Sailing the straits of approval: The nature of FDA approval and its implications for surgeons

Products approved by the US Food and Drug Administration (FDA) for one use are often put to other uses. This practice, known colloquially as off-label usage, is neither illegal nor unethical. Physicians can and should pursue scientifically sound use supported by medical evidence. The FDA requires only that we: --Be well informed about the product --Base its use on firm scientific rationale and sound medical evidence, if available --Maintain records of the product’s use and effects --Carry out good medical practice --Use good judgment --Consider the best interests of the patient before all els

Stretching the Rules: Monocentric Chromosomes with Multiple Centromere Domains

The centromere is a functional chromosome domain that is essential for faithful chromosome segregation during cell division and that can be reliably identified by the presence of the centromere-specific histone H3 variant CenH3. In monocentric chromosomes, the centromere is characterized by a single CenH3-containing region within a morphologically distinct primary constriction. This region usually spans up to a few Mbp composed mainly of centromere-specific satellite DNA common to all chromosomes of a given species. In holocentric chromosomes, there is no primary constriction; the centromere is composed of many CenH3 loci distributed along the entire length of a chromosome. Using correlative fluorescence light microscopy and high-resolution electron microscopy, we show that pea (Pisum sativum) chromosomes exhibit remarkably long primary constrictions that contain 3-5 explicit CenH3-containing regions, a novelty in centromere organization. In addition, we estimate that the size of the chromosome segment delimited by two outermost domains varies between 69 Mbp and 107 Mbp, several factors larger than any known centromere length. These domains are almost entirely composed of repetitive DNA sequences belonging to 13 distinct families of satellite DNA and one family of centromeric retrotransposons, all of which are unevenly distributed among pea chromosomes. We present the centromeres of Pisum as novel ``meta-polycentric'' functional domains. Our results demonstrate that the organization and DNA composition of functional centromere domains can be far more complex than previously thought, do not require single repetitive elements, and do not require single centromere domains in order to segregate properly. Based on these findings, we propose Pisum as a useful model for investigation of centromere architecture and the still poorly understood role of repetitive DNA in centromere evolution, determination, and function

CD20 and CD19 targeted vectors induce minimal activation of resting B lymphocytes

B lymphocytes are an important cell population of the immune system. However, until recently it was not possible to transduce resting B lymphocytes with retro- or lentiviral vectors, making them unsusceptible for genetic manipulations by these vectors. Lately, we demonstrated that lentiviral vectors pseudotyped with modified measles virus (MV) glycoproteins hemagglutinin, responsible for receptor recognition, and fusion protein were able to overcome this transduction block. They use either the natural MV receptors, CD46 and signaling lymphocyte activation molecule (SLAM), for cell entry (MV-LV) or the vector particles were further modified to selectively enter via the CD20 molecule, which is exclusively expressed on B lymphocytes (CD20-LV). It has been shown previously that transduction by MV-LV does not induce B lymphocyte activation. However, if this is also true for CD20-LV is still unknown. Here, we generated a vector specific for another B lymphocyte marker, CD19, and compared its ability to transduce resting B lymphocytes with CD20-LV. The vector (CD19ds-LV) was able to stably transduce unstimulated B lymphocytes, albeit with a reduced efficiency of about 10% compared to CD20-LV, which transduced about 30% of the cells. Since CD20 as well as CD19 are closely linked to the B lymphocyte activation pathway, we investigated if engagement of CD20 or CD19 molecules by the vector particles induces activating stimuli in resting B lymphocytes. Although, activation of B lymphocytes often involves calcium influx, we did not detect elevated calcium levels. However, the activation marker CD71 was substantially up-regulated upon CD20-LV transduction and most importantly, B lymphocytes transduced with CD20-LV or CD19ds-LV entered the G1b phase of cell cycle, whereas untransduced or MV-LV transduced B lymphocytes remained in G0. Hence, CD20 and CD19 targeting vectors induce activating stimuli in resting B lymphocytes, which most likely renders them susceptible for lentiviral vector transduction

Performance related factors are the main determinants of the von Willebrand factor response to exhaustive physical exercise

Background: Physical stress triggers the endothelium to release von Willebrand Factor (VWF) from the Weibel Palade bodies. Since VWF is a risk factor for arterial thrombosis, it is of great interest to discover determinants of VWF response to physical stress. We aimed to determine the main mediators of the VWF increase by exhaustive physical exercise. Methods: 105 healthy individuals (18-35 years) were included in this study. Each participant performed an incremental exhaustive exercise test on a cycle ergometer. Respiratory gas exchange measurements were obtained while cardiac function was continuously monitored. Blood was collected at baseline and directly after exhaustion. VWF antigen (VWF:Ag) levels, VWF collagen binding (VWF:CB) levels, ADAMTS13 activity and common variations in Syntaxin Binding Protein-5 (STXBP5, rs1039084 and rs9399599), Syntaxin-2 (STX2, rs7978987) and VWF (promoter, rs7965413) were determined. Results: The median VWF:Ag level at baseline was 0.94 IU/mL [IQR 0.8-1.1] and increased with 47% [IQR 25-73] after exhaustive exercise to a median maximum VWF:Ag of 1.38 IU/mL [IQR 1.1-1.8] (p<0.0001). VWF:CB levels and ADAMTS13 activity both also increased after exhaustive exercise (median increase 43% and 12%, both p<0.0001). The strongest determinants of the VWF:Ag level increase are performance related (p<0.0001). We observed a gender difference in VWF:Ag response to exercise (females 1.2 IU/mL; males 1.7 IU/mL, p = 0.001), which was associated by a difference in performance. Genetic variations in STXBP5, STX2 and the VWF promoter were not associated with VWF:Ag levels at baseline nor with the VWF:Ag increase. Conclusions: VWF:Ag levels strongly increase upon exhaustive exercise and this increase is strongly determined by physical fitness level and the intensity of the exercise, while there is no clear effect of genetic variation in STXBP5, STX2 and the VWF promoter

Noninvasive Diagnosis of Visceral Leishmaniasis:Development and Evaluation of Two Urine-Based Immunoassays for Detection of Leishmania donovani Infection in India

Visceral leishmaniasis (VL), one of the most prevalent parasitic diseasesin the developing world causes serious health concerns. Post kala-azar dermal leishmaniasis (PKDL) is a skin disease which occurs after treatment as a sequel to VL. Parasitological diagnosis involves invasive tissue aspiration which is tedious and painful. Commercially available immunochromatographic rapid diagnostic test such as rK39-RDT is used for field diagnosis of VL, detects antibodiesin serum samples. Urine sample is however, much easier in collection,storage and handling than serum and would be a better alternative where collection of tissue aspirate or blood is impractical. In this study, we have developed and evaluated the performance of two urine-based diagnostic assays, ELISA and dipstick test, and compared the results with serologicalrK39-RDT. Our study shows the capability of urinebased tests in detecting anti-Leishmania antibodies effectively for both VL and PKDL diagnosis. The ability of dipstick test to demonstrate negative results after six months in 90% of the VL cases after treatment could be useful as a test of clinical cure. Urine-based tests can therefore replace the need for invasive practices and ensure better diagnosi

Recurrent hotspot mutations in HRAS Q61 and PI3K-AKT pathway genes as drivers of breast adenomyoepitheliomas

Adenomyoepithelioma of the breast is a rare tumor characterized by epithelial-myoepithelial differentiation, of which a subset will progress to invasive or metastatic cancer. We sought to define the genomic landscape of adenomyoepitheliomas. Massively parallel sequencing revealed highly recurrent somatic mutations in HRAS and PI3K-AKT pathway-related genes. Strikingly, HRAS mutations were restricted to estrogen receptor (ER)-negative tumors, all affected codon 61, and all but one co-occurred with PIK3CA or PIK3R1 mutations. To interrogate the functional significance of HRAS Q61 mutations in adenomyoepithelial differentiation, we expressed HRASQ61R alone or in combination with PIK3CAH1047R in non-transformed ER-negative breast epithelial cells. HRASQ61R induced characteristic phenotypes of adenomyoepitheliomas such as the expression of myoepithelial markers and loss of e-cadherin, hyperactivation of AKT signaling, and transformative properties that were arrested by combination therapy with AKT and MEK inhibitors. Our results indicate that breast adenomyoepitheliomas often manifest a unique transformation program featuring HRAS activation

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac

Making effective use of healthcare data using data-to-text technology

Healthcare organizations are in a continuous effort to improve health outcomes, reduce costs and enhance patient experience of care. Data is essential to measure and help achieving these improvements in healthcare delivery. Consequently, a data influx from various clinical, financial and operational sources is now overtaking healthcare organizations and their patients. The effective use of this data, however, is a major challenge. Clearly, text is an important medium to make data accessible. Financial reports are produced to assess healthcare organizations on some key performance indicators to steer their healthcare delivery. Similarly, at a clinical level, data on patient status is conveyed by means of textual descriptions to facilitate patient review, shift handover and care transitions. Likewise, patients are informed about data on their health status and treatments via text, in the form of reports or via ehealth platforms by their doctors. Unfortunately, such text is the outcome of a highly labour-intensive process if it is done by healthcare professionals. It is also prone to incompleteness, subjectivity and hard to scale up to different domains, wider audiences and varying communication purposes. Data-to-text is a recent breakthrough technology in artificial intelligence which automatically generates natural language in the form of text or speech from data. This chapter provides a survey of data-to-text technology, with a focus on how it can be deployed in a healthcare setting. It will (1) give an up-to-date synthesis of data-to-text approaches, (2) give a categorized overview of use cases in healthcare, (3) seek to make a strong case for evaluating and implementing data-to-text in a healthcare setting, and (4) highlight recent research challenges.Comment: 27 pages, 2 figures, book chapte

Neuropsychiatric Consequences of COVID-19 Pandemic: A Synthetic Review from a Global Perspective.

Some research suggests that distress, secondary to isolation and fear following COVID-19 infection, can negatively affect the long-term more than the COVID-19 infection itself. This narrative review aims to provide a global view on the neuropsychiatric consequences of COVID-19 that can be ascribed to several factors, ranging from the direct effect of infection, to the bodys responses against the infection, or to the psychological sequelae of social isolation, unemployment, and fear for ones health and livelihood. Current findings show that the more severe the respiratory infection, the more likely are central nervous system (CNS) complications regarding the infection itself. The immune reactions to the infection may result in symptoms similar to chronic fatigue as well as neurocognitive deficits, which last long after the infection is gone. An increase in symptoms of depression, anxiety, and trauma-related stress may also follow upon economic fears and isolation from friends and family. The consequences of the pandemic are not limited to adults; children learning remotely and away from classmates and routine activities may develop adjustment disorders, acute stress disorder, and a variety of manifestations of grief. A summary of case reports suggests that COVID-19-related stress, economic recession, and political unrest increase the risk of suicidal behaviors and acts of violence. However, it is unknown whether manifestations of mental disorders result from social causes or whether CNS complications may be responsible

How to introduce medical ethics at the bedside - Factors influencing the implementation of an ethical decision-making model

BACKGROUND: As the implementation of new approaches and procedures of medical ethics is as complex and resource-consuming as in other fields, strategies and activities must be carefully planned to use the available means and funds responsibly. Which facilitators and barriers influence the implementation of a medical ethics decision-making model in daily routine? Up to now, there has been little examination of these factors in this field. METHODS: A medical ethics decision-making model called METAP was introduced on three intensive care units and two geriatric wards. An evaluation study was performed from 7 months after deployment of the project until two and a half years. Quantitative and qualitative methods including a questionnaire, semi-structured face-to-face and group-interviews were used. RESULTS: Sixty-three participants from different professional groups took part in 33 face-to-face and 9 group interviews, and 122 questionnaires could be analysed. The facilitating factors most frequently mentioned were: acceptance and presence of the model, support given by the medical and nursing management, an existing or developing (explicit) ethics culture, perception of a need for a medical ethics decision-making model, and engaged staff members. Lack of presence and acceptance, insufficient time resources and staff, poor inter-professional collaboration, absence of ethical competence, and not recognizing ethical problems were identified as inhibiting the implementation of the METAP model. However, the results of the questionnaire as well as of explicit inquiry showed that the respondents stated to have had enough time and staff available to use METAP if necessary. CONCLUSIONS: Facilitators and barriers of the implementation of a medical ethics decision-making model are quite similar to that of medical guidelines. The planning for implementing an ethics model or guideline can, therefore, benefit from the extensive literature and experience concerning the implementation of medical guidelines. Lack of time and staff can be overcome when people are convinced that the benefits justify the effort