissue through elevated levels of the EYA3 substrate H2AX-pY142 upon loss of EYA3 or with Benzarone treatment. The efficacy of EYA3 tyrosine phosphatase inhibition in attenuating tumor growth and angiogenesis is corroborated in an Ewing sarcoma patient-derived tumor xenograft. Together, the results presented here validate EYA3 as a target for the development of novel Ewing sarcoma therapeutic strategies, and set the stage for evaluating the efficacy of combining the antiangiogenic and anti-cell survival effects of EYA3 inhibition with cytotoxic chemotherapy., (©2021 American Association for Cancer Research.)

A chronic multi-symptom illness of unknown etiology, Gulf War Illness (GWI) affects 175,000 to 250,000 veterans of the Gulf War. Because inflammation has suspected involvement in the pathophysiology of GWI, botanical treatments that target inflammation may be beneficial in reducing symptoms. No FDA-approved treatments currently exist for GWI, and rapid prioritization of agents for future efficacy testing is important. This study is part of a larger project that screened nine different botanical compounds with purported anti-inflammatory properties for potential treatment of GWI. We tested three botanicals (resveratrol [ Polygonum cuspidatum ], luteolin, and fisetin [ Rhus succedanea ]) on symptom severity of GWI in this placebo-controlled, pseudo-randomized clinical trial. Twenty-one male veterans with GWI completed the study protocol, which consisted of 1 month (30 days ± 3) of baseline symptom reports, 1 month of placebo, 1 month of lower-dose botanical, and 1 month of higher-dose botanical. Participants completed up to 3 different botanicals, repeating the placebo, lower-dose, and higher-dose cycle for each botanical assigned. Linear mixed models were used for analyses. Resveratrol reduced GWI symptom severity significantly more than placebo at both the lower ( p = 0.035) and higher ( p = 0.004) dosages. Luteolin did not decrease symptom severity more than placebo at either the lower ( p = 0.718) or higher dosages ( p = 0.492). Similarly, fisetin did not reduce symptom severity at either the lower ( p = 0.504) or higher ( p = 0.616) dosages. Preliminary findings from this screening study suggest that resveratrol may be beneficial in reducing symptoms of GWI and should be prioritized for future testing. Larger trials are required to determine efficacy, response rates, durability of effects, safety, and optimal dosage. This trial was registered on ClinicalTrials.gov (NCT02909686) on 13 September 2016.

This report is part of a larger study designed to rapidly and efficiently screen potential treatments for Gulf War Illness (GWI) by testing nine different botanicals. In this placebo-controlled, pseudo-randomized, crossover clinical trial of 20 men with GWI, we tested three botanical agents with putative peripheral and central anti-inflammatory actions: curcumin ( Curcuma longa ), boswellia ( Boswellia serrata ), and French maritime pine bark extract ( Pinus pinaster ). Participants completed 30 +/- 3 days of baseline symptom reports, followed by 30 +/- 3 days of placebo, 30 +/- 3 days of lower-dose botanical, and 30 +/- 3 days of higher-dose botanical. Participants then repeated the process with a new botanical until completing up to three botanical cycles. Data were analyzed using linear mixed models. Curcumin reduced GWI symptom severity significantly more than placebo at both the lower ( p < 0.0001) and higher ( p = 0.0003) dosages. Boswellia was not more effective than placebo at reducing GWI symptoms at either the lower ( p = 0.726) or higher ( p = 0.869) dosages. Maritime pine was not more effective than placebo at the lower dosage ( p = 0.954) but was more effective than placebo at the higher dosage ( p = 0.006). This study provides preliminary evidence that curcumin and maritime pine may help alleviate symptoms of GWI. As a screening study, a final determination of the efficacy of these compounds for all individuals with GWI cannot be made, and further studies will need to be conducted to determine strength and durability of effects, as well as optimal dosage. These results suggest that GWI may, at least in part, involve systemic inflammatory processes. This trial was registered on ClinicalTrials.gov (NCT02909686) on 13 September 2016.

The PAX3-FOXO1 fusion protein is the key oncogenic driver in fusion positive rhabdomyosarcoma (FP-RMS), an aggressive soft tissue malignancy with a particularly poor prognosis. Identifying key downstream targets of PAX3-FOXO1 will provide new therapeutic opportunities for treatment of FP-RMS. Herein, we demonstrate that Forkhead Box F1 (FOXF1) transcription factor is uniquely expressed in FP-RMS and is required for FP-RMS tumorigenesis. The PAX3-FOXO1 directly binds to FOXF1 enhancers and induces FOXF1 gene expression. CRISPR/Cas9 mediated inactivation of either FOXF1 coding sequence or FOXF1 enhancers suppresses FP-RMS tumorigenesis even in the presence of PAX3-FOXO1 oncogene. Knockdown or genetic knockout of FOXF1 induces myogenic differentiation in PAX3-FOXO1-positive FP-RMS. Over-expression of FOXF1 decreases myogenic differentiation in primary human myoblasts. In FP-RMS tumor cells, FOXF1 protein binds chromatin near enhancers associated with FP-RMS gene signature. FOXF1 cooperates with PAX3-FOXO1 and E-box transcription factors MYOD1 and MYOG to regulate FP-RMS-specific gene expression. Altogether, FOXF1 functions downstream of PAX3-FOXO1 to promote FP-RMS tumorigenesis.

Introduction: Hypertension (SBP/DBP > 130/80 mmHg) is a leading risk factor for cardiovascular disease worldwide., Aim: To determine the prevalence of hypertension in a homeless community during an interprofessional education (IPE)-based health fair., Methods: Homeless participants were recruited between August 2019-September 2019. Faculty, nursing, and pharmacist students, educated 477 participants, aged 18-80 years, on the risk factors associated with untreated hypertension. Then, participants self-completed the consented demographic survey questionnaire. Finally, the sitting blood pressure (BP) was recorded three times based on a standardized procedure, using Omron BPN monitor with cuff., Results: Seven pharmacy students, nine nursing students, two registered nurses, five registered pharmacists, and two medical doctors collaboratively provided health education to the homeless community and screened their sitting BP. 390/477 (81.8%) of participants satisfied the inclusion criteria. Participants (54.7%) of the reported education level was at the high School level or less. More than the half of the participants (average age of 51 ± 13 years) had hypertension (median SBP/DBP ≥ 130/82.7 mmHg), respectively. The prevalence of hypertension for the overall cohort was 61.52% (95% CI, 56.59-66.35). Age (p value = 0.000) was significantly associated with hypertension based on the binary logistic analysis., Conclusion: This study demonstrated a high prevalence of hypertension in the homeless community in Long Beach, California with high risk of cardio-vascular events or strokes. This works sheds new light on an issue of major public health significance and points to the need for fostering IPE community-based health fairs intervention program for the US homeless population.