Pathophysiology of acute experimental pancreatitis: Lessons from genetically engineered animal models and new molecular approaches

The incidence of acute pancreatitis is growing and worldwide population-based studies report a doubling or tripling since the 1970s. 25% of acute pancreatitis are severe and associated with histological changes of necrotizing pancreatitis. There is still no specific medical treatment for acute pancreatitis. The average mortality resides around 10%. In order to develop new specific medical treatment strategies for acute pancreatitis, a better understanding of the pathophysiology during the onset of acute pancreatitis is necessary. Since it is difficult to study the early acinar events in human pancreatitis, several animal models of acute pancreatitis have been developed. By this, it is hoped that clues into human pathophysiology become possible. In the last decade, while employing molecular biology techniques, a major progress has been made. The genome of the mouse was recently sequenced. Various strategies are possible to prove a causal effect of a single gene or protein, using either gain-of-function (i.e., overexpression of the protein of interest) or loss-of-function studies (i.e., genetic deletion of the gene of interest). The availability of transgenic mouse models and gene deletion studies has clearly increased our knowledge about the pathophysiology of acute pancreatitis and enables us to study and confirm in vitro findings in animal models. In addition, transgenic models with specific genetic deletion or overexpression of genes help in understanding the role of one specific protein in a cascade of inflammatory processes such as pancreatitis where different proteins interact and co-react. This review summarizes the recent progress in this field. Copyright (c) 2005 S. Karger AG, Basel

Operating Different Displays in Military Fast Jets Using Eye Gaze Tracker

This paper investigated the use of an eye-gaze-controlled interface in a military aviation environment. We set up a flight simulator and used the gaze-controlled interface in three different configurations of displays (head down, head up, and head mounted) for military fast jets. Our studies found that the gaze-controlled interface statistically significantly increased the speed of interaction for secondary mission control tasks compared to touchscreen- and joystick-based target designation system. Finally, we tested a gaze-controlled system inside an aircraft both on the ground and in different phases of flight with military pilots. Results showed that they could undertake representative pointing and selection tasks in less than two seconds, on average

Estimating pilots’ cognitive load from ocular parameters through simulation and in-flight studies

Eye tracking is the process of measuring either the point of gaze (where one is looking) or the motion of an eye relative to the head. This paper investigated use of eye gaze trackers in military aviation environment to automatically estimate pilot’s cognitive load from ocular parameters. We used a fixed base variable stability flight simulator with longitudinal tracking task and collected data from 14 military pilots. In a second study, we undertook three test flights with a BAES Hawk Trainer aircraft doing air to ground attack training missions and constant G level turn maneuvers up to +5G. Our study found that ocular parameters like rate of fixation is significantly different in different flying conditions and significantly correlate with altitude gradient during air to ground dive training task, normal load factor (G) of the aircraft during constant G level turn maneuvers and pilot’s control inceptor and tracking error in simulation tasks. Results from our studies can be used for real time estimation of pilots’ cognitive load, providing suitable warnings and alerts to the pilot in cockpit and training of military pilots on cognitive load management during operational missions

Оптимизация магнитной пружины конструкции ''два постоянных магнита''

Изучена возможность оптимизации магнитной пружины типа ''два постоянных магнита''. Проведено теоретическое исследование зависимости усилия втягивания (вытягивания) и длины рабочего хода пружины от ее геометрических размеров. Все полученные результаты были подтверждены экспериментально. Отмечается хорошее соответствие теоретических и экспериментальных результатов. Установлены оптимальные соотношения между диаметрами внешнего и внутреннего цилиндрических магнитов для получения максимального усилия втягивания при заданной длине хода пружины. Предложена перспективная конструкция магнитной пружины с применением торцевого диска и проведены ее экспериментальные исследования.Вивчено можливість оптимізації магнітної пружини типу ''два постійні магніти''. Проведено теоретичне дослідження взаємозв'язку геометричних розмірів пружини з її зусиллям втягування (витягування) і довжиною робочого ходу. Всі отримані результати було підтверджено експериментально. Відзначається хороша відповідність теоретичних і експериментальних результатів. Встановлено оптимальні співвідношення між діаметрами зовнішнього й внутрішнього циліндричних магнітів для отримання максимального зусилля втягування при заданій довжині ходу пружини. Запропоновано перспективну конструкцію магнітної пружини із застосуванням торцевого диску й проведено її експериментальні дослідження.Optimization possibilities of a magnetic spring (''two permanent magnets'' type) are investigated. The theoretical calculation of the relationship of geometrical sizes and forces is carried out. All theoretical results are checked experimentally. A very good agreement of theoretical and experimental data is detected. The optimal ratio between two diameters of cylinder magnets for the maximal force at a given spring length is calculated. The perspective construction of a magnetic spring with applying the butt-end soft magnetic material disk is offered, and its experimental tests are carried out

Educational Case: Mantle Cell Lymphoma

The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, see http://journals.sagepub.com/doi/10.1177/2374289517715040

Synthetic Nanoparticles for Vaccines and Immunotherapy

The immune system plays a critical role in our health. No other component of human physiology plays a decisive role in as diverse an array of maladies, from deadly diseases with which we are all familiar to equally terrible esoteric conditions: HIV, malaria, pneumococcal and influenza infections; cancer; atherosclerosis; autoimmune diseases such as lupus, diabetes, and multiple sclerosis. The importance of understanding the function of the immune system and learning how to modulate immunity to protect against or treat disease thus cannot be overstated. Fortunately, we are entering an exciting era where the science of immunology is defining pathways for the rational manipulation of the immune system at the cellular and molecular level, and this understanding is leading to dramatic advances in the clinic that are transforming the future of medicine.1,2 These initial advances are being made primarily through biologic drugs– recombinant proteins (especially antibodies) or patient-derived cell therapies– but exciting data from preclinical studies suggest that a marriage of approaches based in biotechnology with the materials science and chemistry of nanomaterials, especially nanoparticles, could enable more effective and safer immune engineering strategies. This review will examine these nanoparticle-based strategies to immune modulation in detail, and discuss the promise and outstanding challenges facing the field of immune engineering from a chemical biology/materials engineering perspectiveNational Institutes of Health (U.S.) (Grants AI111860, CA174795, CA172164, AI091693, and AI095109)United States. Department of Defense (W911NF-13-D-0001 and Awards W911NF-07-D-0004

Engineering the surface properties of a human monoclonal antibody prevents self-association and rapid clearance in vivo

Uncontrolled self-association is a major challenge in the exploitation of proteins as therapeutics. Here we describe the development of a structural proteomics approach to identify the amino acids responsible for aberrant self-association of monoclonal antibodies and the design of a variant with reduced aggregation and increased serum persistence in vivo. We show that the human monoclonal antibody, MEDI1912, selected against nerve growth factor binds with picomolar affinity, but undergoes reversible self-association and has a poor pharmacokinetic profile in both rat and cynomolgus monkeys. Using hydrogen/deuterium exchange and cross-linking-mass spectrometry we map the residues responsible for self-association of MEDI1912 and show that disruption of the self-interaction interface by three mutations enhances its biophysical properties and serum persistence, whilst maintaining high affinity and potency. Immunohistochemistry suggests that this is achieved via reduction of non-specific tissue binding. The strategy developed represents a powerful and generic approach to improve the properties of therapeutic proteins

Evaluation of Comparative Efficacy and Safety of Surgical Approaches for Total Hip Arthroplasty: A Systematic Review and Network Meta-analysis.

IMPORTANCE: Each approach for primary total hip arthroplasty (THA) has a long learning curve, so a surgeon's choice to change their preferred approach needs to be guided by clear justifications. However, current evidence does not suggest that any of the THA approaches are more beneficial than others, and the choice of approach is mainly based on the knowledge and experience of the surgeon and individual patient characteristics. OBJECTIVE: To assess the efficacy and safety associated with different surgical approaches for THA. DATA SOURCES: A comprehensive search of PubMed, EMBASE, and Cochrane databases from inception to March 26, 2022; reference lists of eligible trials; and related reviews. STUDY SELECTION: Randomized clinical trials (RCTs) comparing different surgical approaches, including the 2-incision approach, direct anterior approach (DAA), direct lateral approach (DLA), minimally invasive direct lateral approach (MIS-DLA), minimally invasive anterolateral approach (MIS-ALA), posterior approach (PA), minimally invasive posterior approach (MIS-PA), and supercapsular percutaneously assisted total hip arthroplasty (SuperPath), for primary THA. DATA EXTRACTION AND SYNTHESIS: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses, 2 reviewers independently extracted data on study participants, interventions, and outcomes as well as assessed the risk of bias using the Cochrane risk of bias tool and the certainty of evidence using the Grading of Recommendations, Assessment, Development, and Evaluation framework. A frequentist framework was used to inform a series of random-effects network meta-analyses. MAIN OUTCOMES AND MEASURES: The outcomes were hip score (range, 0-100, with higher scores indicating better overall hip condition), pain score (range, 0-100, with higher scores indicating more pain), hospitalization time, operation time, quality of life score, blood loss, cup abduction angle, and cup anteversion angle. RESULTS: Of 2130 retrieved studies, 63 RCTs including 4859 participants (median [IQR] age, 64.0 [60.3-66.5] years; median [IQR] percentage male, 46.74% [38.64%-54.74%]) were eligible for analysis. Eight surgical approaches were evaluated. For hip score, DAA (mean difference [MD], 4.04; 95% CI, 1.92 to 6.16; moderate certainty), MIS-ALA (MD, 3.00; 95% CI, 0.43 to 5.59; moderate certainty), MIS-DLA (MD, 3.37; 95% CI, 1.05 to 5.68; moderate certainty), MIS-PA (MD, 4.46; 95% CI, 1.60 to 7.31; moderate certainty), PA (MD, 4.37; 95% CI, 1.87 to 6.88; high certainty), and SuperPath (MD, 5.00; 95% CI, 0.58 to 9.42; high certainty) were associated with greater improvement in hip score compared with DLA. DLA was associated with lower decrease in pain score than SuperPath (MD, 1.16; 95% CI, 0.13 to 2.20; high certainty) and MIS-DLA (MD, 0.90; 95% CI, 0.04 to 1.76; moderate certainty). PA was associated with shorter operation times compared with 2-incision (MD, -23.85 minutes; 95% CI, -36.60 to -11.10 minutes; high certainty), DAA (MD, -13.94 minutes; 95% CI, -18.79 to -9.08 minutes; moderate certainty), DLA (MD, -10.50 minutes; 95% CI, -16.07 to -4.94 minutes; high certainty), MIS-ALA (MD, -6.76 minutes; 95% CI, -12.86 to -0.65 minutes; moderate certainty), and SuperPath (MD, -13.91 minutes; 95% CI, -21.87 to -5.95 minutes; moderate certainty). The incidence of 6 types of complications did not differ significantly between the approaches. CONCLUSIONS AND RELEVANCE: In this study, moderate to high certainty evidence indicated that compared with PA, all surgical approaches except DLA were associated with similar improvements of hip score but longer operation time. DLA was associated with smaller improvement of hip score. The safety of the different approaches did not show significant differences. These findings will help health professionals and patients with better clinical decision-making and also provide references for policy makers

Improving diabetes and pre-diabetes detection in the uk: insights from hba1c screening in an acute hospital’s emergency department

Introduction Many individuals in the community have undiagnosed glucose intolerance, type 2 diabetes (T2D), and pre-diabetes (Pre-DM). This study explored screening for unknown glucose intolerance in the emergency department (ED) in an acute hospital. Methods 1382 persons attending the ED without T2D were screened using HbA1c. T2D and Pre-DM were classified using American Diabetes Association (ADA) and National Institute for Health and Care Excellence (NICE) criteria. The Finnish Diabetes Risk Score (FINDRISC) was calculated in all patients. Results According to NICE criteria, 80.1% (1107 individuals) exhibited normal glucose tolerance, 11.6% (160 individuals) exhibited pre-diabetes, and 8.3% (115 individuals) exhibited diabetes. Each unit increase in FINDRISC score, using multinomial regression, corresponded to an 8% (5–12%; p < 0.001) higher risk for pre-diabetes and a 16% (10–23%; p < 0.001) higher risk for diabetes (NICE). The risk remained elevated even after adjusting for age, sex, and ethnicity. South-Asians had higher glucose intolerance rates than white British (34.8% versus 18.5%) using the NICE criteria, and even greater at 50.0% versus 37.6% using ADA criteria. The adjusted relative risk of having pre-diabetes in people of color compared with white British individuals was 1.77 (1.04–3.00; p = 0.034, ADA) and 2.84 (1.41–5.65; p = 0.003, NICE). The multinomial relative-risk ratio (RRRs) for having diabetes by ethnicity was 2.97 (1.73–5.08; p < 0.0001, ADA) and 2.80 (1.59–4.94; p < 0.0001, NICE). Conclusions Routine HbA1c screening in the ED, with FINDRISC scoring, successfully identifies individuals with diabetes and pre-diabetes. This approach could enable early intervention, particularly in groups at higher risk of glucose intolerance. Trial registration ClinicalTrials.gov identifier, NCT04653545