On-line electrochemistry–bioaffinity screening with parallel HR-LC-MS for the generation and characterization of modified p38α kinase inhibitors

In this study, an integrated approach is developed for the formation, identification and biological characterization of electrochemical conversion products of p38α mitogen-activated protein kinase inhibitors. This work demonstrates the hyphenation of an electrochemical reaction cell with a continuous-flow bioaffinity assay and parallel LC-HR-MS. Competition of the formed products with a tracer (SKF-86002) that shows fluorescence enhancement in the orthosteric binding site of the p38α kinase is the readout for bioaffinity. Parallel HR-MSn experiments provided information on the identity of binders and non-binders. Finally, the data produced with this on-line system were compared to electrochemical conversion products generated off-line. The electrochemical conversion of 1-{6-chloro-5-[(2R,5S)-4-(4-fluorobenzyl)-2,5-dimethylpiperazine-1-carbonyl]-3aH-indol-3-yl}-2-morpholinoethane-1,2-dione resulted in eight products, three of which showed bioaffinity in the continuous-flow p38α bioaffinity assay used. Electrochemical conversion of BIRB796 resulted, amongst others, in the formation of the reactive quinoneimine structure and its corresponding hydroquinone. Both products were detected in the p38α bioaffinity assay, which indicates binding to the p38α kinase

Who Is at Risk for Diagnostic Discrepancies? Comparison of Pre- and Postmortal Diagnoses in 1800 Patients of 3 Medical Decades in East and West Berlin

<div><h3>Background</h3><p>Autopsy rates in Western countries consistently decline to an average of <5%, although clinical autopsies represent a reasonable tool for quality control in hospitals, medically and economically. Comparing pre- and postmortal diagnoses, diagnostic discrepancies as uncovered by clinical autopsies supply crucial information on how to improve clinical treatment. The study aimed at analyzing current diagnostic discrepancy rates, investigating their influencing factors and identifying risk profiles of patients that could be affected by a diagnostic discrepancy.</p> <h3>Methods and Findings</h3><p>Of all adult autopsy cases of the Charité Institute of Pathology from the years 1988, 1993, 1998, 2003 and 2008, the pre- and postmortal diagnoses and all demographic data were analyzed retrospectively. Based on power analysis, 1,800 cases were randomly selected to perform discrepancy classification (class I-VI) according to modified Goldman criteria. The rate of discrepancies in major diagnoses (class I) was 10.7% (95% CI: 7.7%–14.7%) in 2008 representing a reduction by 15.1%. Subgroup analysis revealed several influencing factors to significantly correlate with the discrepancy rate. Cardiovascular diseases had the highest frequency among class-I-discrepancies. Comparing the 1988-data of East- and West-Berlin, no significant differences were found in diagnostic discrepancies despite an autopsy rate differing by nearly 50%. A risk profile analysis visualized by intuitive heatmaps revealed a significantly high discrepancy rate in patients treated in low or intermediate care units at community hospitals. In this collective, patients with genitourinary/renal or infectious diseases were at particularly high risk.</p> <h3>Conclusions</h3><p>This is the current largest and most comprehensive study on diagnostic discrepancies worldwide. Our well-powered analysis revealed a significant rate of class-I-discrepancies indicating that autopsies are still of value. The identified risk profiles may aid both pathologists and clinicians to identify patients at increased risk for a discrepant diagnosis and possibly suboptimal treatment intra vitam.</p> </div

PLANTAS HOSPEDEIRAS DE Thyrinteina arnobia (LEPIDOPTERA: GEOMETRIDAE) AFETAM O DESENVOLVIMENTO DO PARASITOIDE Palmistichus elaeisis (HYMENOPTERA: EULOPHIDAE)1

O objetivo deste trabalho foi avaliar a eficiência do parasitismo e a biologia da prole do parasitoide Palmistichus elaeisis Delvare e La Salle (Hymenoptera: Eulophidae) em pupas de Thyrinteina arnobia Stoll (Lepidoptera: Geometridae) quando criadas em plantas de Psidium guajava ou Eucalyptus cloeziana. Ovos de T. arnobia foram coletados e colocados em sacos de tecido tipo organza envolvendo galhos de plantas de P. guajava (T1) e E. cloeziana (T2) até as lagartas alcançarem a fase de pupa. Trinta pupas de cada tratamento foram individualizadas em tubos de vidro e expostas ao parasitismo por quatro fêmeas de P. elaeisis por 24 h. Avaliaram-se a emergência da progênie do parasitoide por pupa; a porcentagem de parasitismo, pupas mortas e de adultos de T. arnobia emergidos; a duração do ciclo de vida (ovo-adulto);a longevidade; a razão sexual; e o tamanho da cápsula cefálica e do corpo do parasitoide. A porcentagem de parasitismo, a emergência de P. elaeisis por pupa, a longevidade das fêmeas e o tamanho da cápsula cefálica e do corpo dos machos do parasitoide foram menores quando seu hospedeiro foi criado em plantas de eucalipto. Isso pode ter ocorrido devido à grande quantidade de compostos do metabolismo secundário presentes nesta planta, que podem ser acumulados no corpo do herbívoro ao se alimentar, afetando negativamente o inimigo natural. Palmistichus elaeisis mostrou-se mais adaptado à mirtácea nativa da América P. guajava

STAT2 signaling restricts viral dissemination but drives severe pneumonia in SARS-CoV-2 infected hamsters

Emergence of SARS-CoV-2 causing COVID-19 has resulted in hundreds of thousands of deaths. In search for key targets of effective therapeutics, robust animal models mimicking COVID-19 in humans are urgently needed. Here, we show that Syrian hamsters, in contrast to mice, are highly permissive to SARS-CoV-2 and develop bronchopneumonia and strong inflammatory responses in the lungs with neutrophil infiltration and edema, further confirmed as consolidations visualized by micro-CT alike in clinical practice. Moreover, we identify an exuberant innate immune response as key player in pathogenesis, in which STAT2 signaling plays a dual role, driving severe lung injury on the one hand, yet restricting systemic virus dissemination on the other. Our results reveal the importance of STAT2-dependent interferon responses in the pathogenesis and virus control during SARS-CoV-2 infection and may help rationalizing new strategies for the treatment of COVID-19 patients. SARS-CoV-2 infection can result in severe lung inflammation and pathology, but host response remains incompletely understood. Here the authors show in Syrian hamsters that STAT2 signaling restricts systemic virus dissemination but also drives severe lung injury, playing a dual role in SARS-CoV-2 infection

Enhanced Auditory Brainstem Response and Parental Bonding Style in Children with Gastrointestinal Symptoms

The electrophysiological properties of the brain and influence of parental bonding in childhood irritable bowel syndrome (IBS) are unclear. We hypothesized that children with chronic gastrointestinal (GI) symptoms like IBS may show exaggerated brainstem auditory evoked potential (BAEP) responses and receive more inadequate parental bonding. = 0.024). Multiple regression analysis in females also supported these findings.It is suggested that children with chronic GI symptoms have exaggerated brainstem responses to environmental stimuli and inadequate parental behaviors aggravate these symptoms

Advances in structure elucidation of small molecules using mass spectrometry

The structural elucidation of small molecules using mass spectrometry plays an important role in modern life sciences and bioanalytical approaches. This review covers different soft and hard ionization techniques and figures of merit for modern mass spectrometers, such as mass resolving power, mass accuracy, isotopic abundance accuracy, accurate mass multiple-stage MS(n) capability, as well as hybrid mass spectrometric and orthogonal chromatographic approaches. The latter part discusses mass spectral data handling strategies, which includes background and noise subtraction, adduct formation and detection, charge state determination, accurate mass measurements, elemental composition determinations, and complex data-dependent setups with ion maps and ion trees. The importance of mass spectral library search algorithms for tandem mass spectra and multiple-stage MS(n) mass spectra as well as mass spectral tree libraries that combine multiple-stage mass spectra are outlined. The successive chapter discusses mass spectral fragmentation pathways, biotransformation reactions and drug metabolism studies, the mass spectral simulation and generation of in silico mass spectra, expert systems for mass spectral interpretation, and the use of computational chemistry to explain gas-phase phenomena. A single chapter discusses data handling for hyphenated approaches including mass spectral deconvolution for clean mass spectra, cheminformatics approaches and structure retention relationships, and retention index predictions for gas and liquid chromatography. The last section reviews the current state of electronic data sharing of mass spectra and discusses the importance of software development for the advancement of structure elucidation of small molecules

Clinical- and cost-effectiveness of the STAR care pathway compared to usual care for patients with chronic pain after total knee replacement: study protocol for a UK randomised controlled trial.

Approximately 20% of patients experience chronic pain after total knee replacement. There is little evidence for effective interventions for the management of this pain, and current healthcare provision is patchy and inconsistent. Given the complexity of this condition, multimodal and individualised interventions matched to pain characteristics are needed. We have undertaken a comprehensive programme of work to develop a care pathway for patients with chronic pain after total knee replacement. This protocol describes the design of a randomised controlled trial to evaluate the clinical- and cost-effectiveness of a complex intervention care pathway compared with usual care.This article is freely available via Open Access. Click on the Additional Link above to access the full-text via the publisher's site

Integration of oncology and palliative care : a Lancet Oncology Commission

Full integration of oncology and palliative care relies on the specific knowledge and skills of two modes of care: the tumour-directed approach, the main focus of which is on treating the disease; and the host-directed approach, which focuses on the patient with the disease. This Commission addresses how to combine these two paradigms to achieve the best outcome of patient care. Randomised clinical trials on integration of oncology and palliative care point to health gains: improved survival and symptom control, less anxiety and depression, reduced use of futile chemotherapy at the end of life, improved family satisfaction and quality of life, and improved use of health-care resources. Early delivery of patient-directed care by specialist palliative care teams alongside tumour-directed treatment promotes patient-centred care. Systematic assessment and use of patient-reported outcomes and active patient involvement in the decisions about cancer care result in better symptom control, improved physical and mental health, and better use of health-care resources. The absence of international agreements on the content and standards of the organisation, education, and research of palliative care in oncology are major barriers to successful integration. Other barriers include the common misconception that palliative care is end-of-life care only, stigmatisation of death and dying, and insufficient infrastructure and funding. The absence of established priorities might also hinder integration more widely. This Commission proposes the use of standardised care pathways and multidisciplinary teams to promote integration of oncology and palliative care, and calls for changes at the system level to coordinate the activities of professionals, and for the development and implementation of new and improved education programmes, with the overall goal of improving patient care. Integration raises new research questions, all of which contribute to improved clinical care. When and how should palliative care be delivered? What is the optimal model for integrated care? What is the biological and clinical effect of living with advanced cancer for years after diagnosis? Successful integration must challenge the dualistic perspective of either the tumour or the host, and instead focus on a merged approach that places the patient's perspective at the centre. To succeed, integration must be anchored by management and policy makers at all levels of health care, followed by adequate resource allocation, a willingness to prioritise goals and needs, and sustained enthusiasm to help generate support for better integration. This integrated model must be reflected in international and national cancer plans, and be followed by developments of new care models, education and research programmes, all of which should be adapted to the specific cultural contexts within which they are situated. Patient-centred care should be an integrated part of oncology care independent of patient prognosis and treatment intention. To achieve this goal it must be based on changes in professional cultures and priorities in health care