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We are at a critical stage in managing the response to the COVID-19 outbreak, which requires widespread access to fast and accurate testing. While PCR testing has been the backbone for COVID-19 diagnosis, now there is an urgent need for surveillance of at-risk asymptomatic populations. Antibody tests check for an antibody response to SARS-CoV-2 infection and are used to determine infection and case fatality rates, or potential immunity in recovered patients and in vaccine studies. Effective laboratory SARS-CoV-2 antibody technologies have been developed, and some were validated by the FDA to have Sensitivity (Se) and Specificity (Sp) as high as 99–100%1. For example, an IgG two-step ELISA test measures IgG responses to the recombinant receptor binding domain (RBD) of the SARS-CoV-2 spike protein (1). Positive samples are confirmed in a second step that measures IgG response to the whole spike protein (1), resulting in a 100% Sp (with 92.5% Se)1. However, while accurate, laboratory technologies are slow and rely on expensive equipment. Rapid (minutes vs. hours) and instrument-free SARS-CoV-2 assays are commercially available, and some are already being used in surveillance studies. Debates about the recently reported infection rates in NYC (21.1% as of 04/23/202), or in Santa Clara, CA [2.45% (2)], have raised questions regarding whether antibody testing is sufficiently accurate to guide medical or policy decisions. Recently, the COVID-19 Testing Project validated 10 rapid commercial tests in a head-to-head comparison with samples from 80 SARS-CoV-2 RT-PCR-positive, 108 pre-COVID-19 negative, and 52 recently negative patients (3). Many rapid tests performed worse than their manufacturer's specifications, raising questions about their quality and stability. Moreover, while high specificity is crucial for testing low prevalence population (estimated COVID-19 prevalence is only ~5%), only three out of 10 rapid tests had a Sp of >99%, while maintaining >90% Se (at >16 days after onset of symptoms) (3). More recently, the FDA started their own validation of 13 EUA approved antibody tests and found that only one of the validated rapid tests has a > 99% Sp (with a 95% Se)1. Introducing more stringent FDA criteria has driven the need for highly accurate rapid tests3. Here we summarize some of the limitations of rapid COVID-19 antibody tests and suggested ways for improvement.

This paper proposes an unsupervised way for Phonocardiogram (PCG) analysis, which uses a revised auto encoder based on distribution density estimation in the latent space. Auto encoders especially Variational Auto-Encoders (VAEs) and its variant β−VAE are considered as one of the state-of-the-art methodologies for PCG analysis. VAE based models for PCG analysis assume that normal PCG signals can be represented by latent vectors that obey a normal Gaussian Model, which may not be necessary true in PCG analysis. This paper proposes two methods DBVAE and DBAE that are based on estimating the density of latent vectors in latent space to improve the performance of VAE based PCG analysis systems. Examining the system performance with PCG data from the a single domain and multiple domains, the proposed systems outperform the VAE based methods. The representation of normal PCG signals in the latent space is also investigated by calculating the kurtosis and skewness where DBAE introduces normal PCG representation following Gaussian-like models but DBVAE does not introduce normal PCG representation following Gaussian-like models.

Introduction: Mobile applications promise to improve current health care. However, current mobile app quality ratings are mostly physician-based. The aim of this study was (1) to assess the quality of the self-management app Rheuma Auszeit using the validated uMARS (User Version of the Mobile App Rating Scale) app quality assessment tool and (2) to evaluate the association between uMARS scores and patients' characteristics. Materials and Methods: Consecutive patients with rheumatoid arthritis, psoriatic arthritis and spondyloarthritis were seen at the rheumatology clinic at university hospital Erlangen, Germany. They were asked to test Rheuma Auszeit, evaluate its quality using uMARS and complete a paper-based survey evaluating the individual preferences, attitudes and ehealth literacy. The association between uMARS scores and patients' characteristics was further explored. Results: Between December 2018 and January 2019, a total of 126 patients evaluated Rheuma Auszeit using uMARS and filled out the paper-based survey. The median uMARS score was 3.9, IQR 0.7. Functionality was the domain with the highest rating (median 4.8, IQR 0.8), followed by aesthetics (median 4.0, IQR 0.7), information (median 3.5, IQR 0.8), and engagement (median 3.2, IQR 1.0). Subjective quality was average (median 3.0, IQR 1.0). The lowest scoring individual item was customization with a median of 2.5/5. Lower functionality scores were reported among older female rheumatic patients (P < 0.004). Older male rheumatic patients reported a higher subjective quality score (P < 0.024). Perceived disease activity and disease duration did not significantly correlate with any uMARS subdomain scores. eHealth literacy significantly correlated with functionality uMARS subdomain ratings (Rho = 0.18; P < 0.042). Preferred time of app usage significantly correlated with engagement (Rho = 0.20; P < 0.024), functionality (Rho = 0.19; P < 0.029), total uMARS score (Rho = 0.21; P < 0.017) and subjective quality score (Rho = 0.21; P < 0.017). The vast majority of rheumatic patients would consider recommending Rheuma Auszeit to other patients (117/126; 92.9%). Conclusion: Rheuma Auszeit was well-accepted by German patients suffering from rheumatoid arthritis, psoriatic arthritis and ankylosing spondyloarthritis. Lacking customization could lead to low app compliance and should be improved. Lower functionality scores among older female rheumatic patients highlight the need for patient education. The study underlines the potential and feasibility of therapeutic complementary digital solutions in rheumatology., publishedVersion

The percentage of the world's population living in urban areas is projected to increase in the next decades. Big cities are heterogeneous environments in which socioeconomic and environmental differences among the neighborhoods are often very pronounced. Each individual, during his/her life, is constantly subject to a mix of exposures that have an effect on their phenotype but are frequently difficult to identify, especially in an urban environment. Studying how the combination of environmental and socioeconomic factors which the population is exposed to influences pathological outcomes can help transforming public health from a reactive to a predictive system. Thanks to the application of state-of-the-art spatially enabled methods, patients can be stratified according to their characteristics and the geographical context they live in, optimizing healthcare processes and the reducing its costs. Some public health studies focusing specifically on urban areas have been conducted, but they usually consider a coarse spatial subdivision, as a consequence of scarce availability of well-integrated data regarding health and environmental exposure at a sufficient level of granularity to enable meaningful statistical analyses. In this paper, we present an application of highly fine-grained spatial resolution methods to New York City data. We investigated the link between asthma hospitalizations and a combination of air pollution and other environmental and socioeconomic factors. We first performed an explorative analysis using spatial clustering methods that shows that asthma is related to numerous factors whose level of influence varies considerably among neighborhoods. We then performed a Geographically Weighted Regression with different covariates and determined which environmental and socioeconomic factors can predict hospitalizations and how they vary throughout the city. These methods showed to be promising both for visualization and analysis of demographic and epidemiological urban dynamics, that can be used to organize targeted intervention and treatment policies to address the single citizens considering the factors he/she is exposed to. We found a link between asthma and several factors such as PM2.5, age, health insurance coverage, race, poverty, obesity, industrial areas, and recycling. This study has been conducted within the PULSE project, funded by the European Commission, briefly presented in this paper.

Siloed or singular system approach to disease management is common practice, developing out of traditional medical school education. Textbooks of medicine describe a huge number of discrete diseases, usually in a systematic fashion following headings like etiology, pathology, investigations, differential diagnoses, and management. This approach suggests that the body has a multitude of ways to respond to harmful incidences. However, physiology and systems biology provide evidence that there is a simple mechanism behind this phenotypical variability. Regardless if an injury or change was caused by trauma, infection, non-communicable disease, autoimmune disorders, or stress, the typical physiological response is: an increase in blood supply to the area, an increase in white cells into the affected tissue, an increase in phagocytic activity to remove the offending agent, followed by a down-regulation of these mechanisms resulting in healing. The cascade of inflammation is the body‘s unique mechanism to maintain its integrity in response to macroscopic as well as microscopic injuries. We hypothesize that chronic disease development and progression are linked to uncontrolled or dysfunctional inflammation to injuries regardless of their nature, physical, environmental, or psychological. Thus, we aim to reframe the prevailing approach of management of individual diseases into a more integrated systemic approach of treating the “person as a whole,” enhancing the patient experience, ability to a make necessary changes, and maximize overall health and well-being. The first part of the paper reviews the local immune cascades of pro- and anti-inflammatory regulation and the interconnected feedback loops with neural and psychological pathways. The second part emphasizes one of nature's principles at work—system design and efficiency. Continually overwhelming this finely tuned system will result in systemic inflammation allowing chronic diseases to emerge; the pathways of several common conditions are described in detail. The final part of the paper considers the implications of these understandings for clinical care and explore how this lens could shape the physician-patient encounter and health system redesign. We conclude that healthcare professionals must advocate for an anti-inflammatory lifestyle at the patient level as well as at the local and national levels to enhance population health and well-being.

Primary care providers are critical in providing and optimizing health care to an aging population. This paper describes the volunteer component of a program (Health TAPESTRY) which aims to encourage the delivery of effective primary health care in novel and proactive ways. As part of the program, volunteers visited older adults in their homes and entered information regarding health risks, needs, and goals into an electronic application on a tablet computer. A total of 657 home visits were conducted by 98 volunteers, with 22.45% of volunteers completing at least 20 home visits over the course of the program. Information was summarized in a report and electronically sent to the health care team via clients’ electronic medical records. The report was reviewed by the interprofessional team who then plan ongoing care. Volunteer recruitment, screening, training, retention, and roles are described. This paper highlights the potential role of a volunteer in a unique connection between primary care providers and older adult patients in their homes.

International audience; Editorial on the Research Topic Innovative Radiopharmaceuticals in Oncology and Neurology Personalized medicine is presented as the future of patient care. Nuclear Medicine will play a major role in the selection of patients for targeted therapies and in early therapy assessment with the investigation of phenotypes and functions using sensitive and specific SPECT and PET imaging techniques and theranostic approaches. Nuclear Medicine is already a key in the development of new therapies and targeted radionuclide therapy provides efficacious treatment modalities against cancer. An incredible amount of innovation is related to the use of a variety of radionuclides, new or improved multimodality imaging devices, and numbers of recently marketed radiopharmaceuticals in all medical domains and particularly cardiology, neurology, and oncology. In this context, a network of laboratories and Nuclear Medicine departments, the IRON Laboratory of Excellence (Labex), has been set as part of the French " Investissements d' Avenir " program to help translating innovative radiopharmaceuticals into clinical testing by a multidisciplinary approach from the production of radionuclides using cyclotrons, to basic studies of targets and ligands, clinical trials, and assessment of the societal impacts of innovation in medicine in neurology and oncology. To foster communication between scientists, inside the Labex and with the international community, a series of highly specialized international " Nuclear Technologies for Health Symposia " has been organized annually, with the most recent edition, the third, held in Nantes, France, on March 10–11, 2015. Plenary lectures given by distinguished speakers (Hank Kung, Philadelphia, PA, USA, Tom Bäck, Gothenburg, Sweden, Otto Boerman, Nijmegen, The Netherlands, Franck Bruchertseifer, Karlsruhe, Germany, and Claire Tabouret-Viaud, Geneva, Switzerland) addressed the state of the arts and new developments in the use of radioactivity and radiopharmaceuticals for multimodality imaging and therapy. The latest achievements in clinical nuclear medicine, science, and technology were discussed during interactive oral and poster sessions. Selected talks were organized in four sessions: innovative tracers in neurology: from bench to bedside, multimodality imaging, theranostic in nuclear medicine, and targeted radionuclide therapy. After the meeting, 12 papers were published in the Nuclear Medicine topic open by Frontiers in Medicine. These papers are representative of current research and development in Nuclear Medicine.

This paper analyses the paradigm shift from the disease to the person with the disease against the background of the changes of health systems toward primary health care. The structural changes from hospital to the community and the specialist to the generalist approach are essential to enable this different approach. As a consequence, any assessment of health status, risks, and needs starts with an engagement with an individual. This engagement is the basis from which diagnostic, preventive, and therapeutic interventions are planned, over time, in the continuous working relation primary health care entertains with individuals and populations. Key to the functioning of primary health care is an ongoing renewal or actualization of this working relation, in this paper referred to as the “initial estimate,” that makes it possible to direct resources to those in highest need and at the same time makes it possible to exempt from costly and risky interventions those who have little to gain from it. This “initial estimate” is a major determinant of cost-effective and efficient healthcare, but there is hardly any insight into the process of how professionals in primary health care come to estimate individuals’ risk. This in turn presents a number of challenges and priorities for primary health care research: to build the interaction between practice and researchers in designing and developing tests; secure primary health care research capacity to study and assess tests in the primary health care setting; and secure the implementation of validated tests in routine patient care. to open to research the full setting in which patient and professional interact and integrate in this the contribution of diagnostic tests; to study professionals’ decision making, including the role of “experience” and “intuition,” mechanisms through which the premonition of something being wrong is coming about and to develop methods to train professionals to apply this in an appropriate way; to use these insights to study as well the effectiveness of preventive and therapeutic interventions; as the setting in which professionals operate influences the outcome of their performance, make sure that “every” community is connected to the primary health care research capacity. Introduction Many countries in the world live through a transition of their health care systems toward primary health care. In this, the care of patients is to be led from the community rather than the hospital, by a generalist rather than a specialist. This is in itself a fundamental change – a change in the structure of the health care system, in the conditions and facilities under which it operates and professionals and patients engage. This asks for new structures and models and their implementation is complex in its own right. The development of the concept of “the patient-centered medical home” in the US (1) is a good example of creating approaches that were impossible under the prevailing system. But there is a realistic danger that the transition toward a primary health care structure is seen as just this: replacing the hospital by the community, or the specialist by the generalist, with magical implications attached to this structural solution. Belief in “structural” change, with the generalist-family physician as a super human is often an implicit ingredient of healthcare reform. In this, primary health care continues to operate in the traditions of medicine, with diagnosis and disease as its determining currencies. The orientation on the person is an appreciated and valued add-on with the patient defined to no longer a single disease, but a set of co-existing health problems. But it is highly unlikely that generalists are able to deliver what specialists cannot, only because they practice in another location or there is “family physician” written on their front door. What is essential in the transition of health systems is to secure a different approach, from diseases to individuals with the diseases and populations at risk of the diseases. To be able to achieve this, health care has to be embedded in the environment in which people live and work, run the risk of illness and disease. The health system structural changes are essential exactly because they make a different approach possible, a paradigm shift from the disease to the person with the disease. And this paradigm shift is the pivotal point in reforming health systems. The challenges of primary health care are to capitalize on the working relation it has over time with individuals, families, and communities, in identifying, preventing, and managing health problems. This is the overarching context of continuity and integration of care to provide effective, efficient, safe, and timely health care. However, in the many pressing primary health care research needs, it is an undervalued aspect. This paper explores the challenges of research to support the successful completion of health care reform as a “structure and paradigm shift.” As will be made clear, the experience of seasoned practitioners in the field may well hold the key and research has to be directed to the systematic exploration of this experience, to create the knowledge that is needed to guide the success of how primary health care, how family physicians, can lead the system.

This paper presents the results of a qualitative study based on semi-structured interviews of 10 expert patient advocates on several different issues around Advanced Therapy Medicinal Products (ATMPs). The interviews were conducted between February and May 2020 based on a guideline with a list of 8 topics that covered concerns about safety and ethics, access problems and limitations, pricing of ATMPs and educational needs for patient communities. Overall, the interviewees expressed a high degree of convergence of opinions on most of the topics and especially on the identification of the reasons for concern. Conversely, when asked about possible solutions, quite a wide range of solutions were proposed, although with many common points. However, it highlights that the debate is still in its infancy and that there are not yet consolidated positions across the whole community. A general concern emerging from all the interviews is the potential limitation of access to approved ATMPs, both due to the high prices and to the geographical concentration of treatment centers. However, patients recognize the value of a model with a limited number of specialized clinical centers administering these therapies. On the ethical side, patients do not show particular concern as long as ATMPs and the underlying technology is used to treat severe diseases. Finally, patients are asking for both more education on ATMPs as well as for a more continuous involvement of patient representatives in the whole “life-cycle” of a new ATMP, from the development phase to the authorization, from the definition of the reimbursement scheme to the collection of Real Word Data on safety and long-term efficacy of the treatment.

Background: Rheumatoid arthritis is a chronic disabling disease characterized by chronic inflammation, articular cartilage destruction, and reduced bone mass. Multiple studies have revealed that the development of osteoporosis in rheumatoid arthritis (RA; ORA) patients could be led to a reduced quality of life and increased healthcare costs. Nevertheless, no attempt has been made to analyze the field of ORA research with the bibliometric method. This study aimed to provide a comprehensive overview of the knowledge structure and theme trends in the field of ORA research from a bibliometric perspective.Methods: Articles and reviews regarding ORA from 1998 to 2021 were identified from the Web of Science database. An online bibliometric platform, CiteSpace, and VOSviewer software were used to generate visualization knowledge maps including co-authorship, co-citation, and co-occurrence analysis. SPSS, R, and Microsoft Excel software were used to conduct curve fitting and correlation analysis, and to analyze quantitative indicators, such as publication and citation counts, h-index, and journal citation reports.Results: A total of 1,081 papers with 28,473 citations were identified. Publications were mainly concentrated in North America, Western Europe, and Eastern Asia. Economic strength is an important factor affecting scientific output. The United States contributed the most publications (213) with the highest h-index value (46) as of September 14, 2021. Diakonhjemmet Hospital and professor Haugeberg G were the most prolific institution and influential authors, respectively. Journal of Rheumatology was the most productive journal concerning ORA research. According to the burst references, “anti-citrullinated protein antibodies” and “preventing joint destruction” have been recognized as the hot research issues in the domain. The keywords co-occurrence analysis identified “teriparatide,” “interleukin-6,” “Wnt,” and “vertebral fractures” as the important future research directions.Conclusion: This was the first bibliometric study comprehensively summarizing the trends and development of ORA research. Our findings could offer practical sources for scholars to understand the key information in this field, and identify the potential research frontiers and hot directions in the near future.

Local anesthetics are widely used clinically for perioperative analgesia to achieve comfort in medical treatment. However, when the concentration of local anesthetics in the blood exceeds the tolerance of the body, local anesthetic systemic toxicity (LAST) will occur. With the development and popularization of positioning technology under direct ultrasound, the risks and cases of LAST associated with direct entry of the anesthetic into the blood vessel have been reduced. Clinical occurrence of LAST usually presents as a series of severe toxic reactions such as myocardial depression, which is life-threatening. In addition to basic life support (airway management, advanced cardiac life support, etc.), intravenous lipid emulsion (ILE) has been introduced as a treatment option in recent years and has gradually become the first-line treatment for LAST. This review introduces the mechanisms of LAST and identifies the clinical symptoms displayed by the central nervous system and cardiovascular system. The paper features the multimodal mechanism of LAST reversal by ILE, describes research progress in the field, and identifies other anesthetics involved in the resuscitation process of LAST. Finally, the review presents key issues in lipid therapy. Although ILE has achieved notable success in the treatment of LAST, adverse reactions and contraindications also exist; therefore, ILE requires a high degree of attention during use. More in-depth research on the treatment mechanism of ILE, the resuscitation dosage and method of ILE, and the combined use with other resuscitation measures is needed to improve the efficacy and safety of clinical resuscitation after LAST in the future.

Gastroesophageal reflux disease (GERD) is one of the most frequent gastrointestinal disorders. Proton pump inhibitors (PPIs) are effective in healing lesions and improving symptoms in most cases, although up to 40% of GERD patients do not respond adequately to PPI therapy. Refractory GERD (rGERD) is one of the most challenging problems, given its impact on the quality of life and consumption of health care resources. The definition of rGERD is a controversial topic as it has not been unequivocally established. Indeed, some patients unresponsive to PPIs who experience symptoms potentially related to GERD may not have GERD; in this case the definition could be replaced with “reflux-like PPI-refractory symptoms.” Patients with persistent reflux-like symptoms should undergo a diagnostic workup aimed at finding objective evidence of GERD through endoscopic and pH-impedance investigations. The management strategies regarding rGERD, apart from a careful check of patient's compliance with PPIs, a possible change in the timing of their administration and the choice of a PPI with a different metabolic pathway, include other pharmacologic treatments. These include histamine-2 receptor antagonists (H2RAs), alginates, antacids and mucosal protective agents, potassium competitive acid blockers (PCABs), prokinetics, gamma aminobutyric acid-B (GABA-B) receptor agonists and metabotropic glutamate receptor-5 (mGluR5) antagonists, and pain modulators. If there is no benefit from medical therapy, but there is objective evidence of GERD, invasive antireflux options should be evaluated after having carefully explained the risks and benefits to the patient. The most widely performed invasive antireflux option remains laparoscopic antireflux surgery (LARS), even if other, less invasive, interventions have been suggested in the last few decades, including endoscopic transoral incisionless fundoplication (TIF), magnetic sphincter augmentation (LINX) or radiofrequency therapy (Stretta). Due to the different mechanisms underlying rGERD, the most effective strategy can vary, and it should be tailored to each patient. The aim of this paper is to review the different management options available to successfully deal with rGERD.

Background: This paper aimed to assess the prevalence of human papillomavirus (HPV) infection and the associations of sociodemographic and behavioral characteristics with HPV in unvaccinated men in Henan Province before the mass administration of the HPV vaccine through a baseline survey.Methods: Between June 2015 to June 2020, 3,690 men were tested for the HPV genotype at the Henan Provincial People's Hospital. The HPV genotype was detected by a polymerase chain reaction (PCR)-based hybridization gene chip assay.Results: The overall HPV infection rate was 29.97%; The most prevalent genotypes were HPV 6 (21.76%), 11 (12.68%), 16 (8.94%), 58 (5.37%), 18 (3.41%), 84 (3.25%), 61 (3.09%), and 81 (3.09%). Low-risk HPV (LR-HPV) infection (24.91%) and single infection (17.78%) were the most prevalent forms. Age-specific HPV distribution was presented as a bimodal curve; the youngest age group (≤ 25 years) had the highest HPV infection rate (36.03%), followed by the 36–40-year-old group (33.68%). Men with Junior high school or above were more likely to have Pure-LR HPV infection. Unmarried status and smoking increased single and LR-HPV infection. Multiple lifetime sex partners and not using a condom were more likely to cause LR-HPV infection.Conclusions: The data on the prevalence and HPV infection type distribution in men in Henan Province could serve as a valuable reference to guide nationwide screening. We provide a time-based estimate of the maximum impact of the HPV vaccine and critical reference measurements important for assessing the clinical benefits of HPV vaccination and the increase in non-vaccine HPV types.

Background: Clonidine is an anesthetic with favorable efficacy and safety profiles for caudal epidural block, but comparisons with other adjuvants need to be confirmed in pediatric patients.Aim: To investigate the effects of clonidine as an adjuvant in caudal epidural block to improve the intraoperative and postoperative analgesia in pediatric surgery.Methods: PubMed, Embase, and the Cochrane Library were searched for available papers published up to February 2021. The outcomes were pain score, duration of analgesia, complications, and number of analgesic requirements. The meta-analysis was performed using random-effects models.Results: Fifteen randomized controlled trials (RCTs) were included. There were no differences between clonidine and the control drug regarding the duration of analgesia (SMD = −0.71, 95%CI: −1.64, 0.23; I2 = 95.5%, Pheterogeneity < 0.001), pain score (SMD = 0.35, 95%CI: −0.28, 0.98; I2 = 80.8%, Pheterogeneity < 0.001), and requirement for additional analgesia (OR = 8.77, 95%CI: 0.70, 110.58, I2 = 81.9%, Pheterogeneity = 0.004), but using clonidine resulted in fewer complications than the control drugs (OR = 0.33, 95%CI: 0.20, 0.54, I2 = 21.8%, Pheterogeneity = 0.217). The sensitivity analysis showed that the results were robust. A publication bias was observed.Conclusion: Clonidine has the same efficacy as the other adjuvants for caudal epidural block for pediatric surgery but fewer complications. These results support clonidine as an adjuvant to local anesthetic, but additional studies should be conducted.

The nursing field occupies the largest secion of the cardiovascular healthcare services. Despite this, the roles of nursing within the cardiovascular healthcare system has not been well displayed. The authors searched PubMed and Embase (between January 1, 1950, and June 17, 2021) and created a narrative review of recent publications regarding the role of nursing in the management of geriatric cardiovascular disease (CVD). Patients with geriatric CVD, which includes mainly myocardial ischemia and heart failure, were enrolled. Nursing can improve the outcomes of myocardial ischemia and heart failure. It plays a pivotal role in the recovery, rehabilitation, and outcomes of geriatric CVD, especially for chronic heart diseases. Taken together, this paper compiled is focused on the current status of cardiovascular nursing and may facilitate future treatment and rehabilitation in geriatric CVD.

Background: Atopic dermatitis is a chronic, relapsing and remitting disease that can be difficult to treat despite a recently approved biologic therapy targeting IL-4/IL-13 receptor. Oral janus kinase inhibitors (JAKi) represent a novel therapeutic class of targeted therapy to treat moderate-to-severe atopic dermatitis (AD).Objective: To review the efficacy, safety, and pharmacokinetic characteristics of oral JAKi in the treatment of AD.Methods: A PRISMA systematic review was conducted using MEDLINE, EMBASE (Ovid), and PubMed databases for studies assessing the efficacy, safety, and/or pharmacokinetic properties of oral forms of JAKi in the treatment of AD in pediatric or adult populations from inception to June 2021.Results: 496 papers were reviewed. Of 28 articles that underwent full text screening, 11 met our inclusion criteria for final qualitative review. Four studies examined abrocitinib; three studies examined baricitinib; three examined upadacitinib and one examined gusacitinib (ASN002). Significant clinical efficacy and a reassuring safety profile was reported for all JAKi agents reviewed. Rapid symptom control was reported for abrocitinib, baricitinib and upadacitinib.Limitations: Given the relatively limited evidence for each JAKi and the differences in patient eligibility criteria between studies, the data was not deemed suitable for a meta-analysis at this time.Conclusion: Given their ability to achieve rapid symptom control with a reassuring safety profile, we recommend considering the use of JAKi as a reliable systemic treatment option for adult patients with moderate-to-severe AD, who are unresponsive to topical or skin directed treatments.

ALT is one of the most sensitive biochemical indexes to reflect liver injury. It is generally believed that hepatitis B virus (HBV) infected patients with normal ALT levels are in either immune tolerance or low replication stage of the natural history of hepatitis B, and there is no or only mild inflammation in liver tissue, so antiviral therapy is not recommended. However, chronic HBV-infected patients with normal ALT levels are not always in a stable state. A considerable number of patients will develop active hepatitis or occult progress to liver fibrosis, cirrhosis, and hepatocellular carcinoma. Therefore, whether antiviral therapy should be recommended for chronic HBV infection with normal ALT level has been a hot topic in clinical practice. In this paper, the definition of immune tolerance, the relationship between ALT and liver inflammation, and the benefits of antiviral therapy were reviewed, and we hope it will be helpful for clinicians to have a deeper understanding of whether antiviral therapy should be considered for chronic HBV infection with normal ALT.

Background: Post infection immunity and post vaccination immunity both confer protection against COVID-19. However, there have been many whole genome sequencing proven reinfections and breakthrough infections. Both are most often mild and caused by Variants of Concern (VOC).Methods: The patient in our study underwent serial COVID-19 RT-PCR, blood tests for serology, acute phase reactants, and chest imaging as part of clinical care. We interviewed the patient for clinical history and retrieved reports and case papers. We retrieved stored RT-PCR positive samples for whole genome sequencing (WGS) of SARS-CoV-2 from the patient's breakthrough infections and the presumed index case.Findings: The patient had three RT-PCR confirmed SARS-CoV-2 infections. Two breakthrough infections occurred in quick succession with the first over 3 weeks after complete vaccination with COVISHIELD and despite post-vaccination seroconversion. The first breakthrough infection was due to the Alpha variant and the second due to the Delta variant. The Delta variant infection resulted in hypoxia, hospitalization, and illness lasting seven weeks. Serial serology, acute phase reactants, and chest imaging supported WGS in establishing distinct episodes of infection. WGS established a fully vaccinated family member as the index case.Interpretation: The patient had an Alpha variant breakthrough infection despite past infection, complete vaccination, and seroconversion. Despite boosting after this infection, the patient subsequently had a severe Delta variant breakthrough infection. This was also a WGS proven reinfection and, therefore, a case of breakthrough reinfection. The patient acquired the infection from a fully vaccinated family member.

Background: Abnormal expression levels of microRNAs (miRNAs) were observed in ankylosing spondylitis (AS) in recent articles, suggesting that miRNAs may be used as biomarkers for AS diagnoses. In this paper, we conducted a meta-analysis to identify the overall diagnostic accuracy of miRNA biomarkers in AS patients.Methods: An extensive search was undertaken in PubMed, Embase, Cochrane databases, and Wan Fang database up to 30 December 2020 using the following key words: (“microRNAs” or “microRNA” or “miRNA” or “miR” or “RNA, Micro” or “Primary MicroRNA”) and (“Spondylitis Ankylosing” or “Spondyloarthritis Ankylopoietica” or “Ankylosing Spondylarthritis” or “Ankylosing Spondylarthritides” or “Spondylarthritides Ankylosing” or “Ankylosing Spondylitis”) and (“blood” or “serum” or “plasma”). Statistical evaluation of dysregulated miRNAs using the sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and the area under the curve (AUC).Results: Twenty-nine articles reporting on the miRNAs of AS were included. A total of 42 miRNAs were observed to be up-regulated and 45 miRNAs were down-regulated in the AS cases compared with the controls. Besides, 29 studies from nine articles were included in our meta-analysis. The pooled sensitivity, specificity, PLR, NLR, DOR, and AUC were 0. 76 (95% CI, 0.70–0.81), 0.80 (95% CI, 0.74–0.85), 3.75 (95% CI, 2.82–5.01), 0.30 (95% CI, 0.24–0.39), 12.32 (95% CI, 7.65–19.83), 0.85 (95% CI, 0.81–0.88), respectively, suggesting a good diagnostic accuracy of miRNAs for AS.Conclusions: Circulating miRNAs are deregulated in AS patients. miRNAs may be used as a relatively non-invasive biomarkers for the detection of AS.

Precision medicine is increasingly incorporated into clinical practice via three primary data conduits: environmental, lifestyle, and genetic data. In this manuscript we take a closer look at the genetic tier of precision medicine. The volume and variety of data provides a more robust picture of health for individual patients and patient populations. However, this increased data may also have an adverse effect by muddling our understanding without the proper pedagogical tools. Patient genomic data can be challenging to work with. Physicians may encounter genetic results which are not fully understood. Genetic tests may also lead to the quandary of linking patients with diseases or disorders where there are no known treatments. Thus, physicians face a unique challenge of establishing the proper scope of their duty to patients when dealing with genomic data. Some of those scope of practice boundaries have been established as a result of litigation, while others remain an open question. In this paper, we map out some of the legal challenges facing the genomic component of precision medicine, both established and some questions requiring additional guidance. If physicians begin to perceive genomic data as falling short in overall benefit to their patients, it may detrimentally impact precision medicine as a whole. Helping to develop guidance for physicians working with patient genomic data can help avoid this fate of faltering confidence.

Data Availability Statement: The raw data supporting the conclusions of this paper will be made available from Eliana M. Lacerda upon request. Copyright © 2021 Domingues, Grabowska, Lee, Ameijeiras-Alonso, Westermeier, Scheibenbogen, Cliff, Nacul, Lacerda, Mouriño and Sepúlveda The evidence of an association between Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and chronic herpesviruses infections remains inconclusive. Two reasons for the lack of consistent evidence are the large heterogeneity of the patients' population with different disease triggers and the use of arbitrary cutoffs for defining seropositivity. In this work we re-analyzed previously published serological data related to 7 herpesvirus antigens. Patients with ME/CFS were subdivided into four subgroups related to the disease triggers: S0-42 patients who did not know their disease trigger; S1-43 patients who reported a non-infection trigger; S2-93 patients who reported an infection trigger, but that infection was not confirmed by a lab test; and S3-48 patients who reported an infection trigger and that infection was confirmed by a lab test. In accordance with a sensitivity analysis, the data were compared to those from 99 healthy controls allowing the seropositivity cutoffs to vary within a wide range of possible values. We found a negative association between S1 and seropositivity to Epstein-Barr virus (VCA and EBNA1 antigens) and Varicella-Zoster virus using specific seropositivity cutoff. However, this association was not significant when controlling for multiple testing. We also found that S3 had a lower seroprevalence to the human cytomegalovirus when compared to healthy controls for all cutoffs used for seropositivity and after adjusting for multiple testing using the Benjamini-Hochberg procedure. However, this association did not reach statistical significance when using Benjamini-Yekutieli procedure. In summary, herpesviruses serology could distinguish subgroups of ME/CFS patients according to their disease trigger, but this finding could be eventually affected by the problem of multiple testing. TD, HM, and NS were partially funded by the Fundação para a Ciência e a Tecnologia, Portugal (ref: UIDB/00006/2020 and UIDB/04561/2020). NS, EL, and CS were partially funded by ME Research UK (SCIO Charity Number SC036942) with the financial support of The Fred and Joan Davies Bequest. TD also received travel funding from the EUROMENE Cost Action (ref. CA15111) for a short scientific mission to the London School of Hygiene & Tropical Medicine in 2018. JA-A acknowledged the financial support of the Project MTM2016-76969-P from the Spanish State Research Agency (AEI) co-funded by the European Regional Development Fund (ERDF), the Competitive Reference Groups 2017-2020 (ED431C 2017/38) from the Xunta de Galicia through the ERDF. The UK ME/CFS Biobank was established with a joint grant from the charities ME Association (including continuing support), ME Research UK and Action for ME, as well as private donors. Research reported in this manuscript was supported by the National Institutes of Health (NIH) under award number 2R01AI103629.

Post-keratoplasty infectious keratitis (PKIK) represents a unique clinical entity that often poses significant diagnostic and therapeutic challenges. It carries a high risk of serious complications such as graft rejection and failure, and less commonly endophthalmitis. Topical corticosteroids are often required to reduce the risk of graft rejection but their use in PKIK may act as a double-edged sword, particularly in fungal infection. The increased uptake in lamellar keratoplasty in the recent years has also led to complications such as graft-host interface infectious keratitis (IIK), which is particularly difficult to manage. The reported incidence of PKIK differs considerably across different countries, with a higher incidence observed in developing countries (9.2–11.9%) than developed countries (0.02–7.9%). Common risk factors for PKIK include the use of topical corticosteroids, suture-related problems, ocular surface diseases and previous corneal infection. PKIK after penetrating keratoplasty or (deep) anterior lamellar keratoplasty is most commonly caused by ocular surface commensals, particularly Gramme-positive bacteria, whereas PKIK after endothelial keratoplasty is usually caused by Candida spp. Empirical broad-spectrum antimicrobial treatment is the mainstay of treatment for both PKIK, though surgical interventions are required in medically refractory cases (during the acute phase) and those affected by visually significant scarring (during the late phase). In this paper, we aim to provide a comprehensive overview on PKIK, encompassing the epidemiology, risk factors, causes, management and outcomes, and to propose a treatment algorithm for systematically managing this challenging condition.

Pregnancy is a complicated and insidious state with various aspects to consider, including the well-being of the mother and child. Developing better non-invasive tests that cover a broader range of disorders with lower false-positive rates is a fundamental necessity in the prenatal medicine field, and, in this sense, the application of metabolomics could be extremely useful. Metabolomics measures and analyses the products of cellular biochemistry. As a biomarker discovery tool, the integrated holistic approach of metabolomics can yield new diagnostic or therapeutic approaches. In this review, we identify and summarize prenatal metabolomics studies and identify themes and controversies. We conducted a comprehensive search of PubMed and Google Scholar for all publications through January 2020 using combinations of the following keywords: nuclear magnetic resonance, mass spectrometry, metabolic profiling, prenatal diagnosis, pregnancy, chromosomal or aneuploidy, pre-eclampsia, fetal growth restriction, pre-term labor, and congenital defect. Metabolite detection with high throughput systems aided by advanced bioinformatics and network analysis allowed for the identification of new potential prenatal biomarkers and therapeutic targets. We took into consideration the scientific papers issued between the years 2000–2020, thus observing that the larger number of them were mainly published in the last 10 years. Initial small metabolomics studies in perinatology suggest that previously unidentified biochemical pathways and predictive biomarkers may be clinically useful. Although the scientific community is considering metabolomics with increasing attention for the study of prenatal medicine as well, more in-depth studies would be useful in order to advance toward the clinic world as the obtained results appear to be still preliminary. Employing metabolomics approaches to understand fetal and perinatal pathophysiology requires further research with larger sample sizes and rigorous testing of pilot studies using various omics and traditional hypothesis-driven experimental approaches.

Macrophage Activation Syndrome (MAS) is a very severe complication of different rheumatic diseases, including pediatric Systemic Lupus Erythematosus (pSLE). MAS is not considered as a frequent complication of pSLE; however, its occurrence could be under-estimated and the diagnosis can be challenging. In order to address this issue, we performed a systematic review of the available medical literature, aiming to retrieve all those papers providing diagnostic (clinical/laboratory) data on patients with pSLE-related MAS, in individual or aggregated form. The selected case reports and series provided a pool of 46 patients, accounting for 48 episodes of MAS in total. We re-analyzed these patients in light of the diagnostic criteria for MAS validated in systemic Juvenile Idiopathic Arthritis (sJIA) patients and the preliminary diagnostic criteria for MAS in pSLE, respectively. Five clinical studies were also selected and used to support this analysis. This systematic review confirms that MAS diagnosis in pSLE patients is characterized by several diagnostic challenges, which could lead to delayed diagnosis and/or under-estimation of this complication. Specific criteria should be considered to diagnose MAS in different rheumatic diseases; as regards pSLE, the aforementioned preliminary criteria for MAS in pSLE seem to perform better than the sJIA-related MAS criteria, because of a lower ferritin cut-off.

Background: Novel coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-COV-2), is now sweeping across the world. A substantial proportion of infections only lead to mild symptoms or are asymptomatic, but the proportion and infectivity of asymptomatic infections remains unknown. In this paper, we proposed a model to estimate the proportion and infectivity of asymptomatic cases, using COVID-19 in Henan Province, China, as an example.Methods: We extended the conventional susceptible-exposed-infectious-recovered model by including asymptomatic, unconfirmed symptomatic, and quarantined cases. Based on this model, we used daily reported COVID-19 cases from January 21 to February 26, 2020, in Henan Province to estimate the proportion and infectivity of asymptomatic cases, as well as the change of effective reproductive number, Rt.Results: The proportion of asymptomatic cases among COVID-19 infected individuals was 42% and the infectivity was 10% that of symptomatic ones. The basic reproductive number R0 = 2.73, and Rt dropped below 1 on January 31 under a series of measures.Conclusion: The spread of the COVID-19 epidemic was rapid in the early stage, with a large number of asymptomatic infected individuals having relatively low infectivity. However, it was quickly brought under control with national measures.

Background: Respiratory viruses are known to contribute to asthma exacerbations. A meta-analysis of three studies reported no association between coronavirus disease 2019 (COVID-19) mortality and preexisting asthma. This study aimed to investigate the mortality of patients with COVID-19 in relation to preexisting asthma and other allergic diseases associated with changes in respiratory function.Methods: PubMed, Embase, and the Cochrane Library were queried for papers published up to April 9, 2021: (1) population: patients who tested positive for SARS-CoV-2 according to the WHO guidelines; (2) exposure: preexisting asthma or allergic rhinitis; (3) outcomes: mortality, ICU admission, and/or hospitalization; and (4) language: English. For studies that reported adjusted models, the most adjusted model was used for this meta-analysis; otherwise, unadjusted results were used.Results: Twenty-four studies (1,169,441 patients) were included in this meta-analysis. Patients who died of COVID-19 were not more likely to have preexisting asthma (OR = 0.95, 95%CI: 0.78–1.15, P = 0.602; I2 = 63.5%, Pheterogeneity < 0.001). Patients with COVID-19 and admitted to the ICU (OR = 1.17, 95%CI: 0.81–1.68, P = 0.407; I2 = 91.1%, Pheterogeneity = 0.407), or hospitalized (OR = 0.91, 95%CI: 0.76–1.10, P = 0.338; I2 = 79.1%, Pheterogeneity < 0.001) were not more likely to have preexisting asthma. The results for mortality and hospitalization remained non-significant when considering the adjusted and unadjusted models separately. The results from the sensitivity analyses were consistent with the primary analyses, suggesting the robustness of our results.Conclusion: This meta-analysis suggests that the patients who died from COVID-19, were admitted to the ICU, or hospitalized were not more likely to have asthma.

The US Food and Drug Administration in 2008 required new type 2 diabetes (T2D) medications to be subject to cardiovascular outcomes safety requirements. Accordingly, the global LEADER trial investigated cardiovascular outcomes of T2D treatment with liraglutide, a glucagon-like peptide-1 receptor agonist. LEADER (NCT01179048) was a multiregional clinical trial (MRCT) conducted from 2010 to 2016, thus completed before publication of the International Council for Harmonization (ICH) E17 guideline on MRCTs in 2017. Novo Nordisk pre-specified analysis of regional cardiovascular outcomes of LEADER participants. This paper assesses the pre-specified regional outcomes based on the ICH E17 guidelines on consistency evaluation. Regional LEADER participant numbers were broadly aligned with ICH E17 guidance and equally balanced across Europe, Asia, North America, and rest of the world. Overall primary major adverse cardiovascular events (MACE) composite outcome for the trial: hazard ratio (HR) (95% CI) 0.87 (0.78; 0.97); regional results varied, ranging from HR (95% CI) 0.62 (0.37; 1.04) (Asia) to 1.01 (0.84; 1.22) (North America). However, pre-specified Cox proportional-hazard regression analyses did not show clear evidence of interaction between regions and primary outcome (p = 0.20). Furthermore, post hoc analysis of the US population in the North American region found that adjusting for extrinsic or intrinsic factors did not account for this difference [HR (95% CI) 1.03 (0.84; 1.25)]. LEADER data evaluation demonstrated general consistency in cardiovascular safety across regions, except for US participants. Discrepancies in the North American region may relate to drug exposure or chance, but, as these were post hoc findings, the overall primary result is valid, aligned with ICH E17 guidelines.

Background: An association between lower urinary tract symptoms (LUTS) and risk of sexual dysfunction in male remains controversial in recent decades.Materials and Methods: PubMed and Web of Science were searched up to October 28, 2020, for articles reporting the prevalence of sexual dysfunction in men with LUTS. The main outcomes were results from sexual dysfunction assessments. Pooled odds ratio (OR) and weighted mean difference (WMD) with 95% confidence interval (CI) were calculated. The quality assessment of the included studies was performed by using The Newcastle-Ottawa Scale (NOS) or JBI Meta-Analysis of Statistics Assessment and Review Instrument (JBI-MAStARI).Results: A total of 24 full-manuscript papers met the inclusion criteria. The pooled OR for 21 studies suggested that patients with severer LUTS had a higher risk of sexual dysfunction (OR = 3.31, 95% CI: 2.43 to 4.49, p < 0.001, I2 = 90%). A significant decrease in scores of assessment tools for sexual dysfunction was observed in the patients with higher severity of LUTS compared with those patients with lower severity (WMD = −5.49, 95%CI: −7.25 to −3.27, P < 0.001, I2 = 96%). Similar outcomes were also found in subgroup analyses. In a detailed analysis of specific sexual function domains, the severity of LUTS was associated with erectile dysfunction, intercourse satisfaction, and overall satisfaction, except for sexual desire.Conclusion: The study demonstrates an association between exposure of lower urinary tract symptoms and risk of sexual dysfunction in male. Assessment of sexual function is necessary for patients with lower urinary tract symptoms.Systematic Review Registration:http://www.crd.york.ac.uk/prospero, identifier: CRD42020208747.

Stigma and discrimination are major challenges facing People Living with HIV/AIDS (PLWHA) globally due to their HIV status. As part of a larger qualitative study in Yogyakarta and Belu, Indonesia, using in-depth interviews with 92 PLWHA (52 women, 40 men) and 20 healthcare providers, this paper describes perspectives and personal experiences of the 20 healthcare providers, relating to HIV stigma and discrimination toward PLWHA in both study settings. The healthcare providers were recruited from healthcare facilities providing HIV-related healthcare services, using a snowball sampling technique. A qualitative framework analysis was used to guide data analysis. Health stigma and discrimination framework guided the conceptualisation and discussion of the findings. The findings presented the views and perspectives of healthcare providers that HIV stigma and discrimination toward PLWHA still occurred within families, communities and healthcare settings. These were reflected in negative labelling, separation of personal belongings, avoidance, denial of treatment and rejection of PLWHA by healthcare providers, family and community members. Some healthcare providers reported that they had personally stigmatised and discriminated against PLWHA. A lack of knowledge about HIV, fear of contracting HIV, personal values, religious thoughts and sociocultural values and norms, were reported as drivers or facilitators behind this HIV-related stigma and discrimination. The findings indicate the importance of continued HIV/AIDS education for families, community members and healthcare providers, to raise awareness and to ensure that healthy and professional support systems are in place for PLWHA. The findings indicate the need to enhance improvement within the healthcare or HIV care system to adequately address the needs of PLWHA, which may facilitate their early initiation of HIV treatment and better treatment adherence and retention to increase Cluster of Differentiation 4 (CD4) count and suppress viral load. Future studies are also needed to explore the role that government and non-government institutions can play in improving health service delivery for people newly diagnosed with HIV and those living with HIV/AIDS.

Whilst the entire world is battling the second wave of COVID-19, a substantial proportion of patients who have suffered from the condition in the past months are reporting symptoms that last for months after recovery, i. e., long-term COVID-19 symptoms. We aimed to assess the current evidence on the long-term symptoms in COVID-19 patients. We did a systematic review on PubMed, Web of Science, EMBASE, and Google Scholar from database inception to February 15, 2021, for studies on long-term COVID-19 symptoms. We included all type of papers that reported at least one long-term COVID-19 symptom. We screened studies using a standardized data collection form and pooled data from published studies. Cohort cross-sectional, case-report, cases-series, case-control studies, and review were graded using specific quality assessment tools. Of 11,361 publications found following our initial search we assessed 218 full-text articles, of which 145 met all selection criteria. We found that 20.70% of reports on long-term COVID-19 symptoms were on abnormal lung functions, 24.13% on neurologic complaints and olfactory dysfunctions, and 55.17% on specific widespread symptoms, mainly chronic fatigue, and pain. Despite the relatively high heterogeneity of the reviewed studies, our findings highlighted that a noteworthy proportion of patients who have suffered from SARS-CoV-2 infection present a “post-COVID syndrome.” The multifaceted understanding of all aspects of the COVID-19 pandemic, including these long-term symptoms, will allow us to respond to all the global health challenges, thus paving the way to a stronger public health.

Three-dimensional (3D) liver tumor segmentation from Computed Tomography (CT) images is a prerequisite for computer-aided diagnosis, treatment planning, and monitoring of liver cancer. Despite many years of research, 3D liver tumor segmentation remains a challenging task. In this paper, we propose an effective and efficient method for tumor segmentation in liver CT images using encoder-decoder based octave convolution networks. Compared with other convolution networks utilizing standard convolution for feature extraction, the proposed method utilizes octave convolutions for learning multiple-spatial-frequency features, thus can better capture tumors with varying sizes and shapes. The proposed network takes advantage of a fully convolutional architecture which performs efficient end-to-end learning and inference. More importantly, we introduce a deep supervision mechanism during the learning process to combat potential optimization difficulties, and thus the model can acquire a much faster convergence rate and more powerful discrimination capability. Finally, we integrate octave convolutions into the encoder-decoder architecture of UNet, which can generate high resolution tumor segmentation in one single forward feeding without post-processing steps. Both architectures are trained on a subset of the LiTS (Liver Tumor Segmentation) Challenge. The proposed approach is shown to significantly outperform other networks in terms of various accuracy measures and processing speed.

Automatic segmentation of brain tumors from multi-modalities magnetic resonance image data has the potential to enable preoperative planning and intraoperative volume measurement. Recent advances in deep convolutional neural network technology have opened up an opportunity to achieve end-to-end segmenting the brain tumor areas. However, the medical image data used in brain tumor segmentation are relatively scarce and the appearance of brain tumors is varied, so that it is difficult to find a learnable pattern to directly describe tumor regions. In this paper, we propose a novel cross-modalities interactive feature learning framework to segment brain tumors from the multi-modalities data. The core idea is that the multi-modality MR data contain rich patterns of the normal brain regions, which can be easily captured and can be potentially used to detect the non-normal brain regions, i.e., brain tumor regions. The proposed multi-modalities interactive feature learning framework consists of two modules: cross-modality feature extracting module and attention guided feature fusing module, which aim at exploring the rich patterns cross multi-modalities and guiding the interacting and the fusing process for the rich features from different modalities. Comprehensive experiments are conducted on the BraTS 2018 benchmark, which show that the proposed cross-modality feature learning framework can effectively improve the brain tumor segmentation performance when compared with the baseline methods and state-of-the-art methods.

General Practice/Family Medicine (GP/FM) is a key discipline within primary health care and so by extension for the whole health care system. An essential condition for effective GP/FM care is a work force that is highly qualified. As society is changing rapidly, a revision of the GP/FM definition is ongoing, in addition to a recent movement of identifying related core values. In this paper, we want to give an overview on how these new paths and perspectives are currently reflected in GP/FM teaching and training. We selected four core values that fit in with possible future visions: person-centered care, continuity of care, cooperation in care, and community-oriented care. By a narrative review, we observed that GP/FM education toward core values is often built around overarching topics. Teaching and learning take place in specific contexts, most of all through placements within communities, primary care settings, or hospital wards. Mixed teaching- and training methods are used combining knowledge, skills, and attitude. Furthermore, collaboration with other health professionals and peers is stressed, in addition to the importance of role models, a holistic focus and the involvement of patients. Since these core values are important within GP/FM and rather few studies on the educational aspects and learning tools were found we advocate encouraging each other more to share good practices, certainly the innovative ones specifically related to GP/FM.

Purpose: Deficiency of adenosine deaminase 2 (DADA2) is a rare autosomal recessive systemic autoinflammatory disorder. We describe a rare case of an adult patient with DADA2 who presented with unilateral frosted branch angiitis (FBA) combined with branch retinal vein occlusion and panuveitis.Method: This paper is a clinical case report.Results: A 31-year-old male patient complained of blurred vision in his right eye for 2 days. His fundus examination showed FBA combined with branch retinal vein occlusion and panuveitis. He had a medical history of intermittent and recurrent fever, skin rash and aphthous ulcer for 5 years, and lacunar infarction for 1 month. Laboratory examinations showed hypogammaglobulinemia and mild prolonged activated partial thromboplastin time (APTT). Brain magnetic resonance imaging (MRI) revealed old lacunar infarction in the right basal ganglia and the lateral ventricle and fresh lacunar infarction in the right pons, respectively. The perivascular sheathing of FBA and macular edema were resolved after steroid administration and treatment of intravitreal anti-VEGF injection. During the period of follow-up, the patient subsequently suffered from recurrence of strokes, abnormality of coagulation function, sudden hearing loss of the left ear, and diplopia. His gene sequencing results demonstrated several deletion mutations in ADA2, and the diagnosis of DADA2 was eventually confirmed.Conclusions: FBA represents a very rare ocular feature of DADA2 and may in some cases be the presenting manifestation. Therefore, ophthalmologists need to be aware of this rare autoinflammatory disease.

Public health screening for COVID-19 and its mutations are becoming a routine activity, as we assess the safety of resuming interactions with each another. Control efforts have included social distancing, hygiene, masks, and lockdowns. Where available, testing can confirm exposure to COVID-19. Prior to testing, screening is conducted, typically consisting of assessing one's temperature and asking questions related to symptoms and exposures. However, the efficacy of symptom-based screening (temperature and self-report) for COVID-19 has been called into question in recent studies for both the general population and healthcare workers (1, 2). Older adults are another population in which symptom-based screening for COVID-19 should be questioned. As the pandemic unfolded, older adults have been hardest hit. The statistics are staggering, with older adults making up 45–80% of all hospitalizations, 53% of intensive care admissions, and 80% of deaths (3, 4). However, the media's tone has been that this was not alarming but expected due to age and comorbidities. This paper offers suggestions to mitigate these statistics.

Funding: The authors are grateful for the funding provided by the Fundação para a Ciência e Tecnologia (FCT) through the project Revolutionizing Healthcare: Empowering patients by valuing innovation and promoting entrepreneurship (PTDC/EGEOGE/32573/2017). Until recently, innovation in healthcare was mainly achieved through the development of new drugs, therapies, and medical devices by big pharma and medtech companies; however, the innovative potential for this field is much broader. The patients and caregivers' role in healthcare is often associated with disease management, demand for their own illness data, and its exchange with other patients. However, the patients and caregivers' capacity to innovate to cope with limitations associated with their health condition is a growing phenomenon and starting to be supported by healthcare stakeholders to achieve a truly patient-centric system. Our previous research has shown that these uncommon innovators can develop a wide range of solutions, from simple adaptations and products to highly technological biomedical devices. In this paper, we present novel solutions developed by rheumatic patients, their caregivers, and collaborators, published on the “Patient Innovation” platform (https://patient-innovation.com/), with a focus on the innovator profile, the need that triggers the innovative process, the type of motivation behind the product, and the products developed. The most significant needs that motivate innovation are the will to increase the level of independence (71%) and to be able to perform daily routine activities (65%). In over 80% of cases, the fact that the market does not fully fulfill the needs felt during daily activities is the main motivation to innovate. It is thus concluded that there is room for innovation in rheumatic diseases with solutions developed by patients and informal caregivers that intend to solve needs that the healthcare market is not covering. publishersversion published

Respiratory symptoms can be caused by different underlying conditions, and are often caused by viral infections, such as Influenza-like illnesses or other emerging viruses like the Coronavirus. These respiratory viruses, often, have common symptoms: coughing, high temperature, congested nose, and difficulty breathing. However, early diagnosis of the type of the virus, can be crucial, especially in cases, such as the COVID-19 pandemic. Among the factors that contributed to the spread of the COVID-19 pandemic were the late diagnosis or misinterpretation of COVID-19 symptoms as regular flu-like symptoms. Research has shown that one of the possible differentiators of the underlying causes of different respiratory diseases could be the cough sound, which comes in different types and forms. A reliable lab-free tool for early and accurate diagnosis, which can differentiate between different respiratory diseases is therefore very much needed, particularly during the current pandemic. This concept paper discusses a medical hypothesis of an end-to-end portable system that can record data from patients with symptoms, including coughs (voluntary or involuntary) and translate them into health data for diagnosis, and with the aid of machine learning, classify them into different respiratory illnesses, including COVID-19. With the ongoing efforts to stop the spread of the COVID-19 disease everywhere today, and against similar diseases in the future, our proposed low cost and user-friendly theoretical solution could play an important part in the early diagnosis.

At the beginning of 2021, anti-SARS-CoV-2 vaccination campaigns had been launched in almost 60 countries with more than 500 million doses having been distributed. In addition to the few vaccines already in use, many other candidates are in preclinical phases or experimental stages in humans. Despite the fact that the availability of anti-SARS-CoV-2 vaccine constitutes a major advance and appear to be the only way to control the pandemic, some investigation remains to be carried out, and this is notably concerning the impact on transmissibility, the duration of the conferred protection in the mid- and long term, the effectiveness against present and future viral mutants, or the ideal schedule that should be applied. In this paper, we review the circumstances that facilitated such a rapid development of anti-SARS-CoV-2 vaccines and summarize the different vaccine platforms under investigation as well as their present results and perspectives in different settings. We also discuss the indications of vaccination under special conditions, such as a history of previous COVID-19 infection or belonging to extreme age categories like children and elderly. Overall, this review highlights the multiple challenges to face if aiming to find a global solution to the pandemic through high vaccination coverage all over the world., SCOPUS: re.j, info:eu-repo/semantics/published

Objective: Examine the possible beneficial effects of early, D-dimer driven anticoagulation in preventing thrombotic complications and improving the overall outcomes of COVID-19 intubated patients.Methods: To address COVID-19 hypercoagulability, we developed a clinical protocol to escalate anticoagulation based on serum D-dimer levels. We retrospectively reviewed all our first 240 intubated patients with COVID-19. Of the 240, 195 were stratified into patients treated based on this protocol (ON-protocol, n = 91) and the control group, patients who received standard thromboprophylaxis (OFF-protocol, n = 104). All patients were admitted to the Stony Brook University Hospital intensive care units (ICUs) between February 7th, 2020 and May 17, 2020 and were otherwise treated in the same manner for all aspects of COVID-19 disease.Results: We found that the overall mortality was significantly lower ON-protocol compared to OFF-protocol (27.47 vs. 58.66%, P < 0.001). Average maximum D-dimer levels were significantly lower in the ON-protocol group (7,553 vs. 12,343 ng/mL), as was serum creatinine (2.2 vs. 2.8 mg/dL). Patients with poorly controlled D-dimer levels had higher rates of kidney dysfunction and mortality. Transfusion requirements and serious bleeding events were similar between groups. To address any possible between-group differences, we performed a propensity-matched analysis of 124 of the subjects (62 matched pairs, ON-protocol and OFF-protocol), which showed similar findings (31 vs. 57% overall mortality in the ON-protocol and OFF-protocol group, respectively).Conclusions: D-dimer-driven anticoagulation appears to be safe in patients with COVID-19 infection and is associated with improved survival.What This Paper Adds: It has been shown that hypercoagulability in patients with severe COVID-19 infection leads to thromboembolic complications and organ dysfunction. Anticoagulation has been variably administered to these patients, but it is unknown whether routine or escalated thromboprophylaxis provides a survival benefit. Our data shows that escalated D-dimer driven anticoagulation is associated with improved organ function and overall survival in intubated COVID-19 ICU patients at our institution. Importantly, we found that timely escalation of this anticoagulation is critical in preventing organ dysfunction and mortality in patients with severe COVID-19 infection.

There are trillions of microorganisms in the human body, consisting of bacteria, viruses, fungi, and archaea; these collectively make up the microbiome. Recent studies suggest that the microbiome may serve as a biomarker for disease, a therapeutic target, or provide an explanation for pathophysiology in lung diseases. Studies describing the impact of the microorganisms found in the respiratory tract on lung health have been published and are discussed here in the context of interstitial lung diseases. Additionally, epidemiological and experimental evidence highlights the importance of cross-talk between the gut microbiota and the lungs, called the gut–lung axis. The gut-lung axis postulates that alterations in gut microbial communities may have a profound effect on lung disease. Dysbiosis in the microbial community of the gut is linked with changes in immune responses, homeostasis in the airways, and inflammatory conditions in the gastrointestinal tract itself. In this review, we summarize studies describing the role of the microbiome in interstitial lung disease and discuss the implications of these findings on the diagnosis and treatment of these diseases. This paper describes the impact of the microbial communities on the pathogenesis of lung diseases by assessing recent original research and identifying remaining gaps in knowledge.

Objectives: In this paper, we investigated the effects of the European Paediatric Regulation (EC) N° 1901/2006 with respect to satisfying the paediatric therapeutic needs, assessed in terms of the increased number of paediatric medicinal products, new therapeutic indications in specific high-need conditions (neonates, oncology, rare disease, etc.) and increased number of paediatric clinical studies supporting the marketing authorisation.Methods: We analysed the paediatric medicinal products approved by the European Medicines Agency in the period January 2007-December 2019, by collecting the following data: year of approval, active substance, legal basis for the marketing authorisation, type of medicinal product (i.e., chemical, biological, or ATMP), orphan drug status, paediatric indication, Anatomical Therapeutic Chemical code (first-level), number and type of paediatric studies. Data were compared with similar data collected in the period 1996–2006.Results: In the period January 1996–December 2019, in a total of 1,190 medicinal products and 843 active substances, 34 and 38%, respectively, were paediatric. In the two periods, before and after the Paediatric Regulation implementation, the paediatric/total medicinal products ratio was constant while the paediatric/total active substances ratio decreased. Moreover, excluding generics and biosimilars, a total of 106 and 175 paediatric medicines were granted a new paediatric indication, dosage or age group in the two periods; out of 175, 128 paediatric medicines had an approved Paediatric Investigational Plan. The remaining 47 were approved without an approved Paediatric Investigational Plan, following the provisions of Directive 2001/83/EC and repurposing an off-patent drug. The analysis of the clinical studies revealed that drugs with a Paediatric Investigational Plan were supported by 3.5 studies/drug while drugs without a Paediatric Investigational Plan were supported by only 1.6 studies/drug.Discussion: This report confirms that the expectations of the European Paediatric Regulation (EC) N° 1901/2006 have been mainly satisfied. However, the reasons for the limited development of paediatric medicines in Europe, should be further discussed, taking advantage of recent initiatives in the regulatory field, such as the Action Plan on Paediatrics, and the open consultation on EU Pharmaceutical Strategy.

The pandemic of coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, has become a global challenge to public health. While its typical clinical manifestations are respiratory disorders, emerging evidence of cardiovascular complications indicates the adverse interaction between SARS-CoV-2 infection and cardiovascular outcomes. Given that viral infection has emerged as an additional risk factor for atherosclerosis, in this paper, we attempt to clarify the susceptibility to new-onset atherosclerosis in individuals infected with SARS-CoV-2. Mechanistically, serving as functional receptors for SARS-CoV-2, angiotensin-converting enzyme 2 (ACE2) mediates SARS-CoV-2 infection of endothelial cells (ECs) directly, leading to endothelial dysfunction and dysregulation of the renin-angiotensin system (RAS). In addition, high expression of CD147, an alternative receptor, and activation of the NLRP3 inflammasome may also contribute to atherosclerosis in the context of COVID-19. More importantly, SARS-CoV-2 attacks the immune system, which results in excessive inflammation and perpetuates a vicious cycle of deteriorated endothelial dysfunction that further promotes inflammation. The alterations in the blood lipid profile induced by COVID-19 should not be ignored in assessing the predisposition toward atherosclerosis in victims of COVID-19. A better understanding of the underlying mechanisms of SARS-CoV-2 infection and the long-term monitoring of inflammatory factors and endothelial function should be considered in the follow-up of patients who have recovered from COVID-19 for early detection and prevention of atherosclerosis.

Background: Chronic spontaneous urticaria (CSU) is a common recurrent skin disease that adversely affect patient's quality of life condition to treat. Economic evaluations of health care often include patient preferences for health outcomes using utilities.Objectives: The study aimed to determine pooled estimates of utility-based quality of life in patients with CSU.Methods: We conducted a systematic review, meta-analysis, and meta-regression of peer-reviewed articles and conference papers that published from database inception to 31 April 2019 that reported utility estimates in patients with CSU. Scores reported with the EQ-5D, SF-6D, SF-12, and SF-36 instruments were converted to utilities using published mapping algorithms. Meta-analysis was used to calculate the pooled and meta-regression was used to examine the effects of possible factors.Results: The pooled utility estimate for CSU was 0.68 [95% confidence interval (CI): 0.67–0.70]. The pooled utility estimate that converted from SF-36 or SF-12 was 0.66 (95% CI: 0.58–0.74), 0.72 (95% CI: 0.70–0.74) for EQ-5D, and 0.65 (95% CI: 0.63–0.67) for SF-6D, respectively. According to the meta-regression, higher proportion of female patients was significantly associated lower utility estimates (p = 0.013).Conclusions: The study provides evidence-based utility estimates to inform health-related burden analysis of CSU and reference for the follow-up cost-effectiveness evaluation of chronic spontaneous urticaria intervention. These results highlight differences in common utility-based instruments and need to be cognizant of the specific instruments used when comparing the results of outcome studies.

Photoplethysmography (PPG) is increasingly used in digital health, exceptionally in smartwatches. The PPG signal contains valuable information about heart activity, and there is lots of research interest in its means and analysis for cardiovascular diseases. Unfortunately, to our knowledge, there is no arrhythmic PPG dataset publicly available-this paper attempt to provide a toolbox that can generate synthesized arrhythmic PPG signals. The model of a single PPG pulse in this toolbox utilizes two combined Gaussian functions. This toolbox supports synthesizing PPG waveform with regular heartbeats and three irregular heartbeats: compensation, interpolation, and reset. The user can generate a large amount of PPG data with a certain irregularity, with different sampling frequency, time length, and a range of noise types (Gaussian noise and multi-frequency noise) can be added to the synthesized PPG which can all be modified from the interface, and different types of arrhythmic PPGs (as calculated by the model) generated. The generation for large PPG datasets that simulate PPG collected from real humans could be used for testing the robustness of developed algorithms that are targeting arrhythmic PPG signals. Our PPG synthesis tool is publicly available.

Cooperative research that addresses infectious disease surveillance and outbreak investigations relies heavily on availability and effective use of appropriate diagnostic tools, including serological and molecular assays, as exemplified by the current COVID-19 pandemic. In this paper, we stress the importance of using these assays to support collaborative epidemiological studies to assess risk of rickettsial disease outbreaks among international partner countries. Workforce development, mentorship, and training are important components in building laboratory capability and capacity to assess risk of and mitigate emerging disease outbreaks. International partnerships that fund cooperative research through mentoring and on-the-job training are successful examples for enhancing infectious disease surveillance. Cooperative research studies between the Naval Medical Research Center's Rickettsial Diseases Research Program (RDRP) and 17 institutes from nine countries among five continents were conducted to address the presence of and the risk for endemic rickettsial diseases. To establish serological and molecular assays in the collaborative institutes, initial training and continued material, and technical support were provided by RDRP. The laboratory methods used in the research studies to detect and identify the rickettsial infections included (1) group-specific IgM and IgG serological assays and (2) molecular assays. Twenty-six cooperative research projects performed between 2008 and 2020 enhanced the capability and capacity of 17 research institutes to estimate risk of rickettsial diseases. These international collaborative studies have led to the recognition and/or confirmation of rickettsial diseases within each of the partner countries. In addition, with the identification of specific pathogen and non-pathogenRickettsiaspecies, a more accurate risk assessment could be made in surveillance studies using environmental samples. The discoveries from these projects reinforced international cooperation benefiting not only the partner countries but also the scientific community at large through presentations (n= 40) at international scientific meetings and peer-reviewed publications (n= 18). The cooperative research studies conducted in multiple international institutes led to the incorporation of new SOPs and trainings for laboratory procedures; biosafety, biosurety, and biosecurity methods; performance of rickettsia-specific assays; and the identification of known and unknown rickettsial agents through the introduction of new serologic and molecular assays that complemented traditional microbiology methods.

Biomarkers, especially biochemical markers, are important in osteoarthritis (OA) research, clinical trials, and drug development and have potential for more extensive use in therapeutic monitoring. However, they have not yet had any significant impact on disease diagnosis and follow-up in a clinical context. Nevertheless, the development of immunoassays for the detection and measurement of biochemical markers in OA research and therapy is an active area of research and development. The evaluation of biochemical markers representing low-grade inflammation or extracellular matrix turnover may permit OA prognosis and expedite the development of personalized treatment tailored to fit particular disease severities. However, currently detection methods have failed to overcome specific hurdles such as low biochemical marker concentrations, patient-specific variation, and limited utility of single biochemical markers for definitive characterization of disease status. These challenges require new and innovative approaches for development of detection and quantification systems that incorporate clinically relevant biochemical marker panels. Emerging platforms and technologies that are already on the way to implementation in routine diagnostics and monitoring of other diseases could potentially serve as good technological and strategic examples for better assessment of OA. State-of-the-art technologies such as advanced multiplex assays, enhanced immunoassays, and biosensors ensure simultaneous screening of a range of biochemical marker targets, the expansion of detection limits, low costs, and rapid analysis. This paper explores the implementation of such technologies in OA research and therapy. Application of novel immunoassay-based technologies may shed light on poorly understood mechanisms in disease pathogenesis and lead to the development of clinically relevant biochemical marker panels. More sensitive and specific biochemical marker immunodetection will complement imaging biomarkers and ensure evidence-based comparisons of intervention efficacy. We discuss the challenges hindering the development, testing, and implementation of new OA biochemical marker assays utilizing emerging multiplexing technologies and biosensors.

Objective: Oral and maxillofacial surgery (OMFS) is a high-risk specialty involving airway and aerosol-generating procedures, which is potentially of more risk in the era of coronavirus disease 2019 (COVID-19). We aimed to identify the impact of COVID-19 on the disease pattern of OMFS inpatients and surgeries under general anesthesia in a comparative study.Materials and Methods: We reviewed the admission and operating theater records of OMFS patients from Jan 1 to Aug 31 in 2020 and 2019. The total number of cases, presenting disease patterns, and proportion of essential and non-essential medical services were compared between 2020 and 2019.Results: There were 664 admissions and 356 general anesthesia surgical procedures included in this study. Both admission and surgery numbers were significantly reduced in 2020, compared with 2019 (p = 0.012 and 0.007, respectively). The proportion of malignancy cases increased significantly, whereas that of cleft lip and palate and temporomandibular disorder (TMD) decreased. There was a significant increase in the proportion of essential services compared with non-essential services in 2020 compared with 2019.Conclusion: Our results first reported the epidemiological data of the impact of COVID-19 on OMFS disease pattern in a comparative study. The change of disease pattern and caseload will have a long-term impact on OMFS patient care, education, and training during the pandemic. Our paper provides evidence for health policy makers to consider the relocation of medical resources and optimization of medical education and services.

The current global spread of COVID-19, a highly contagious disease, has challenged healthcare systems, and placed immense burdens on medical staff globally. With a sharp increase in the number of newly confirmed cases and the rapid progression of the disease into a critically ill state, overstretched critical care units have had to contend with a shortage of beds, specialist personnel, and medical resources. Temporary intensive care units (ICUs) were therefore set up in isolated hospitals to provide the required standardized care for all severe cases. The current paper describes the authors' experience of setting up and managing such an ICU in Wuhan, Hubei Province, China, from the identification of critically ill COVID-19 patients through to the arranging and equipping of the unit, providing training and protection for staff, and standardizing all aspects of care.

Using unbiased proteomics, we had previously discovered that the catalytic proteasome subunit β type 7 (PSB7) protein is frequently overexpressed in colorectal adenocarcinomas. In this paper, we validate this finding and derive a prognostic significance for PSB7 by examining an expanded, well-annotated clinical cohort of 318 colorectal cancer patients. We found PSB7 protein levels to be similarly increased in both advanced stage primary disease and metastatic lesions. We then examined the prognostic value of PSB7 protein expression. Elevated PSB7 protein as well as PSMB7 mRNA levels showed associations with lower overall survival, particularly in female patients. The prognostic value of elevated PSB7 protein levels was highest for female patients who were older (>60 years of age at diagnosis) or who had received adjuvant chemotherapy. While high PSB7 did not retain its prognostic significance on multivariate analysis, we discuss the potential significance of PSB7 as a biomarker, considering its differential prognostic strength in different colorectal cancer patient groups and given its role as a subunit of the immunoproteasome for antigen presentation.

The need to optimize drug development and facilitate faster access for patients has ignited discussions around the importance of improving interactions between health technology assessment (HTA) bodies and regulatory agencies. In this study, we conducted a systematic review to examine processes, progress, outcomes, and challenges of harmonization/interaction initiatives between HTA bodies and regulatory agencies. MEDLINE, EMBASE, and the International Pharmaceutical Abstracts database were searched up to 21 October 2019. Searches for gray literature (working papers, commissioned reports, policy documents, etc.) were performed via Google scholar and several institutional websites. An online cross-sectional survey was also conducted among HTA (n = 22) and regulatory agencies (n = 6) across Europe to supplement the systematic review. Overall, we found that while there are areas of divergence, there has been progress over time in narrowing the gap in evidentiary requirements for HTA bodies and regulatory agencies. Most regulatory agencies (4/6; 67%) and half (11/22, 50%) of the HTA bodies reported having a formal link for "collaborating" with the other. Several mechanisms such as early tripartite dialogues, parallel submissions (reviews), adaptive licensing pathways, and postauthorization data generation have been explored as avenues for improving collaboration. A number of pilot initiatives have shown positive effects of these models to reduce the time between regulatory and HTA decisions, which may translate into faster access for patients to life-saving therapies. Thus, future approaches aimed at improving harmonization/interaction between HTA bodies and regulatory agencies should build on these existing models/mechanisms while examining their long-term impacts. Several barriers including legal, organizational, and resource-related factors were also identified, and these need to be addressed to achieve greater alignment in the current regulatory and reimbursement landscape.