Changes in immune and coagulation systems and possible viral spread through the blood–brain barrier have been described in SARS-CoV-2 infection. In this study, we evaluated the possible retinal involvement and ocular findings in severe COVID-19 pneumonia patients. A cross-sectional study was conducted on 46 patients affected by severe COVID-19 who were hospitalized in one intensive care unit (ICU) and in two infectious disease wards, including bedside eye screening, corneal sensitivity assessment and retinography. A total of 43 SARS-CoV-2-positive pneumonia patients affected with COVID-19 pneumonia were included, including 25 males and 18 females, with a median age of 70 years [IQR 59–78]. Except for one patient with unilateral posterior chorioretinitis of opportunistic origin, of whom aqueous tap was negative for SARS-CoV-2, no further retinal manifestation related to COVID-19 infection was found in our cohort. We found 3 patients (7%) with bilateral conjunctivitis in whom PCR analysis on conjunctival swabs provided negative results for SARS-CoV-2. No alterations in corneal sensitivity were found. We demonstrated the absence of retinal involvement in SARS-CoV-2 pneumonia patients. Ophthalmologic evaluation in COVID-19, particularly in patients hospitalized in an ICU setting, may be useful to reveal systemic co-infections by opportunistic pathogens. As a life-threatening condition, most of the research has primarily focused on the respiratory system for survival rate improvement, leaving the effects on other systems or districts still unclear or unknown7. Regarding eye involvement in COVID-19, only few data are currently available8. The subfamily of Orthocoronavirinae—in which SARS-CoVs belong to the Betacoronavirus genus—is already known to occasionally affect ocular structures12. Several manifestations, such as uveitis, retinitis and optic neuritis, have been described in animal models of murine and feline species; however, these findings have never been confirmed in humans13. The first evidence on humans came from a few studies conducted during the early 2000s severe acute respiratory syndrome (SARS) outbreak caused by SARS-CoV-1. SARS RNA was detected in the tears of small cohorts of patients, suggesting the eye as an entrance window for infection and/or as a hypothetical source of viral spread16. In more recent times, the SARS-CoV-2 epidemic has revived interest in ocular manifestations, especially since associated conjunctivitis has been described and colonization of the ocular surface has been reported. The same unsolved questions emerged in the 2000s, suggesting the implementation of quick precautionary strategies to protect ophthalmologists and their patients21. Nevertheless, although recent data suggest that COVID-19 infection may be associated with changes in immune and coagulation systems and possible viral spread through the blood–brain barrier, with clinical and anatomopathological findings of disseminated intravascular coagulopathy (DIC), the effects of these alterations on the eye, specifically regarding posterior segment involvement, have not been fully elucidated24.As a result of its pandemic spread and the very limited therapeutic options, COronaVIrus Disease 19 (COVID-19) is considered an unprecedented global health challenge. Italy was the first European country affected by a severe outbreak of the SARS-CoV-2 epidemic that emerged from the Wuhan region (China) and currently has 241.611 total cases and 34.861 deathsThe main objective of the present cross-sectional study was to explore the possible retinal involvement in COVID-19 and to provide data on ocular findings from SARS-CoV-2-positive pneumonia patients.Policlinico Umberto I, a large teaching hospital in Rome , that included a cohort of patients affected by COVID-19 who were hospitalized in one intensive care unit (ICU) and in two infectious disease wards from April 24 to May 24, 2020. The study and data accumulation were in conformity with the Italian laws. The research protocol was approved by the ethical board of the Sapienza University of Rome  and was conducted in accordance with the tenets of the Declaration of Helsinki. All patients gave written informed consent to the study protocol, including clinical data and biological sample collection.We conducted a prospective cross-sectional study at the 25. The inclusion criteria were as follows: (1) written informed consent signed, (2) age between 18 and 90 years, (3) confirmed positive results for SARS-CoV-2 from nasopharyngeal or oropharyngeal swab testing at the time of the ophthalmological assessment, and (4) lung involvement related to COVID-19. We excluded patients who had (1) active neoplasia or (2) a history of any ocular diseases such as glaucoma, uveitis, retinal vascular occlusion or major eye surgery performed within the previous six months. Based on the clinical conditions, patients were stratified following the COVID-19 phenotypic classification proposed by the Italian Society of Anesthesiology, Analgesia, Resuscitation and Intensive Care (SIAARTI): paucisymptomatic disease (Stage I), mild pneumonia (Stage II), moderate to severe pneumonia (Stage III), acute respiratory distress syndrome , sepsis (Stage V), and septic shock (Stage VI)26. To classify anamnestic and prognostic comorbidities at baseline, we used the Charlson Comorbidity Index (CCI)27. Finally, at the time of ophthalmological screening, to assess the patient inflammatory status and thrombotic risk, we recorded the laboratory tests of the day. Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), white blood cell (WBC) count and lymphocyte (LYM) values were collected to evaluate the subject’s inflammatory status, while thrombotic risk was scored using the International Society on Thrombosis and Haemostasis (ISTH) criteria for DIC28.During the study period, 68 patients were hospitalized at any stage of the disease in the abovementioned units. Twenty-one patients were not able to be screened because of continuous positive airway pressure (CPAP) therapy, and one patient denied consent. Therefore, we finally screened a total of 92 eyes of 46 patients. Patients were treated with ad interim best available therapy (BAT) according to the Italian Society of Infectious and Tropical Diseases (SIMIT): hydroxychloroquine 200 mg bid and azithromycin 500 mg daily plus tocilizumab 8 mg/kg (up to a maximum of 800 mg per dose) twice with an interval of 12 h. All patients were on weight-based low-molecular-weight heparin and systemic steroid treatment 0.5–1 mg/kgOropharyngeal and nasopharyngeal swabs for diagnosis of COVID-19 were performed in duplicate for SARS-CoV-2 E-, S-, N-, RdRp- and RdRp/N- genes by a standardized reverse transcriptase polymerase chain reaction (RT-PCR) routinely used for diagnostic purposes. RT-PCR was run immediately after sample collection and results were available on the same day. The search for SARS-CoV-2 on biological samples coming from the eye was carried out with the same laboratory method.29. Ocular fundus examination was performed after pharmacological pupil dilation with 1% tropicamide using binocular indirect ophthalmoscopy and a 20-dioptre lens. Images of the posterior pole were acquired by the same investigator (MPP) using a handheld fundus camera with a 40-degree field of view, 9 internal fixation targets for peripheral imaging and 5-megapixel resolution .Bedside ophthalmologic evaluation was performed in both eyes and included ocular annexes and anterior segment examination using direct lighting and a 20-dioptre lens for magnification. In those cases, presenting unilateral or bilateral conjunctival hyperaemia, a conjunctival swab was performed in both eyes and a concomitant nasopharyngeal swab was repeated for RNA SARS-CoV-2 detection. Quantitative corneal sensitivity, scored from 0 to 6 (0 corresponding to the absence of sensitivity and 6 to the highest sensitivity), was further assessed following a previously described protocol, only in awake patients, using the Cochet-Bonnet aesthesiometer (COBO)electronic case report form (eCRF) by one investigator (GV). Data are then securely transferred to a central database, where missing data or every discrepancy was corrected by a double-check analysis or after a collegial evaluation.For every patient included in the study, we collected demographic data, systemic and ocular history, laboratory test results, medical administration data, and ocular findings. All data were recorded using an The primary outcome of the study was the rate of retinal involvement in SARS-CoV-2 -positive pneumonia patients. Secondary outcome was the rate of anterior segment findings, mainly conjunctival changes and corneal sensitivity alterations.P values of < 0.05 were considered as statistically significant. All analyses were performed using SPSS v. 25.0 .Considering the relatively small sample size, normal distribution of data was analysed by the Shapiro–Wilk test. Continuous variables were reported as the mean, median, maximum and minimum values and interquartile ranges (IQR 25% and 75%). Categorical variables were reported as counts and percentages. Starting from 46 screened patients, based on the inclusion and exclusion criteria, we excluded two patients with active neoplasia and one with chronic glaucoma. Finally, a total of 43 subjects  with a median age of 70 [IQR 59–78] were included in the present study. The patients were hospitalized after a median of 4 days  from COVID-19 symptom onset, and ophthalmological screening was performed after a median of 21.5 days  from hospitalization. The comorbidity index was calculated at admission and ranged from 0 to 7, with a median of 1. Ten out of 43 patients  were screened in an ICU setting. The baseline anamnestic and clinical characteristics of the study cohort are shown in Table Candida parapsilosis infection. Chorioretinitis gradually improved . The patient with chorioretinitis, was a 67-year-old male, hospitalized in the ICU for stage V disease, who presented grade 1 vitreous haze, and a wide area of deep chorioretinal whitening involving the posterior pole, associated with deep retinal haemorrhages  of bilateral conjunctivitis characterized by mild serous secretion, both bulbar and tarsal conjunctival hyperemia with no chemosis: two patients were in stage II and one was in stage III of the SIAARTI COVID-19 classification. In all three patients, the PCR assay from conjunctival swabs for the detection of SARS-CoV-2 provided negative results while the virus RNA was still present from nasopharyngeal swab testing. The corneal sensitivity score in screened eyes, as assessed by esthesiometry, ranged from 4 to 6 with a median of 5. Table 31. In our patients, of whom we carefully considered baseline anamnestic, the results of fundus examination seem to demonstrate that neither the retina nor retinal vessels are involved in the active phase of COVID-19 infection.The primary outcome of the study was to evaluate the presence of posterior segment alterations through a cross-sectional sample at different stages of the COVID-19, and to the best of our knowledge, this is the first study to address this issue in a cohort of hospitalized people positive for SARS-CoV-2. All available evidence in humans is focused on the ocular surface, where almost only conjunctivitis has been described, and most data come from case reports or findings from human conjunctival samplesOrthocoronavirinae. The occasional onset of uveitis or retinitis in feline and murine models has been described and linked to an underlying autoimmune process inducing vasculitis or to viral-mediated inflammation13. Recent clinical and anatomopathological reports have described endothelial damage as one of the most prominent causes of the systemic vascular thromboembolic and/or inflammatory manifestations of COVID-1934. In this setting, the retina, as a privileged district for noninvasive and in vivo evaluation of systemic diseases, may reveal alterations such as vascular occlusion related to thrombotic susceptibility and chorioretinitis or vasculitis directly mediated by the virus. Hence, as reported in the brain, we considered the possibility of a direct ocular spread of SARS-CoV-2 through the two blood-retinal barriers (BRBs). In the recent literature on COVID-19, there are only anecdotal reports of virus spread through the blood–brain barrier37. Although two proven cases of positive CSF testing for SARS-CoV-2 have been described and one post-mortem, there are no certain data proving that the virus is able to directly affect the central nervous system39. Our findings, on a cohort of subjects in different stages of the disease, including ICU patients, seem to demonstrate that SARS-CoV-2 may not be able to cross ocular BRBs. Furthermore, to the best of our knowledge, we report the first attempt to isolate SARS CoV-2 in human aqueous humour.The rationale for focusing on potential ocular fundus alterations relies on previous studies conducted in animals infected by viruses belonging to the large subfamily of With respect to the known thrombotic susceptibility described in COVID-19, we did not find any sign of retinal vascular involvement, such as venous or arterial occlusion. However, it should be considered that all patients in our cohort were treated with low-molecular-weight heparin to prevent systemic vascular complications, and only one patient addressed the criteria for DIC.43. In our cohort, largely composed of subjects with severe COVID-19, we merged retinal findings with baseline anamnestic findings. Nevertheless, our negative results should also be attributed to the ongoing immune modulating treatment, including steroids or tocilizumab, that could have concealed ophthalmoscopic findings. Finally, with regard to patients with chorioretinitis from fungal sepsis, it should be considered that severe COVID-19 patients, especially when hospitalized in an ICU setting, may be affected by superinfection due to several opportunistic pathogens with possible eye localization44.At the present time, there is only one report that described retinal lesions in a small cohort of asymptomatic SARS-CoV-2-positive patients. The authors found cotton-wool-like lesions and microhaemorrhages in 4 out of 12 patients and inner retinal OCT hyperreflective spots in the whole sample. However, apart from “normal blood parameters”, the authors did not provide any specific information enabling the clinical characterization of their patients. Indeed, no data regarding the presence of systemic comorbidities as well as no details regarding the patients’ ongoing therapy were given. Hence, it cannot be excluded that their findings may be ascribed to pre-existing non-COVID-19-related systemic diseases affecting the retina, such as hypertensive or diabetic retinopathy or other infectious diseases45. In all three patients presenting bilateral conjunctivitis that was observed in our study, the conjunctival swab was negative for SARS-CoV-2. Nevertheless, since other viruses  are known to induce and have been detected in conjunctivitis, we cannot exclude the transient presence of SARS-CoV-2 on the ocular surface at any time before or after our swab46. Alternatively, conjunctivitis may represent an epiphenomenon in hospitalized patients. Since it has been definitely demonstrated that COVID-19 affects the peripheral nervous system, as shown by the reported 85–88% rate of olfactory and gustatory dysfunction, we investigated the possible involvement of trigeminal sensory pathways by exploring corneal sensitivity47. However, the results of aesthesiometry seem to demonstrate that, unlike herpes viruses, SARS-CoV-2 does not affect corneal sensitivity48.Regarding the anterior segment findings, the literature describes conjunctivitis as a part of the clinical manifestation of COVID-19 with a variable rate of presentation, ranging from 0 to 32%. Only in 4–7% of cases did PCR reveal the presence of SARS-CoV-2 from conjunctival swabsOne strength of this cross-sectional study is to have explored posterior segment involvement in COVID-19 pneumonia patients at different stages of disease and in patients who had different comorbidities at the time of their hospitalization. Furthermore, considering our brief study period and the actual feasibility of an ophthalmological evaluation in a bedside setting, we obtained data from a relevant sample size even if a larger study population is probably necessary to confirm our findings. One important limitation of the present study is the unavailability of genomic characterization and phylogenetic analysis of SARS‐COV‐2 involved in the infections of our cohort. Among the other shortcomings, potential bias resulting from systemic therapies put in place before the ophthalmological evaluation and those deriving from the exclusion of patients in CPAP therapy should be disclosed. Finally, we cannot exclude the presence of COVID-19 related subclinical retinal alterations. Hence, future studies investigating retinal involvement in COVID-19 patients should consider the use of diagnostic tools, such as optical coherence tomography or fluorescein angiography, to confirm our findings.In conclusion, our study demonstrated the absence of retinal manifestations in SARS-CoV-2 pneumonia patients. Given the frequent drug-induced immunological dysfunction, ophthalmological evaluation may be useful to reveal systemic coinfections by opportunistic pathogens, especially in ICU patients.Ethical approval was obtained from the Ethics Committee of Policlinico Umberto I .


This cross-sectional study describes the sensitivity and specificity of patient self-assessment for atrial arrhythmia compared with 12-lead electrocardiogram and describes the association of patient perception of arrhythmia with symptom burden. Atrial fibrillation (AF) is the most common arrhythmia in adults, and treatment of AF is often focused on improving symptoms. Patient-reported outcomes can provide standardized, health-related, quality-of-life end points to guide and support clinical decisions. The association of patient symptoms with arrhythmia may be confounded. We sought to understand the accuracy of patients’ identification of their arrhythmia and association with perceived symptom burden. Specifically, the objectives of this cross-sectional study were to describe the sensitivity and specificity of patient self-assessment for atrial arrhythmia compared with 12-lead electrocardiogram (ECG) and to describe the association of patient perception of arrhythmia with symptom burden.This study was approved by the University of Utah institutional review board. A waiver of consent was granted because the study used anonymous, aggregate data that were collected as part of routine clinical care.1 The details of our system have been described previously.3 Among its 4 domains, the AFSS requests that patients identify their current rhythm; it also yields a 35-point symptom score (referred to hereafter as the AFSS symptom score), with higher scores reflecting increasing patient perceived AF symptom burden . We compared single-visit patient self-awareness results with the results of same-day, in-clinic, 12-lead ECG (reference standard) to understand patient accuracy of atrial arrhythmia self-identification. We also assessed perceived vs actual atrial arrhythmia compared with AFSS symptom score.All patients with AF in our electrophysiology clinic are asked to complete the Toronto Atrial Fibrillation Severity Scale (AFSS) patient-reported outcomes assessment immediately before the clinic visit.2 tests for categorical variables and analysis of variance for continuous variables. Two-sided P < .05 was considered statistically significant. All analyses were performed using R statistical software version 3.5.2 and RStudio version 1.2.1335 , with specialty packages. Data analysis was performed from September 2018 to September 2019.Categorical variables are summarized as number (percentage), and continuous variables are summarized as mean (SD). Univariate comparisons were performed with χFrom October 2016 to February 2019, 656 patients  responded to the AFSS question regarding current atrial rhythm and had an interpretable ECG from the same day. Baseline characteristics of these patients, stratified by ECG rhythm and response, are shown in the Among 160 patients in arrhythmia, patients’ own assessment of rhythm was 64% sensitive for detecting it (102 of 160 patients). On the basis of ECG, 496 patients were in sinus rhythm and demonstrated an accuracy of 91% for detecting it (453 correctly indicated no arrhythmia). Overall, 85% of patients responded consistently with their ECG, including patients with normal rhythm and those in atrial arrhythmia . Sensitivities for rhythm self-identification, by subgroups of interest, are shown in the The mean (SD) overall AFSS symptom score was 8.95 (7.4), with 16% missing. The AFSS symptom score was higher for those who believed they were currently in atrial arrhythmia  compared with those who did not believe they were in atrial arrhythmia . In sum, the AFSS symptom score was lowest in the population who were in atrial arrhythmia but were unaware of it.Our analysis of patient self-identification of arrhythmia yields several important observations that may affect treatment decisions for patients with AF. First, the sensitivity of patient identification for atrial arrhythmia is low; only two-thirds (64%) of patients in atrial arrhythmia correctly identified it. Second, there are important subgroup differences regarding self-identification of cardiac rhythm; younger patients and those receiving an antiarrhythmic drug appear particularly sensitive to detecting atrial arrhythmia. Finally, AFSS symptom score measuring perceived AF symptoms appears to track more closely with perceived vs actual arrhythmia. There are few data available regarding a patient’s ability to correctly identify symptoms of AF, yet we rely on this information nearly every day for clinical decision-making. Naturally, this analysis is limited by the real-world uncontrolled setting, and we were not present while patients answered patient-reported outcomes questions. Regardless, these findings have important implications for both routine, symptomatic management of AF, as well as clinical trials with symptom-driven outcomes. Our data highlight the limitations of relying solely on patient symptom self-reporting for arrhythmia burden and impact and support the routine use of confirmatory testing to diagnose AF and to evaluate the association of symptoms with arrhythmia.


Interstitial lung disease (ILD) is a leading cause of mortality in systemic sclerosis (SSc). However, mortality is improving as pathogenesis is being better understood and new therapies emerge. The roles of the inflammasome and NETosis in fibrosis are being elucidated. Epigenetic targets like DNA methylation and microRNA show promise as new targets for anti-fibrotic agents. The IL17-23 pathway has been shown to be active in SSc-ILD. Newer biomarkers are being described like CCL18 and the anti-eIF2B antibody. Hypothesis-free approaches are identifying newer genes like the ALOX5AP and XRCC4 genes. Computer-aided interpretations of CT scans, screening with ultrasonography and magnetic resonance imaging (MRI) are gradually emerging into practice. Imaging can also predict prognosis. A plethora of studies has shown the benefit of immunosuppression in halting ILD progression. Extent of lung involvement and PFT parameters are used to initiate therapy. The best evidence is for cyclophosphamide and mycophenolate. Besides these, corticosteroids and rituximab are being used in cases refractory to the first line drugs. Stem cell transplant is also backed by evidence in SSc. Longer studies on maintenance therapy are awaited. The inflammation in SSc is mostly subclinical and there is great interest in developing anti-fibrotic drugs for SSc-ILD. Perfinidone and nintedanib are under trial. The last resort is lung transplantation. Clinically significant ILD has increased over the last two decades; in spite of this, the associated mortality has come down.1 ILD patterns on computerized tomography scans (CT) include certain patterns named as nonspecific interstitial pneumonia (NSIP), usual interstitial pneumonia (UIP), desquamative interstitial pneumonia (DIP), cryptogenic organizing pneumonia, diffuse alveolar damage, acute interstitial pneumonia, and lymphocytic interstitial pneumonia. The most common pattern in SSc is NSIP that has a prominent inflammatory component. The predictors for SSc-ILD are male gender and presence of anti-Scl70 antibodies while presence of anti-centromere antibodies is a protective factor.The scenario for outcomes of SSc is no longer as bleak as it once was. Nihtyanova SI et al. have shown that survival has increased with better diagnosis and monitoring.3In the present review, we searched Medline database for “Systemic sclerosis [MeSH] AND ” and manually screened for relevant articles looking into the pathogenesis, biomarkers, outcome and therapies of SSc-ILD, utilising a previously published search strategy for narrative reviews.4 But, in majority of SSc, no clear aetiological factor can be found.SSc may be the phenotypic expression of the result of various different aetiopathological processes. Possible evidence for such a hypothesis is the Erasmus syndrome. Reported in less than 1% of SSc patients, it is described as the development of SSc after exposure to silica.Figure 1).The trigger for onset of fibrosis may be an injury either to the lung epithelium or to the endothelium of the supplying vessels. In SSc there seems to be an altered and unregulated repair process. As in the skin and other organs, the lung also has unregulated repair leading to fibrosis. This leads to overproduction of signalling peptides like transforming growth factor-β (TGF-β), endothelin-1, platelet derived growth factor (PDGF), etc. TGF-β has both canonical and non-canonical downstream pathways and both have been implicated in fibrosis. Under the influence of these cytokines, endothelial cells are supposed to have a mesenchymal transition (EMT). Ultimately, genes like type I collagen, fibronectin, α-smooth muscle actin and connective tissue growth factor (CTGF) are over-expressed leading to extracellular matrix deposition (5 NETosis has been reported to increase organ fibrosis in aging mice.6Newer concepts in fibrosis include the role of the Inflammasome and of NETosis. Inflammasomes activate pro-IL1β to IL-1β initiating an inflammatory cascade. Silencing of NLRP3 (component of the inflammasome) in a bleomycin model of fibrosis reduced levels of TGF-β, E-cathedrin and α-smooth muscle actin; thus, it may influence epithelial-mesenchymal transition that is the forerunner of fibrosis.7 The other facet of epigenetics is DNA methylation. It has been shown that hypomethylation of integrin genes8 occurs in SSc that may lead to increased TGF-β expression9 and myofibroblast differentiation.10 These have opened up new avenues for targeting fibrosis in SSc.Shifting from genetics to epigenetics has revealed the importance of microRNA like miR-155. miR-155 has been reported to influence NLRP3 inflammasome activation.11 However, in exhaled breath of SSc-ILD patients, there was increased TNF-α, TGF-β, IL-17 and IL-23; possibly implying a possible local role of this axis in the pathogenesis of fibrosis.12Interestingly, a study on IL17-23 pathway observed that IL-17 and IL-23 were reduced and IL-21 was elevated in SSc as compared to sera of healthy controls.13The clinical biomarker for SSc-ILD has been the six-minute walk test, originally described for use in patients with pulmonary hypertension. A meta-analysis on the six-minute walk test showed it to be a validated marker for SSc-ILD with or without pulmonary arterial hypertension (PAH).14Autoantibody production is a predictor of internal organ involvement in SSc. Classically; the strongest risk has been described with anti-topoisomerase (anti-Scl-70) antibodies, whereas anti-centromere antibodies are likely protective. A serum immunoprecipitation study of 548 SSc patients has revealed a new antibody directed against Anti-Eukaryotic Initiation Factor 2B (Anti-eIF2B) in seven patients. There was correlation of this antibody with presence of ILD and diffuse disease.15 CCL18, previously known as macrophage inflammatory protein-4 (MIP-4), attracts naïve B lymphocytes and immature monocyte-derived dendritic cells to germinal centres. Normal lung does not have CCL18 gene transcripts.16 Thus, its presence may imply ongoing inflammation and perpetuation of fibrosis. Recently, high serum CCL18 was shown to predict highest rates of annual deterioration of forced vital capacity (FVC). It was reported that ILD patients with high CCL18 also had lower 5-year and 10-year survival compared with patients with low CCl18 levels.17Previously established serum biomarkers include surfactant proteins A and D and Krebs von den lungen-6 (KL-6). KL-6 is a glycoprotein that is expressed by type II pneumocytes, and especially found in areas of tissue injury in the lung. It can help in screening for ILD, and has good utility in evaluating disease activity and predicting prognosis in SSc-ILD.18 A whole exome sequencing of 32 patients found BANK1 and TERT to be over-expressed. These had already been described in ILD and in SSc. However, the new discovery was over-expression of the 2-LTR circle formation pathway, mainly the XRCC4 DNA repair gene.19The rs10507391 polymorphism (T/A) of arachidonate 5-lipoxygenase activating protein (ALOX5AP) was identified in the EUSTAR cohort to predict the risk of SSc  as well as that of ILD in SSc .20 Even difference with treatment can be quantified by computer-aided analysis.21In the field of imaging, computer-aided analysis of computerized tomography (CT) scan of ILD and use of ultrasound (USG) for lung imaging are emerging. Conventional visual reader-based score (CoVR) with a computer-aided diagnosis (CaM) were comparable in a study and correlated with pulmonary function test (PFT) parameters, Borg dyspnea score and Health assessment questionnaire disability index (HAQ-DI).22 but the question remains if the exposure to radiation is justifiable by the benefits of detecting asymptomatic ILD. MRI technology is catching up with CT for ILD. Though still inferior to CT, current high-Tesla MRI machines can offer a radiation-free alternative for ILD detection.23PFT is much less sensitive than CT in picking up ILD,24 in SSc. A review has looked into different scoring systems for lung USG, but points out that limitations remain. Firstly, the origin of B-lines are still debated, and secondly, comprehensiveness of a scan correlates inversely to the time spent on the scan.25 Other factors predicting ILD on US include blurring or irregularities of the pleural line and subpleural consolidations.26A promising screening strategy for ILD can be the use of ultrasound (US). The number of B-lines (“comet” artifact) has shown correlation with CT scoresAs we have seen, serum markers like CCL18 and non-irradiating imaging like MRI and USG hold a promise for screening for SSc-ILD. They can also predict mortality and morbidity. However, this is based on preliminary data only, and need to undergo further evaluation before coming to clinical practice.27 Short term changes in PFT can predict long-term outcome including mortality: a fall of Forced vital capacity (FVC) >10% or a fall of DLCO >15% with a fall in FVC of 5–9% seemed to be the best predictor in a study.28Acute exacerbations of SSc-ILD are not uncommon and presence of dermatomyositis or polymyositis overlap predicts higher risk of acute exacerbations.29Besides presence of ILD, predictors of mortality in SSc include male gender, age more than 65 years at onset, presence of digital ulcers, pulmonary hypertension, cardiac involvement, scleroderma renal crisis (SRC), presence of anti-topoisomerase I and absence of anti-centromere antibodies, and an active pattern on capillaroscopy.30Analysis of the placebo arm of the SLS1 study has shown that ILD progresses independent of the disease duration and the best predictor of rate of progression is the quantity of fibrosis on CT underscoring the need for treatment.At present, no treatment has shown to reverse lung fibrosis in a patient with SSc-ILD. Thus, it is of paramount importance to understand the risk of progression in order to decide when therapy should be started. Since immunosuppressive therapies represent a double-edged sword with increased incidence of infections in SSc-ILD, their use should be rationalised. It may not be ethical to treat an early ILD who has no progression, but no deserving patient should be denied therapy. Thus, in real life there is always a dilemma, as we have no definite marker to predict ILD progression.31 (i) all patients presenting at first observation with either an extent of lung disease >20% on HRCT or an indeterminate extent of disease plus an FVC < 70%, and (ii) during follow-up, all patients experiencing a significant decrease of DLCO (>15%) or FVC (>10%) or both, whatever the extent of lung involvement. In both, the SLS studies only symptomatic patients (at least grade 2 on Mahler Dyspnea Index) were recruited. In the treatment of ILD in SSc commonly used drugs are corticosteroids, cyclophosphamide, mycophenolate, azathioprine, and rituximab. The evidence for each is examined below. Most of these studies deal with induction therapy. Maintenance studies with longer follow-up are required.Most authors support treatment according to the following criteria:Trials with biological therapies -α]), etc. are underway. However, they are for SSc and not specifically for SSc-ILD. These therapies are not recommended outside a clinical trial.32A small study classifying SSc-ILD into usual intersitital pattern (UIP) versus non-UIP found that UIP pattern had a poorer outcome with immunosuppression.34 and one unblinded35 randomised controlled trials (RCTs), have shown a significant increase in FVC in patients treated with cyclophosphamide (CYC). (Table 1)It was the first evidence-based therapy for SSc-ILD. Two double-blind36Scleroderma lung study (SLS I) was the first RCT to demonstrate efficacy of oral CYC. Patients had a modest improvement in FVC as compared to placebo which persisted for 18 months after discontinuing treatment, but effect was lost by 24 months. This reiterates the requirement for some maintenance therapy. Apart from the primary endpoint, there was significant improvement in a number of secondary endpoints like total lung capacity (TLC), the patient-reported outcome of dyspnea (Mahler Dyspnea Index), and several quality of life measures. Furthermore, a retrospective, multivariate regression analysis of SLS I found patients with maximal severity of reticular infiltrates on chest HRCT, high mRSS scores and the Mahler baseline dyspnea index at baseline had better response to CYC compared to those with less severe fibrosis on HRCT.2 monthly) for 6 months followed by daily oral azathioprine 2.5 mg/kg/d (maximum 200 mg/d), or placebo infusions followed by oral placebo.34 At 12 months, a modest but statistically non-significant improvement in FVC was seen in the actively treated group.In the Fibrosing Alveolitis in Scleroderma Trial (FAST) trial, patients with SSc-ILD were randomized to receive either intravenous cyclophosphamide  group recommends CYC for the treatment of SSc-ILD.38 An interesting observation was that deaths with CYC was 10/73 versus 5/69 with MMF. Though not statistically significant, the SLSII study was not powered to look at a difference in mortality.Earlier observational studies had shown the effectiveness of Mycophenolate in treatment of SSc-ILD. The SLS II study, a randomised, double-blind, parallel group trial comparing mycophenolate at dose of 1.5gm twice daily for 24 months with oral CYC for 12 months resulted in significant improvements in prespecified measures of lung function over the 2 year course of the study in both the arms. Although mycophenolate mofetil was better tolerated and associated with less toxicity, the hypothesis that it would have greater efficacy at 24 months than CYC was not confirmed. These findings support the potential clinical effectiveness of both CYC and mycophenolate mofetil for progressive SSC-ILD. The present preference for mycophenolate mofetil is possibly because of its better tolerability and toxicity profile.35 However, studies are encouraging with regard to its use in maintenance phase particularly following CYC induction.40In an RCT comparing azathioprine with CYC as first line of therapy for SSc-ILD, a decline in FVC and DLCO at 10 months was observed in the azathioprine group.2) versus CYC with high dose prednisolone found no benefit of adding prednisolone.41Corticosteroid pulses have been used in association with CYC in the treatment of ILD-SSc with favourable results. However, a word of caution is advised while using corticosteroids in SSc patients in view of precipitating scleroderma renal crisis. A small study comparing CYC  showed significant improvement in FVC & DLCO at 2 years.without CD34+ cell selection, had showed improvement in comparison to CYC.45 The ASTIS  and SCOT (Scleroderma: Cyclophosphamide Or Transplantation) trials have compared the safety and efficacy of HSCT versus monthly pulse intravenous CYC. In ASTIS, patients treated with autologous HSCT experienced more deaths and other adverse events in the first year, but had improved long-term event-free survival compared with patients treated with CYC.46 The SCOT trial has shown unprecedented success with superior event free survival (74% with SCT versus 47% with CYC) and overall survival (86% with SCT versus 51% with CYC) at 72 months.47Intense immunosuppression followed by hematopoietic stem cell transplantation (HSCT) has emerged as a new therapeutic modality in treatment of SSc-ILD. First ASSIST , a single-centre, open-label phase II trial of autologous HSCT Other trials on HSCT like STAT (Scleroderma Treatment With Autologous Transplant) trial are ongoing. Future studies on larger patient groups will determine if this modality becomes routine procedure in management of patients with SSc-ILD. However, the success of less toxic therapies may also relegate it to the background.48 Many other new therapeutics that target specific growth factors, cytokines or pathways , as well as multiple existing drugs that might be repurposed to treat fibrosis  are being tried for SSc-ILD.Given the role of fibrosis in SSc ILD, anti-fibrotic agents are definitely on the cards for future drug development. Perfinidone and nintedanib, both FDA approved for idiopathic pulmonary fibrosis (IPF), are now undergoing studies in SSc-ILD patients. The SENCIS trial is a phase III trial of nintedanib in SSc-ILD that is currently ongoing.49 Even combination of imatinib with CYC has been tried in a small cohort but failed to show much benefit.50 Bosentan had been tried for anti-fibrotic effects in ILD but it did not have benefit.51In a study of imatinib in 30 patients unresponsive to CYC, 50% were shown to have stable disease while four had improvement in FVC (>15%). However there was no placebo arm and the late effect of CYC cannot be ruled out.52Lung transplantation is a life-saving option for SSc-ILD patients who are not responsive to medical treatment. Unfortunately, lung transplantation is not always possible due to the involvement of other organs. The survival is similar in patients of IPF, but recently specific SSc contraindications have been proposed. They include active inflammatory myopathy, active digital ulcers, severe gastrointestinal involvement, cardiac arrhythmias, unstable renal function in the past 3 months, an interval of <3 years between scleroderma renal crisis (SRC) and transplantation.Thus, the landscape for SSc-ILD is evolving within newer insights into pathogenesis, newer and better biomarkers, and the ingress of USG and MRI to reduce exposure to ionizing radiation. There is a plethora of immunosuppressive drugs that are being tried for SSc-ILD with varying degrees of success. But success until now is defined in arresting the disease. Fibrosis still cannot be reversed. With these newer insights into the pathogenesis, possibly we can look forward to novel approaches to SSc-ILD therapy in the coming decade.


Alzheimer’s disease (AD) is a neurodegenerative disorder featuring the behavioral and psychological symptoms of dementia. Patients with early-onset AD that exhibits first as psychotic symptoms usually lack obvious cognitive impairment, so they may be misdiagnosed with late-onset schizophrenia.SORL1 gene was found to carry a heterozygrous mutation (c.296A > G). The patient was eventually diagnosed with early-onset AD.We report a patient who had prominent psychotic symptoms at the age of 60 and was initially diagnosed with very-late-onset-schizophrenia-like psychosis. Psychotic symptoms disappeared rapidly after treatment with olanzapine, and the patient later showed extrapyramidal symptoms and decline in cognitive function. Brain magnetic resonance imaging (MRI) showed frontotemporal atrophy, and positron emission tomography (PET) showed extensive areas of hypometabolism in the frontal cortex and head of the caudate nucleus. The patient’s SORL1 mutations.Our case suggests that clinicians should consider the possibility of early-onset AD in middle-aged or elderly patients whose first symptoms are the behavioral and psychological symptoms of dementia. To distinguish early-onset AD from late-onset schizophrenia, clinicians should evaluate cognitive function, perform MRI and PET, and search for  Alzheimer’s disease (AD) is a common neurodegenerative disorder characterized by progressive cognitive impairment , 2. In 2AD is typically classified as early-onset if it occurs before the age of 65, or late-onset if it occurs later , 8. It cSORL1 gene, which encodes a protein involved in the processing of amyloid-beta (Aβ) precursor protein and in secretion of the Aβ peptide, have been associated with AD [APP, PSEN1 and PSEN2 [Mutations in the  with AD . The potnd PSEN2  .SORL1 mutations whose first-episode psychotic symptoms occurred before the age of 65 and who was initially misdiagnosed with schizophrenia. To the best of our knowledge, this is the first report of a patient with early-onset AD whose first symptoms were psychotic and extrapyramidal.Here we present a patient with AD and A right-handed, 63-year-old Chinese woman, with 12 years of education, was admitted to our hospital in September 2018 at the request of her family members.In 2016, the patient had developed psychotic symptoms, including delusions and auditory hallucination, without an apparent cause. She said someone wanted to harm her and was talking about her. Sometimes she told her family members that she heard knocking on the door, and she exhibited diminished emotional expression and avolition. She required the support of family members to conduct daily activities and communicate with others. Her sleep quality was poor, but she showed no disturbance of consciousness. She did not seek medical advice and receive any remedy at that time.After these symptoms had continued for about 12 months, she was taken by her family to the outpatient department of our hospital. Brain magnetic resonance imaging (MRI) did not reveal any obvious structural abnormalities . She showed a higher score of 20/30 on both the MMSE and MoCA. She was prescribed with memantine (10 mg/d) and donepezil (10 mg/d) and stopped taking benzhexol hydrochloride, but her cognitive function showed no change at follow-up in July 2019. At follow-up in August 2019, brain MRI detected moderate frontotemporal atrophy that appeared more serious than in 2018  precursor protein and in secretion of the Aβ peptide. The SORL1 has been found to be associated with age-related cognitive decline in episodic memory and processing speed in non-demented older adults [SORL1 in Aβ processing and secretion. Therefore, the early cognitive decline of our patients including temporal disorientation, deficits in attention, calculation and language competence, significant episodic memory impairment may associate with the mutations in this gene.Our previous work has linked the following 21 well-studied genes with AD:  and TLR . Other wonset AD . Althougr adults . The mutr adults  and may r adults , consistThe previous study indicated that the mutations in SORL1 gene are associated with parkinsonian features in AD patients, such as tremor at rest, hypophonia, micrographia, masked facial expression, smaller steps on gait, and overall bradykinesia . In addiSORL1 mutation has not been associated with frontotemporal dementia, led us to favor a diagnosis of early-onset AD. A recent neuroimaging study has found that the volumes of frontal, temporal and other brain regions can predict the behavioral and psychological symptoms in AD, and the frontal lobe volume was the most powerful predictor [Our patient had frontotemporal lobe atrophy, but not frontotemporal dementia. She did not display the impaired language function typical of semantic variant primary progressive aphasia or the non-fluent/agrammatic variant of primary progressive aphasia , 17. Sheredictor . TherefoThere is an overlapping syndrome with diffuse brain structural, metabolic changes, cognitive decline and parkinsonian motor symptoms related to SORL1 gene mutation. Early-onset AD should be considered when a patient initially presenting psychotic symptoms and SORL1 gene mutation is older than the typical age of schizophrenia onset. Our patient was initially misdiagnosed with schizophrenia because of misattribution of the behavioral and psychological symptoms of dementia. We suggest that diagnosis of middle-aged or elderly patients with behavioral and psychological symptoms of dementia as the first presentation should involve detailed cognitive function assessment, brain MRI and PET, and analysis of mutations in AD-associated genes.


The last ten years have seen a continuous debate on whether platelet function tests (PFTs) should be used to tailor antiplatelet drugs to cardiovascular patients. Large-scale randomized studies investigating the escalation of antiplatelet therapies according to the results of PFTs were mostly negative. Potent P2Y12 inhibitors are recommended as a first-line treatment in acute coronary syndrome patients, bringing the bleeding risk at the forefront. De-escalation from prasugrel or ticagrelor to clopidogrel is now considered, with or without the use of a PFT. This review covers recent advances in escalation and de-escalation strategies based on PFTs in various clinical settings. It also describes the main features of the most popular platelet function tests as well as the potential added value of genetic testing. Finally, we detail practical suggestions on how PFTs could be used in clinical practice.In the field of antithrombotics, precision medicine is of particular interest, as it may lower the incidence of potentially life-threatening side effects. Indeed, antiplatelet drugs such as P2Y Th. Th33]. 2, a stable metabolite of TxA2 obtained after incubation of whole blood at 37 °C for 1 h. Using this assay, aspirin’s inability to suppress TxA2 generation is very rare [2 by aspirin, non-target-centered PFTs are of interest since they show a more variable inter-individual phenotype. These methods may thus capture non-TxA2-dependent platelet activation pathways mediating platelet aggregation despite adequate inhibition of TxA2 by aspirin [®  has been particularly well investigated since it is an easy-to-use point-of-care assay (see aspirin resistant) [2 did not correlate with PFA-100® results [Currently, the most target-centered assay for assessing aspirin’s biological response relies on the quantification of serum TxBery rare ,35. Howeery rare . Diabete aspirin ,38. For ssay see . Accordisistant) . As expe results .12 receptor, PFTs evaluating the biological effects of these drugs use ADP as the agonist. The vasodilator-stimulated phosphoprotein (VASP) assay is the most target-centered assay evaluating the degree of P2Y12 receptor inhibition [Since clopidogrel, prasugrel, and ticagrelor target the ADP P2Yhibition . Other Ahibition . Similarhibition .12 inhibitor [® assays [Prasugrel is a third-generation thienopyridine. It is more potent than clopidogrel, but its pharmacodynamics’ variability is equally high. This has been best demonstrated in pharmacokinetic/pharmacodynamic studies ,43 showinhibitor . Since p® assays . The con® assays .As PFTs explore different platelet activation pathways and do not correlate well with one another, the prevalence of HPR and LPR varies considerably depending on the test. Pragmatically, all interventional studies aiming to tailor antiplatelet drug treatments with reference to platelet reactivity measurements were performed using easy-to-use, standardized, point-of-care assays using consensus cut-offs that had been chosen by investigators .12-dedicated PFTs. Indeed, studies of the association between the levels of serum TxB2, a target-centered marker of the platelet response to aspirin, and the occurrence of ischemic events are scarce and conflicting [Some observational studies have shown associations between HPR in patients treated with aspirin and the occurrence of ischemic events. These studies were summarized in a meta-analysis which showed nearly a four-fold increase in the risk of a recurrence of ischemic events among those patients deemed to be aspirin resistant . Howeverflicting ,50. Neveflicting . Howeverflicting , a conce12 inhibitors. As often in clinical research, the first observational studies revealed the high relative risks or ORs of HPR for the outcome of ischemic events. This was consistent across a wide array of both target-centered and non-target-centered PFTs. Interestingly, these relative risks became lower as more recent and larger association studies were conducted, and this time-effect was significant in a meta-regression [Indeed, there are numerous studies and meta-analyses ,54,55 ongression . Importagression , HPR wasgression . This legression . A meta-gression  showed tgression .12 inhibitors, and as mentioned above, LPR may be quite frequent with next-generation drugs prasugrel and ticagrelor, but the association with bleeding events has been studied more among patients treated with clopidogrel. The available evidence is more consistent than when using PFTs targeting aspirin response, and the largest meta-analysis, gathering individual data from more than 20,000 cardiovascular patients, clearly showed that LPR on clopidogrel was associated with an increased risk of bleeding events  [sweet spot where the net clinical benefit of treatment is highest, while ischemic and bleeding events occur more frequently in HPR and LPR patients, respectively [Clinical association studies have linked LPR (as established using aspirin-dedicated PFTs) with bleeding; these used aggregation-based assays and were conflicting. Two large registries, the ADAPT-DES and ISAR-ASPI studies, found a borderline-significant increased risk associated with LPR in the former   but not 47–2.06) . All thi12 drug treatment for all cardiovascular patients, particularly those without a high cardiovascular risk (such as those without ACS), for whom clopidogrel is recommended [12 inhibitor, even among patients with ACS. Since in ACS patients, prasugrel or ticagrelor are preferred over clopidogrel and recommended as the first line anti-P2Y12 treatment, any concern regarding HPR in these patients is mitigated.These clinical association studies raised the hypothesis that tailoring antiplatelet therapy according to PFT results might decrease the risk/benefit ratio. Early RCTs involving personalized clopidogrel dosing following a PFT were performed among PCI patients, half of whom were suffering from an ACS at inclusion ,61. The ommended . Moreove12 inhibitors are only suggested as options for patients with specific high-thrombotic risk or for selected complex stenting procedures with a low level of evidence (Class IIbC) [Among chronic coronary syndrome patients undergoing stenting, dual antiplatelet therapy with aspirin and clopidogrel remains the standard of care (Class IA grading), whereas more potent P2Yss IIbC) .12 inhibitors, bleeding risk is now the most frequent adverse event among patients with ACS after stenting. This has led to the emergence of alternate antithrombotic strategies, such as de-escalation. De-escalation aims to minimize exposure to DAPT involving potent P2Y12 inhibitors (prasugrel or ticagrelor) by replacing them with clopidogrel in selected clinical settings where bleeding risk is a particular concern and outweighs the thrombotic risk. The concept of de-escalation has been supported by pivotal trials such as the TRITON-TIMI 38 study, which showed that the benefit of prasugrel over clopidogrel in terms of ischemic event reduction was mainly observed within the first 30 days, while the associated increased risk of bleeding persisted over the follow-up period [In recent years, evolving stent technology has led to a dramatic reduction in stent thrombosis rates and other stent-related ischemic events . In the p period . In the p period .12 inhibitors or to switch to a DAPT with clopidogrel. After one year of follow-up, the primary composite endpoint of ischemic and bleeding events occurred less frequently among patients assigned to the switched DAPT (13.4%) than among the control group  [p < 0.001), with no difference in ischemic endpoints (p < 0.001 for non-inferiority). This strategy of short, uniform de-escalation, irrespective of PFT results, has also been supported by other recent trials involving several thousand patients and showing that rapid de-escalation of antiplatelet therapy was effective and associated with fewer bleeding events after ACS, including STEMI [These results, together with findings that variability in platelet reactivity did not predict ischemic events in stable cardiovascular patients ,52,70,71 < 0.01) . This ef < 0.01) . The rec < 0.01) . This stng STEMI ,76.n = 511, 39%) were switched back to prasugrel. The primary endpoint was a composite of cardiovascular death, myocardial infarction, stroke, or bleeding events throughout the 1-year follow-up. The study showed that the strategy guided by PFT was not inferior to standard DAPT, with the primary endpoint occurring in 7% of the de-escalation group and 9% of the control group. There were no significant differences between the arms regarding either ischemic or (more surprisingly) bleeding events. This study suggested that a de-escalation strategy guided by a PFT was an option for patients with ACS with estimated comparable ischemic and bleeding risks if treated for 12 months with a potent P2Y12 inhibitor such as prasugrel.TROPICAL-ACS was a landmark study for strategies involving de-escalation guided by PFTs; its 2610 ACS patients were randomized to a conventional DAPT arm with prasugrel or a strategy guided by a PFT. In the latter arm, 1306 patients began DAPT with prasugrel for 7 days and then switched to clopidogrel for a further 7 days. A PFT was then performed, and patients with HPR  were prescribed clopidogrel instead. All patients received ticagrelor or prasugrel at the time of PCI, drugs that were continued until randomization. The study showed that the approach guided by genotype was not inferior to the standard approach in terms of net clinical benefits (a composite of ischemic and bleeding events), and it displayed fewer (mostly minor) bleeding events . Another large study of a similar design—the PHARMACLO trial—included patients with ACS, but the intervention arm included screening for three genetic polymorphisms of the 2C19 and ABCB1 genes, as well as consideration of clinical parameters with which the treating physician would select the P2Y12 inhibitor after PCI. This study showed promising results, with a composite of ischemic and bleeding outcomes occurring in 15.9% of patients allocated to genetic testing and in 25.9% of those receiving standard care . It is of note that after enrolling only 888 patients (25% of the planned population), this study was terminated prematurely because of a legal issue regarding the genetic assay. In addition, clopidogrel was often prescribed, including more frequently in the standard-care arm (50.7% vs. 43.3%), which did not comply with current guidelines.Genetic testing aims to predict the pharmacodynamic effects of a given antiplatelet drug without the need for a PFT. It has several key advantages over PFTs, including quickly available, unequivocal results using current point-of-care assays, the absence of inter-individual variability, and, most importantly, there being no need to potentially challenge the patient with an antiplatelet drug for several days before a PFT. However, and as mentioned above, the currently available knowledge of the genetic background governing antiplatelet drug pharmacodynamics only explains between 3.5% and 12% of clopidogrel response ,30,31,32Finally, a sub-study of the TROPICAL-ACS study observed no added benefits from using genotyping to predict ischemic and bleeding risks among patients who had undergone a de-escalation treatment guided by a PFT . This la12 inhibitors has almost closed the discussion about antithrombotic drug escalation based on PFTs. For most patients, the main challenge and the foremost risk is now bleeding. PFTs may be useful for deciding on a de-escalation from prasugrel or ticagrelor to clopidogrel. However, trials investigating de-escalation strategies have so far lacked the power to assess PFTs’ impact on thrombotic events. Therefore, de-escalation strategies should be restricted to patients with a non-low bleeding risk.The current recommended first-line treatment combining the low thrombogenicity of the latest stents with potent P2Y12 inhibitors are not licensed for PCIs without ACS, and that interventional studies have not shown that low-risk patients get any benefits from a tailored treatment approach based on PFTs, we recommend that PFTs not be performed on patients without ACS (see 12 inhibitors prescribed only if the patient is deemed a poor responder to clopidogrel (TROPICAL-ACS study management). For patients with the highest bleeding/thrombotic risk ratio , DAPT with clopidogrel seems the best option, without a PFT, since escalating antiplatelet therapy, in this case, would likely be associated with a major increase in the risk of bleeding. For other patients, a uniform, short-term DAPT with prasugrel or ticagrelor, followed by de-escalation, should be considered (TOPIC or TWILIGHT study management).In daily practice, considering that ACS is a major factor in cardiovascular risk-level assessment, that next-generation P2Y ACS see . For pat ACS see . For pat


Introduction: Gastroesophageal reflux disease (GERD) affects various elements of life including sleep, daily and social functioning, and physical and emotional activities. This study aims to determine the impact of laparoscopic Nissen’s fundoplication (LNF) on health-related quality of life.Methods: This prospective study was conducted in a tertiary care hospital, Pakistan, from Jan 2019 to Feb 2020. Forty-seven participants completed the study. All patients completed the Gastroesophageal Reflux Disease Health-Related Quality of Life (GERD-HRQoL) questionnaire both pre-operatively and three months after LNF.Results: There was significant difference in pre- and post-operative median Health-Related Quality of Life score . There was improvement in items related to heartburn in HRQoL questionnaire, while questions related to swallowing and bloating either showed no change or worsening.Conclusion: LNF has a significant impact on health-related quality of life. It is important for the physician to consider the impact of GERD in daily life. Management goals for GERD should also include improvement in quality of life of the patient. Gastroesophageal reflux disease (GERD) is a common major upper gastrointestinal (GI) problem with 10-20% of the population reporting weekly GERD symptoms. The prevalence of symptom-based GERD varies from 5.2-8.5% in Eastern Asia to 6.3-18.3% in Iran. Pakistan reports a significantly higher prevalence of 22.2% and 24.0% based on hospital-based studies [GERD symptoms and complications impact general health, such as daily and social functioning and physical and emotional activities. It also influences health-related quality of life (HRQoL) due to frequent interruptions during sleep, work, and social activities . GERD syMedical treatment with proton pump inhibitors is effective in 90% of patients. Patients often require lifelong medication. Despite there are effective maintenance therapies, compliance with long-term therapy is difficult -7. KelloDespite GERD being prevalent in Pakistan, minimal data is available, particularly on the impact on the quality of life with various treatment options. This study aims to compare the impact on the quality of life pre- and post-laparoscopic fundoplication.This prospective study was conducted in a tertiary care hospital, Pakistan, from Jan 2019 to Feb 2020. Fifty patients with GERD were included after informed consent. Patients with a previous history of gastric and esophageal surgery, ulcers, and short esophagus were excluded from the study. All patients underwent thorough clinical evaluation followed by upper endoscopy esophageal manometry and 24-hour pH-metry. All cases underwent laparoscopic Nissen’s fundoplication (LNF) by the same surgeon. After hiatal dissection, hiatal repair was performed. All patients completed the Gastroesophageal Reflux Disorder Health-Related Quality of Life (GERD-HRQoL) questionnaire both pre-operatively and three months after the operation. GERD-HRQoL has ten items with each item that can be scored from 0 (best) to 5 (worst)  participants were male, and 24 (51.1%) participants were female. Mean stay in hospital after fundoplication was 5 ± 2 days. There was significant improvement in pre- and post-operative median Health-Related Quality of Life score . There was improvement in Items 1-6 and 10. Item 8 and Item 9 worsed after the procedure. There was no change in Item 7  is a chronic long-lasting disease, with ability to relapse and develop complications . GERD maSurgical intervention, such as laparoscopic Nissen’s fundoplication (LNF), is reserved for patients who are intolerant or have relapsed to therapy with medical therapy. It is also offered to non-compliant patients . SalmineTo the best of our knowledge, this is the first study that compares the health-related quality of life pre- and post-laparoscopic Nissen's fundoplication in a local setting. The study has its limitations as well. The study was conducted in one institute, hence reducing the diversity of sample. The participants were followed up for three months only, because to follow up is fairly common in Pakistan.In this study, there was a significant improvement in Items 1 to 6 and 10 of the HRQoL questionnaire. Items 1 to 6 relate to symptoms of heartburn. Hamid et al. also showed significant improvement in items related to heartburn in the GERD-HRQoL questionnaire . In thisMinimally invasive surgery, such as LNF, have advances the surgical treatment of GERD. Various studies have shown that functional result of both laparoscopic anti-reflux procedures and open surgery are comparable. Laparoscopic procedures have the advantage of significantly lower postoperative morbidity and shorter hospital stay. Minimally invasive surgeries, however, are associated with complications and it is necessary that we manage this complication to ensure maximum long-term benefit of laparoscopic procedures .There is significant improvement in health-related quality of life three months after LNF. There was significant improvement in the heartburn component of GERD-HRQoL component of the questionnaire, while there was either no change or worsening of median scores related to bloating and swallowing. It is important for physicians to address the impact of GERD on quality of life and daily routine. Management should focus on not only alleviating the symptoms but improving quality of life as well.


Helping Mothers Survive Bleeding after Birth on knowledge and skills of health workers and whether such effect varies by health workers characteristics.Our study aimed to assess the effect of Nested in a cluster-randomised trial to assess the effect of the training on health outcomes, we assessed changes in knowledge and simulated skills in 61 facilities. The assessments were done i) before, ii) immediately-after training session and iii) at 10-month follow-up for subset of health-workers of implementation facilities as defined by the trial. We used a self-administered questionnaire and Objective Structures Clinical Examinations to assess three skill sets: Active Management of Third Stage of Labour, removal of retained placenta and management of severe postpartum haemorrhage. We computed summary statistics and used the paired t-test to assess change of knowledge and skills immediately post-training and at 10-month follow-up. Linear regression was done to assess association of scores and health worker characteristics.Of the 636 health workers included, 606 (96.7%) and 591 (91.4%) completed the knowledge and skills assessments, respectively. Majority of the participants (68%) were nurse-midwives. Knowledge scores increased by 15 percentage-points from 77.5% to 93% , and skills scores by 47 percentage-points  from 37.5% to 83%. There was a 4.0% decline of skills at 10-month follow-up. The decline was higher in auxiliary staff (-11.8%) and least in nurse-midwives (-2.1%) p-value <0.001. Health workers who assisted less than 5 deliveries in the last month, those who never attended postpartum haemorrhage in-service training and profession experience >8 years were associated with lower mean skill change immediately post-training.Helping Mothers Survive Bleeding after Birth training to increase knowledge and skills of postpartum haemorrhage among all professional groups. Auxiliary staff benefited most from the training but also showed higher skill decline at 10-month. Our study highlights the importance to disaggregate knowledge and skills by health workers characteristics.Our study supports the potential of the  To end preventable deaths and reduce the maternal mortality ratio (MMR) below 70 per 100,000 livebirths by 2030, countries need to invest in strengthening the health workforce . These pIn-service training is a frequent method to address the lack of skills among the existing health workforce in order to strengthening knowledge, skills and attitudes , commonlWhile various trainings may address similar content in terms of intrapartum and newborn care, they differ in content details, duration, site of implementation, training modalities, use of simulation and other components such as teamwork . A recenHowever, few studies have assessed determinants of knowledge and skills improvement such as factors associated with knowledge gains, knowledge retention. We only found one 9-country study that reported on associations of knowledge and skill acquisition following emergency obstetric training and this put forward associations with country, health workers’ profession and years of professional experience but no association with proportion of maternity work done . Two revHelping Mothers Survive Bleeding after Birth (HMS BAB) training is a competency-based simulation training delivered in health facilities to all health workers in a maternity unit [The ity unit . Implemeity unit , 23 and ity unit . The impity unit . Also, iity unit . There iAs other low- and middle-income countries, Tanzania has high maternal mortality of 556 deaths per 100,000 live birth, 25% of which are contributed by haemorrhage , 25. LowNested in a cluster-randomised trial to assess the effect of the training on health outcomes, we assessed changes in knowledge and simulated skills before and after the training in 61 facilities we assessed whether the effect of the HMS BAB training on change in knowledge and skills, including retention of the same 10-month follow-up, varied by health workers’ characteristics , 28This before-after study with no comparison group was done within the HMS BAB cluster trial setting registered with Pan African Clinical Trials Registry, PACTR201604001582128 on 12 April 2016, details published elsewhere , 28Health workers in maternity ward include medical doctors, other clinicians who are either clinical officers with three years of training or Assistant Medical officers who have additional skill training of two years . All nurThe HMS BAB training intervention was provided to all maternity health workers using the 2013 basic HMS BAB curriculum developed by Laerdal Global Health and Jhpiego , 22 as pFirst Jhpiego HMS BAB master trainers trained 12 district-HMS BAB trainers during a one-week training in a central location and later travelled to the districts where the HMS BAB in-facility trainings were conducted , 28. OneIn this secondary data analysis, we included all the trained maternity ward health workers of participating health facilities: 636 health workers were trained. 337 in January 2016 in 31 intervention facilities of HMS BAB trial and 299 in January 2017 in 30 comparison facilities after the end of the trial. The 10-month assessment in a subset of health workers were done only in intervention facilities for operational reasons.We used the standard Jhpiego pre- and post-training assessments , 22 whicAdditionally, the participants’ professional qualification, years of professional experience working in the maternity ward, number of deliveries assisted in the last 30 days, and whether they had ever received previous in-service training in AMTSL or PPH was documented.Data were manually entered in MS excel and checked for completeness. To analyse the data, we created a new score variable combining the three OSCE skill scores into a mean skill score. Analysis was done by STATA software version 15. Tables of summary statistics were prepared to describe the data: mean or median and standard deviation or Interquartile Range (IQR) were used to summarize continuous variable, frequencies and percentages to summarize categorical variables. Years of professional experience was categorized into <2 year, 2–4 years, 5–7 years, and ≥ 8 years. Number of assisted deliveries in the last one-month was categorized in ≤5 deliveries, 6–15 deliveries, and ≥16 deliveries assisted in the last one-month. Professional qualifications were categorized into (1) medical doctors (2) other clinicians ; (3) nurse-midwives included all nurse-midwives with diploma and above; (4) auxiliary staff and (5) others included laboratory technicians. The facility level was categorized into hospitals, larger health centres that performed Caesarean sections (C-sections) and lower health centre without C-sections. Previous in-service training (ever) of AMTSL or PPH was set as a binary variable.The outcome variables were absolute scores and mean change of scores in knowledge and aggregate OSCE skills. Aggregate OSCE skill score was an average of all three OSCE scores: AMTSL, simulated retained placenta and severe PPH due to atony and is referred as skill scores throughout. Immediate change of scores was calculated as the difference between immediate post-training score and pre-training score and change at follow-up (decline) was calculated as difference between scores at follow-up and that of immediate post-training All scores were summarized and mean with 95% confidence intervals presented in tables. We compared individual health workers’ knowledge and skill scores to assess change immediately and that at follow-up period using paired t-test and reported significance results at p-value <0.05.We used linear regression analysis to assess the predictors of change of knowledge and skill scores 1) immediately after the training and 2) at 10-month follow-up, for each of the independent variables and present coefficients with 95% confidence intervals. Significance level was set at p<0.05.Ethical clearance was granted from Muhimbili University of Health and Allied Sciences IRB with permit number 2015-11-18/AEC/Vol X/71 and 2016-12-14/AEC/Vol XIII/03. All participants were informed about the study and written informed consent sought and obtained. The benefit of participating in the study was improving knowledge and skills that lead to better performance and job satisfaction. There was no potential harm from participating in the training, except for the inconvenience of assessments. All participants were given codes to ensure follow up of scores without identifying individual performance. All personal identifiers were removed from electronic data.A total of 636 health workers received the training, 95.2% (606/636) completed the knowledge assessment and 92.9% (591/636) completed the knowledge and skills for both pre- and immediate post-training assessment. Twenty-five participants, 3.9% (25/636) dropped out of the training; thus, only the pre-training knowledge assessment is available for these participants . A sub-sA total of 636 health workers participated in the study, 435 (68.4%) nurse-midwives, 56 other clinicians (8.8%), 13 medical doctors (2%) and 128 (20.1%) auxiliary staff , 4 (0.6%) health workers were missing their profession level as shown in Main outcomes for pre-training, immediate post-training and 10-month follow-up scores for knowledge and aggregate skill scores by health workers’ characteristics are shown in There was a significant overall decline of skills at 10-month follow-up from 85.4%  to 81.1%  with p-value 0.002. Skill decline was significant in auxiliary staff from 76.6%  to 63.8% . Distribution of knowledge and skills scores at the different times per profession is shown in In At follow-up we observed less skill decline among health workers with 6–15 and with >16 deliveries compared to the referent group, this was statistically significant .Our study indicated significant increase of health workers knowledge from 74.2%  to 89.2%  and skills from 38.2%  to 85.4% , a 47.8 percentage-point increase  immediately-after the training. Pre-training skill scores were lower than knowledge scores. Auxiliary staff showed a larger increase in scores from the training  compared to other professions, but the 10-month follow-up assessment also indicated that this group had the largest decline of -11.4% .Profession, number of deliveries assisted in the last month and years of professional experience were associated with skill change immediately post-training. Health workers assisting 6–15 deliveries in the last month gained 2.4 percentage-points more than those assisting <5 deliveries  immediately post-training and displayed less skill decline at 10-month follow-up. Health workers with more than 8 years of profession experience significantly scored less than those with <2 years of experience. Working in health centres that performed C-section and ever attending prior in-service PPH training (but not AMTSL) were associated with higher gain in skill scores.Our study supports the existing evidence that the HMS BAB one-day training with mandatory weekly practice sessions is beneficial to upgrade health workers’ knowledge and skills in prevention, assessment and basic management of PPH , 22, 23.We observed the largest gain in skills score among auxiliary staff. Although auxiliary staff is not officially counted as ‘skilled birth attendants’, they assist deliveries as part of their routine care in the studied facilities. A recent publication by Rao et al. (2018) from India proposed that lower cadre health professionals that are not trained for delivery care can be trained and mentored to perform routine delivery care and manage PPH to the same level as nurse-midwives . While tOur study concur with similar studies of in-service trainings that reported being active in clinical duties in the maternity ward was associated with better skills and also more retention of acquired skills following a training , 19, 22.Studies on knowledge and skills retention reported different results on retention depending on time from initial in-service training from 3–24 months , 20, 32.We were only able to include 63.7% of health workers in our 10-month assessment due to a variety of reasons illustrated in The strength of our study is the large number of participants which allowed us to disaggregate the effects of the training in several sub-groups. We included 636 participants from 61 facilities: 605 had complete immediate post/pre-training knowledge scores and 591 complete immediate post/pre-training skills scores. Previous studies had smaller sample size of between 30 to 145 health workers , 24.Another strength is that we used OSCE assessment for observation of simulated skills and used the same assessment tools during all the assessments periods, hence improve comparability. We report on aggregate skill score and change for three core competences at 10-month follow-up: rather than single skill scores as we were interested in a single score that may represent prevention and basic management of PPH portraying a more comprehensive score.However, our study has limitations. We chose the 10-month follow-up for reassessing knowledge and skills retention, for pragmatic reasons, as we provided at this time period the training to the comparison facilities after the finalisation of the HMS BAB trial. While other authors did follow-up at several points, this was financially not possible for this study. Another limitation is that we missed fourteen health workers due to poor road infrastructures. We only reassessed 63.7% of the eligible number of participants, the remainder were absent or refused. We do not know whether those who refused or could not participate for other reasons had poorer or better performance and how this would have affected the results. However, the absentees were mainly medical doctors (3), other clinicians (14) and nurse-midwives (68), we hypothesize that perhaps their absence should not have affected overall results. Furthermore, our sample had few medical doctors at the initial training. We were only able to include two doctors and eleven clinicians in the 10-month assessment. Seven of thirteen medical doctors included in the training were interns and had moved to other employment areas. This limits the generalisability of our findings in relation to clinical professions. We also acknowledge that using same assessment tools for before and after assessment could mislead as health workers may be familiar with the questions and could have studied them to pass.As part of the overall HMS BAB trial, health workers were to perform weekly practice drills for 8 weeks. We assumed all those trained in January 2016 had an opportunity to have done the practice drills as outlined by the intervention prior to the 10-month follow-up however, this may not be true. Twenty-three of 31 facilities trained in January 2016 completed the weekly practice drills within three months, three facilities did five sessions and five facilities did two sessions at this time. Although there were logbooks that showed participation of health workers during weekly drills, it was not possible to link individual providers to the number of drills attended and the decline of knowledge and skills. Nonetheless, a recent publication by William et al (2019) utilizing similar training practice drills reported less than one practice session per 8-weeks per health worker .We report here on test scores. While preferably we would have reported on improved clinical practice, such assessments are logistically and practically difficult. However, we believe that our findings reflect training outcomes of improved test scores and retention was also reflected in the findings of the larger HMS BAB trial .For some categories, for example the number of deliveries assisted in the last month or years of professional experience We have used cut-off points informed by mean and median exploration of the data for some categories. There are no clear standards and different authors have used different cut-off points which reduces comparability , 35, 37.Our study illustrates the potential of the HMS BAB training to improve knowledge and skills of health workers in maternity wards. While all health professionals benefited from the training, auxiliary staff benefited most, but they also had the lowest skills retention. This finding cautions the integration of lower trained staff into service delivery and a careful context specific assessment of advantages and disadvantages needs to be done if such professionals are used to fill shortages of qualified staff.In-service training is widely used to improve health worker performance and the relevance has been underscored by systematic reviews , 9. The Our study highlights gaps around understanding health workers characteristics that can strengthen training and use of resource.The HMS BAB was effective to improve knowledge and skills of health workers in the included hospitals and health centres. Both knowledge and skills increased significantly following the one-day HMS BAB training, followed by weekly practice drills for 6–8 weeks. Retention at 10-month follow-up was high. Profession and number of deliveries in the last month were associated with better skill outcomes and less decline at 10-month follow-up. We believe that more research on knowledge and skills decline need is needed to help facility management and policy makers plan for sustaining skills and performance of available health workers.S1 Fig(TIF)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S1 Checklist(DOC)Click here for additional data file.S1 Appendix(PDF)Click here for additional data file.S2 Appendix(PDF)Click here for additional data file.S1 Data(DTA)Click here for additional data file.


Inonotus obliquus (IO), also known as chaga mushroom. IO commonly grows in Asia, Europe and North America and is widely used as a raw material in various medical conditions. In this review, we have evaluated the most effective herbs and mushrooms, in terms of the antiviral and anti-inflammatory effects which have been assessed in laboratory conditions.The 2019 novel coronavirus, SARS-CoV-2, producing the disease COVID-19 is a pathogenic virus that targets mostly the human respiratory system and also other organs. SARS-CoV-2 is a new strain that has not been previously identified in humans, however there have been previous outbreaks of different versions of the beta coronavirus including severe acute respiratory syndrome (SARS-CoV1) from 2002 to 2003 and the most recent Middle East respiratory syndrome (MERS-CoV) which was first identified in 2012. All of the above have been recognised as major pathogens that are a great threat to public health and global economies. Currently, no specific treatment for SARS-CoV-2 infection has been identified; however, certain drugs have shown apparent efficacy in viral inhibition of the disease. Natural substances such as herbs and mushrooms have previously demonstrated both great antiviral and anti-inflammatory activity. Thus, the possibilities of natural substances as effective treatments against COVID-19 may seem promising. One of the potential candidates against the SARS-CoV-2 virus may be  The novel coronavirus, SARS-CoV-2, causes severe acute respiratory syndrome and has quickly become a serious threat to public health . Since tCoronaviruses have been described as zoonotic infections, with alpha and beta coronaviruses found primarily in mammals such as bats whereas gamma and delta are more common in pigs and birds. Additionally, investigations into the previous coronavirus outbreaks found that SARS-CoV1 was transmitted from bats to humans and MERS-CoV from dromedary camels to humans . Much liThe primary mode of human to human transmission of SARS-CoV-2 has been identified to be through respiratory droplets . Once thn = 19). The remaining 20% of cases, however, were more critical and severe [COVID-19 symptoms appear after an incubation period of around 2–14 days. The duration from the onset of symptoms to death has ranged from 6 to 41 days. However, this duration is dependent on both the age of the patient and the status of their immune system . Patientd severe . COVID-1d severe . Despited severe . A recend severe . Moreoved severe . In addid severe .Due to the increasing number of human casualties, research has focused on understanding the nature of the disease in order to develop effective treatments. Currently, no specific treatment has been identified for COVID-19. The race to develop a preventive vaccine is still ongoing, with many still in the early stages of clinical trials. Therefore, there is a dire need to develop an effective antiviral with enhanced efficacy for the prophylaxis and treatment of coronavirus infection. Various medications have now been identified and developed as a means for controlling and suppressing inflammatory crises such as steroids, nonsteroidal anti-inflammatory drugs and immunosuppressants . In pracCurrently, no specific treatment for COVID-19 has been recognised; however, certain drugs have shown apparent efficacy in viral inhibition of the disease . Using aThere are many populations that prefer the use of natural products in place of commercial pharmaceutically developed products for treating and preventing medical illnesses. Many cultures around the world have historically relied on medicinal plants for primary care, with some continuing use till this date . Herbs aPrunella vulgaris (PV)  due to its several thousand-year histories as an antipyretic and antidotal herb used in traditional Chinese medicine [Prunella is a genus of perennial herbaceous plants in the Labiatae family. Approximately 15 species have been identified worldwide, most of which are distributed in the temperate regions of Europe and Asia. From this genus, the most extensively studied is medicine ,25. The medicine . PV is amedicine . PV has medicine . Previoumedicine ,30. It hmedicine . Interesmedicine ,32,33. Tmedicine . This naThe spike of Prunella vulgaris, also known as Prunellae Spica, is often used for the prevention and remedy of various diseases, in traditional Chinese medicine. Prunellae Spica contains various bioactive compounds within its chemical composition including triterpenes, flavonoids, phenolic compounds and carbohydrates. These compounds have been associated with a variety of protective effects such as anticancer, anti-inflammatory, neuroprotective, immunosuppressive activity and anti-HIV activity . In regaAllium sativum) is an aromatic herbaceous plant that has been extensively used worldwide, especially in the Far East, for centuries, in many food dishes due to its appetising property, bitter taste and the flavour it gives to dishes. Despite the use of garlic being such a common practice, this particular plant is of great medical importance, as garlic has exhibited antibacterial, antiviral, antifungal and even antitumor effects [A. sativum is rich in alliin, allicin, ajoenes, vinyldithiins and flavonoids such as quercetin, all of which are sulphur-containing phytoconstituents [A. sativum but the experiments that have been conducted have shown that A. sativum is effective against influenza B, herpes simplex viruses, cytomegalovirus, rhinovirus, HIV, HSV type 1 and 2 and viral pneumonia [Garlic  or they can have fruiting bodies above the ground (epigeous). It is becoming widely known that different mushrooms possess a variety of biological and pharmacologically active molecules. Previous research has shown that bioactive components and extracts derived from mushrooms exhibit strong anticancer activities . In addiLentinus edodes mycelia (shiitake) as well as looking at the antiviral activity against infectious hematopoietic necrosis virus (IHNV). Lentinus edodes mycelia extract is a powder that is extracted from shiitake mushrooms known as Lentinus edodes. The novel lentinan (LNT-1) was extracted and purified via anion exchange and the structural characterisation was carried out by a range of experiments including gas chromatography-mass spectrometry and 1D-nuclear magnetic resonance spectroscopy. The results obtained displayed that LNT-1 had an overall molecular weight of 3.79 × 105 Da. Structural characterisation of LNT-1 showed that it was a β—(1 → 3)—glucan backbone with—(1 → 6)—glucosyl side-branching units terminated by mannosyl and galactosyl residues. Additionally, the study found prominent antiviral activity against INHV, and the main antiviral mechanisms of LNT-1 were direct inactivation as well as inhibition of viral replication. As well as this, administration of LNT-1 also caused significant downregulation in the expression of pro-inflammatory cytokines such as TNF-α, IL-2 and IL-11, whilst also upregulating the expressions of IFN-1 and IFN-γ, cytokines that are known to induce antiviral, anti-proliferative and immunomodulatory effects [A study conducted in 2018, determined the structural characterisation of lentinan from  effects . Overall effects . Grifola frondosa,  a species of Basidiomycotina. This is an example of an edible mushroom that has been used in herbal medicine. In comparison to the shiitake mushroom, Grifola frondosa has a higher nutritional value. The major biologically active component of the mushroom is the β-glucan in the G. frondosa polysaccharide (GFP). Moreover, GFP has shown great anticancer potential with it being approved as a therapeutic drug for the treatment of cancer in China [Grifola frondosa using ammonium sulphate precipitation and DEAE ion exchange chromatography. GFAHP has a reported molecular weight of 29.5 kDa, and the N-terminal sequence of GFAHP consists of 11 amino acid peptides. This peptide sequence did not match any known amino acid sequences, thus indicating that GFAHP is likely to be a novel antivirus protein. This protein extract displayed great ability to inhibit in vitro replication of HSV type 1 (HSV-1). In murine models, higher concentrations of GFAHP, in particular at the doses of 125 and 500 μg/mL, strongly reduced the severity of blepharitis, neovascularisation and stromal keratitis induced by HSV-1. Gu et al. (2007) found that topical administration of the GFAHP protein extract to the cornea of mice caused a significant decrease in virus production. This study demonstrated that GFAHP was able to both directly inactivate HSV-1 and inhibit HSV-1 infiltration into Vero cells [Grifola frondosa (GF-D) and was used in combination with human IFN α-2b (IFN) in order to investigate the inhibitory effect of hepatitis b virus (HBV). Following analysis of HBV DNA and viral antigens, the results obtained showed that GF-D or IFN alone were able to inhibit HBV DNA in cells with a 50% inhibitory concentration (IC50) of 0.59 mg/mL for GF-D and 1399 IU/mL for IFN. Upon further analysis, researchers found that combined use of GFD and IFN synergistically inhibited HBV replication. When combined with 0.45 mg/mL GF-D, the IC50 for IFN was reported to be 154 IU/mL, thus suggesting that in combination, there was a 9-fold increase in antiviral activity. The results indicate the possibility of using GF-D and IFN combination therapy as a potentially effective therapy against hepatitis b virus infections [Another species of mushroom that has shown promising antiviral effects is in China . A previfections . In anotfections . Ganoderma lucidum aqueous extract (GLE) and Egyptian Chlorella vulgaris ethanolic extract (CVE). The main finding of this study shows that GLE-CVE exhibited higher antioxidant and anti-radical effects in comparison to individual extracts. GLE-CVE also attenuated lipopolysaccharide-induced inflammation and oxidative stress in white blood cells, which occurred through the process of downregulating inflammatory mediators such as TNF-α, cyclooxygenase-2, nuclear factor kappa-beta (κβ) as well as the expression of inducible nitric oxide synthase. In addition, the combined extracts also exhibited great ability in enhancing the cellular antioxidant indices. These changes caused by GLE-CVE also led to suppression of cellular increase in nitric oxide and lipid peroxidation. This study also concluded that the combined extract had an antioxidant effect that was significantly greater than that of a commercial anti-inflammatory drug, dexamethasone. As oxidative stress and inflammation are two factors that are consistently linked to the pathogenesis of COVID-19, there may be a great possibility of this combined extract as an alternative treatment [Abu-Serie et al. evaluated the antioxidant and the anti-inflammatory effects of Malaysian reatment .Inonotus obliquus (IO), also known as the chaga mushroom. IO commonly grows in Asia, Europe and North America and is widely used as a raw material in various medical conditions [Inonotus obliquus mushrooms possess a powerful enzymatic system and a strong system of defence, due to their parasitic mode of life [Inonotus obliquus polysacharides in cats with feline viruses including feline calcivirus, feline herpesvirus 1, feline influenza virus, feline infectious peritonitis virus and feline panleukopenia virus. Inhibition of RNA viruses and DNA viruses in all the five viral subtypes was observed [Inonotus obliquus against (HSV and found that the aqueous extract derived from I. obliquus (AEIO) led to an overall reduction in HSV infection in Vero cells. This study also elucidated the anti-HSV mechanism of action, as it found that AEIO had the ability to inhibit viral-induced membrane fusion, thus acting against the early stages of HSV viral infection. Consequently, the results showed that aqueous extracts from I. obliquus were able to successfully prevent HSV-1 entry by directly acting on viral glycoproteins, which in turn prevented membrane fusion. Currently, the treatment for HSV infection is a nucleoside analogue antiherpetic. However, increasing resistance to these drugs has resulted in a need to develop alternative treatments. This study has highlighted that the mechanism of action for AEIO is different from that seen in nucleoside analogue antiherpetics and thus provides an alternative treatment to overcome the developing resistance [A potential candidate against the SARS-COV-2 virus may be nditions . IO has nditions . It has  of life . Extract of life . Moreove of life . A studyobserved . Suppresobserved . Additiosistance .IOP can inhibit the induction of NO and other similar cytokines, a phenomenon that has been associated with COVID-19 [Inonotus obliquus polysaccharides (IOP) were shown to alleviate inflammatory responses by inhibiting JAK-STAT signalling pathways that regulate the release of T Helper subsets [IOP extracts on Hepatitis C and human immunodeficiency disease have also been elucidated [+ T cells, responsible for inflammation [IOPs have shown promising results in treating various viral diseases, the effect of this mushroom in COVID-19 infection could prove to be beneficial.Chronic inflammation is the underlying pathogenesis of a series of diseases, including numerous types of carcinomas, atherosclerosis, autoimmune diseases and obesity, among others. Following stimulation caused by lipopolysaccharides (LPS), a series of pro-inflammatory cytokines are released including prostaglandin mediators, cytokines  and nitric oxide (NO) ,61. It wCOVID-19 . Similar subsets . Further subsets ,65. Addiucidated ,66. It wammation . In addiInonotus obliquus as a natural antiviral treatment against SARS-COV-2. Earlier studies into this mushroom have laid the groundwork into the antiviral capabilities of Inonotus obliquus, however further research into characterising the bioactive ingredients, understanding the underlying mechanisms as well as assessing the efficacy and potential application in vivo should be encouraged in order to develop an effective antiviral treatment against COVID-19. Until the present time, there has not been much research regarding the potential of natural agents against COVID-19, thus opening the research into this field may unlock the potential such extracts may have against SARS-CoV-2. Developing viruses such as Ebola virus (EBOV), Lassa virus (LASV), avian influenza virus H5N1 (AIV) and the more recent SARS-COV-2 virus are seen as global health concerns. Despite many advancements in science, no effective vaccine or specific therapy has been approved for humans against these viruses, and so there is an urgent need to develop therapeutic treatments against these threats . Traditi