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Abstract Background Emerging randomized data, mostly from phase II trials, have suggested that patients with oligometastatic cancers may benefit from ablative treatments such as stereotactic ablative radiotherapy (SABR). However, phase III data testing this paradigm are lacking, and many studies have examined SABR in the setting of metachronous oligometastatic disease. The goal of the SABR-SYNC trial is to assess the effect of SABR in patients with oligometastatic cancers and a synchronous primary tumor. Methods One hundred and eighty patients will be randomized in a 1:2 ratio between standard of care (SOC) palliative-intent treatments vs. SOC + ablative therapy (SABR preferred) to all sites of known disease. Randomization will be stratified based on histology and number of metastases at enrollment. SABR may be delivered in 1-, 3- and 5-fraction regimens, with recommended doses of 20 Gy, 30 Gy, and 35 Gy, respectively. Non-SABR local modalities (e.g. surgery, thermal ablation, conventional radiation) may be used for treatment of the primary or metastases at the discretion of the treating physicians, if those modalities are clinically preferred. The primary endpoint is overall survival, and secondary endpoints include progression-free survival, time to development of new metastatic lesions, time to initiation of next systemic therapy, quality of life, and toxicity. Translational endpoints include assessment of circulating tumor DNA and immunological predictors of outcomes. Discussion SABR-SYNC will provide phase III data to assess the impact of SABR on overall survival in a population of patients with synchronous oligometastases. The translational component will attempt to identify novel prognostic and predictive biomarkers to aid in clinical decision making. Trial registration Clinicaltrials.gov NCT05717166 (registration date: Feb. 8, 2023).

Abstract Background In healthcare systems in general, access to diabetic retinopathy (DR) screening is limited. Artificial intelligence has the potential to increase care delivery. Therefore, we trained and evaluated the diagnostic accuracy of a machine learning algorithm for automated detection of DR. Methods We included color fundus photographs from individuals from 4 databases (primary and specialized care settings), excluding uninterpretable images. The datasets consist of images from Brazilian patients, which differs from previous work. This modification allows for a more tailored application of the model to Brazilian patients, ensuring that the nuances and characteristics of this specific population are adequately captured. The sample was fractionated in training (70%) and testing (30%) samples. A convolutional neural network was trained for image classification. The reference test was the combined decision from three ophthalmologists. The sensitivity, specificity, and area under the ROC curve of the algorithm for detecting referable DR (moderate non-proliferative DR; severe non-proliferative DR; proliferative DR and/or clinically significant macular edema) were estimated. Results A total of 15,816 images (4590 patients) were included. The overall prevalence of any degree of DR was 26.5%. Compared with human evaluators (manual method of diagnosing DR performed by an ophthalmologist), the deep learning algorithm achieved an area under the ROC curve of 0.98 (95% CI 0.97–0.98), with a specificity of 94.6% (95% CI 93.8–95.3) and a sensitivity of 93.5% (95% CI 92.2–94.9) at the point of greatest efficiency to detect referable DR. Conclusions A large database showed that this deep learning algorithm was accurate in detecting referable DR. This finding aids to universal healthcare systems like Brazil, optimizing screening processes and can serve as a tool for improving DR screening, making it more agile and expanding care access.

Abstract Colistin remains an important antibiotic for the therapeutic management of drug-resistant Klebsiella pneumoniae. Despite the numerous reports of colistin resistance in clinical strains, it remains unclear exactly when and how different mutational events arise resulting in reduced colistin susceptibility. Using a bioreactor model of infection, we modelled the emergence of colistin resistance in a susceptible isolate of K. pneumoniae. Genotypic, phenotypic and mathematical analyses of the antibiotic-challenged and un-challenged population indicates that after an initial decline, the population recovers within 24 h due to a small number of “founder cells” which have single point mutations mainly in the regulatory genes encoding crrB and pmrB that when mutated results in up to 100-fold reduction in colistin susceptibility. Our work underlines the rapid development of colistin resistance during treatment or exposure of susceptible K. pneumoniae infections having implications for the use of cationic antimicrobial peptides as a monotherapy.

Submetering with mobile measurement technology offers substantial benefits for energy system analysis in small and medium-sized enterprises. However, the effective and systematic analysis of submetering datasets is challenging due to the lack of a standardized concept and the limited measurement period. Based on empirically collected submetering data from selected case studies, this study investigates which data analyses are relevant for a systematic data analysis approach. In addition, key indicators and limitations of these analyses are examined and discussed. The results indicate that the use of standardized data analyses contributes to a more efficient and targeted energy system analysis. By applying various disaggregation analyses (e.g. base load disaggregation) and load profile characterization to the datasets, relevant electrical consumers and inefficiencies can be identified. The developed standardized data analyses address the initial step of analysis, which is “detection”. Limitations of standardized data analyses point to the need for individual detailed analyses that cover “diagnosis” and “optimization” as further steps of analysis. In conclusion, the results provide a first approach towards a standardized data analysis for short-term measurements.

Nachrichtenpublika sind heute mit der Heterogenität und Hybridität von Medienbotschaften konfrontiert. Neue Anbieter wie Social-Media-Influencer und nicht-journalistische Informationsquellen etablieren sich auf Plattformen als epistemische Autoritäten. Dieser Strukturwandel der Öffentlichkeit schlägt sich nicht nur in einem veränderten Nachrichtenverständnis nieder, sondern betrifft auch Meinungsbildungsprozesse. In 32 leitfadengestützten Tiefeninterviews wurde der Frage nachgegangen, nach welchen Indikatoren Nutzer:innen Quellen und Inhalte als relevant für ihre persönliche Meinungsbildung definieren. Aus den Ergebnissen lassen sich die spezifischen Vermittlungsleistungen unterschiedlicher Informationsquellen aus der Publikumsperspektive bewerten und, abhängig von Stärke und Aktivität der Meinungsbildung, sechs Meinungsbildungstypen ableiten. So zeigt sich, dass Rezipient:innen Nachrichtenmedien, Social-Media-Influencer und nicht-journalistische Informationsquellen nach affektiven und funktionalen Kriterien als meinungsbildungsrelevant bewerten – typenübergreifend sind Glaubwürdigkeit und (antizipierte) Meinungskongruenz zentral. Zwischen den lebensweltlich geprägten Meinungsbildungstypen zeichnen sich jedoch unterschiedliche Qualitäts- und Relevanzzuweisungen ab, die nicht nur persönliche Informationswelten, sondern auch unterschiedliche Wirkungspotenziale kreieren.

The neurophysiological mechanisms in the human amygdala that underlie post-traumatic stress disorder (PTSD) remain poorly understood. In a first-of-its-kind pilot study, we recorded intracranial electroencephalographic data longitudinally (over one year) in two male individuals with amygdala electrodes implanted for the management of treatment-resistant PTSD (TR-PTSD) under clinical trial NCT04152993. To determine electrophysiological signatures related to emotionally aversive and clinically relevant states (trial primary endpoint), we characterized neural activity during unpleasant portions of three separate paradigms (negative emotional image viewing, listening to recordings of participant-specific trauma-related memories, and at-home-periods of symptom exacerbation). We found selective increases in amygdala theta (5-9 Hz) bandpower across all three negative experiences. Subsequent use of elevations in low-frequency amygdala bandpower as a trigger for closed-loop neuromodulation led to significant reductions in TR-PTSD symptoms (trial secondary endpoint) following one year of treatment as well as reductions in aversive-related amygdala theta activity. Altogether, our findings provide early evidence that elevated amygdala theta activity across a range of negative-related behavioral states may be a promising target for future closed-loop neuromodulation therapies in PTSD.

Background In non-small cell lung cancer (NSCLC), chemoradiotherapy (CRT) yields pathological complete response (pCR) rates of approximately 30%. We investigated using ipilimumab plus nivolumab (IPI-NIVO) with neoadjuvant CRT in resectable, and borderline resectable NSCLC.Methods This single-arm, phase-II trial enrolled operable T3-4N0–2 patients with NSCLC without oncogenic drivers. Primary study endpoints were safety, major pathological response (MPR) and pCR. Treatment encompassed platinum-doublet concurrent CRT, IPI 1 mg/kg intravenous and NIVO 360 mg intravenous on day-1, followed by chemotherapy plus NIVO 360 mg 3 weeks later. Thoracic radiotherapy was 50 or 60 Gy, in once-daily doses of 2 Gy. Resections were 6 weeks post-radiotherapy.Results In a total of 30 patients in the intention-to-treat (ITT) population, grades 3–4 treatment-related adverse events (TRAEs) occurred in 70%, one TRAE grade 5 late-onset pneumonitis on day 96 post-surgery (1/30, 3.3%) occurred, and one non-TRAE COVID-19 death (1/30, 3.3%). pCR and MPR were achieved in 50% (15/30) and 63% (19/30) of the ITT; and in 58% (15/26) and 73% (19/26) of the 26 patients who underwent surgery, respectively. Postoperative melanoma was seen in one non-pCR patient. The R0 rate was 100% (26/26), and no patient failed surgery due to TRAEs. In peripheral blood, proliferative CD8+ T cells were increased, while proliferative regulatory T cells (Tregs) were not. On-treatment, pCR-positives had higher CD8+CD39+ T cells and lower HLA-DR+ Tregs.Conclusions Neoadjuvant IPI-NIVO-CRT in T3-4N0–2 NSCLC showed acceptable safety with pCR and MPR in 58% and 73% of operated patients, respectively. No patient failed surgery due to TRAEs.Trial registration number NCT04245514.

O objetivo deste trabalho é apresentar a matriz de indicadores de monitoramento da implantação do cuidado farmacêutico e os resultados da fase inicial do Programa Farmácia Cuidar+. A matriz de indicadores foi elaborada, validada e valorada por especialistas e após, aplicada em 446 municípios do Rio Grande do Sul que aderiram ao programa. A adesão pelos municípios ao Programa Farmácia Cuidar+ compreende o recebimento de auxílio financeiro estadual municipal para desenvolvimento de atividades relacionadas ao cuidado farmacêutico. A matriz é composta por 22 indicadores que compõem uma nota de zero a 100, distribuídos em oito dimensões: efetividade do tratamento de Asma, efetividade do tratamento de DPOC, Adesão, Atividades clínicas do farmacêutico, Consultório, Segurança, Educação em saúde e Educação continuada. A mediana da nota dos municípios que responderam o formulário (n=351) aplicado na fase inicial do programa foi de 12,00 pontos variando de zero a 50,00, refletindo a incipiente realização do cuidado farmacêutico nas farmácias ambulatoriais que dispensam medicamentos do Componente Especializado da Assistência Farmacêutica. Municípios com até 500 atendimentos mensais alcançaram melhores notas. Orientação para o transporte e armazenamento foram as atividades clínicas com melhor pontuação. A mesma matriz será aplicada nas fases intermediária e avançada do programa. O instrumento apresentou viabilidade de aplicação e identificou fragilidades relacionadas ao cuidado farmacêutico em todas as dimensões avaliadas. Espera-se com esses indicadores monitorar os resultados da implantação do Programa Farmácia Cuidar+ relacionados às ações de cuidado farmacêutico.

This study examines the impact of integrating solar photovoltaic (PV) systems on power factor (PF) within low-voltage radial distribution networks, using empirical data from the Energy Self-Sufficiency for Health Facilities in Ghana (EnerSHelF) project sites in Ghana. The research included simulations focusing on optimal PV integration, with and without PF considerations, and the strategic placement of PV and shunt capacitors (SC). Three scenarios evaluated PV injection at high-load demand nodes, achieving penetration levels of 85.00 percent, 82.88 percent with high voltage drop, and 100.00 percent with high loss nodes. Additionally, three scenarios assessed SC allocation methods: proportional to the node's reactive power demand (Scenario I), even distribution (Scenario II), and proportional to installed PV capacity at PV nodes (Scenario III).The analysis used a twin-objective index (TOI), combining voltage deviations and power factor degradation. Results showed significant PV curtailment was necessary to achieve standard PF. Optimal penetration levels, considering TOI, reduced PV penetration from 85.00 percent to 63.75 percent, 82.88 percent to 57.38 percent, and 100.00 percent to 72.50 percent for high load, high voltage drops, and high loss nodes, respectively. Notably, all scenarios showed a concerning PF of 0.00 at dead-end nodes (P20, P21, P22).Scenario I achieved PF ranges of -0.26 to 1.00 with PV at high load, -0.69 to 1.00 with PV at high voltage drop, and 0.95 to 1.00 with PV at high loss nodes. Scenario II produced similar ranges, -0.48 to 1.00, -1.00 to 0.99, and 0.30 to 0.96, with PV placement at high load, voltage drops, and loss nodes, respectively. Scenario III yielded ranges of -0.19 to 0.97 (high load), -0.23 to 1.00 (high voltage drop), and 0.86 to 0.96 (high losses).The study concluded that the most effective strategy involves installing PVs at high-loss nodes and distributing SCs proportionally to the node's reactive power demand (Scenario I). This approach achieved a more uniform PF pattern throughout the network, highlighting the practical implications of strategic PV placement and targeted reactive power compensation for maintaining a healthy and efficient distribution system with solar PV integration.

Klebsiella pneumoniae is a global public health concern due to the rising myriad of hypervirulent and multidrug-resistant clones both alarmingly associated with high mortality. The molecular mechanisms underpinning these recalcitrant K. pneumoniae infection, and how virulence is coupled with the emergence of lineages resistant to nearly all present-day clinically important antimicrobials, are unclear. In this study, we performed a genome-wide screen in K. pneumoniae ECL8, a member of the endemic K2-ST375 pathotype most often reported in Asia, to define genes essential for growth in a nutrient-rich laboratory medium (Luria-Bertani [LB] medium), human urine, and serum. Through transposon directed insertion-site sequencing (TraDIS), a total of 427 genes were identified as essential for growth on LB agar, whereas transposon insertions in 11 and 144 genes decreased fitness for growth in either urine or serum, respectively. These studies not only provide further knowledge on the genetics of this pathogen but also provide a strong impetus for discovering new antimicrobial targets to improve current therapeutic options for K. pneumoniae infections.

In the present study, we tested whether processing information in the context of an ancestral survival scenario enhances episodic memory performance in older adults and in stroke patients. In an online study (Experiment 1), healthy young and older adults rated words according to their relevance to an ancestral survival scenario, and subsequent free recall performance was compared to a pleasantness judgment task and a moving scenario task in a within-subject design. The typical survival processing effect was replicated: Recall rates were highest in the survival task, followed by the moving and the pleasantness judgment task. Although older adults showed overall lower recall rates, there was no evidence for differences between the age groups in the condition effects. Experiment 2 was conducted in a neurological rehabilitation clinic with a sample of patients who had suffered from a stroke within the past 5 months. On the group level, Experiment 2 revealed no significant difference in recall rates between the three conditions. However, when accounting for overall memory abilities and executive function, independently measured in standardized neuropsychological tests, patients showed a significant survival processing effect. Furthermore, only patients with high executive function scores benefitted from the scenario tasks, suggesting that intact executive function may be necessary for a mnemonic benefit. Taken together, our results support the idea that the survival processing task – a well-studied task in the field of experimental psychology – may be incorporated into a strategy to compensate for memory dysfunction.

With >7000 species the order of rust fungi has a disproportionately large impact on agriculture, horticulture, forestry and foreign ecosystems. The infectious spores are typically dikaryotic, a feature unique to fungi in which two haploid nuclei reside in the same cell. A key example is Phakopsora pachyrhizi, the causal agent of Asian soybean rust disease, one of the world's most economically damaging agricultural diseases. Despite P. pachyrhizi's impact, the exceptional size and complexity of its genome prevented generation of an accurate genome assembly. Here, we sequence three independent P. pachyrhizi genomes and uncover a genome up to 1.25 Gb comprising two haplotypes with a transposable element (TE) content of ~93%. We study the incursion and dominant impact of these TEs on the genome and show how they have a key impact on various processes such as host range adaptation, stress responses and genetic plasticity.

Purpose: Stereotactic body radiotherapy (SBRT) is an effective treatment for adrenal gland metastases, but it is technically challenging and there are concerns about toxicity. We performed a multi-institutional pooled retrospective analysis to study clinical outcomes and toxicities after MR-guided SBRT (MRgSBRT) using for adrenal gland metastases. Methods and Materials: Clinical and dosimetric data of patients treated with MRgSBRT on a 0.35 T MR-Linac at 11 institutions between 2016 and 2022 were analyzed. Local control (LC), local progression-free survival (LPFS), distant progression-free survival (DPFS) and overall survival (OS) were estimated using Kaplan-Meier method and log-rank test. Results: A total of 255 patients (269 adrenal metastases) were included. Metastatic pattern was solitary in 25.9 % and oligometastatic in 58.0 % of patients. Median total dose was 45 Gy (range, 16–60 Gy) in a median of 5 fractions, and the median BED10 was 100 Gy (range, 37.5–132.0 Gy). Adaptation was done in 87.4 % of delivered fractions based on the individual clinicians' judgement. The 1- and 2- year LPFS rates were 94.0 % (95 % CI: 90.7–97.3 %) and 88.3 % (95 % CI: 82.4–94.2 %), respectively and only 2 patients (0.8 %) experienced grade 3 + toxicity. No local recurrences were observed after treatment to a total dose of BED10 > 100 Gy, with single fraction or fractional dose of > 10 Gy. Conclusions: This is a large retrospective multi-institutional study to evaluate the treatment outcomes and toxicities with MRgSBRT in over 250 patients, demonstrating the need for frequent adaptation in 87.4 % of delivered fractions to achieve a 1- year LPFS rate of 94 % and less than 1 % rate of grade 3 + toxicity. Outcomes analysis in 269 adrenal lesions revealed improved outcomes with delivery of a BED10 > 100 Gy, use of single fraction SBRT and with fraction doses > 10 Gy, providing benchmarks for future clinical trials.

Traumatic brain injury (TBI) is a significant contributor to mortality and morbidity in people, both young and old. There are currently no approved therapeutic interventions for TBI. Following TBI, cyclooxygenase (COX) enzymes generate prostaglandins and reactive oxygen species that perpetuate inflammation, with COX-1 and COX-2 isoforms providing differing responses. Selective COX-2 inhibitors have shown potential as neuroprotective agents. Results from animal models of TBI suggest potential treatment through the alleviation of secondary injury mechanisms involving neuroinflammation and neuronal cell death. Additionally, early clinical trials have shown that the use of celecoxib improves patient mortality and outcomes. This review aims to summarize the therapeutic effects of COX-2 inhibitors observed in TBI animal models, highlighting pertinent studies elucidating molecular pathways and expounding upon their mechanistic actions. We then investigated the current state of evidence for the utilization of COX-2 inhibitors for TBI patients.