Showing papers in "Frontiers of Medicine in China in 2019"

From Big Data to Precision Medicine.

Abstract: For over a decade the term "Big data" has been used to describe the rapid increase in volume, variety and velocity of information available, not just in medical research but in almost every aspect of our lives. As scientists, we now have the capacity to rapidly generate, store and analyse data that, only a few years ago, would have taken many years to compile. However, "Big data" no longer means what it once did. The term has expanded and now refers not to just large data volume, but to our increasing ability to analyse and interpret those data. Tautologies such as "data analytics" and "data science" have emerged to describe approaches to the volume of available information as it grows ever larger. New methods dedicated to improving data collection, storage, cleaning, processing and interpretation continue to be developed, although not always by, or for, medical researchers. Exploiting new tools to extract meaning from large volume information has the potential to drive real change in clinical practice, from personalized therapy and intelligent drug design to population screening and electronic health record mining. As ever, where new technology promises "Big Advances," significant challenges remain. Here we discuss both the opportunities and challenges posed to biomedical research by our increasing ability to tackle large datasets. Important challenges include the need for standardization of data content, format, and clinical definitions, a heightened need for collaborative networks with sharing of both data and expertise and, perhaps most importantly, a need to reconsider how and when analytic methodology is taught to medical researchers. We also set "Big data" analytics in context: recent advances may appear to promise a revolution, sweeping away conventional approaches to medical science. However, their real promise lies in their synergy with, not replacement of, classical hypothesis-driven methods. The generation of novel, data-driven hypotheses based on interpretable models will always require stringent validation and experimental testing. Thus, hypothesis-generating research founded on large datasets adds to, rather than replaces, traditional hypothesis driven science. Each can benefit from the other and it is through using both that we can improve clinical practice.

Treatment of Infections Due to MDR Gram-Negative Bacteria.

Abstract: The treatment of multidrug-resistant Gram-negative bacteria (MDR-GNB) infections in critically ill patients presents many challenges. Since an effective treatment should be administered as soon as possible, resistance to many antimicrobial classes almost invariably reduces the probability of adequate empirical coverage, with possible unfavorable consequences. In this light, readily available patient's medical history and updated information about the local microbiological epidemiology remain critical for defining the baseline risk of MDR-GNB infections and firmly guiding empirical treatment choices, with the aim of avoiding both undertreatment and overtreatment. Rapid diagnostics and efficient laboratory workflows are also of paramount importance both for anticipating diagnosis and for rapidly narrowing the antimicrobial spectrum, with de-escalation purposes and in line with antimicrobial stewardship principles. Carbapenem-resistant Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter baumannii are being reported with increasing frequencies worldwide, although with important variability across regions, hospitals and even single wards. In the past few years, new treatment options, such as ceftazidime/avibactam, meropenem/vaborbactam, ceftolozane/tazobactam, plazomicin, and eravacycline have become available, and others will become soon, which have provided some much-awaited resources for effectively counteracting severe infections due to these organisms. However, their optimal use should be guaranteed in the long term, for delaying as much as possible the emergence and diffusion of resistance to novel agents. Despite important progresses, pharmacokinetic/pharmacodynamic optimization of dosages and treatment duration in critically ill patients has still some areas of uncertainty requiring further study, that should take into account also resistance selection as a major endpoint. Treatment of severe MDR-GNB infections in critically ill patients in the near future will require an expert and complex clinical reasoning, of course taking into account the peculiar characteristics of the target population, but also the need for adequate empirical coverage and the more and more specific enzyme-level activity of novel antimicrobials with respect to the different resistance mechanisms of MDR-GNB.

Translational AI and Deep Learning in Diagnostic Pathology

Abstract: There has been an exponential growth in the application of AI in health and in pathology. This is resulting in the innovation of deep learning technologies that are specifically aimed at cellular imaging and practical applications that could transform diagnostic pathology. This paper reviews the different approaches to deep learning in pathology, the public grand challenges that have driven this innovation and a range of emerging applications in pathology. The translation of AI into clinical practice will require applications to be embedded seamlessly within digital pathology workflows, driving an integrated approach to diagnostics and providing pathologists with new tools that accelerate workflow and improve diagnostic consistency and reduce errors. The clearance of digital pathology for primary diagnosis in the US by some manufacturers provides the platform on which to deliver practical AI. AI and computational pathology will continue to mature as researchers, clinicians, industry, regulatory organizations and patient advocacy groups work together to innovate and deliver new technologies to health care providers: technologies which are better, faster, cheaper, more precise, and safe.

Deep Learning for Whole Slide Image Analysis: An Overview.

Abstract: The widespread adoption of whole slide imaging has increased the demand for effective and efficient gigapixel image analysis. Deep learning is at the forefront of computer vision, showcasing significant improvements over previous methodologies on visual understanding. However, whole slide images have billions of pixels and suffer from high morphological heterogeneity as well as from different types of artifacts. Collectively, these impede the conventional use of deep learning. For the clinical translation of deep learning solutions to become a reality, these challenges need to be addressed. In this paper, we review work on the interdisciplinary attempt of training deep neural networks using whole slide images, and highlight the different ideas underlying these methodologies.

Gut Microbiota and Chronic Constipation: A Review and Update.

Abstract: Background: Chronic constipation, including functional constipation and constipation-type irritable bowel syndrome, is a prevalent, multifactorial gastrointestinal disorder, and its etiology and pathophysiology remain poorly understood. Recently studies using 16S rRNA-based microbiota profiling have demonstrated dysbiosis of gut microbiota in chronic constipation. Aims: To provide an overview of recent studies for microbiota in chronic constipation and treatments for chronic constipation using probiotics, prebiotics, synbiotics, antibiotics and fecal microbiota transplantation (FMT). Methods: PubMed searches were performed up to 1 August 2018 using keywords: "IBS," "IBS-C," "irritable bowel syndrome," "irritable bowel syndrome with constipation," "functional constipation," "chronic constipation" in combination with "gut microbiota," "dysbiosis," "gut microflora" for microbiota in chronic constipation, and in combination with "probiotics," "prebiotics," "synbiotics," "antibiotics," and "fecal microbiota transplantation." Results: The findings of gut microbiota in functional constipation are inconsistent, and currently no consensus exists. Although no clear consensus exists, compared with healthy subjects, IBS-C patients have a lower level of Actinobacteria, including Bifidobacteria, in their fecal samples and a higher level of Bacteroidetes in their mucosa. In most randomized controlled and parallel-group trials, probiotics, prebiotics, synbiotics, antibiotics, and FMT therapy for chronic constipation were effective with few side effects. However, there are many studies in a small number and the types of probiotics are different, it is difficult to evaluate the effect. Conclusions: Evidence indicates that dysbiosis of gut microbiota may contribute to functional constipation and constipation-type irritable bowel syndrome. Targeting treatments for the dysbiosis of constipation by probiotics, prebiotics, synbiotics, antibiotics, and FMT may be a new option, especially for refractory constipation to conventional therapies.

Biomarkers for Immune Checkpoint Inhibitor-Mediated Tumor Response and Adverse Events.

Abstract: In the last decade, inhibitors targeting immune checkpoint molecules such as cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death 1 (PD-1), and programmed cell death-ligand 1 (PD-L1) brought about a major paradigm shift in cancer treatment. These immune checkpoint inhibitors (ICIs) improved the overall survival of a variety of cancer such as malignant melanoma and non-small lung cancer. In addition, numerous clinical trials for additional indication of ICIs including adjuvant and neo-adjuvant therapies are also currently ongoing. Therefore, more and more patients will receive ICIs in the future. However, despite the improved outcome of the cancer treatment by ICIs, the efficacy remains still limited and tumor regression have not been obtained in many cancer patients. In addition, treatment with ICIs is also associated with substantial toxicities, described as immune-related adverse events (irAEs). Therefore, biomarkers to predict tumor response and occurrence of irAEs by the treatment with ICIs are required to avoid overtreatment of ICIs and minimize irAEs development. Whereas, numerous factors have been reported as potential biomarkers for tumor response to ICIs, factors for predicting irAE have been less reported. In this review, we show recent advances in the understanding of biomarkers for tumor response and occurrence of irAEs in cancer patients treated with ICIs.

Frailty as a predictor of cognitive disorders: A systematic review and meta-analysis

Abstract: Background/Aim: Current evidence in the literature supports associations between frailty, cognitive impairment and dementia. The study aim was to describe the risk of cognitive disorders associated with physical frailty in older adults from community-based studies. Methods: We performed a systematic review and meta-analysis, using MEDLINE, PsycINFO, Scopus and Web of Science as databases for the search. Cohort and longitudinal studies were included in qualitative analysis and quantitative synthesis. For inclusion, studies had to assess dementia and cognitive impairment as a primary or secondary outcome, and describe the prevalence of frailty among participants at baseline and follow-up. Results: Of the 2,210 studies retrieved by the systematic review, 6 relevant studies were included in a meta-analysis. Baseline frailty was significantly associated with an increased risk of geriatric cognitive disorders (pooled OR = 1.80, 95% CI = 1.11-2.92; p = 0.02). Heterogeneity across the studies was significant (I2 = 79%). Conclusions: The analyses confirmed that frail older adults were at higher risk of incident cognitive disorders than non-frail elders. Frailty status seems to be most associated with the risk of incident dementia. Frailty may represent a risk factor for dementia and could constitute a novel modifiable target in early cognitive impairment.

Cardiovascular Risk in Fatty Liver Disease: The Liver-Heart Axis-Literature Review.

Abstract: According to the World Health Organization, cardiovascular disease (CVD) remains the leading cause of death worldwide, accounting for approximately 18 million deaths per year. Nevertheless, the worldwide prevalence of metabolic diseases, such as type 2 diabetes mellitus, obesity, and non-alcoholic fatty liver disease (NAFLD), also known to be common risk factors for CVD, have dramatically increased over the last decades. Chronic alcohol consumption is a major cause of chronic liver diseases (CLD) as well as being a major health care cost expenditure accounting for the spending of tremendous amounts of money annually. NAFLD has become one of the major diseases plaguing the world while standing as the most common cause of liver disease in the Western countries by representing about 75% of all CLD. Currently, the most common cause of death in NAFLD remains to be CVD. Several mechanisms have been suggested to be responsible for associating FLD with CVD through several mechanisms including low-grade systemic inflammation, oxidative stress, adipokines, endoplasmic reticulum stress, lipotoxicity and microbiota dysbiosis which may also be influenced by other factors such as genetic and epigenetic variations. Despite of all this evidence, the exact mechanisms of how FLD can causally contribute to CVD are not fully elucidated and much remains unknown. Moreover, the current literature supports the increasing evidence associating FLD with several cardiovascular (CV) adverse events including coronary artery disease, increased subclinical atherosclerosis risk, structural alterations mainly left ventricular hypertrophy, increased epicardial fat thickness, valvular calcifications including aortic valve sclerosis and mitral annular calcification and functional cardiac modifications mainly diastolic dysfunction in addition to cardiac arrhythmias such as atrial fibrillation and ventricular arrythmias and conduction defects including atrioventricular blocks and bundle branch blocks. Patients with FLD should be evaluated and managed accordingly in order to prevent further complications. Possible management methods include non-pharmacological strategies including life style modifications, pharmacological therapies as well as surgical management. This review aims to summarize the current state of knowledge regarding the pathophysiological mechanisms linking FLD with an increased CV risk, in addition to associated CV adverse events and current management modalities.

Health and Well-Being in Late Life: Gender Differences Worldwide

Abstract: Maintaining health and quality of life and decreasing the number of years lived with disabilities in old age are among the main challenges of aging societies worldwide. This paper aims to present current worldwide health-related gender inequalities throughout life, and especially in late life, as well as gender gaps in social and personal resources which affect health, functioning and well-being. This paper also addresses the question of whether gender gaps at younger ages tend to narrow in late life, due to the many biological and social changes that occur in old age. Based on international data regarding these gender gaps and the trends of change in personal resources and health-related lifestyles in the more and less developed nations, conclusions regarding future changes in gender gaps are presented, along with practical implications for future improvements in women's health and well-being.

Frailty and Intrinsic Capacity: Two Distinct but Related Constructs.

Abstract: Frailty is a clinical condition characterized by the individual's increased vulnerability to endogenous and exogenous stressors. It is determined by the reduction of homeostatic capacities of the organism and responsible for a marked risk of adverse health outcomes (including functional loss and mortality). Frailty originates from the geriatric background and may pave the way toward a model of care centered on the person, deviating from the traditional and obsolete disease-focused approach. Unfortunately, many controversies have affected the field of frailty over the years and ambiguities have been growing. In particular, the common use of frailty as condition to "exclude" from interventions is a worrisome trend. In fact, the detection of frailty should instead represent the entry point for a more in-depth analysis with the aim of identifying the causes of individual's increased vulnerability and implementing a person-tailored intervention plan. With the aim of promoting a more comprehensive and appropriate assessment of the aging population, the World Health Organization introduced the concept of intrinsic capacity (IC), defined as the composite of all physical and mental capacities that an individual can draw upon during his/her life. Frailty and IC are two constructs stemming from the same need of overcoming traditional medical paradigms that negatively impact on the correct way clinical and research practice should be conducted in older persons. In this article, we describe the similarities and differences between the two constructs, highlighting how geriatric medicine contributed to their development and will be crucial for their further integration in future healthcare models.

IL-17 in Rheumatoid Arthritis and Precision Medicine: From Synovitis Expression to Circulating Bioactive Levels.

Abstract: Interleukin (IL)-17A has a direct contribution in early induction and late chronic stages of various inflammatory diseases. In vitro and in vivo experiments have first characterized its local effects on different cell types and then its systemic effects. For instance, IL-17 axis is now identified as a key driver of psoriasis through its effects on keratinocytes. Similar observations apply for rheumatoid arthritis (RA) where IL-17A triggers changes in the synovium that lead to synovitis and maintain local inflammation. These results have prompted the development of biologics to target this cytokine. However, while convincing studies are reported on the efficacy of IL-17 inhibitors in psoriasis, there are conflicting results in RA. Patient heterogeneity but also the involvement of mediators that regulate IL-17 function may explain these results. Therefore, new tools and concepts are required to identify patients that could benefit from these IL-17 targeted therapies in RA and the development of predictive biomarkers of response has started with the emergence of various bioassays. Current strategies are also focusing on synovial biopsies that may be used to stratify patients. From local to systemic levels, new approaches are developing and move the field of RA management into the era of precision medicine.

Dental stem cell and dental tissue regeneration

Abstract: The teeth are highly differentiated chewing organs formed by the development of tooth germ tissue located in the jaw and consist of the enamel, dentin, cementum, pulp, and periodontal tissue. Moreover, the teeth have a complicated regulatory mechanism, special histologic origin, diverse structure, and important function in mastication, articulation, and aesthetics. These characteristics, to a certain extent, greatly complicate the research in tooth regeneration. Recently, new ideas for tooth and tissue regeneration have begun to appear with rapid developments in the theories and technologies in tissue engineering. Numerous types of stem cells have been isolated from dental tissue, such as dental pulp stem cells (DPSCs), stem cells isolated from human pulp of exfoliated deciduous teeth (SHED), periodontal ligament stem cells (PDLSCs), stem cells from apical papilla (SCAPs), and dental follicle cells (DFCs). All these cells can regenerate the tissue of tooth. This review outlines the cell types and strategies of stem cell therapy applied in tooth regeneration, in order to provide theoretical basis for clinical treatments.

The FGF metabolic axis

Abstract: Members of the fibroblast growth factor (FGF) family play pleiotropic roles in cellular and metabolic homeostasis. During evolution, the ancestor FGF expands into multiple members by acquiring divergent structural elements that enable functional divergence and specification. Heparan sulfate-binding FGFs, which play critical roles in embryonic development and adult tissue remodeling homeostasis, adapt to an autocrine/paracrine mode of action to promote cell proliferation and population growth. By contrast, FGF19, 21, and 23 coevolve through losing binding affinity for extracellular matrix heparan sulfate while acquiring affinity for transmembrane α-Klotho (KL) or β-KL as a coreceptor, thereby adapting to an endocrine mode of action to drive interorgan crosstalk that regulates a broad spectrum of metabolic homeostasis. FGF19 metabolic axis from the ileum to liver negatively controls diurnal bile acid biosynthesis. FGF21 metabolic axes play multifaceted roles in controlling the homeostasis of lipid, glucose, and energy metabolism. FGF23 axes from the bone to kidney and parathyroid regulate metabolic homeostasis of phosphate, calcium, vitamin D, and parathyroid hormone that are important for bone health and systemic mineral balance. The significant divergence in structural elements and multiple functional specifications of FGF19, 21, and 23 in cellular and organismal metabolism instead of cell proliferation and growth sufficiently necessitate a new unified and specific term for these three endocrine FGFs. Thus, the term “FGF Metabolic Axis,” which distinguishes the unique pathways and functions of endocrine FGFs from other autocrine/paracrine mitogenic FGFs, is coined.

Epidermolysis Bullosa Acquisita: The 2019 Update

Abstract: Epidermolysis bullosa acquisita (EBA) is an orphan autoimmune disease. Patients with EBA suffer from chronic inflammation as well as blistering and scarring of the skin and mucous membranes. Current treatment options rely on non-specific immunosuppression, which in many cases, does not lead to a remission of treatment. Hence, novel treatment options are urgently needed for the care of EBA patients. During the past decade, decisive clinical observations, and frequent use of pre-clinical model systems have tremendously increased our understanding of EBA pathogenesis. Herein, we review all of the aspects of EBA, starting with a detailed description of epidemiology, clinical presentation, diagnosis, and current treatment options. Of note, pattern analysis via direct immunofluorescence microscopy of a perilesional skin lesion and novel serological test systems have significantly facilitated diagnosis of the disease. Next, a state-of the art review of the current understanding of EBA pathogenesis, emerging treatments and future perspectives is provided. Based on pre-clinical model systems, cytokines and kinases are among the most promising therapeutic targets, whereas high doses of IgG (IVIG) and the anti-CD20 antibody rituximab are among the most promising "established" EBA therapeutics. We also aim to raise awareness of EBA, as well as initiate basic and clinical research in this field, to further improve the already improved but still unsatisfactory conditions for those diagnosed with this condition.

Rhenium-188 Labeled Radiopharmaceuticals: Current Clinical Applications in Oncology and Promising Perspectives

Abstract: Rhenium-188 (188Re) is a high energy beta-emitting radioisotope with a short 16.9 h physical half-life, which has been shown to be a very attractive candidate for use in therapeutic nuclear medicine. The high beta emission has an average energy of 784 keV and a maximum energy of 2.12 MeV, sufficient to penetrate and destroy targeted abnormal tissues. In addition, the low-abundant gamma emission of 155 keV (15%) is efficient for imaging and for dosimetric calculations. These key characteristics identify 188Re as an important therapeutic radioisotope for routine clinical use. Moreover, the highly reproducible on-demand availability of 188Re from the 188W/188Re generator system is an important feature and permits installation in hospital-based or central radiopharmacies for cost-effective availability of no-carrier-added (NCA) 188Re. Rhenium-188 and technetium-99 m exhibit similar chemical properties and represent a "theranostic pair." Thus, preparation and targeting of 188Re agents for therapy is similar to imaging agents prepared with 99mTc, the most commonly used diagnostic radionuclide. Over the last three decades, radiopharmaceuticals based on 188Re-labeled small molecules, including peptides, antibodies, Lipiodol and particulates have been reported. The successful application of these 188Re-labeled therapeutic radiopharmaceuticals has been reported in multiple early phase clinical trials for the management of various primary tumors, bone metastasis, rheumatoid arthritis, and endocoronary interventions. This article reviews the use of 188Re-radiopharmaceuticals which have been investigated in patients for cancer treatment, demonstrating that 188Re represents a cost effective alternative for routine clinical use in comparison to more expensive and/or less readily available therapeutic radioisotopes.

iPSC-Derived Hepatocytes as a Platform for Disease Modeling and Drug Discovery.

Abstract: The liver is one of the largest organs in the body and is responsible for a diverse repertoire of metabolic processes. Such processes include the secretion of serum proteins, carbohydrate and lipid metabolism, bile acid and urea synthesis, detoxification of drugs and metabolic waste products, and vitamin and carbohydrate storage. Currently, liver disease is one of the most prevalent causes of mortality in the USA with congenital liver defects contributing to a significant proportion of these deaths. Historically the study of liver disease has been hampered by a shortage of organ donors, the subsequent scarcity of healthy tissue, and the failure of animal models to fully recapitulate human liver function. In vitro culture of hepatocytes has also proven difficult because primary hepatocytes rapidly de-differentiate in culture. Recent advances in stem cell technology have facilitated the generation of induced pluripotent stem cells (iPSCs) from various somatic cell types from patients. Such cells can be differentiated to a liver cell fate, essentially providing a limitless supply of cells with hepatocyte characteristics that can mimic the pathophysiology of liver disease. Furthermore, development of the CRISPR-Cas9 system, as well as advancement of miniaturized differentiation platforms has facilitated the development of high throughput models for the investigation of hepatocyte differentiation and drug discovery. In this review, we will explore the latest advances in iPSC-based disease modeling and drug screening platforms and examine how this technology is being used to identify new pharmacological interventions, and to advance our understanding of liver development and mechanisms of disease. We will cover how iPSC technology is being used to develop predictive models for rare diseases and how information gained from large in vitro screening experiments can be used to directly inform clinical investigation.

Management of cytokine release syndrome related to CAR-T cell therapy

Abstract: Chimeric antigen receptor T (CAR-T) cell therapy is a novel cellular immunotherapy that is widely used to treat hematological malignancies, including acute leukemia, lymphoma, and multiple myeloma. Despite its remarkable clinical effects, this therapy has side effects that cannot be underestimated. Cytokine release syndrome (CRS) is one of the most clinically important and potentially life-threatening toxicities. This syndrome is a systemic immune storm that involves the mass cytokines releasing by activated immune cells. This phenomenon causes multisystem damages and sometimes even death. In this study, we reported the management of a patient with recurrent and refractory multiple myeloma and three patients with acute lymphocytic leukemia who suffered CRS during CAR-T treatment. The early application of tocilizumab, an anti-IL-6 receptor antibody, according to toxicity grading and clinical manifestation is recommended especially for patients who suffer continuous hyperpyrexia, hypotensive shock, acute respiratory failure, and whose CRS toxicities deteriorated rapidly. Moreover, low doses of dexamethasone (5-10 mg/day) were used for refractory CRS not responding to tocilizumab. The effective management of the toxicities associated with CRS will bring additional survival opportunities and improve the quality of life for patients with cancer.

A Ledger of Me: Personalizing Healthcare Using Blockchain Technology

Abstract: Personal Health Records (PHRs) have the potential to give patients fine-grained, personalized and secure access to their own medical data and to enable self-management of care. Emergent trends around the use of Blockchain, or Distributed Ledger Technology, seem to offer solutions to some of the problems faced in enabling these technologies, especially to support issues consent, data exchange, and data access. We present an analysis of existing blockchain-based health record solutions and a reference architecture for a "Ledger of Me" system that extends PHR to create a new platform combining the collection and access of medical data and digital interventions with smart contracts. Our intention is to enable patient use of the data in order to support their care and to provide a strong consent mechanisms for sharing of data between different organizations and apps. Ledger of Me is based on around the principle that this combination of event-driven smart contracts, medical record data, and patient control is important for the adoption of blockchain-based solutions for the PHR. The reference architecture we present can serve as the basis of a range of future blockchain-based medical application architectures.

Is There a Preferred Mode of Exercise for Cognition Enhancement in Older Age?—A Narrative Review

Abstract: The aim of this review is to examine the moderating effect of the mode of exercise on the exercise-cognition relationship. Is one mode of exercise more efficient in enhancing cognition than the other? For example, is aerobic exercise preferable over balance training? Based on official guidelines for old age, exercise modes include aerobic activity, strength (resistance) training, flexibility, balance, and coordination. In relation to cognition, these exercise modes are further divided into two categories: physical training-aerobic and strength, and motor training-balance, coordination, and flexibility. The physical training activities are repetitive and automatic in nature, and require high metabolic energy and relatively low neuromuscular effort. The motor activities involve high neuromuscular demands and relatively low metabolic demands. In addition, there are specific movement skills that require more neuromuscular effort (e.g., Tai Chi), and sometimes also greater metabolic demands (e.g., tennis). Selected studies examining the effect of various modes of exercise on cognition contend that both training categories affect neuroplasticity, and consequently cognitive functioning. However, there are two main differences between them: (1) Physical training affects cognition via improvement in cardiovascular fitness, whereas motor training affects cognition directly; (2) Physical training affects neuroplasticity and cognition in a global manner, while motor training is task-specific in increasing brain neuroplasticity and in affecting cognition. Examining the underpinnings of these pathways reveals that there is a difference in the underlying forces behind the two training categories. In the physical training category, it is the intensity of training that enhances neuroplasticity and consequently improves cognition, while in the motor activities it is the task complexity that increases neuroplasticity, which improves cognition. Dual-task training, which includes cognitive demands in addition to physical or motor activity, has proven more effective in improving cognitive functioning than a single task. The implications are that if all training components traditionally recommended by official bodies-physical as well as motor training-are efficient in enhancing cognition, then we merely have to emphasize the inclusion of all exercise modes in our routine exercise regimen for physical as well as cognitive health in advanced age.

SERPINs-From Trap to Treatment.

Abstract: Excessive enzyme activity often has pathological consequences. This for example is the case in thrombosis and hereditary angioedema, where serine proteases of the coagulation system and kallikrein-kinin system are excessively active. Serine proteases are controlled by SERPINs (serine protease inhibitors). We here describe the basic biochemical mechanisms behind SERPIN activity and identify key determinants that influence their function. We explore the clinical phenotypes of several SERPIN deficiencies and review studies where SERPINs are being used beyond replacement therapy. Excitingly, rare human SERPIN mutations have led us and others to believe that it is possible to refine SERPINs toward desired behavior for the treatment of enzyme-driven pathology.

Antimicrobial Resistance in Nepal.

Abstract: Antimicrobial resistance (AMR) is a global problem to animal and public health. It has drawn the attention of public health experts, stakeholders, and medical science due to the substantial economic loss that it causes to individuals and nation as a whole. Various cross-sectional studies and some national surveys in developing countries have shown increase in the burden of antimicrobial resistance. Nepal is one of the major contributors to the growing burden of AMR due to widespread irrational use of antibiotics along with poor health care systems poor infection control and prevention measures. This review was conducted to summarize the situation of AMR in Nepal, determinants of AMR, current government intervention strategies and the way forward to reduce the AMR burden in Nepal. Available cross sectional reports warn that bacterial pathogens are becoming highly resistant to most first- and some second-line antibiotics. The irrational and injudicious use of high doses of antibiotics for therapy and sub-optimal doses as growth promoters are leading causes of AMR in Nepal. Establishment of a surveillance programme and a national plan for containment of AMR, following the National Antibiotics Treatment Guideline 2014 and generation of awareness among veterinarians, technicians, and medical physicians on prudent use of antimicrobial drugs in Nepal could reduce the burden of AMR. In addition, there is a need to develop a national laboratory strategic plan to provide guidance and governance to national laboratories.

Endoglin as an Adhesion Molecule in Mature and Progenitor Endothelial Cells: A Function Beyond TGF-β.

Abstract: Endoglin (ENG) is a transmembrane glycoprotein expressed on endothelial cells that functions as a co-receptor for several ligands of the transforming growth factor beta (TGF-β) family. ENG is also a recognized marker of angiogenesis and mutations in the endoglin gene are responsible for Hereditary Hemorrhagic Telangiectasia (HHT) type 1, a vascular disease characterized by defective angiogenesis, arteriovenous malformations, telangiectasia, and epistaxis. In addition to its involvement in the TGF-β family signaling pathways, several lines of evidence suggest that the extracellular domain of ENG has a role in integrin-mediated cell adhesion via its RGD motif. Indeed, we have described a role for endothelial ENG in leukocyte trafficking and extravasation via its binding to leukocyte integrins. We have also found that ENG is involved in vasculogenic properties of endothelial progenitor cells known as endothelial colony forming cells (ECFCs). Moreover, the binding of endothelial ENG to platelet integrins regulate the resistance to shear during platelet-endothelium interactions under inflammatory conditions. Because of the need for more effective treatments in HHT and the involvement of ENG in angiogenesis, current studies are aimed at identifying novel biological functions of ENG which could serve as a therapeutic target. This review focuses on the interaction between ENG and integrins with the aim to better understand the role of this protein in blood vessel formation driven by progenitor and mature endothelial cells.

Methotrexate-Associated Pneumonitis and Rheumatoid Arthritis-Interstitial Lung Disease: Current Concepts for the Diagnosis and Treatment

Abstract: Rheumatoid arthritis (RA) is a type of inflammatory arthritis that affects ~1% of the general population. Although arthritis is the cardinal symptom, many extra-articular manifestations can occur. Lung involvement and particularly interstitial lung disease (ILD) is among the most common. Although ILD can occur as part of the natural history of RA (RA-ILD), pulmonary fibrosis has been also linked with methotrexate (MTX); a condition also known as MTX-pneumonitis (M-pneu). This review aims to discuss epidemiological, diagnostic, imaging and histopathological features, risk factors, and treatment options in RA-ILD and M-pneu. M-pneu, usually has an acute/subacute course characterized by cough, dyspnea and fever. Several risk factors, including genetic and environmental factors have been suggested, but none have been validated. The diagnosis is based on clinical and radiologic findings which are mostly consistent with non-specific interstitial pneumonia (NSIP), more so than bronchiolitis obliterans organizing pneumonia (BOOP). Histological findings include interstitial infiltrates by lymphocytes, histiocytes, and eosinophils with or without non-caseating granulomas. Treatment requires immediate cessation of MTX and commencement of glucocorticoids. RA-ILD shares the same symptomatology with M-pneu. However, it usually has a more chronic course. RA-ILD occurs in about 3-5% of RA patients, although this percentage is significantly increased when radiologic criteria are used. Usual interstitial pneumonia (UIP) and NSIP are the most common radiologic patterns. Several risk factors have been identified for RA-ILD including smoking, male gender, and positivity for anti-citrullinated peptide antibodies and rheumatoid factor. Diagnosis is based on clinical and radiologic findings while pulmonary function tests may demonstrate a restrictive pattern. Although no clear guidelines exist for RA-ILD treatment, glucocorticoids and conventional disease modifying antirheumatic drugs (DMARDs) like MTX or leflunomide, as well as treatment with biologic DMARDs can be effective. There is limited evidence that rituximab, abatacept, and tocilizumab are better options compared to TNF-inhibitors.

Best Practices of Blood Cultures in Low- and Middle-Income Countries

Abstract: Bloodstream infections (BSI) have a substantial impact on morbidity and mortality worldwide. Despite scarcity of data from many low- and middle-income countries (LMICs), there is increasing awareness of the importance of BSI in these countries. For example, it is estimated that the global mortality of non-typhoidal Salmonella bloodstream infection in children under 5 already exceeds that of malaria. Reliable and accurate diagnosis of these infections is therefore of utmost importance. Blood cultures are the reference method for diagnosis of BSI. LMICs face many challenges when implementing blood cultures, due to financial, logistical, and infrastructure-related constraints. This review aims to provide an overview of the state-of-the-art of sampling and processing of blood cultures, with emphasis on its use in LMICs. Laboratory processing of blood cultures is relatively straightforward and can be done without the need for expensive and complicated equipment. Automates for incubation and growth monitoring have become the standard in high-income countries (HICs), but they are still too expensive and not sufficiently robust for imminent implementation in most LMICs. Therefore, this review focuses on "manual" methods of blood culture, not involving automated equipment. In manual blood cultures, a bottle consisting of a broth medium supporting bacterial growth is incubated in a normal incubator and inspected daily for signs of growth. The collection of blood for blood culture is a crucial step in the process, as the sensitivity of blood cultures depends on the volume sampled; furthermore, contamination of the blood culture (accidental inoculation of environmental and skin bacteria) can be avoided by appropriate antisepsis. In this review, we give recommendations regarding appropriate blood culture sampling and processing in LMICs. We present feasible methods to detect and speed up growth and discuss some challenges in implementing blood cultures in LMICs, such as the biosafety aspects, supply chain and waste management.

A High-Performance System for Robust Stain Normalization of Whole-Slide Images in Histopathology

Abstract: Stain normalization is an important processing task for computer-aided diagnosis (CAD) systems in modern digital pathology. This task reduces the color and intensity variations present in stained images from different laboratories. Consequently, stain normalization typically increases the prediction accuracy of CAD systems. However, there are computational challenges that this normalization step must overcome, especially for real-time applications: the memory and run-time bottlenecks associated with the processing of images in high resolution, e.g., 40X. Moreover, stain normalization can be sensitive to the quality of the input images, e.g., when they contain stain spots or dirt. In this case, the algorithm may fail to accurately estimate the stain vectors. We present a high-performance system for stain normalization using a state-of-the-art unsupervised method based on stain-vector estimation. Using a highly-optimized normalization engine, our architecture enables high-speed and large-scale processing of high-resolution whole-slide images. This optimized engine integrates an automated thresholding technique to determine the useful pixels and uses a novel pixel-sampling method that significantly reduces the processing time of the normalization algorithm. We demonstrate the performance of our architecture using measurements from images of different sizes and scanner formats that belong to four different datasets. The results show that our optimizations achieve up to 58x speedup compared to a baseline implementation. We also prove the scalability of our system by showing that the processing time scales almost linearly with the amount of tissue pixels present in the image. Furthermore, we show that the output of the normalization algorithm can be adversely affected when the input images include artifacts. To address this issue, we enhance the stain normalization pipeline by introducing a parameter cross-checking technique that automatically detects the distortion of the algorithm's critical parameters. To assess the robustness of the proposed method we employ a machine learning (ML) pipeline that classifies images for detection of prostate cancer. The results show that the enhanced normalization algorithm increases the classification accuracy of the ML pipeline in the presence of poor-quality input images. For an exemplary ML pipeline, our new method increases the accuracy on an unseen dataset from 0.79 to 0.87.

The Revival of the Notes Field: Leveraging the Unstructured Content in Electronic Health Records

Abstract: Problem: Clinical practice requires the production of a time- and resource-consuming great amount of notes. They contain relevant information, but their secondary use is almost impossible, due to their unstructured nature. Researchers are trying to address this problems, with traditional and promising novel techniques. Application in real hospital settings seems not to be possible yet, though, both because of relatively small and dirty dataset, and for the lack of language-specific pre-trained models. Aim: Our aim is to demonstrate the potential of the above techniques, but also raise awareness of the still open challenges that the scientific communities of IT and medical practitioners must jointly address to realize the full potential of unstructured content that is daily produced and digitized in hospital settings, both to improve its data quality and leverage the insights from data-driven predictive models. Methods: To this extent, we present a narrative literature review of the most recent and relevant contributions to leverage the application of Natural Language Processing techniques to the free-text content electronic patient records. In particular, we focused on four selected application domains, namely: data quality, information extraction, sentiment analysis and predictive models, and automated patient cohort selection. Then, we will present a few empirical studies that we undertook at a major teaching hospital specializing in musculoskeletal diseases. Results: We provide the reader with some simple and affordable pipelines, which demonstrate the feasibility of reaching literature performance levels with a single institution non-English dataset. In such a way, we bridged literature and real world needs, performing a step further toward the revival of notes fields.

The Multitasking Potential of Alarmins and Atypical Chemokines.

Abstract: When the human genome was sequenced, it came as a surprise that it contains "only" 21,306 protein-coding genes. However, complexity and diversity are multiplied by alternative splicing, non-protein-coding transcripts, or post-translational modifications (PTMs) on proteome level. Here, we discuss how the multi-tasking potential of proteins can substantially enhance the complexity of the proteome further, while at the same time offering mechanisms for the fine-regulation of cell responses. Discoveries over the past two decades have led to the identification of "surprising" and previously unrecognized functionalities of long known cytokines, inflammatory mediators, and intracellular proteins that have established novel molecular networks in physiology, inflammation, and cardiovascular disease. In this mini-review, we focus on alarmins and atypical chemokines such as high-mobility group box protein-1 (HMGB-1) and macrophage migration-inhibitory factor (MIF)-type proteins that are prototypical examples of these classes, featuring a remarkable multitasking potential that allows for an elaborate fine-tuning of molecular networks in the extra- and intracellular space that may eventually give rise to novel "task"-based precision medicine intervention strategies.

The Prevalence of Sensitive Skin.

Abstract: Sensitive skin has been described as unpleasant sensory responses to stimuli that should not provoke such sensations. Objectively measurable signs of irritation are not always present in individuals with sensitive skin, however, subjective sensory effects such as, itching, burning, stinging, tightness, and dryness, are consistently present. Given the subjective nature of the phenomenon known as sensitive skin, surveys have been a popular approach to evaluating the prevalence of this condition among the general population, and a number of them have been conducted worldwide. Overall, ~60-70% of women and 50-60% of men report having some degree of sensitive skin. However, there are differences between populations in various geographies, and perceptions of sensitive skin at specific anatomic sites. This article is a review of survey data on the prevalence of self-declared sensitive skin in various geographies, among different gender and age groups, and at various anatomic sites. In addition, we review the factors that may contribute to sensitive skin, and the physiological characteristics associated with this condition, including impaired barrier function and heightened neural reactions.

Infections in the Elderly Critically-Ill Patients.

Abstract: Infections are leading causes of morbidity and mortality in the advanced aged. Various factors including immunosenescens, comorbid chronic diseases, and alterations in normal physiological organ functions may modify the frequency and severity of infections in elderly patients. Normal body reactions to ensuing infection, such as increased body temperature, may be blunted in those patients causing difficulties in differential diagnosis between infection and other diseases. In severe infections the respiratory and urinary tracts are the most frequently involved systems which may be accompanied by severe sepsis. Bacteremia and sepsis are also associated with indwelling vascular catheters in the elderly who are admitted to the intensive care unit (ICU). Older patients are more vulnerable to the Clostridioides difficile infection, as well. Although the general management of infections in severely ill elderly patients is not different than in younger patients, meticulous care in fluid management and careful individualized optimization in antibiotic therapy, along with the other principals of antimicrobial stewardship are warranted in order to prevent increased mortality caused by infection. Organized team management when treating critically ill elderly patients in the ICU is essential and will reduce the morbidity and mortality due to infection in such patients.

Hybrid polymer biomaterials for bone tissue regeneration

Abstract: Native tissues possess unparalleled physiochemical and biological functions, which can be attributed to their hybrid polymer composition and intrinsic bioactivity. However, there are also various concerns or limitations over the use of natural materials derived from animals or cadavers, including the potential immunogenicity, pathogen transmission, batch to batch consistence and mismatch in properties for various applications. Therefore, there is an increasing interest in developing degradable hybrid polymer biomaterials with controlled properties for highly efficient biomedical applications. There have been efforts to mimic the extracellular protein structure such as nanofibrous and composite scaffolds, to functionalize scaffold surface for improved cellular interaction, to incorporate controlled biomolecule release capacity to impart biological signaling, and to vary physical properties of scaffolds to regulate cellular behavior. In this review, we highlight the design and synthesis of degradable hybrid polymer biomaterials and focus on recent developments in osteoconductive, elastomeric, photoluminescent and electroactive hybrid polymers. The review further exemplifies their applications for bone tissue regeneration.