Glioma-BioDP: database for visualization of molecular profiles to improve prognosis of brain cancer.

Cancer researchers often seek user-friendly interactive tools for validation, exploration, analysis, and visualization of molecular profiles in cancer patient samples. To aid researchers working on the both low- and high-grade gliomas, we developed Glioma-BioDP, a web tool for exploration and visualization of RNA and protein expression profiles of interest in these tumor types. Glioma-BioDP is user friendly application that include expression data from both the low- and high-grade glioma patient samples from The Cancer Genome Atlas and enabled querying by mRNA, microRNA, and protein level expression data from Illumina HiSeq and RPPA platforms respectively. Glioma-BioDP provides advance query interface and enables users to explore the association of genes, proteins, and miRNA expression with molecular and/or histological subtypes of gliomas, surgical resection status and survival. The prognostic significance and visualization of the selected expression profiles can be explored using interactive utilities provided. This tool may also enable validation and generation of new hypotheses of novel therapies impacting gliomas that aid in personalization of treatment for optimum outcomes.

Aspergillus fumigatus sternal osteomyelitis following cardiac surgery: Case report and literature review.

BACKGROUND: Sternal osteomyelitis caused by Aspergillus spp is uncommon in cardiac surgery patients requiring sternotomy. CASE PRESENTATION: We report a 77-year-old male with a history of poorly controlled diabetes who was diagnosed with Aspergillus sternal osteomyelitis, three months following an uneventful coronary artery bypass surgery. He underwent multiple debridement surgeries and was treated with voriconazole. Despite a complicated post-operative course, the patient responded well to voriconazole with clinical and biochemical evidence of remission. Unfortunately, he died of an unrelated cause due to decompensated heart failure. DISCUSSION: Though uncommon, Aspergillus sternal osteomyelitis should be considered in the differential diagnosis of immunocompetent patients with post-operative sternal wound infections and negative bacterial tissue cultures. Management should include a combination of medical and surgical therapy.

HISTORIQUE: L'ostéomyélite sternale causée par des espèces d'Aspergillus est rare chez les patients en chirurgie cardiaque qui ont besoin d'une sternotomie. PRÉSENTATION DE CAS: Les chercheurs présentent le cas d'un homme de 77 ans ayant des antécédents de diabète mal contrôlé qui a obtenu un diagnostic d'ostéomyélite sternale à Aspergillus trois mois après un pontage aortocoronarien sans histoire. Il a subi de multiples opérations de débridement et a reçu un traitement au voriconazole. Malgré une évolution postopératoire complexe, il a bien répondu au voriconazole et a obtenu des résultats cliniques et biochimiques de rémission. Malheureusement, il est décédé d'une décompensation cardiaque non apparentée. DISCUSSION: Bien qu'elle soit rare, l'ostéomyélite sternale à Aspergillus devrait faire partie du diagnostic différentiel des patients immunocompétents présentant une infection postopératoire de la plaie sternale et des cultures tissulaires bactériennes négatives. La prise en charge doit inclure un traitement médical et chirurgical associé.

Sensitive genetically encoded sensors for population and subcellular imaging of cAMP in vivo.

Cyclic adenosine monophosphate (cAMP) signaling integrates information from diverse G-protein-coupled receptors, such as neuromodulator receptors, to regulate pivotal biological processes in a cellular-specific and subcellular-specific manner. However, in vivo cellular-resolution imaging of cAMP dynamics remains challenging. Here, we screen existing genetically encoded cAMP sensors and further develop the best performer to derive three improved variants, called cAMPFIREs. Compared with their parental sensor, these sensors exhibit up to 10-fold increased sensitivity to cAMP and a cytosolic distribution. cAMPFIREs are compatible with both ratiometric and fluorescence lifetime imaging and can detect cAMP dynamics elicited by norepinephrine at physiologically relevant, nanomolar concentrations. Imaging of cAMPFIREs in awake mice reveals tonic levels of cAMP in cortical neurons that are associated with wakefulness, modulated by opioids, and differentially regulated across subcellular compartments. Furthermore, enforced locomotion elicits neuron-specific, bidirectional cAMP dynamics. cAMPFIREs also function in Drosophila. Overall, cAMPFIREs may have broad applicability for studying intracellular signaling in vivo.

A declaração PRISMA 2020: diretriz atualizada para relatar revisões sistemáticas / The PRISMA 2020 statement: an updated guideline for reporting systematic reviews / Declaración PRISMA 2020: una guía actualizada para la publicación de revisiones sistemáticas

RESUMO A declaração dos Principais Itens para Relatar Revisões Sistemáticas e Meta-análises (PRISMA), publicada em 2009, foi desenvolvida para ajudar revisores sistemáticos a relatar de forma transparente por que a revisão foi feita, os métodos empregados e o que os autores encontraram. Na última década, os avanços na metodologia e terminologia de revisões sistemáticas exigiram a atualização da diretriz. A declaração PRISMA 2020 substitui a declaração de 2009 e inclui novas orientações para relato que refletem os avanços nos métodos para identificar, selecionar, avaliar e sintetizar estudos. A estrutura e apresentação dos itens foram modificadas para facilitar a implementação. Neste artigo, apresentamos a lista de checagem PRISMA 2020 de 27 itens, uma lista de checagem expandida que detalha as recomendações para relato para cada item, a lista de checagem PRISMA 2020 para resumos e os fluxogramas revisados para novas revisões e para atualização de revisões.

ABSTRACT The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement, published in 2009, was designed to help systematic reviewers transparently report why the review was done, what the authors did, and what they found. Over the past decade, advances in systematic review methodology and terminology have necessitated an update to the guideline. The PRISMA 2020 statement replaces the 2009 statement and includes new reporting guidance that reflects advances in methods to identify, select, appraise, and synthesise studies. The structure and presentation of the items have been modified to facilitate implementation. In this article, we present the PRISMA 2020 27-item checklist, an expanded checklist that details reporting recommendations for each item, the PRISMA 2020 abstract checklist, and the revised flow diagrams for original and updated reviews.

RESUMEN La declaración PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses), publicada en 2009, se diseñó para ayudar a los autores de revisiones sistemáticas a documentar de manera transparente el porqué de la revisión, qué hicieron los autores y qué encontraron. Durante la última década, ha habido muchos avances en la metodología y terminología de las revisiones sistemáticas, lo que ha requerido una actualización de esta guía. La declaración PRISMA 2020 sustituye a la declaración de 2009 e incluye una nueva guía de presentación de las publicaciones que refleja los avances en los métodos para identificar, seleccionar, evaluar y sintetizar estudios. La estructura y la presentación de los ítems ha sido modificada para facilitar su implementación. En este artículo, presentamos la lista de verificación PRISMA 2020 con 27 ítems, y una lista de verificación ampliada que detalla las recomendaciones en la publicación de cada ítem, la lista de verificación del resumen estructurado PRISMA 2020 y el diagrama de flujo revisado para revisiones sistemáticas.

Noninvasive Scale Measurement of Stroke Volume and Cardiac Output Compared With the Direct Fick Method: A Feasibility Study.

Background Objective markers of cardiac function are limited in the outpatient setting and may be beneficial for monitoring patients with chronic cardiac conditions. We assess the accuracy of a scale, with the ability to capture ballistocardiography, electrocardiography, and impedance plethysmography signals from a patient's feet while standing on the scale, in measuring stroke volume and cardiac output compared with the gold-standard direct Fick method. Methods and Results Thirty-two patients with unexplained dyspnea undergoing level 3 invasive cardiopulmonary exercise test at a tertiary medical center were included in the final analysis. We obtained scale and direct Fick measurements of stroke volume and cardiac output before and immediately after invasive cardiopulmonary exercise test. Stroke volume and cardiac output from a cardiac scale and the direct Fick method correlated with r=0.81 and r=0.85, respectively (P<0.001 each). The mean absolute error of the scale estimated stroke volume was -1.58 mL, with a 95% limits of agreement of -21.97 to 18.81 mL. The mean error for the scale estimated cardiac output was -0.31 L/min, with a 95% limits of agreement of -2.62 to 2.00 L/min. The changes in stroke volume and cardiac output before and after exercise were 78.9% and 96.7% concordant, respectively, between the 2 measuring methods. Conclusions In a proof-of-concept study, this novel scale with cardiac monitoring abilities may allow for noninvasive, longitudinal measures of cardiac function. Using the widely accepted form factor of a bathroom scale, this method of monitoring can be easily integrated into a patient's lifestyle.

Translation Initiation Machinery as a Tumor Selective Target for Radiosensitization.

Towards improving the efficacy of radiotherapy, one approach is to target the molecules and processes mediating cellular radioresponse. Along these lines, translational control of gene expression has been established as a fundamental component of cellular radioresponse, which suggests that the molecules participating in this process (i.e., the translational machinery) can serve as determinants of radiosensitivity. Moreover, the proteins comprising the translational machinery are often overexpressed in tumor cells suggesting the potential for tumor specific radiosensitization. Studies to date have shown that inhibiting proteins involved in translation initiation, the rate-limiting step in translation, specifically the three members of the eIF4F cap binding complex eIF4E, eIF4G, and eIF4A as well as the cap binding regulatory kinases mTOR and Mnk1/2, results in the radiosensitization of tumor cells. Because ribosomes are required for translation initiation, inhibiting ribosome biogenesis also appears to be a strategy for radiosensitization. In general, the radiosensitization induced by targeting the translation initiation machinery involves inhibition of DNA repair, which appears to be the consequence of a reduced expression of proteins critical to radioresponse. The availability of clinically relevant inhibitors of this component of the translational machinery suggests opportunities to extend this approach to radiosensitization to patient care.

General Review on the Current Management of Incidental Findings on Cross-Sectional Imaging: What Guidelines to Use, How to Follow Them, and Management and Medical-Legal Considerations.

"Incidentalomas" are a common part of daily practice for radiologists, and knowledge of appropriate management guidelines is important in ensuring that no potentially clinically relevant findings are missed or are lost to follow-up in asymptomatic patients. Incidental findings of the brain, spine, thyroid, lungs, breasts, liver, adrenals, spleen, pancreas, kidneys, bowel, and ovaries are discussed, including where to find guidelines for management recommendations, how to follow them, and medical-legal considerations.

The PRISMA 2020 statement: An updated guideline for reporting systematic reviews.

The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement, published in 2009, was designed to help systematic reviewers transparently report why the review was done, what the authors did, and what they found. Over the past decade, advances in systematic review methodology and terminology have necessitated an update to the guideline. The PRISMA 2020 statement replaces the 2009 statement and includes new reporting guidance that reflects advances in methods to identify, select, appraise, and synthesise studies. The structure and presentation of the items have been modified to facilitate implementation. In this article, we present the PRISMA 2020 27-item checklist, an expanded checklist that details reporting recommendations for each item, the PRISMA 2020 abstract checklist, and the revised flow diagrams for original and updated reviews.

Creating a Program to Support Registering and Reporting Clinical Trials at Johns Hopkins University.

PROBLEM: The Food and Drug Administration Amendments Act of 2007 (FDAAA) and the National Institutes of Health (NIH) require that many clinical trials register and report results on ClinicalTrials.gov. Noncompliance with these policies denies research participants and scientists access to potentially relevant findings and could lead to monetary penalties or loss of funding. After discovering hundreds of potentially noncompliant trials affiliated with the institution, the Johns Hopkins University School of Medicine (JHUSOM) sought to develop a program to support research teams with registration and reporting requirements. APPROACH: JHUSOM conducted a baseline assessment of institutional compliance in 2015, launched the ClinicalTrials.gov Program in June 2016, and expanded the program to the Sidney Kimmel Comprehensive Cancer Center in April 2018. The program is innovative in its comprehensive approach, and it was among the first to bring a large number of trials into compliance. OUTCOMES: From September 2015 to September 2020, JHUSOM brought completed and ongoing trials into compliance with FDAAA and NIH policies and maintained almost perfect compliance for new trials. During this period, the proportion of trials potentially noncompliant with the FDAAA decreased from 44% (339/774) to 2% (32/1,304). NEXT STEPS: JHUSOM continues to develop and evaluate tools and procedures that facilitate trial registration and results reporting. In collaboration with other academic medical centers, JHUSOM plans to share resources and to identify and disseminate best practices. This report identifies practical lessons for institutions that might develop similar programs.

Moving Genomics to Routine Care: An Initial Pilot in Acute Cardiovascular Disease.

BACKGROUND: Whole-genome sequencing (WGS) costs are falling, yet, outside oncology, this information is seldom used in adult clinics. We piloted a rapid WGS (rWGS) workflow, focusing initially on estimating power for a feasibility study of introducing genome information into acute cardiovascular care. METHODS: A prospective implementation study was conducted to test the feasibility and clinical utility of rWGS in acute cardiovascular care. rWGS was performed on 50 adult patients with acute cardiovascular events and cardiac arrest survivors, testing for primary and secondary disease-causing variants, cardiovascular-related pharmacogenomics, and carrier status for recessive diseases. The impact of returning rWGS results on short-term clinical care of participants was investigated. The utility of polygenic risk scores to stratify coronary artery disease was also assessed. RESULTS: Pathogenic variants, typically secondary findings, were identified in 20% (95% CI, 11.7-34.3). About 60% (95% CI, 46.2-72.4) of participants were carriers for one or more recessive traits, most commonly in HFE and SERPINA1 genes. Although 64% (95% CI, 50.1-75.9) of participants carried at least one pharmacogenetic variant of cardiovascular relevance, these were actionable in only 14% (95% CI, 7-26.2). Coronary artery disease prevalence among participants at the 95th percentile of polygenic risk score was 88.2% (95% CI, 71.8-95.7). CONCLUSIONS: We demonstrated the feasibility of rWGS integration into the inpatient management of adults with acute cardiovascular events. Our pilot identified pathogenic variants in one out of 5 acute vascular patients. Integrating rWGS in clinical care will progressively increase actionability.

Clinical trial registration and reporting: a survey of academic organizations in the United States.

BACKGROUND: Many clinical trials conducted by academic organizations are not published, or are not published completely. Following the US Food and Drug Administration Amendments Act of 2007, "The Final Rule" (compliance date April 18, 2017) and a National Institutes of Health policy clarified and expanded trial registration and results reporting requirements. We sought to identify policies, procedures, and resources to support trial registration and reporting at academic organizations. METHODS: We conducted an online survey from November 21, 2016 to March 1, 2017, before organizations were expected to comply with The Final Rule. We included active Protocol Registration and Results System (PRS) accounts classified by ClinicalTrials.gov as a "University/Organization" in the USA. PRS administrators manage information on ClinicalTrials.gov. We invited one PRS administrator to complete the survey for each organization account, which was the unit of analysis. RESULTS: Eligible organization accounts (N = 783) included 47,701 records (e.g., studies) in August 2016. Participating organizations (366/783; 47%) included 40,351/47,701 (85%) records. Compared with other organizations, Clinical and Translational Science Award (CTSA) holders, cancer centers, and large organizations were more likely to participate. A minority of accounts have a registration (156/366; 43%) or results reporting policy (129/366; 35%). Of those with policies, 15/156 (11%) and 49/156 (35%) reported that trials must be registered before institutional review board approval is granted or before beginning enrollment, respectively. Few organizations use computer software to monitor compliance (68/366; 19%). One organization had penalized an investigator for non-compliance. Among the 287/366 (78%) accounts reporting that they allocate staff to fulfill ClinicalTrials.gov registration and reporting requirements, the median number of full-time equivalent staff is 0.08 (interquartile range = 0.02-0.25). Because of non-response and social desirability, this could be a "best case" scenario. CONCLUSIONS: Before the compliance date for The Final Rule, some academic organizations had policies and resources that facilitate clinical trial registration and reporting. Most organizations appear to be unprepared to meet the new requirements. Organizations could enact the following: adopt policies that require trial registration and reporting, allocate resources (e.g., staff, software) to support registration and reporting, and ensure there are consequences for investigators who do not follow standards for clinical research.

The quality of systematic reviews about interventions for refractive error can be improved: a review of systematic reviews.

BACKGROUND: Systematic reviews should inform American Academy of Ophthalmology (AAO) Preferred Practice Pattern® (PPP) guidelines. The quality of systematic reviews related to the forthcoming Preferred Practice Pattern® guideline (PPP) Refractive Errors & Refractive Surgery is unknown. We sought to identify reliable systematic reviews to assist the AAO Refractive Errors & Refractive Surgery PPP. METHODS: Systematic reviews were eligible if they evaluated the effectiveness or safety of interventions included in the 2012 PPP Refractive Errors & Refractive Surgery. To identify potentially eligible systematic reviews, we searched the Cochrane Eyes and Vision United States Satellite database of systematic reviews. Two authors identified eligible reviews and abstracted information about the characteristics and quality of the reviews independently using the Systematic Review Data Repository. We classified systematic reviews as "reliable" when they (1) defined criteria for the selection of studies, (2) conducted comprehensive literature searches for eligible studies, (3) assessed the methodological quality (risk of bias) of the included studies, (4) used appropriate methods for meta-analyses (which we assessed only when meta-analyses were reported), (5) presented conclusions that were supported by the evidence provided in the review. RESULTS: We identified 124 systematic reviews related to refractive error; 39 met our eligibility criteria, of which we classified 11 to be reliable. Systematic reviews classified as unreliable did not define the criteria for selecting studies (5; 13%), did not assess methodological rigor (10; 26%), did not conduct comprehensive searches (17; 44%), or used inappropriate quantitative methods (3; 8%). The 11 reliable reviews were published between 2002 and 2016. They included 0 to 23 studies (median = 9) and analyzed 0 to 4696 participants (median = 666). Seven reliable reviews (64%) assessed surgical interventions. CONCLUSIONS: Most systematic reviews of interventions for refractive error are low methodological quality. Following widely accepted guidance, such as Cochrane or Institute of Medicine standards for conducting systematic reviews, would contribute to improved patient care and inform future research.

Acute HIV infection presenting as hemophagocytic lymphohistiocytosis: case report and review of the literature.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is an uncommon systemic inflammatory condition that can result from infections, autoimmune diseases and malignancies. It is a rarely reported life threatening complication of an acute HIV infection, with only ten documented case reports per our literature search. We present a case of HLH secondary to acute HIV infection with a negative HIV antibody-based assay and high plasma viral load. CASE PRESENTATION: A 45 year old male with a past medical history of well controlled hypertension presented with fever, dizziness and non-bloody diarrhea. Initial lab work revealed a new thrombocytopenia, marked renal failure and an elevated creatine kinase, ferritin, lactate dehydrogenase and D-dimer. A bone marrow biopsy revealed HLH. As part of the work up for thrombocytopenia, a rapid HIV antibody based assay was done and was negative. The sample was later routinely tested with a fourth generation antigen/antibody assay as per local protocol and was strongly positive. The plasma RNA viral load was >10,000,000 copies /mL confirming the diagnosis of an acute HIV infection. The patient was urgently started on antiretroviral therapy and recovered. CONCLUSION: This case illustrates a diagnostic approach to HLH which is an uncommon but life threatening multisystem disease, requiring the involvement of a multidisciplinary team of experts. Following any diagnosis of HLH, rapid identification and treatment of the underlying condition is critical. A negative rapid HIV antibody test can be misleading in the context of early HIV infection and the additional use of fourth generation antigen/antibody test or plasma RNA viral load may be required within the right clinical context for diagnosis.

Anatomical Evaluation of the Proximity of Neurovascular Structures During Arthroscopically Assisted Acromioclavicular Joint Reconstruction: A Cadaveric Pilot Study.

PURPOSE: The purpose of this study was to examine the safety of an arthroscopic technique for acromioclavicular joint (ACJ) reconstruction by investigating its proximity to important neurovascular structures. METHODS: Six shoulders from 4 cadaveric specimens were used for ACJ reconstruction in this study. The procedure consists of performing an arthroscopic acromioclavicular (AC) reduction with a double button construct, followed by coracoclavicular ligament reconstruction without drilling clavicular tunnels. Shoulders were subsequently dissected in order to identify and measure distances to adjacent neurovascular structures. RESULTS: The suprascapular artery and nerve were the closest neurovascular structures to implanted materials. The mean distances were 8.2 (standard deviation [SD] = 3.6) mm to the suprascapular nerve and 5.6 (SD = 4.2) mm to the suprascapular artery. The mean distance of the suprascapular nerve from implants was found to be greater than 5 mm (P = .040), while the distance to the suprascapular artery was not (P > .5). Neither difference was statistically significant (P = .80 for artery; P = .08 for nerve). CONCLUSIONS: Mini-open, arthroscopically assisted ACJ reconstruction safely avoids the surrounding nerves, with no observed damage to any neurovascular structures including the suprascapular nerve and artery, and may be a viable alternative to open techniques. However, surgeons must remain cognizant of possible close proximity to the suprascapular artery. CLINICAL RELEVANCE: This study represents an evaluation of the safety and feasibility of a minimally invasive ACJ reconstruction as it relates to the proximity of neurovascular structures.

Preventive zinc supplementation for children, and the effect of additional iron: a systematic review and meta-analysis.

OBJECTIVE: Zinc deficiency is widespread, and preventive supplementation may have benefits in young children. Effects for children over 5 years of age, and effects when coadministered with other micronutrients are uncertain. These are obstacles to scale-up. This review seeks to determine if preventive supplementation reduces mortality and morbidity for children aged 6 months to 12 years. DESIGN: Systematic review conducted with the Cochrane Developmental, Psychosocial and Learning Problems Group. Two reviewers independently assessed studies. Meta-analyses were performed for mortality, illness and side effects. DATA SOURCES: We searched multiple databases, including CENTRAL and MEDLINE in January 2013. Authors were contacted for missing information. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised trials of preventive zinc supplementation. Hospitalised children and children with chronic diseases were excluded. RESULTS: 80 randomised trials with 205 401 participants were included. There was a small but non-significant effect on all-cause mortality (risk ratio (RR) 0.95 (95% CI 0.86 to 1.05)). Supplementation may reduce incidence of all-cause diarrhoea (RR 0.87 (0.85 to 0.89)), but there was evidence of reporting bias. There was no evidence of an effect of incidence or prevalence of respiratory infections or malaria. There was moderate quality evidence of a very small effect on linear growth (standardised mean difference 0.09 (0.06 to 0.13)) and an increase in vomiting (RR 1.29 (1.14 to 1.46)). There was no evidence of an effect on iron status. Comparing zinc with and without iron cosupplementation and direct comparisons of zinc plus iron versus zinc administered alone favoured cointervention for some outcomes and zinc alone for other outcomes. Effects may be larger for children over 1 year of age, but most differences were not significant. CONCLUSIONS: Benefits of preventive zinc supplementation may outweigh any potentially adverse effects in areas where risk of zinc deficiency is high. Further research should determine optimal intervention characteristics and delivery strategies.

Poxvirus infection-associated downregulation of C-type lectin-related-b prevents NK cell inhibition by NK receptor protein-1B.

Innate immune recognition of virus-infected cells includes NK cell detection of changes to endogenous cell-surface proteins through inhibitory receptors. One such receptor system is the NK cell receptor protein-1B (NKR-P1B) and its ligand C-type lectin-related-b (Clr-b). NKR-P1B and Clr-b are encoded within the NK cell gene complex, a locus that has been linked to strain-dependent differences in susceptibility to infection by poxviruses. In this study, we report the impact of vaccinia virus (VV) and ectromelia virus infection on expression of Clr-b and Clr-b-mediated protection from NK cells. We observed a loss of Clr-b cell-surface protein upon VV and ectromelia virus infection of murine cell lines and bone marrow-derived macrophages. The reduction of Clr-b is more rapid than MHC class I, the prototypic ligand of NK cell inhibitory receptors. Reduction of Clr-b requires active viral infection but not expression of late viral genes, and loss of mRNA appears to lag behind loss of Clr-b surface protein. Clr-b-mediated protection from NK cells is lost following VV infection. Together, these results provide the second example of Clr-b modulation during viral infection and suggest reductions of Clr-b may be involved in sensitizing poxvirus-infected cells to NK cells.