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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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Faced with the rapid spread of the novel coronavirus disease (COVID-19), a global public health threat, psychiatric hospitals are under huge pressure to prevent and control nosocomial infection. The current research analyzed the COVID-19 infection control practices in a regional mental health center in China and addressed how this type of medical institutions could enhance their ability to prevent and control hospital transmission of major respiratory diseases and general management of nosocomial infection risks. Firstly, hospital-related risks of COVID-19 were analyzed, and targeted prevention and control measures were then established. Pre- and post-intervention theoretical knowledge of nosocomial infection control, hand hygiene compliance and accuracy, use of personal protective equipment, and disinfection and sterilization effectiveness were evaluated and compared. All the indexes displayed significant improvements following the implementation of the prevention and control measures. Up to the submission of this paper, the mental health center had obtained no suspected or confirmed case of COVID-19 infection due to hospital transmission. The findings provide empirical evidence for the effectiveness of the COVID-19 preventive strategies and have important implications for integrated and characterized infection control in mental health centers during a major epidemic. The establishment of the transitional isolation ward and air fumigation using traditional Chinese medicine for patients and staff are preventive measures worthy of further discussion and dissemination.

Skin lesion border irregularity, which represents the B feature in the ABCD rule, is considered one of the most significant factors in melanoma diagnosis. Since signs that clinicians rely on in melanoma diagnosis involve subjective judgment including visual signs such as border irregularity, this deems it necessary to develop an objective approach to finding border irregularity. Increased research in neural networks has been carried out in recent years mainly driven by the advances of deep learning. Artificial neural networks (ANNs) or multilayer perceptrons have been shown to perform well in supervised learning tasks. However, such networks usually don't incorporate information pertaining the ambiguity of the inputs when training the network, which in turn could affect how the weights are being updated in the learning process and eventually degrading the performance of the network when applied on test data. In this paper, we propose a fuzzy multilayer perceptron (F-MLP) that takes the ambiguity of the inputs into consideration and subsequently reduces the effects of ambiguous inputs on the learning process. A new optimization function, the fuzzy gradient descent, has been proposed to reflect those changes. Moreover, a type-II fuzzy sigmoid activation function has also been proposed which enables finding the range of performance the fuzzy neural network is able to attain. The fuzzy neural network was used to predict the skin lesion border irregularity, where the lesion was firstly segmented from the skin, the lesion border extracted, border irregularity measured using a proposed measure vector, and using the extracted border irregularity measures to train the neural network. The proposed approach outperformed most of the state-of-the-art classification methods in general and its standard neural network counterpart in particular. However, the proposed fuzzy neural network was more time-consuming when training the network.

Regulatory T cells (Tregs) have a prominent role in the control of immune homeostasis. Pharmacological impact on their activity or balance with effector T cells could contribute to (impaired) clinical responses or adverse events. Monitoring treatment-related effects on T cell subsets may therefore be part of (pre-)clinical studies for medicinal products. However, the extent of immune monitoring performed in studies for marketing authorisation and the degree of correspondence with data available in the public domain is not known. We evaluated the presence of T cell immunomonitoring in 46 registration dossiers of monoclonal antibodies indicated for immune-related disorders and published scientific papers. We found that the depth of Treg analysis in registration dossiers was rather small. Nevertheless, data on treatment-related Treg effects are available in public academia-driven studies (post-registration) and suggest that Tregs may act as a biomarker for clinical responses. However, public data are fragmented and obtained with heterogeneity of experimental approaches from a diversity of species and tissues. To reveal the potential added value of T cell (and particular Treg) evaluation in (pre-)clinical studies, more cell-specific data should be acquired, at least for medicinal products with an immunomodulatory mechanism. Therefore, extensive analysis of T cell subset contribution to clinical responses and the relevance of treatment-induced changes in their levels is needed. Preferably, industry and academia should work together to obtain these data in a standardised manner and to enrich our knowledge about T cell activity in disease pathogenesis and therapies. This will ultimately elucidate the necessity of T cell subset monitoring in the therapeutic benefit-risk assessment.

In recent years inhaled systems have shown momentum as patient-personalized therapies emerge. A significant improvement in terms of therapeutic efficacy and/or reduction adverse systemic effects is anticipated from their use owing these systems regional accumulation. Nevertheless, whatever safety and efficacy evidence required for inhaled formulations regulatory approval, it still poses an additional hurdle to gaining market access. In contrast with the formal intravenous medicines approval, the narrower adoption of pulmonary administration might rely on discrepancies in pre-clinical and clinical data provided by the marketing authorization holder to the regulatory authorities. Evidences of a diverse and inconsistent regulatory framework led to concerns over toxicity issues and respiratory safety. However, an overall trend to support general concepts of good practices exists. Current regulatory guidelines1 that supports PK/PD (pharmacokinetics/pharmacodynamic) assessment seeks attention threatening those inhaled formulations set to be approved in the coming years. A more complex scenario arises from the attempt of implementing nanomedicines for pulmonary administration. Cutting-edge image techniques could play a key role in supporting diverse stages of clinical development facilitating this pharmaceutics take off and speed to patients. The ongoing challenge in adapting conventional regulatory frameworks has proven to be tremendously difficult in an environment where market entry relies on multiple collections of evidence. This paper intention is to remind us that an acceptable pre-clinical toxicological program could emerge from, but not only, an accurate and robust data imaging collection. It is our conviction that if implemented, inhaled nanomedicines might have impact in multiple severe conditions, such as lung cancer, by fulfilling the opportunity for developing tailored treatments while solving dose-related toxicity issues; the most limiting threat in conventional lung cancer clinical management.

Artificial intelligence-powered medical technologies are rapidly evolving into applicable solutions for clinical practice. Deep learning algorithms can deal with increasing amounts of data provided by wearables, smartphones, and other mobile monitoring sensors in different areas of medicine. Currently, only very specific settings in clinical practice benefit from the application of artificial intelligence, such as the detection of atrial fibrillation, epilepsy seizures, and hypoglycemia, or the diagnosis of disease based on histopathological examination or medical imaging. The implementation of augmented medicine is long-awaited by patients because it allows for a greater autonomy and a more personalized treatment, however, it is met with resistance from physicians which were not prepared for such an evolution of clinical practice. This phenomenon also creates the need to validate these modern tools with traditional clinical trials, debate the educational upgrade of the medical curriculum in light of digital medicine as well as ethical consideration of the ongoing connected monitoring. The aim of this paper is to discuss recent scientific literature and provide a perspective on the benefits, future opportunities and risks of established artificial intelligence applications in clinical practice on physicians, healthcare institutions, medical education, and bioethics., SCOPUS: ar.j, info:eu-repo/semantics/published

It has long been observed in clinical practice that a subset of patients with Lyme disease report a constellation of symptoms such as fatigue, cognitive difficulties, and musculoskeletal pain, which may last for a significant period of time. These symptoms, which can range from mild to severe, have been reported throughout the literature in both prospective and population-based studies in Lyme disease endemic regions. The etiology of these symptoms is unknown, however several illness-causing mechanisms have been hypothesized, including microbial persistence, host immune dysregulation through inflammatory or secondary autoimmune pathways, or altered neural networks, as in central sensitization. Evaluation and characterization of persistent symptoms in Lyme disease is complicated by potential independent, repeat exposures to B. burgdorferi, as well as the potential for co-morbid diseases with overlapping symptom profiles. Antibody testing for B. burgdorferi is an insensitive measure after treatment, and no other FDA-approved tests currently exist. As such, diagnosis presents a complex challenge for physicians, while the lived experience for patients is one marked by uncertainty and often illness invalidation. Currently, there are no FDA-approved pharmaceutical therapies, and the safety and efficacy of off-label and/or complementary therapies have not been well studied and are not agreed-upon within the medical community. Post-treatment Lyme disease represents a narrow, defined, mechanistically-neutral subset of this larger, more heterogeneous group of patients, and is a useful definition in research settings as an initial subgroup of study. The aim of this paper is to review the current literature on the diagnosis, etiology, risk factors, and treatment of patients with persistent symptoms in the context of Lyme disease. The meaning and relevance of existing patient subgroups will be discussed, as will future research priorities, including the need to develop illness biomarkers, elucidate the biologic mechanisms of disease, and drive improvements in therapeutic options.

Background: Ischemia-reperfusion injury (IRI) has been considered an inevitable event in organ transplantation since the first successful kidney transplant was performed in 1954. To avoid IRI, we have established a novel procedure called ischemia-free organ transplantation. Here, we describe the first case of ischemia-free kidney transplantation (IFKT). Materials and Methods: The kidney graft was donated by a 19-year-old brain-dead donor. The recipient was a 47-year-old man with end-stage diabetic nephropathy. The graft was procured, preserved, and implanted without cessation of blood supply using normothermic machine perfusion. Results: The graft appearance, perfusion flow, and urine production suggested that the kidney was functioning well-during the whole procedure. The creatinine dropped rapidly to normal range within 3 days post-transplantation. The levels of serum renal injury markers were low post-transplantation. No rejection or vascular or infectious complications occurred. The patient had an uneventful recovery. Conclusion: This paper marks the first case of IFKT in humans. This innovation may offer a unique solution to optimizing transplant outcomes in kidney transplantation.

Irreproducibility of research results is one of the major contributing factors to the failure of translating basic research results into tangible bedside progress. To address this, the University Biobank Limburg (UBiLim) was founded by a collaboration between Hasselt University, the Hospital East-Limburg, and the Jessa Hospital. This paper describes the evolution of this process and the barriers encountered on the way. UBiLim evolved from an archival collection over a single-site biobank into a federated structure, supporting translational research at the founding institutions. Currently, UBiLim is a federated biobank, with an established organizational structure and processing, and storage facilities at each of the three sites. All activities are integrated in an ISO15189-accredited Quality Management System and based on (inter)national biobank guidelines. Common methods for processing and storage of a plethora of sample types, suitable for state-of-the-art applications, were validated and implemented. Because the biobank is embedded in two hospitals, the request of researchers to include certain sample types or enroll specific patient groups can quickly be met. Funding has been a major challenge in each step of its evolution and remains the biggest issue for long-term biobank sustainability. To a lesser extent, the Belgian legislation and the operational cost of information management system are also concerns for smooth biobank operations. Nonetheless, UBiLim serves as a facilitator and accelerator for translational research in the Limburg area of Belgium that, given the fields of research, may have an impact on international patient care.

Pulmonary arterial hypertension (PAH) is a devastating, life-limiting disease driven by small vessel vascular remodeling leading to a rise in pulmonary vascular resistance (PVR). Patients present with a range of symptoms including shortness of breath, exercise intolerance, palpitations or syncope. Symptoms may be related to vascular disease progression or arrhythmia secondary to the adaptation of the right heart to pressure overload. Arrhythmic burden is high in patients with left heart disease and guideline-based treatment of arrhythmias improves quality of life and prognosis. In PAH the incidence and prevalence of arrhythmias is less well-defined and there are no PAH-specific guidelines for arrhythmia management. We undertook a literature search identifying 13 relevant papers; detection of arrhythmias was acquired from 12-lead electrocardiogram (ECG) or Holter monitors. In all forms of pulmonary hypertension (PH) the prevalence of supraventricular arrhythmias (SVA) was 26-31%, ventricular arrhythmias (VA) 24% and a 5-year incidence of SVA ~13.2-25.1%. Prevalence and incidence of arrhythmias in PAH is less clear due to limited study numbers and the heterogenous nature of the patient population studied. For arrhythmia treatment, only single-arm studies of therapeutic strategies were reported using antiarrhythmic drugs (AAD), direct current cardioversion (DCCV) and ablation. Periods between ECG or Holter have not been investigated, highlighting the possibility that significant arrhythmias may be undetected. Advances in monitoring allow long-term surveillance via implanted/non-invasive monitors. Use of such technologies may provide an accurate estimate of incidence and prevalence of arrhythmias in patients with PAH, further defining relationships to adverse outcomes, and therapeutic options.

Vaccines remain the best measure to reduce total influenza burden. However, presently available influenza vaccines have some limitations that cause a reduced efficacy compared to immunization practices with other respiratory pathogens. This paper shows the clinical roles of antiviral drugs against influenza that have been licensed in at least one country and the potential roles of compounds that are in development. Several attempts have been made to develop new agents against influenza viruses to overcome the supposed or demonstrated limitations of neuraminidase inhibitors (NAIs). Antibodies against the highly conserved stem region of the haemagglutinin molecule of influenza A viruses and drugs that target different stages of the influenza virus life cycle than NAIs in human cells have been developed and tested. Among these preparations, baloxavir marboxil (BAM), and favipiravir (FP) (i.e., polymerase inhibitors) are the only drugs that have reached the market (the first in Japan and the USA, and the second only in Japan). Other antiviral compounds and monoclonal antibodies are in advanced stage of development, but none of these new drugs and monoclonal antibodies in development have adequate characteristics to substitute for NAIs at present. However, although NAIs remain the drug of choice for influenza treatment, their overuse has to be avoided. Accurate selection of patients for whom treatment is truly needed is required.

Although patient preferences have been studied broadly for marketed products or around the time of submission to authorities and launch, patient preference studies have rarely been used during the early drug development phases. In this paper, we formulate three hypotheses supporting the use of patient preference studies in early product development: (1) integration of the patient perspective into the development process from phase 1 onwards will result in healthcare solutions with outcomes that best address patients' needs; (2) a structured process to build patient-based evidence involving partnerships between patients and other key stakeholders will improve alignment of development activities with the needs of patients; (3) quantitative patient preference research built on robust qualitative insights is necessary to strengthen development decisions in the interests of patients. To illustrate such a structured process, we describe qualitative insights research (social media analysis and online bulletin boards) and quantitative patient preference studies in dry eye disease and non-alcoholic steatohepatitis conducted during early product development by a pharmaceutical company to generate patient-based evidence. The outputs from such early patient preference studies are being used to inform patient reported outcome strategies, clinical development strategies, product design and delivery features, and form the basis for early dialog with regulators, health technology assessment (HTA) bodies and payers to ensure focus and alignment on patient-relevant endpoints. Furthermore, to discuss and theoretically substantiate our hypotheses, we review how different groups and organizations are working to embrace fully the patient perspective in product development and healthcare decision-making. The hypotheses are commensurate with the general trend toward patient-centered healthcare and the activities initiated by regulators, HTA agencies, and patient organizations. We advocate that all healthcare players should actively contribute to aligning on best practices concerning choice of methodologies and engage in multi-stakeholder dialog along the entire product development chain, to realize health technologies that best meet the needs of patients.

The balance between systemic anticoagulation and clotting is challenging. In normal hemostasis, the endothelium regulates the balance between anticoagulant and prothrombotic systems. It becomes particularly more challenging to maintain this physiologic hemostasis when we are faced with extracorporeal life support therapies, where blood is continuously in contact with a foreign extracorporeal circuit surface predisposing a prothrombotic state. The blood-surface interaction during extracorporeal life support therapies requires the use of systemic anticoagulation to decrease the risk of clotting. Unfractionated heparin is the most common anticoagulant agent widely used in this setting. New trends include the use of direct thrombin inhibitor agents for systemic anticoagulation; and surface modifications that aim to overcome the blood-biomaterial surface interaction by modifying the hydrophilicity or hydrophobicity of the polymer surface; and coating the circuit with substances that will mimic the endothelium or anti-thrombotic agents. To improve hemocompatibility in an extracorporeal circuit, replication of the anti-thrombotic and anti-inflammatory properties of the endothelium is ideal. Surface modifications can be classified into three major groups: biomimetic surfaces (heparin, nitric oxide, and direct thrombin inhibitors); biopassive surfaces [phosphorylcholine, albumin, and poly- 2-methoxyethylacrylate]; and endothelialization of blood contacting surface. The focus of this paper will be to review both present and future novel surface modifications that can obviate the need for systemic anticoagulation during extracorporeal life support therapies.

Sun exposure is the main risk factor for cutaneous malignant melanoma (CMM). However, the UV-related pathogenetic mechanisms leading to CMM are far to be fully elucidated. In this paper we will focus on what we still don't fully know about the relationship between UVR and CMM. In particular, we will discuss: the action spectrum of human CMM, how different modalities of exposure (continuous/ intermittent; erythemal/ suberythemal) relate to different CMM variants, the preferential UVR induced DNA mutations observed in different CMM variants, the role of UV-related and UV-unrelated genetic damages in the same melanoma cells. Moreover, we will debate the importance of UVA induced oxidative and anaerobic damages to DNA and other cell structures and the role of melanins, of modulation of innate and acquired immunity, of vitamin D and of chronic exposure to phototoxic drugs and other xenobiotics. A better understanding of these issues will help developing more effective preventative strategies and new therapeutic approaches.

Fibromyalgia syndrome (FMS) is a chronic, complex, and heterogeneous disorder of still poorly understood etiopathophysiology associated with important musculoskeletal widespread pain, fatigue, non-restorative sleep, and mood disturbances. It is estimated to afflict 2-3% of the worldwide population, with clean prevalence among women. The objective of this paper is to propose a novel treatment for symptomatic remission of FMS, grounded in biochemistry and consisting in the withdrawal from the diet of molecules that can indirectly trigger the symptoms. The hypothesis develops from the evidence that low serotonin levels are involved in FMS. Serotonin is synthesized starting from the essential amino acid tryptophan. The presence of non-absorbed molecules in the gut, primarily fructose, reduces tryptophan absorption. Low tryptophan absorption leads to low serotonin synthesis that triggers FMS symptoms. Moreover not-absorbed sugars could also produce a microbiota deterioration activating a positive feedback loop: the increasing microbiota deterioration reduces the functionality of absorption both of fructose and tryptophan in the gut, entering a vicious circle. The therapeutic idea is to sustain serotonin synthesis allowing the proper tryptophan absorption. The core of the cure treatment is the exclusion from the diet of some carbohydrates and the marked reduction of some others. The main target is the limitation of total dietary fructose as marked as possible. It could be an effective strategy to get the remission of symptoms acting on the impaired biochemical pathways. The straying from the treatment is expected to cause the reappear of the symptoms.

Context The Creighton Model FertilityCareTM System (CrM) is a standardized approach for educating women about the biomarkers of their fertility. Couples can use this information for timing intercourse during “fertile” or “infertile” days in order to try to conceive or to avoid pregnancy. Objectives The study of Creighton Model Effectiveness, Intentions, and Behaviors Assessment (CEIBA) was conducted to assess fertility motivations, intentions, fertility-related sexual behaviors, and their impact on effectiveness to avoid and to conceive among new users of the CrM. This paper reports enrollment baseline characteristics. Settings and design We conducted this prospective cohort study at 17 CrM FertilityCareTM Centers; 16 in the USA and one in Toronto, Canada. Materials and methods Couples who were new or returning users of the CrM were eligible. Couples who were initially trying to conceive or had a history of subfertility were excluded. Couples were enrolled and followed prospectively by their CrM instructors and also by CEIBA study staff. They completed baseline questionnaires. Results 1,132 new couples were assessed; 1,090 (96%) couples were screened; 429 (39%) couples were eligible; 305 women (71%) and 290 (95%) male partners were enrolled. The majority of women was engaged (39%) or married (51%), college graduates (77%), Caucasian non-Hispanic (80%), and Roman Catholic (80%). The most common reasons for learning CrM (women) were to use a natural method for family planning (91%), for moral/ethical/religious reasons (70%), the lack of side effects (71%), or insight into the menstrual cycle and fertility (62%). Women and men intended to have a mean of three and two additional children, respectively. Of women, 21% intended to have a child within a year and 60% between 1 and 3 years. The mean positive childbearing motivation score was 3.3 for both women and men (range 1–4, with 4 being most positive). Conclusion Couples beginning use of the CrM to avoid pregnancy have high levels of motivation, desire, and intention for future childbearing. The CEIBA study has prospective measures of desires, intentions, and sexual/fertility behaviors for up to 1 year. We will assess the impact of desires, intentions, and behaviors on the pregnancy rates among these couples.

The introduction of Operational Excellence in the Maastricht University Medical Center (MUMC+) has been the first of its kind and scale for a university hospital. The policy makers of the MUMC+ have combined different elements from various other business, management, and healthcare philosophies and frameworks into a unique mix. This paper summarizes the journey of developing this system and its most important aspects. Special attention is paid to the role of the operating rooms and the improvements that have taken place there, because of their central role in the working of the hospital. The MUMC+ is the leading tertiary healthcare center for the South-East region of The Netherlands and beyond. Regional, national, and international developments encouraged the MUMC+ to start significantly reorganizing its care processes from 2009 onward. First experiments with Lean Six Sigma and Business Modeling were combined with lessons learned from other centers around the world to form the MUMC+'s own type of Operational Excellence. At the time of writing, many improvement projects of different types have been successfully completed. Every single department in the hospital now uses Operational Excellence and design thinking in general as a method to develop new models of care. An evaluation in 2014 revealed several opportunities for improvement. A large number of projects were in progress, but 75% of all projects had not been completed, despite the first projects being initiated back in 2012. This led to a number of policy changes, mainly focusing on more intensive monitoring of projects and trying to do more improvement projects directly under the responsibility of the line manager. Focusing on patient value, continuous improvement, and the reduction of waste have proven to be very fitting principles for healthcare in general and specifically for application in a university hospital. Approaching improvement at a systems level while directly involving the people on the work floor in observing opportunities for improvement and realizing these has shown itself to be essential.

The advent of precision medicine and predictive molecular pathology led to a revolution in clinical management of patients with non-small cell lung cancer. The discovery of oncogene addiction allowed the development of targeted therapies that represent newer therapeutic options reserved to those patients harboring specific gene alterations, such as EGFR mutations, ALK, and ROS1 translocations (Lazzari et al.; Sullivan and Planchard; Tran and Klempner; Köhler). In addition, the introduction of immunotherapy, with anti PD-1 Pembrolizumab, in first-line treatment of NSCLC represents the best choice for EGFR, ALK, and ROS1 wild-type patients expressing PD-L1 on ≥50% of neoplastic cells (Cortinovis et al.). Despite the survival improvement achieved with these new therapeutic options in first-line treatment, about 30% of patients do not obtain a tumor response (Lazzari et al.). Moreover, those patients, initially sensitive to these treatments, acquire resistance and develop tumor progression. Approximately 60% of the patients progressing from first-line therapy receiving further systemic treatment in the second-line setting (Lazzari et al.; Cortinovis et al.) Also in second line, the armamentarium for the treatment of patients with NSCLC, includes a pletora of new drugs, such as immune checkpoint inhibitors (Pembrolizumab, Nivolumab) (Cortinovis et al.), third generation tyrosine kinase inhibitors (Osimertinib) (Molina-Vila et al.; Zugazagoitia et al.), and anti-angiogenic agents (Nintedanib and Ramucirumab) (Corrales et al.; Manzo et al.). This exciting therapeutic scenario for NSCLC patients still has unsolved questions and challenging issues, in particular regarding the optimal selection of the patient population through the individualization of the correct methodology and biological source of material (tissues vs liquid biopsy) for clinical relevant biomarkers assessment (Molina-Vila et al.). Probably the right way is to give all the available opportunities to patients, but challenges and pitfalls should be carefully debated. Taken together, the papers published in Research Topic “Second Line Treatment of Non-Small Cell Lung Cancer: Clinical, Pathological and Molecular Aspects of Novel Promising Drugs” represent a critical discussion focused on the older therapies and the historical development of second line, putting into perspective the new agents available in clinical practice, defining their importance from a clinical point of view, but also to consider and exploit the complex molecular mechanisms responsible of their efficacy or of the subsequently observed resistance phenomena, to support the oncologist to design the best therapeutic strategies for NSCLC patients.

The treatment of voice disorders includes physiotherapy and complementary therapies. However, research to support these treatments is scarce. Objective: to verify the effectiveness of physiotherapy and complementary therapies on voice disorders. Research on electronic databases PubMed/Medline, SciELO, and LILACS was performed using the combination: voice AND (treatment OR intervention) according to PRISMA guidelines. Only randomized controlled trials (RCTs) were included in the review. Studies were analyzed using the physiotherapy evidence database (PEDro) scale and the Center for Evidence-Based Medicine’s Levels of Evidence scale. Eight papers met the inclusion criteria. From the RCTs included in this review, six assessed massage, one transcutaneous electrical nerve stimulation (TENS), one refer to spinal manipulative therapy, and one to acupuncture. The literature regarding the effectiveness of physiotherapy and complementary therapies was good in both quality and results, indicating that massage, TENS, and acupuncture seem to be effective treatments to reduce voice complaints and improve voice quality, supporting the inclusion of complementary therapies but mostly physiotherapy interventions in the treatment of patients with voice disorders.

Male sexual dysfunction is common in chronic kidney disease, particularly in end-stage renal disease. Historically this cause of considerable morbidity has been under-reported and under-recognized. The ideal approach to diagnosis and management remains unclear due to a paucity of good quality data, but an understanding of the pathophysiology is necessary in order to address the burden of this important complication of chronic kidney disease. This paper will review the endocrine dysfunction that occurs in renal disease, particularly the hypothalamic-pituitary-gonadal axis, discuss the causes of erectile dysfunction, infertility and altered body image and libido in these patients, and suggest appropriate treatment interventions.

Parkinson’s disease (PD) is a neurological disorder that is associated with both motor and non-motor symptoms. The management of PD is primarily via pharmaceutical treatment, however non-pharmaceutical interventions have become increasingly recognised in the management of motor and non-motor symptoms (NMS). In this review, the efficacy of physical activity, including physiotherapy and occupational therapy, as an intervention in NMS will be assessed. The papers were extracted between the 20th to 22th of June 2016 from Pubmed, Web of Science, Medline, Ovid, SportsDiscuss and Scopus using the MeSH search terms ‘Parkinson’s’, ‘Parkinson’ and ‘Parkinsonism’ in conjunction with ‘exercise’, ‘physical activity’, ‘physiotherapy’, ‘occupational therapy’, ‘physical therapy’, ‘rehabilitation’, ‘dance’ and ‘martial arts’. Twenty studies matched inclusion criteria of having ten or more participants with diagnosed idiopathic PD participating in the intervention as well as having to evaluate the effects of physical activity on NMS in PD as controlled, randomized intervention studies. The outcomes of interest were NMS, including depression, cognition, fatigue, apathy, anxiety and sleep. Risk of bias in the studies was evaluated using the Cochrane Collaboration’s tool for assessing risk of bias. Comparability of the various intervention methods however was challenging due to demographic variability and methodological differences. Nevertheless, physical activity can positively impact the global NMS burden including depression, apathy, fatigue, day time sleepiness, sleep and cognition, thus supporting its therapeutic potential in neurodegenerative conditions such as PD. It is recommended that further adequately powered studies are conducted to assess the therapeutic role of physical activity on both motor and non-motor aspects of PD. These studies should be optimally designed to assess non-motor elements of disease using instruments validated in PD.