Long-term Clinical Manifestations Research Articles

Is SARS-CoV-2 the only cause of long-COVID?

Around 10% of adults infected with SARS-CoV-2 that survive a first episode of COVID-19 appear to experience long-term clinical manifestations. The signs and symptoms of this post-acute COVID-19 syndrome (PACS) include fatigue, dyspnea, joint pain, myalgia, chest pain, cough, anosmia, dysgeusia, headache, depression, anxiety, memory loss, concentration difficulties, and insomnia. These sequelae remind the constellation of clinical manifestations previously recognized as myalgic encephalomyelitis (ME) or chronic fatigue syndrome (CFS). This condition has been described following distinct infectious events, mostly acute viral illnesses. In this way, the pathophysiology of PACS might overlap with mechanisms involved in other post-infectious fatigue syndromes. The risk of PACS is more frequent in women than men. Additional host genetic factors could be involved. There is a dysregulation of multiple body organs and systems, involving the immune system, the coagulation cascade, endocrine organs, autonomic nervous system, microbiota-gut-brain axis, hypothalamic-pituitary-adrenal axis, hypothalamic-pituitary-thyroid axis, etc. Hypothetically, an abnormal response to certain infectious agents could trigger the development of postinfectious fatigue syndromes.

Molecular and Clinical Features of Congenital Hypothyroidism Due to Multiple DUOX2 Variants.

Background: DUOX2 is one of the major causative genes of congenital hypothyroidism (CH). Still, the mutation spectrum and clinical outcomes of biallelic DUOX2 variants are not fully understood. This study aimed to elucidate the molecular features and long-term clinical manifestations of CH caused by multiple pathogenic DUOX2 variants. Methods: A total of 255 patients with CH were screened for rare variants of 11 known causative genes. DUOX2 variants were classified according to their protein structure and residual activity. In vitro assays were performed for several variants of unknown functions. Clinical analyses were conducted for patients with multiple pathogenic variants of DUOX2 but not of other genes. Results: We identified 24 pathogenic variants of DUOX2, together with two benign variants and seven variants of uncertain significance, in 63 patients. The pathogenic variants included three missense substitutions and one frameshift variant that have not yet been linked to CH. Twenty-one patients carried multiple pathogenic DUOX2 variants without any other pathogenic gene variants. Three of the 21 patients harbored homozygous variants. Family analysis, long-read amplicon sequencing, and haplotype phasing confirmed compound heterozygosity of the DUOX2 variants in 14 patients, whereas the allelic positions of the variants in the remaining four patients could not be determined. Of the 21 patients, 19 were treated with levothyroxine; their ages at drug withdrawal ranged from 9 months to 21.4 years. Three patients required retreatment after drug-free intervals of 6 months, 8 months, and 10 years. There were no differences in clinical severity among patients with DUOX2 amorphic/amorphic, amorphic/hypomorphic, and hypomorphic/hypomorphic variants. Conclusions: These results broaden the mutational spectrum of DUOX2. Furthermore, our data imply that patients with multiple pathogenic DUOX2 variants typically exhibit transient CH without significant genotype-phenotype correlations. Most importantly, this study demonstrated for the first time that these patients are at risk of developing recurrent hypothyroidism after a long drug-free interval.

Organ-specific manifestations of "long COVID"

The COVID-19 pandemic has severely affected the healthcare system across the globe and caused significant morbidity and mortality. The occurrence and importance of the post-COVID-19 sequelae was realized when a sizable proportion of patients appeared to continue suffering from various symptoms for many months and years after having recovered from the acute phase of infection. These complications were observed in multiple organ systems and not only in the respiratory tract. Multidisciplinary efforts are required to manage these patients as the complications are variable in terms of location and severity.
 The post COVID-19 condition (long COVID) represents a number of different post-viral syndromes that require an appropriate classification. Collection of a large amount of data is required for all the physical and neuropsychiatric symptoms that persist for more than 12 weeks without an alternative explanation. The process of data collection and analysis should be controlled for all confounding factors including the consequences of intensive care hospitalization, social isolation, and other effects.
 The current absence of the effective treatment reflects the unclear causes of the post COVID-19 conditions which cannot be targeted properly until their mechanism is established. Timely collection of data and identification of physiological mechanisms underlying the long-term clinical manifestations of C0VID-19 are vital for the relevant design of effective therapies.

#4432 ECYSCO: A EUROPEAN COHORT DEDICATED TO CYSTINOSIS

Abstract Background and Aims Cystinosis is a rare multisystem lysosomal storage disease due to variants in the CTNS gene, coding for the carrier protein cystinosine, a lysosome membrane transporter causing cystine accumulation with a reported incidence of 1:180,000 live births. Specific treatment by cysteamine decreases renal and extrarenal complications frequency and increases life expectancy. Recently, new treatments for cystinosis entered into the European market with an extended-release formulation of cysteamine and a new formulation of eye drops. The aim of this project is to describe the natural history of the disease and long-term clinical manifestations. Method We set up a European, multi-centre, longitudinal, non-interventional cohort, ECYSCO, that uses observational study methods to collect uniform data. 243 patients with a confirmed diagnosis of cystinosis and followed in 25 French and 5 European centers (Belgium, Italy, Spain and Germany) were included. Data are collected on the secure RaDiCo platform, via an e-CRF (REDCap). Results Data from 180 patients (50.0% male) were analyzed. Median age at diagnosis was 1.3 years [IQ 0.8; 1.9], with earlier diagnosis since the 1980s, but no further improvement in the 2000s. Genetic analysis was available for 174 patients: 57 (32.8%) presented with homozygous 57kb deletion in the CTNS gene, 71 (40.8%) with heterozygous 57kb deletion associated with another variant and 46 (26.4%) with other variants. The type of variant had no impact on the age at diagnosis. Median age at cysteamine start was 1,6 years (IQ 1.0-3.0). An improvement on age at treatment start was observed after the 1990s. All but 6 patients were treated with cysteamine. 71 patients received immediate release formulation (Cystagon®) and 103 received extended release formulation (Procysbi®). Median white blood cell cystine level was correct at 1.2 nmol ½ cystine/mg protein (IQ 0.59; 2.20). The median duration of treatment was 21.5 years [IQ 11.7; 31.1]. 167 (95,9%) patients also received cysteamine ocular gel, Cystadrops®. Median age at inclusion was 19.08 years (IQ 10.43; 31.41). At that time, 104 patients (57.8%) had reached end-stage renal disease (ESRD). There was no impact of genotype on age at ESRD. Median age at ESRD was 12.9 years [IQ 9.9; 18.0]. A 5-year gain in renal survival was observed after the 1990s. 102 patients (56.7%) received a kidney transplant. Among these transplanted patients: 76 (74.5%) received 1 transplant, 23 (22.5%) received 2 consecutive transplants, and 3 (2.9%) received 3. Median eGFR in the remaining patients was 58.9 ml/min [IQ 40.4; 82.2]. Extrarenal manifestations included hypothyroidism in 61 (33.9%) patients, diabetes mellitus in 11 (6.1%), skeletal manifestations in 73 (40.5%), myopathy in 32 (17.8%), and neurological disorders in 22 (12.2%). At inclusion, 36 patients had no ESRD and no extra-renal complication. Conclusion Cystinosis is a good example of a pediatric disease with multiorgan involvement extending into adult care. More than half of patients are adults and have reached ESRD even if age at renal replacement therapy start has increased. The high frequency of extra-renal manifestations demonstrates the importance of a multidisciplinary follow up of these patients.

Disease perception, impacts and coping strategies for onchocerciasis in Southeast Nigeria: a qualitative study among patients and program managers

BackgroundOnchocerciasis is a disease of public health concern due to the devastating consequences of the disease which impacts negatively on the lives of the people. The negative impact of the disease may affect its perception and lead to the adoption of some coping strategies. Therefore, understanding the disease perception, impacts and coping strategies used by onchocerciasis patients will help plan health interventions aimed at improving their general well-being.MethodsThis was a community-based study that employed a qualitative method through Key informant interviews (KII) with program managers and focus group discussions (FGD) among people who had Onchocerciasis. Four sessions of FGDs with a total of thirty-two (32) participants and eleven KIIs were conducted to ascertain their in-depth experience in five thematic areas.ResultsIn these communities, onchocerciasis is perceived to have been caused mainly by the bite of blackflies. Other presumed causes by the patients included drinking polluted water, poor environmental sanitation and witchcraft. The disease had a significant detrimental influence on both the physical and financial aspects of life with limited emotional and social impacts. The long-term clinical manifestations of onchocerciasis triggered pain and insufficient mobility. Thus, onchocerciasis patients experienced impairment in normal daily life activities (farming, etc.), dependency, depression and inability to participate in social events. These manifestations stimulated various coping strategies, mainly, nodulectomy by traditional healers. Others included self-medication, taking an overdose of ivermectin, and the use of alcohol.ConclusionMisconceptions about the cause of onchocerciasis still exist among people with the disease. The consequences of the disease impact negatively on various aspects of their lives and stimulate various coping strategies. Therefore, health promotion messages to the public should aim at dispelling misconceptions about the disease and promote healthy coping strategies.

«Long COVID»: the current state of the problem. A review of foreign scientific and medical publications

Not all the patients diagnosed with COVID-19 can completely recover; some of them experience various persistent symptoms which wax and wane. As the COVID-19 pandemic continues, the number of people with long-term symptoms is rapidly increasing, adding to the burden on the healthcare and society.
 The prevalence of the COVID-19 consequences varies between studies, with some researchers reporting that more than half of hospitalized patients suffer from long-lasting symptoms for at least 6 months after the acute SARS-CoV-2 infection, and others observing such symptoms for more than 12 months. The overall prevalence of residual symptoms in patients infected with SARS-CoV-2 is currently estimated as 1030%. This clinical syndrome is commonly referred to as post-acute COVID syndrome (PACS) or long COVID.
 This multifactorial syndrome is characterised by a variety of debilitating symptoms, including fatigue, brain fog, postural hypotension with tachycardia, and post-exertional malaise. Many of the post COVID-19 condition observations, including changes in the immune, cardiovascular, gastrointestinal, nervous and autonomic systems, are shared with those for myalgic encephalitis/chronic fatigue syndrome (ME/CFS) patients. A comprehensive longitudinal symptom monitoring is required to confirm the diagnosis, uncover the mechanisms of post-COVID-19-associated ME/CFS, and develop the prevention and treatment measures. The current absence of an effective treatment reflects the unclear causes of the post COVID-19 conditions which cannot be targeted properly until the mechanism is established and confirmed.
 The multisystem aspects of long COVID remain poorly understood. The COVID-19 pandemic has exposed a significant gap in the knowledge about the post-acute consequences of infectious diseases and the need for a unified nomenclature and classification, diagnostic criteria, and a reliable assessment of post-COVID conditions. Unraveling the complex biology of PACS relies on the identification of biomarkers in the plasma and tissue samples harvested from individuals infected with SARS-CoV-2 that will allow classification of the phenotypes of patients who develop PACS.
 For a comprehensive treatment of patients with post-COVID syndrome, multidisciplinary therapy and rehabilitation are required. Understanding the physiological mechanisms underlying the long-term clinical manifestations of COVID-19 and the post-COVID-19 state is vital for the development of appropriate effective therapies.

Association among early life stress, mood features, hopelessness and suicidal risk in bipolar disorder: The potential contribution of insomnia symptoms

IntroductionMood disorders are complex illnesses possibly resulting from the interaction of genetic, physiological, psychological, and environmental factors.Within this framework, a role for early life stressors has been proposed. Although this association is probably not specific to Bipolar Disorders BDs, with early life stressors predisposing to trans nosological indicators for severity of psychiatric disorders, it may represent an early marker both for triggering and long-term clinical manifestations of BDs.Insomnia likely plays a triggering role in the onset and maintenance of BDs, as it may might play a key role in BDs by potentially dysregulating the systems involved in mood and emotion regulation, including stress and inflammatory systems and circadian rhythms alterations. Early life stressors have been demonstrated to alter sleep regulation. It has been hypothesized that sleep disruption related to early life stressors might contribute to the development pathways towards BDs in adult life through the epigenetic re-reprogramming of stress and inflammatory systems.ObjectivesWe aimed to study their association with mood symptoms and suicidal risk in BDs with and without clinically significant insomnia symptoms. Since hopelessness is a construct strongly predicting depressive symptoms and suicidal risk in BDs and it has also been related to early life stress and to insomnia symptoms we aimed to specifically assess this symptom in our research.Methodsa sample of 162 adult participants with BD I or II were assessed during depressed phase using the Structural Clinical Interview for DSM-5 (SCID-5), the Beck Depression Inventory-II (BDI-II), the Young Mania Rating Scale (YMRS), the Early Trauma Inventory Self Report-Short Form (ETISR-SF), the Beck Hopelessness Scale (BHS), the Insomnia Severity Index (ISI) and the Scale for Suicide Ideation (SSI). Participants with or without clinically significant insomnia were compared and we carried out correlations, regression and mediation analyses.ResultsParticipants with insomnia showed a greater severity of depressive symptoms,of suicidal risk, of the cognitive component of hopelessness and of early life stressors. Insomnia symptoms mediated the association among early life stress and depressive symptoms (Z = 2.72, p = 0.0006), the cognitive component of hopelessness (Z = 3.02, p = 0.0001) and suicidal ideation and plans (Z = 2.07 p = 0.0006).Conclusionsfnsomnia may mediate the relationship between early life stress and clinical manifestations of BD. Assessing the evolution of insomnia symptoms could offer an approach to characterize BD and to formulate treatment strategies. In particular targeting insomnia symptoms might potentially modify the clinical features of BD in response to early life stressful events.Disclosure of InterestNone Declared

Evaluation of the effects of COVID-19 on semen parameters and male infertility.

The new coronavirus pandemic resulted in millions of deaths in Brazil and around the world, and presented substantial challenges to society. The shortand long-term clinical manifestations tied to COVID-19 are still poorly understood, and may involve several organs and systems, including the male genital tract, which may lead to impaired fertility. The present study aimed to analyze, through an integrative literature review of articles available in databases, the effects of COVID-19 on parameters related to human semen quality. The analyzed studies reported significant decreases in sperm motility and morphology related to COVID-19. Reductions in concentration and volume were also observed. Inflammatory response is one of the leading mechanisms that may potentially explain the observed changes, although others may also be involved. More studies are needed to better understand the effects, modes of action, as well as other aspects involved in this complex phenomenon.

The clinical manifestation and the influence of age and comorbidities on long-term chikungunya disease and health-related quality of life: a 60-month prospective cohort study in Curaçao

BackgroundPersistent rheumatic symptoms and its impact on health-related quality of life (QoL), induced by the Indian Ocean Lineage (IOL) chikungunya virus (CHIKV) genotype have been widely studied. In 2014, a major CHIKV outbreak of the Asian genotype occurred in Curaçao, after which we established a longitudinal cohort in 2015, to follow the long-term CHIKV sequalae. Currently, the long-term clinical manifestations and its impact on QoL induced by the Asian CHIKV genotype, followed prospectively through time, and the association of age and comorbidities with rheumatic symptoms persistence, 60 months (M60) after disease onset is unknown.MethodsThe cohort of 304 laboratory confirmed patients were followed prospectively in time at 3–16 months (M3-16), 30 months (M30), and M60 after disease onset. Demographic and clinical characteristics, and the 36-item short-form survey (SF-36) QoL status were collected through questionnaires. At M60, QoL scores were compared to general population (CHIK-) norms.ResultsA total of 169 (56%) patients participated (74.6% female, mean age 56.1 years) at all time points, 107 (63%) were classified as recovered and 62 (37%) as affected. The affected patients reported an increase in the prevalence of arthralgia (P .001) and arthralgia in the lower extremities (P < .001), at M30 compared to M3-16. At M60, in comparison to recovered patients, affected patients reported a higher prevalence of recurrent rheumatic symptoms of moderate to severe pain, irrespective of age and comorbidities, and a higher prevalence of non-rheumatic symptoms (P < .001). Arthralgia in the upper (odds ratio (OR): 4.79; confidence interval (CI): 2.01–11.44; P < .001) and lower (OR: 8.68; CI: 3.47–21.69; P < .001) extremities, and headache (OR: 3.85; CI: 1.40–10.54; P = .009) were associated with being affected. The SF-36 QoL scores of the recovered patients were less impaired over time compared to the QoL scores of the affected patients. At M60, the QoL scores of the recovered patients were comparable to the CHIK- QoL scores.ConclusionsRheumatic and non-rheumatic symptoms, and QoL impairment may persist, 60 months following infection with the Asian CHIKV genotype, similar to the IOL genotype disease sequelae. Further research is needed to follow the clinical manifestations and QoL impact of each CHIKV genotype.

Manifestaciones clínicas en post COVID en adultos en la República de Panamá

Introduction: individuals who suffer from COVID-19 can either be asymptomatic or have symptoms that can range from mild, moderate to severe. However, a significant amount of the population can present a group of long-term clinical manifestations that have been englobed by the term post-COVID syndrome. Methodology: we executed an observational and transverse study on patients with a history of SARS-CoV-2 infection, between March 2020- March 2021 in the Republic of Panama. Simple random sampling was utilized on post-COVID clinic patients and the general population with the help of a self-administered digital survey. Results: the answers of 248 participants were analyzed; 64.5% were female with an average age of 36.7 years. Arterial hypertension (14.5%) and obesity/overweight (18.1%) were the most frequent comorbidities among the studied population. Around 87% were mild and 85.9% suffered from at least one long- term symptom. Risk factors associated with symptom persistence includes the presence of 7 or more symptoms during the acute phase of disease (OR 9.46), as well as the female gender (OR 5.07). Other factors include ventilatory support (OR 2.58) and hypertension (OR 2.46). Acute phase symptoms that persisted long-term include headaches, dyspnea, general malaise and fatigue. Conclusions: post-COVID syndrome is a public health issue that requires solutions obtained through research and their application within the healthcare system. To our knowledge, this is the first prevalence study concerning post-COVID symptoms executed in the Republic of Panama. It provides current information to the limited knowledge on symptoms that appear after an acute infection of COVID-19.&nbsp;

SARS-CoV-2-induced host metabolic reprogram (HMR): nutritional interventions for global management of COVID-19 and post-acute sequelae of COVID-19 (PASC)

‘Severe acute respiratory syndrome coronavirus 2’ (SARS-CoV-2) is a highly transmissible viral pathogen responsible for the ongoing ‘coronavirus disease 2019’ (COVID-19) pandemic. The current re-purposed antiviral interventions against SARS-CoV-2 are classified into two major groups: Group-1 represents the family of drugs, mainly the vaccines that directly target the virus, and Group-2 includes a specific class of inhibitors that interfere with the host-cell machinery, which is critical for viral infection and replication. Global efforts to control COVID-19 pandemic with vaccines and repurposed therapeutics represent only a phased victory. The emergence of several SARS-CoV-2 variants of concern (VOCs) has compromised several vaccinations and pharma-therapeutic protocols, which highlights the dire necessity for specific antiviral interventions that target highly conserved domains, which are less likely to mutate in the SARS-CoV-2 genome. Several bioactive phytochemicals that block viral enzymes such as nsp5/main proteinase (Mpro) and RNA-dependent nsp7/nsp8/nsp12 RNA-dependent RNA-polymerase (RdRp) complex, are extensively investigated in this direction. The SARS-CoV-2 infection triggers a complex human host-pathogen interaction(s) resulting in ‘host metabolic reprogramming’ (HMR), iron (Fe)-redox dysregulation (FeRD), and altered mitochondrial function that cumulatively disrupt several metabolic pathways involved in cellular energy and antioxidant enzyme function; thereby, compromise the innate host defense. The circulatory/RAAS axis contributes to FeRD and any alteration or imbalance in the Fe-redox homeostasis (Fe-R-H) may lead to ‘new onset’ metabolic disorders (i.e., diabetes). Such inherent body damage and its long-term health consequences in post-acute sequelae of COVID-19 (PASC) require effective nutritional intervention strategies, particularly at the interface of organ system functions and immune system dynamics. The long-term sequelae of PASC indicate an accelerated rate of immune exhaustion in COVID-19 patients, due to prolonged antigen stimulation (also due to vaccine exposure). Abnormal immune metabolism may also cause systemic perturbations (i.e., FeRD), ROS/RNS production, oxidative and nitrosative stress, which could trigger multi-organ disorders ranging from mild symptoms to an incapacitating state and reduced quality of life that could last for weeks or longer following recovery from COVID-19. The five most long-term clinical manifestations of PASC include fatigue, headache, attention disorder, hair loss, and dyspnea. This narrative review elucidates the intricate impairments and sequelae associated with eight major physiological systems in COVID-19 survivors (i.e., pulmonary, neuro-cognitive, cardiovascular, renal, gastrointestinal/hepato-biliary, endocrinal, skeleton-muscular, and reproductive) – triggered by the FeRD, amplified by the HMR, altered mitochondrial function and ACE2/RAAS axis. We have attempted to explain the ongoing epidemic of the residual, non-viral host metabolic disorders and complications in COVID-19 survivors and the supportive role of specific host system-targeted nutritional interventions such as natural plant-based anti-inflammatories, immune-modulators, antioxidants, and macro-/micronutrient metabolic optimizers to manage PASC, the newly emerged post-COVID metabolic syndrome.

Impact of COVID-19 on Future Ischemic Stroke Incidence.

With the ever-expanding population of patients infected with SARS-CoV-2, we are learning more about the immediate and long-term clinical manifestations of coronavirus disease 2019 (COVID-19). Ischemic stroke (IS) is now one of the well-documented additional clinical manifestations of COVID-19. Most COVID-19 related IS cases have been categorized as cryptogenic or embolic stroke of undetermined source (ESUS), which are most often suspected to have an undiagnosed cardioembolic source. COVID-19 is known to also cause cardiac dysfunction, heart failure, and atrial arrhythmias (AA), but the long-term impact of this cardiac dysfunction on stroke incidence is unknown. With millions afflicted with COVID-19 and the ever-rising infection rate, it is important to consider the potential long-term impact of COVID-19 on future IS incidence. Accomplishing these goals will require novel strategies that allow for diagnosis, data capture, and prediction of future IS risk using tools that are adaptable to the evolving clinical challenges in patient care delivery and research.

Postacute COVID-19: An Overview and Approach to Classification.

As the coronavirus disease 2019 (COVID-19) pandemic has progressed, a large volume of literature has developed delineating the clinical manifestations of acute infection. Recent reports have also started to describe persistent symptoms extending beyond the period of initial illness or hospitalization. Anecdotes of different signs and symptoms occurring after acute infection have also arisen in the lay press. Here we describe the current existing medical literature on the emerging concept of postacute COVID-19 and suggest an approach to classifying different manifestations of the syndrome. We also review long-term clinical manifestations observed in patients who recovered from infection due to other epidemic coronaviruses and briefly discuss potential mechanisms driving the phenomenon of postacute COVID-19.

General Anesthetic Use in Fragile X Spectrum Disorders.

The fragile X premutation is characterized by a repeat expansion mutation (between 55 to 200 CGG repeats) in the fragile X mental retardation 1 (FMR1) gene, which leads to RNA toxicity at the cellular level. This may cause patients with the premutation to be particularly susceptible to environmental toxins, which could manifest clinically as new or worsening ataxia and memory loss. Multiple published case reports have also suggested general anesthetics as a potential toxin leading to negative side effects when used in patients with fragile X-associated disorders. However, at this time, there have been no formal research studies regarding cellular changes or long-term clinical manifestations after general anesthetic use in this population. This review aims to highlight previous case reports regarding sequelae related to general anesthetic use in fragile X-associated disorders. New case reports related to this phenomenon are also included.

Association of Nitric Oxide With Delayed Skin Problems After Sulfur Mustard Exposure: Part of Sardasht-Iran Cohort Study

Background: Exposure to Sulfur Mustard (SM) leads to short- and long-term adverse effects on various organs, including the skin. Despite several studies on long-term clinical manifestations of skin toxicity in SM-exposed individuals, the pathogenesis of SM-induced skin disorders is not fully understood. Materials and Methods: As part of Sardasht-Iran Cohort Study (SICS), this study aimed to find out the possibility of any correlation between the serums level of Nitric Oxide (NO) and skin problems due to the long-term effect of SM as well as the kind of skin illness. In this historical cohort study, 372 male SM-exposed subjects and 128 age-matched unexposed controls were studied. Clinical evaluation was carried out for all participants, and their serum concentration of NO was measured. Results: According to our results, the Mean±SD serum level of NO in the exposed group with skin disorders were significantly higher than that in the exposed group without skin disorders (1483.00±488.754µg/mL vs. 1364.50±487.887µg/mL; P=0.024). Also, among the exposed group, there was a significant elevation of serum NO associated with the type of lesion. For ezxample, specific lesions like mustard scar were associated with higher levels of NO compared to non-specific lesions like xerosis, itching, seborrheic dermatitis, etc. Also, a significant elevation in serum NO levels was found in the exposed subjects with pigmentation disorders (both hypo- and hyper-pigmentation) compared to the exposed participants without these skin problems (PConclusion: Our results show the highest serum level of NO in the exposed group with specific lesions and the lowest or normal level of NO in the unexposed group with no skin illness. The elevated serum levels of NO may be associated with the progression of some skin complications in the SM-exposed subjects. This finding serves as a basis for further research on the molecular mechanisms and pathways involved in the pathogenesis of skin disorders in SM-exposed patients.

Genotype-Phenotype Correlation in Long-Term Cohort of Japanese Patients with Moyamoya Disease

Background: Homozygosity of this p.R4810K founder variant of RNF213moyamoya disease (MMD) susceptibility gene is known to influence the severity of the clinical disease phenotype at disease onset. However, the association between this genotype and long-term clinical manifestations has remained unclear. Objectives: The principal goal of this study was to investigate whether and how the p.R4810K variant of RNF213influences the long-term phenotype in Japanese patients with MMD. Method: This retrospective cohort study included 94 Japanese patients with MMD who underwent direct or combined bypass for revascularization with the p.R4810K genotype determined in our hospital. The following phenotypic parameters were analyzed at disease onset and over a long-term period: age and initial presentation at onset, recurrent stroke after initial revascularization, and final modified Rankin Scale. Results: The p.R4810K genotype was significantly associated with the phenotype at onset, especially in younger patients. Over a median follow-up period of 100 months, recurrent stroke occurred in 6 out of 94 patients: none out of 5 patients with the homozygous variant, 5 out of 64 with the heterozygous variant, and 1 out of 25 in the wild-type group. There were no significant differences among the genotypes. In particular, recurrent cerebral hemorrhage occurred in 5 patients, all possessing the heterozygous variant. The log-rank test showed no difference between the genotypes in the stroke-free survival rate. Furthermore, the p.R4810K genotype was not associated with a poor functional condition. Conclusions: The p.R4810K founder variant of RNF213 affects the phenotype at disease onset. However, the optimal revascularization may be effective, regardless of the genotype, even for the homozygous variant, which has been thought to be the most pathogenic. This genotype may not strongly influence the long-term clinical manifestations or poor prognosis in MMD.

Chikungunya virus outbreak in Sint Maarten: Long-term arthralgia after a 15-month period.

The first chikungunya (CHIK) epidemic in the Americas was reported in December 2013. Chikungunya virus (CHIKV) causes an acute febrile illness and is transmitted to humans by Aedes mosquitoes. Although earlier studies have described long-term clinical manifestations of CHIK patients infected with the East/Central/South African (ECSA) genotype, little is known about persistent manifestations in the Caribbean region, for which the Asian genotype is responsible. The objective of this study was to describe the presence of persisting clinical manifestations, specifically arthralgia, in CHIKV-infected patients on the Caribbean Island, Sint Maarten, 15 months after onset of the disease. This retrospective cohort study included confirmed CHIK patients that were recorded by the participating general practitioners (GPs) during the chikungunya outbreak in 2014 in Sint Maarten. Between March and July 2015, 15 months after the onset of disease, patients were interviewed via telephone about the presence, duration and impact of clinical CHIKV manifestations. In total, 56 patients were interviewed (median age 47 yr), of which 30 (54%) were females. Out of the total interviewed patients, 52 (93%) reported arthralgia for the first three months after the disease onset, of which 23 (44%) patients reported to have persistent arthralgia, 15 months after the disease onset. Pain intensity of persistent arthralgia was perceived as mild in the majority of patients (n = 14; 60%), moderate in 7 (30%) patients and severe in 2 (9%) patients. During the acute phase of disease, most patients had to miss school or work (n = 39; 72%) due to clinical CHIKV manifestations and reported a negative impact on daily activities (n = 36; 57%). Results suggested that persisting arthralgia is a frequent complication in CHIK patients included in the study. Future research on strain-specific clinical long-term manifestations and on their impact on daily life of patients, in the form of a comparative study between patients and controls, is recommended.

An integrative translational approach to study heart failure with preserved ejection fraction: a position paper from the Working Group on Myocardial Function of the European Society of Cardiology.

As heart failure with preserved ejection fraction (HFpEF) rises to epidemic proportions, major steps in patient management and therapeutic development are badly needed. With the current position paper we seek to update our view on HFpEF as a highly complex systemic syndrome, from risk factors and mechanisms to long-term clinical manifestations. We will revise recent advances in animal model development, experimental set-ups and basic and translational science approaches to HFpEF research, highlighting their drawbacks and advantages. Directions are provided for proper model selection as well as for integrative functional evaluation from the in vivo setting to in vitro cell function testing. Additionally, we address new research challenges that require integration of higher-order inter-organ and inter-cell communication to achieve a full systems biology perspective of HFpEF.

Ebola virus infection induces autoimmunity against dsDNA and HSP60

Ebola virus (EBOV) survivors are affected by a variety of serious illnesses of unknown origin for years after viral clearance from the circulation. Identifying the causes of these persistent illnesses is paramount to develop appropriate therapeutic protocols. In this study, using mouse and non-human primates which survived EBOV challenge, ELISA, western blot, mass spectrometry and flow cytometry were used to screen for autoantibodies, identify their main targets, investigate the mechanism behind their induction and monitor autoantibodies accumulation in various tissues. In infected mice and NHP, polyclonal B cell activation and autoantigens secretion induced autoantibodies against dsDNA and heat shock protein 60 as well as antibody accumulation in tissues associated with long-term clinical manifestations in humans. Finally, the presence of these autoantibodies was confirmed in human EBOV survivors. Overall, this study supports the concept that autoimmunity is a causative parameter that contributes to the various illnesses observed in EBOV survivors.

Long-term outcome of patients with hereditary transthyretin V30M amyloidosis with polyneuropathy after liver transplantation

Background: Liver transplantation halts production of mutated transthyretin (TTR), and thus it is an accepted treatment, with improved survival, in patients with hereditary (familial) amyloidosis with polyneuropathy (FAP). However, the effects of transplantation on the clinical manifestations of FAP have not yet been adequately clarified. This study aimed to investigate whether liver transplantation would improve the long-term clinical manifestations in FAP patients who had undergone transplantations.Patients and methods: We assessed 29 non-transplant and 36 transplant FAP V30M patients using an FAP clinical scoring system.Results: The total clinical score of the non-transplant group increased and was significantly correlated with FAP duration; that of the transplant group increased slowly after transplantation. In patients 5 years or more after FAP onset, the total clinical scores of the transplant group were significantly lower than those of the non-transplant group. In the same patients, scores for sensory, motor, autonomic and organ impairments of the transplant group were significantly lower than those of the non-transplant group.Conclusions: Liver transplantation had beneficial effects on FAP clinical manifestations in patients with FAP TTR V30M. Liver transplantation should therefore be considered as an effective treatment in the clinical management of patients with FAP TTR V30M.