Myocardial infarction (MI) patients presenting without chest pain are a diagnostic challenge. They receive suboptimal prehospital management and have high mortality. To elucidate potential benefits of improved management, we analysed expected outcome among non-chest pain MI patients if hypothetically they (1) received emergency ambulances/acetylsalicylic acid (ASA) as often as observed for chest pain patients, and (2) all received emergency ambulance/ASA.We sampled calls to emergency and non-emergency medical services for patients hospitalized with MI within 24 h and categorized calls as chest pain/non-chest pain. Outcomes were 30-day mortality and a 1-year combined outcome of re-infarction, heart failure admission, and mortality. Targeted minimum loss-based estimation was used for all statistical analyses.Among 5418 calls regarding MI patients, 24% (1309) were recorded with non-chest pain. In total, 90% (3689/4109) of chest pain and 40% (525/1309) of non-chest pain patients received an emergency ambulance, and 73% (2668/3632) and 37% (192/518) of chest pain and non-chest pain patients received prehospital ASA. Providing ambulances to all non-chest pain patients was not associated with improved survival. Prehospital administration of ASA to all emergency ambulance transports of non-chest pain MI patients was expected to reduce 30-day mortality by 5.3%  from 12.8% to 7.4%. No significant reduction was found for the 1-year combined outcome . In comparison, the observed 30-day mortality was 3% among ambulance-transported chest pain MI patients.Our study found large differences in the prehospital management of MI patients with and without chest pain. Improved prehospital ASA administration to non-chest pain MI patients could possibly reduce 30-day mortality, but long-term effects appear limited. Non-chest pain MI patients are difficult to identify prehospital and possible unintended effects of ASA might outweigh the potential benefits of improving the prehospital management. Future research should investigate ways to improve the prehospital recognition of MI in the absence of chest pain.The online version contains supplementary material available at 10.1186/s12872-022-03000-1. Despite advances in the treatment and survival of patients with myocardial infarction (MI) , 2, bothEffective treatment of MI requires timely intervention and potential life-saving efforts that can be implemented prior to hospitalization including the immediate dispatch of an ambulance to patients and provision of acetylsalicylic acid (ASA) upon arrival of the ambulance , 8. No rIn consequence, we have examined a large dataset of calls to an emergency and a non-emergency medical service in Copenhagen, Denmark, where prehospital care and emergency ambulance dispatches are recorded. We investigated whether MI patients without chest pain could be expected to benefit from increased emergency ambulance dispatch and prehospital ASA treatment.In Copenhagen, Denmark, citizens having a medical emergency should dial 1-1-2, equivalent to 9-1-1 in the United States, to receive assistance. At the 1-1-2 emergency number, the call takers are paramedics and nurses, and they assess the medical urgency and prioritize dispatching of the ambulances. Citizens with non-emergency medical conditions can contact their general practitioner or call 1813 to reach the regional 24-h medical helpline  which is intended to cover outside the working hours for general practitioners. Here, primarily nurses, but also medical doctors provide medical guidance, refer to emergency departments, and dispatch ambulances. The 1813-medical helpline and the 1-1-2 emergency number is a combined medical service operated by Copenhagen Emergency Medical Services, serving 1.8 million inhabitants, approximately one-third of the Danish population . AlthougIn Denmark, all citizens with permanent residency are assigned a unique civil registration number. This number is registered when calling for help at the 1813-medical helpline and 1-1-2 emergency number and in most other encounters with the public sector , 18.We retrieved information on age, sex, ethnicity (Danish and immigrant/descendant of immigrant), and country of emigration from the Danish Civil Registration System. From the Population Educational Registers  patientsAll contacts for patients above age 30 to the prehospital services in Copenhagen  between April 1st, 2015, and December 31st, 2018 were considered. We included calls regarding patients hospitalized with a confirmed MI no later than 24 h after the call. We defined MI as a primary diagnosis of ICD-10 I21 identified from the Danish National Patient Registry. The same patients can occur multiple times in the study population, given that the same patient could; have experienced more than one MI during the study period, or have more than one call to the Copenhagen Emergency Medical Service within the 24-h time span. We excluded patients who were terminal, living at nursing homes, suspected dead at the time of call, unconscious, and calls with missing criteria or criteria that were non-informative of the patient's condition. For the analysis of prehospital ASA assignment, only MI patients who received an emergency ambulance response were included. Additionally, we excluded patients with contraindications for ASA treatment, defined by occurrence of any of the following words in the electronic prehospital medical record: ‘blood’, ‘bleeding’, ‘aneurysm’, or ‘ulcer’, or notation of allergy to ASA.Health care professionals at the 1813-medical helpline and 1-1-2 emergency number choose one criterion (symptom/description) to describe the situation/symptoms of the patients using criteria-based systems. The criteria are used for registration but also for the assigning of vehicles. Notably, the two services use different protocols. A locally developed electronic decision support system is used at the 1813-medical helpline and Danish Index is used at the 1-1-2 emergency number . For thiThis study aims to investigate if the excess mortality observed among MI patients with non-chest pain could be reduced if we hypothetically intervened on two prehospital factors, (1) receiving an emergency ambulance and (2) receiving prehospital ASA treatment. Receiving an emergency ambulance was defined as the dispatch of an emergency ambulance with lights and sirens, which is a mobile intensive care unit of type A. The service aim of emergency ambulances in Copenhagen, Denmark is 90% arriving at the patient within less than 13 min. All other dispatches including non-emergency ambulances, self-transport to hospital, home visits were defined as no emergency ambulance. Further details of the remaining types of dispatches/non-dispatches are available , 26.Our secondary aim was to investigate the prehospital management of MI patients after they received emergency ambulances. Prior to data access, ASA was chosen as the intervention of interest, as ASA is recommended as the prehospital treatment of MI patients regardless of later in-hospital treatment , 27. PreThe primary outcome was 30-day all-cause mortality, and the secondary outcome was a 1-year combined outcome. We defined 30-day mortality from The Danish Civil Registration System , 18 and All analyses were repeated for both outcomes. We defined effect measures in a causal inference framework  in termsFour main analyses were performed as outlined in Table as chest pain-intervention). In the second analysis, we estimated the expected outcome risk if all MI patients recorded without chest pain had received an emergency ambulance, referred to as the all-intervention. Both hypothetical interventions were compared to the observed outcome risk in non-chest pain MI patients and our target parameter for each analysis was the expected reduction in outcome risk under the hypothetical intervention of interest. The third and fourth analyses considered only patients who received an emergency ambulance and did not have contraindications towards ASA. In this subgroup, the third analysis targeted the expected outcome risk had non-chest pain MI patients received ASA treatment with the same probability as observed for chest pain patients (as chest pain-intervention), and the fourth analysis targeted the expected outcome probability had all non-chest pain MI patients received ASA treatment . Similarly, these hypothetical interventions were compared to the observed outcome risk among non-chest pain MI patients who received an emergency ambulance and our target parameter was the expected reduction in outcome risk under the hypothetical interventions of interest.In the first and third analysis, we estimated the interventional disparity indirect effect  among noThe target parameters in all analyses were estimated using targeted minimum loss-based estimation (TMLE) . Initialhttps://github.com/amalielykkemark/tmleExposed). All analyses were performed in R version 4.0.3   and similarly for 1-year combined outcome ranging from 1.3% CI 95% (as chest pain-intervention) to 1.6% CI 95% .In the main analysis of the hypothetical intervention on emergency ambulance, 5418 MI patients were included of which 1309 (24.2%) were recorded without chest pain. The observed 30-day mortality among MI patients without chest pain with no hypothetical intervention was 11% and 1-year combined outcome was 31.6%. In comparison, the observed 30-day mortality without intervention among MI patients recorded with chest pain was 2.8% and the 1-year combined outcome was 18.5%. We found a small non-significant increase for both 30-day mortality and 1-year combined outcome, with 30-day mortality increases ranging from 1.5% CI 95%  were recorded without chest pain. The observed 30-day mortality without intervention among non-chest pain MI patients was 12.8% and 1-year combined outcome was 33.9%. Similarly, among MI patients with chest pain, the observed 30-day mortality and 1-year combined outcome without intervention was 3% and 18.7%, respectively. Under the hypothetical intervention where non-chest pain MI patients had the same probability of receiving ASA as those with chest pain, 30-day mortality was reduced with 3.3% CI 95%. The reduction increased to 5.3% CI 95% for the intervention where all non-chest pain MI patients hypothetically received ASA. No significant changes were found for the hypothetical intervention on ASA for the 1-year combined outcome.To investigate the impact of the type of MI on the results, we repeated the main analyses of the two hypothetical prehospital interventions; emergency ambulance and ASA in subpopulations of STEMI and NSTEMI patients. Additionally, subgroup analyses for calls to the 1-1-2 emergency number were performed to assess whether the effects of the prehospital interventions differed according to the choice of medical service.as chest pain-intervention) and 2.4% CI 95%  . In the subgroup analysis of the hypothetical intervention on prehospital ASA, we included only emergency ambulance transported MI patients without contraindication of ASA. Here, the subgroups consisted of 1442 STEMI patients, 1738 NSTEMI patients, and 3057 patients who had called the 1-1-2 emergency number  MI patients who were recorded without chest pain, the observed 30-day mortality and 1-year combined outcome to 11% and 31.6%, respectively. Large differences in the prehospital management of MI patients with and without chest pain exists, where 90% of chest pain versus 40% of non-chest pain patients received emergency ambulances, and 73% and 37% of chest pain and non-chest pain patients received prehospital ASA. We found no improvement in 30-day survival when hypothetically increasing chance of receiving emergency ambulance dispatch to all non-chest pain MI patients. Increasing prehospital administration of ASA to emergency ambulance transported non-chest pain MI patients was found to reduce 30-day mortality by 3.3% CI 95% to 5.3% CI 95% depending on the intervention. However, no significant reduction was found for the 1-year combined outcome when hypothetically increasing chance of receiving ASA in the prehospital setting. Despite the reductions found for the hypothetical interventions on ASA, 30-day mortality remained two to three times higher among non-chest pain MI patients compared to chest pain.Contrary to our hypothesis, the hypothetical intervention on the probability of receiving an emergency ambulance did not change the risk of 30-day mortality and 1-year combined outcome. In fact, increasing emergency ambulance dispatch seemed to increase outcome likelihood slightly. The finding could be explained by the fact that MI patients with more severe symptoms are more likely to receive an emergency ambulance. These patients are equally more likely to have a more severe or progressed MI probably affecting the chance of survival. Unfortunately, we do not have data that can help us differentiate the severity of the patient's infarct at the time of the call.We found a relatively large reduction in the risk of 30-day mortality among non-chest pain MI patients when hypothetically increasing prehospital ASA assignment. We cannot determine the exact cause of this reduction. It is possible that the reduction is at least partly caused by the effect of ASA, but we also expect that other factors such as early diagnostics influence the result. Providing ASA to a patient indicates that the ambulance rescue team has suspected MI and initiated a multi-faceted strategy including recording a prehospital electrocardiogram (ECG) and possibly consulting the cardiologist on duty at the invasive cardiac centre, which in addition increases the patient's chances of receiving timely in-hospital treatment. Non-chest pain MI patients are less likely to be referred directly to a cardiac centre and have previously been found to have a lower chance of receiving ASA as well as other medications within 24 h of hospitalization, indicating that they are likely to also experience in-hospital delays in treatment . SecondlWe found a small but not statistically significant reduction for 1-year combined outcome under the hypothetical interventions on ASA administration, and the expected 1-year combined outcome remained around 1.5 to 2 times higher among non-chest pain MI patients compared to chest pain MI patients. The differences in outcomes are expected to, at least partly, be explained by dissimilarities in age, comorbidities, and educational level. A larger comorbidity burden and lower educational level among non-chest pain MI patients was anticipated, as they were older. However, research have indicated that people’s knowledge of MI symptoms vary according to educational level , and we The Danish guidelines are in accordance with the international guidelines and advocate prehospital administration of ASA to all eligible patients suspected of acute coronary syndrome . In thisIn this study, the criterion recorded at the Copenhagen EMS was used as a proxy of the primary symptom. However, because patients can develop chest pain between the time of call and ambulance arrival, we do not know if the non-chest pain MI patients who were administered ASA received it because they developed chest pain or because of prehospital diagnosis with ECG.The study population, covariates, and outcomes were defined using data recorded in the Danish national registers. We cannot rule out that coding errors and imprecise or missing registrations can affect the validity of the data , 40. FurMI patients included in this study were diagnosed in-hospital. Thus, identification of these patients is not possible at the time of their call, and as a result, the hypothetical interventions of emergency ambulances and ASA treatment among MI patients examined in the present study cannot be identified in a real-world setting, hindering a direct causal interpretation of the results. Identification of MI patients based on symptoms alone is not sufficient, as non-chest pain MI patients present with a variety of symptoms. Broader use of ECG and point-of-care cardiac necrosis markers could possibly improve identification of MI patients during ambulance transport, and thus, be a tool for selecting patients for ASA administration, although we know very little about their effectiveness in patients presenting without chest pain.A real-world intervention of emergency ambulance dispatch and prehospital ASA administration to suspected MI patients would also include dispatching ambulances and administering ASA to many patients not suffering an MI. Administration of ASA to patients not suffering from an MI could lead to severe adverse events including increased risk of bleeding. Likewise, increasing emergency ambulance dispatch would be expected to have economic and administrative consequences. Neither of these adverse effects were assessed in the present study. If this study was to be investigated in a real-world setting adverse effects of both increased emergency dispatch and ASA administration should be investigated thoroughly to be able to assess the cost versus benefits of the suggested prehospital interventions. Nevertheless, this study aimed to provide information on whether there is an indication of a possible benefit of improved prehospital management among the target population, namely MI patients presenting without chest pain.Compared to MI patients with chest pain, MI patients without chest pain had three times higher 30-day mortality and twofold increased 1-year combined outcome, regardless of any of the hypothetical interventions considered in this paper. Although some potential reductions in 30-day mortality were found when improving prehospital management, overall, MI patients recorded without chest pain still have a very poor prognosis. MI patients without chest pain had a higher prevalence of severe diagnosis during their admission including heart failure, COPD, and cardiogenic shock. The high prevalence of COPD aligns with the differences in comorbidity before the MI, but given that MI patients with and without chest pain had a similar prevalence of heart failure prior to the MI, the difference in heart failure diagnoses during the admission is alarming. In combination, these findings indicate that MI patients without chest pain are truly high-risk patients.Non-chest pain MI patients are difficult to identify prehospital and real-world interventions would inevitably include many patients not suffering from an MI. Thus, one should carefully weigh the potential risk of adverse effects, including bleeding risk, when increasing prehospital ASA administration. Bleeding is a serious complication and bleeding risk assessment of patients in the prehospital setting is important but might be challenging, as accurate risk discrimination remains difficult .Additionally, one must consider the possible large increase in economic as well as human resources needed to increase emergency ambulance dispatch, ASA administration, and presumably prehospital diagnostics, given the absence of long-term benefits and the uncertainty of the true cause of the reduction in 30-day mortality discussed in this paper.We found large differences in the prehospital management of MI patients with and without chest pain. Non-chest pain MI patients have low chance of receiving an emergency ambulance dispatch when calling for help and do often not receive ASA during the ambulance transport, indicating a need for improved prehospital management of non-chest pain MI patients. We found that hypothetically increasing ASA administration could lead to reduced 30-day mortality among non-chest pain MI patients. Still, the potential effect of increasing ambulance dispatch and ASA administration appears limited as non-chest pain MI patients currently are very difficult to identify in the prehospital setting and possible unintended side effects of ASA (e.g. bleeding risk) might outweigh the benefits. Early diagnosis among those receiving ASA is expected to contribute to the magnitude of our results for increased ASA use and confounding cannot be ruled out. A randomized trial investigating the beneficial as well as adverse effects of prehospital administration of ASA is warranted. Additionally, further research is needed to determine whether identification of non-chest pain MI patients could be improved by alternative medical telephone consultation techniques or broader criteria for using prehospital ECG and point-of-care cardiac necrosis markers.Additional file 1: Table S1 ICD-10 codes for comorbidities registered prior to MI diagnosis and for diagnoses registered during MI admission. Table S2 ATC-codes for claimed prescribed medication used to define presence of disease and use of medication. Table S3 ICD-10 codes for MI diagnoses. Table S4 Subset of diagnosis registered during admission with MI (for which the patient was included in this study). Table S5 Minutes from call to hospital arrival for subgroups of chest pain and non-chest pain and emergency response.


Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, clinicians have been overwhelmed by questions beyond the SARS-CoV-2 infection itself. In dermatology practice, clinicians have been facing difficulties concerning therapeutic management of chronic immune-mediated skin disease, above all psoriasis. Major challenges arisen were to understand the role of immunosuppression or immunomodulation on COVID-19 evolution, the benefit/risk ratio related to discontinuation or modification of ongoing treatment, and the appropriateness of initiating new treatments, the optimization of timing in vaccination administration to patients under immunomodulatory treatments, and finally how to find new strategy of patients’ management through remote assistance. In this comprehensive review, we present the current evidence about the course and management of psoriasis during the COVID-19 pandemic. The general message from dermatologists was that data did not suggest that having PSO or its treatment significantly increased risk of SARS-CoV-2 infection or more severe COVID-19 course, the vaccination is highly recommended in all psoriatic patients, beyond ongoing treatment, and that the telehealth experience was a success overall. Moderate to severe psoriasis is a chronic systemic inflammatory disease whose prevalence in Europe is about 2–3% of general population.The coronavirus disease 2019 (COVID-19) pandemic has led clinicians to explore the effect of SARS-CoV-2 infection on psoriasis course and management. Starting from February 2020, with the pandemic progressively spreading throughout Europe, our understanding of the impact of COVID-19 on psoriasis (and of psoriasis treatment on COVID-19) is rapidly evolving. There are many reasons why COVID can have crucial effects on psoriasis: psoriasis is a chronic disease whose clinical course can be exacerbated by a viral infection. Psoriasis is associated with the metabolic syndrome which can be a risk factor for evolution to a severe form of COVID-19. Patients with severe forms are frequently on immunosuppressive treatment, with potential negative repercussions on the evolution of COVID-19. For all these reasons, psoriatic patients could be considered as frail patients  thereforAll these topics will be considered in the light of the most recent literature data, to provide useful information on a practical level to all dermatologists who manage psoriasis patients daily in this pandemic healthcare context.This systematic review was based on the approach developed by Arksey and O’Malley ,3 that iA brainstorming approach involving the entire research team was used to identify the research questions. The research group included five dermatologists with expertise in psoriasis.At the initial meeting, the research group identified the research question and determined the research strategy. The research question was: “how COVID-19 pandemic can influence clinical expression and management of psoriasis?”We performed a worldwide systematic review of studies reporting on COVID-19 and psoriasis, using three electronic medical databases–PubMed, EMBASE, Web of Science considering articles dated 1 January 2019 through 31 December 2021.The search terms were selected to identify studies describing the relation between COVID-19 and psoriasis.The keywords used were “COVID-19 AND psoriasis”, “COVID-19 AND psoriasis AND biologics”, “COVID-19 AND psoriasis AND systemic treatments”, “SARS-CoV-2 vaccinations AND psoriasis”.All selected databases were searched from their respective inception, without any time interval. In addition, we searched by hand the reference lists of other relevant articles on COVID-19 and psoriasis.In this first phase 298 records were identified from selected database. Records after duplicates removed were 237. Among the selected record, none was marked as ineligible by automation tools. Relevant studies were then selected. This process occurred in three phases. In the first phase, four researchers  independently selected articles based on title. Any disagreements were resolved by consulting a senior researcher (A.O.). In the second phase, abstracts were evaluated. Two members of the research team , independently evaluated each abstract. The research group resolved all discrepancies through unanimous consent. Ninety-five articles were excluded and 142 were evaluated for full-text analysis. Among them 15 manuscripts were not retrieved.The third phase consisted of critical appraisal of the full text of the 127 selected papers. Ultimately, 82 studies were selected for the final qualitative synthesis. To be included into our review, studies had to be focused on COVID-19 course in psoriasis patients, on psoriasis course in patients affected by COVID-19, on effect of vaccines against SARS-CoV-2 infection in psoriasis patients, on systemic treatment strategies in psoriasis patients during pandemic. All included studies had to be published in English, with abstract available. No restrictions on study design were considered, and randomized controlled trial, case-control study, cross-sectional study, and case series were included. Articles were excluded from our review for only three reasons: reason 1 = review article (12 reports had been excluded following this reason), reason 2 = case reports (20 reports had been removed for this reason), reason 3 = reports in languages other than English (13 reports had been neglected for this reason). A data extraction module was designed by A.C before data extraction to accelerate the entire process. To answer the research question, the following information was extracted from the included articles: Author(s) name and publication date; study design; study population; sample size; measured outcomes; study results; and study recommendations.The flowchart of the PRISMA study is shown in Data found have shown that COVID-19 pandemic plays a conditional role in many clinical and therapeutic aspects of psoriasis patients management. Moreover, the increased clinicians experience during pandemic led to gradual changes in the paradigm of patient care.All selected studies are reported in Beyond the evidence that COVID-19 can present with cutaneous involvement, a growing concern about the potential exacerbation of preexisting psoriasis following COVID-19 emerged since the beginning of the pandemic. Viral infections are known to trigger the induction and exacerbation of psoriasis, and several mechanisms have been proposed to explain this process: antigen mimicry, epitope spreading, cytokine imbalance, and amplification of tissue destruction that increases the availability of self-antigens. In addition, SARS-CoV-2 infection is characterized by an overreaction of the immune response that could potentially shift the delicate immune balance in psoriasis .A recent systematic review evaluated presentations, post-infection changes in the manifestation, diagnosis, and management of flare-ups of underlying dermatologic disease in patients with COVID-19. Authors reported nine patients with psoriasis and COVID-19, the flare-ups in five cases were attributed to either hydroxychloroquine or systemic corticosteroids which were initially considered promising treatments for COVID-19, and are well-known causes of drug-induced psoriasis .The exacerbation of psoriasis in two cases could have resulted from the discontinuation of treatments (secukinumab and cyclosporine). In one case the COVID-19 treatment was not mentioned, the exacerbation of psoriasis in only one case could be confidently linked to COVID-19.In the literature, cases of development and exacerbation of pustular psoriasis (PP) during COVID-19 infection have also been reported ,6,7,8. MThus, of all the cases in the literature, only a few can be assumed to have psoriasis induced by SARS-CoV-2 infection. This is not surprising, as viral infections have always been considered possible triggers of psoriasis onset . Some auIn summary, although there are not enough scientific evidence to demonstrate this phenomenon and no studies have been conducted to assess its prevalence, it cannot be ruled out that COVID-19 may exacerbate existing psoriasis, trigger psoriasis de novo, or change the phenotype of the disease . All studies selected for this topic are summarized in Skin has been described as one of the most common involved target organ in SARS-CoV-2 infection ; howeverFirst, Dadras et al. hypothesized a strict connection between psoriasis and COVID-19 disease focusing their attention on the role of angiotensin-converting enzyme (ACE). In humans, ACE2 receptor is widely expressed in the lung, heart, kidney, endothelium and intestine, and also in the basal epidermal layer and sebaceous gland cells in normal skin .It has already been demonstrated that SARS-CoV spike protein has a strong binding affinity to the human ACE2 receptor, and this could explain why skin may be a possible specific target for the SARS-CoV-2, which in fact can be also isolated from skin specimens ,24,25,26Moreover, serum level of ACE is increased among psoriasis patients, and directly correlates with increased risk of cardiovascular comorbidities, including subclinical atherosclerosis . In patients with severe psoriasis  the increased ACE skin activity decreases after UVB treatment . Conversely, the ACE inhibitors administration in patients with personal history of psoriasis may be associated with psoriasis exacerbation .The link between ACE2 receptor and SARS-CoV-2 could result in ACE2 downregulation and in over-production of angiotensin by the ACE enzyme, the opposing physiological homolog of ACE2 . Overall, the overexpression of ACE in COVID-19 patients may aggravate psoriasis favoring also cardiovascular complications, particularly in patients with severe psoriasis . According to Dadras et al., psoriasis patients may be at a higher risk of worsening cardiovascular events in case of COVID-19 infection ,29. ThesPatrick et al.  publishePeople affected by an inflammatory skin disease have increased risk of being infected with SARS-CoV-2. Differently from results of Dadras et al. , having Authors postulated on the existence of different immunological rates of viral response in patients with inflammatory skin diseases, owing to the continuing activation of immunologic system ,33,34,35Finally, more recent studies, focusing on patients with psoriasis receiving oral or biologic treatment conclude that patients with psoriasis show similar rates of infection with SARS-CoV-2 and COVID-19 prognosis as the general population, supporting our initial recommendation ,15,36.The same has been observed for psoriatic arthritis (PsA) ,17,18. Severity of COVID-19 is primarily driven by smoking status, sex , older age, and underlying comorbidities ,21,37,38Moreover, National Psoriasis Foundation guidelines on the management of psoriatic disease during the pandemic (Version 2), confirm that age, male sex, and pre-existing comorbidities are crucial drivers for poor COVID-19 outcome in patients with psoriasis ,39.All retrieved data are reported in SARS-CoV-2 infection can be associated with increased, aberrant, and ineffective host immune response causing the acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) typical of the serious forms of COVID-19 ,59. Five hyperinflammatory cell subtypes leading the inflammatory storm in lung injury, have been identified by Ren et al. : a subtyThese hyper-inflammatory subtypes produce specific cytokines, Macro_c2-CCL3L1, specifically expresses CCL8, CXCL10/11, and interleukin (IL)-6; Mono_c1-CD14-CCL3 expresses high levels of IL-1β, CCL20, CXCL2, CXCL3, CCL3, CCL4, HBEGF, and tumor necrosis factor (TNF); and neutrophils express cytokines including TNFSF13B, CXCL8, FTH1, and CXCL16 .Auto-inflammation driven by T cells, TNF-α, IL-23, and IL-17 underlies the pathogenic pathway of psoriasis . ConventSeveral studies have already shown that psoriatic patients treated with systemic or biological immunosuppressants are exposed to a higher overall infection rate ,63,64,65However, these studies did not consider the risk of virus infection separately  and noneMoreover, recently published data suggest that SARS-CoV1 may be associated with specific and distinct immune activation, unlike other respiratory viruses . For all these reasons it is not appropriate to remark the susceptibility to SARS-CoV-2 in psoriatic patients based on these previous studies, but it is mandatory to understand the specific risk in psoriatic subjects under systemic therapies. Our review summarizes information currently available about the impact of systemic treatments on risk of SARS-CoV-2 infection and severe COVID-19 outcomes in psoriatic patients, according to different systemic drugs. n = 9) and those not using biologics (n = 14) [Piaserico et al.  in a coh(n = 14) .TNF alpha inhibitors are the cornerstone in the treatment of psoriasis with biologics . As increased serum levels of TNF alpha have been detected in many patients with severe COVID-19 compared to subjects with mild disease, the use of TNF-α inhibitors was proposed at the beginning of the outbreak with therapeutic purpose against COVID-19 ,70. n = 1943), with those treated by methotrexate (n = 1929), ustekinumab (n = 348), and acitretin (n = 1892) concerning all previously mentioned COVID-19 outcomes. The risk of COVID-19 infection was comparable among subjects treated with TNF alpha inhibitors vs. methotrexate, ustekinumab, and acitretin. Exposure to TNF alpha inhibitors reduced the risk of COVID-19-associated hospitalization compared to methotrexate and ustekinumab, but not with acitretin. Although TNF alpha inhibitors were associated with a decreased risk of COVID-19-related hospitalizations, no significant difference in COVID-19-associated mortality was observed among the treatment groups. These results support the maintenance of TNF alpha inhibitors treatment throughout the pandemic. Patients with moderate to severe psoriasis who require systemic treatment during the pandemic can safely resort to TNF alpha inhibitors [Recently, Kridin et al. conducted a population-based cohort study in Israel to evaluate the risk of COVID-19 infection, COVID-19-associated hospitalization, and mortality among patients with psoriasis treated by TNF alpha inhibitors compared with psoriatic patients receiving other systemic agents; in detail, psoriatic patients under treatment with TNF alpha inhibitors  experienced upper respiratory tract infection; three patients (5.3%) had contact with SARS-CoV-2- infected subjects; and none among them developed SARS-CoV-2 disease . SeveralCyclosporine (CsA) is capable of inhibiting several viruses, including two very life-threatening viruses such as severe acute respiratory syndrome virus (SARS-CoV) and Middle Eastern respiratory syndrome coronavirus (MERS-CoV) . For thiDi Lernia and colleagues assessed the risk of contracting the COVID-19 infection and its severity in a group of 114 adult patients with psoriasis treated with CsA. Neither COVID-related deaths nor hospitalizations for COVID-19-related interstitial pneumonia have been reported in this study. Two psoriatic patients reported mild respiratory symptoms, with no need for hospital admission. In these cases, a preventive suspension of CsA was proposed at the onset of symptoms until their complete remission and after the fever had disappeared for at least a week . AlthougConsistent data on the safety profile of methotrexate (MTX) in psoriasis during the pandemic are still lacking. However, data from the literature demonstrate that the overall frequency of contracting pneumonia in patients with psoriasis using methotrexate is 0.8% .The use of methotrexate has in some rare cases been associated with more severe episodes of COVID-19. One case-control study on psoriasis reported an increased hospitalization risk independently associated with its use . In another study including 104 psoriasis patients, no significant difference in COVID-19 severity between the 13 COVID-19 patients treated with methotrexate (10–22.5 mg/week) and the psoriasis patients who did not receive any systemic treatment was found . A retroHowever, one study demonstrated that MTX use in psoriasis patients has been associated with an increased hospitalization risk from COVID-19, without increased mortality . As the impact of MTX on COVID-19 infection is still not clear, despite MTX is one of the most used immunosuppressive agent for psoriasis, studies focusing on MTX on SARS-CoV-2 infection or COVID-19 evolution in patients with psoriasis under treatment are warranted and needed.Apremilast is a phosphodiesterase-4 inhibitor that has been authorized by the FDA for the treatment of psoriasis. It affects the function of innate and adaptive immune systems by increasing intracellular cyclic adenosine monophosphate levels . At the A 45-year-old man with erythrodermic psoriasis who was using Apremilast 30 mg twice daily and prednisone 12.5 mg daily was recently reported to have gotten SARS-CoV-2 pneumonia. He continued to use Apremilast and recovered after six days of therapy with lopinavir/ritonavir 400/100 mg twice daily and intravenous ceftriaxone 2 g/day .As a result, people on Apremilast may be less prone to acquire a dangerous type of COVID-19 infection.Retrieved studies are reported in Following SARS-CoV-2 vaccine delivery, a variety of cutaneous adverse effects have been recorded, including early or delayed site injection responses, maculopapular rash, erythema multiforme, perniones, and urticaria . Along wSotiriou et al. described 14 episodes of aggravation of psoriasis following COVID-19 immunization. Nine of them had a minor untreated history during the past year. Five patients were receiving topical therapy , and the disease was well controlled. Exacerbation of psoriasis occurred in all patients shortly after vaccination with no difference in timing  or severity between the vaccinations employed (50% mRNA technology vaccines and 50% adenovirus vaccine). Following immunization, five cases of psoriasis flare were treated with topical calcipotriol/betamethasone and nine cases with systemic drugs or phototherapy . PsoriasFollowing that, Megna et al. documented 11 occurrences of psoriasis aggravation  following COVID-19 immunization with Pfizer mRNABNT162b2, Moderna mRNA-1273, or AstraZeneca-Oxford AZD1222 from February to July 2021, in contrast to Sotiriou. Contrary to Sotiriou et al., 54.5% of psoriasis flares associated with the COVID-19 vaccination occurred in individuals receiving biologic therapy. To control flares in these patients, topical calcipotriol/betamethasone and/or phototherapy were added to existing biologic therapy in four cases, while switching biologic agents was essential in the other two cases .Musumeci et al. conducted a survey to determine the safety of SARS-CoV-2 vaccinations in patients with psoriasis who were receiving biologic therapy. Over a three-month period, 150 patients with stable plaque psoriasis who had been treated with biologics for at least two months were examined. Fifty patients  received just the first and second doses of SARS-CoV-2 vaccination. All patients were instructed to abstain from biological agents for ten days prior to and ten days following each dose of vaccination. A total of 24 patients received anti-TNF therapy, 14 got anti-IL17, 7 underwent anti-IL12-23 treatment, and 5 received anti-IL23. Following vaccination, all patients were examined for local and/or systemic side effects and/or potential adverse drug responses to SARS-CoV-2 vaccinations on days 2, 7, and 14. There were no adverse effects or psoriatic flares in any of the individuals. Only one patient treated with an infliximab biosimilar was referred to for psoriasis aggravation following vaccination. The remaining 100 patients stated they had not received the immunization as of yet .Bostan et al. described two episodes of aggravation of plaque psoriasis following administration of COVID-19 vaccines inactivated and BNT162b2 mRNA. One instance occurred one month after the second dose of vaccination was administered , and another happened after the first dosage was administered , with extensive plaque expansion two weeks following the second dose of vaccine. Both individuals did not get systemic psoriasis therapy .Onsun et al. described the beginning of generalized pustular psoriasis four days after receiving the first dose of the inactivated SARS-CoV-2 vaccine  in a 72-year-old man who had previously been treated with topicals .Lehhman et al. described a case of new-onset guttate psoriasis in a 79-year-old female following the BNT162b2 mRNA vaccination. The rash began 10 days after the first dosage and flared up following the second treatment. Topical calcipotriol/betamethasone ointment and UVB phototherapy have been used to treat flares .Krajewski et al. described an aggravation of plaque psoriasis in a patient who had previously obtained full remission following deucravacitinib treatment during a clinical study. Five days after receiving the second dose of BNT162b2 mRNA SARS-CoV-2 vaccination, the patient developed psoriasis .However, Kadali et al. observed that, in a group of 131 individuals with psoriatic arthritis, the PASI value remained constant in the majority of cases following immunization .The international scientific community’s worry regarding vaccine hesitancy (apprehension about receiving a vaccination) and vaccine resistance  is growing as new variants of SARS-CoV-2 continue to develop.At the present, a significant task in avoiding this phenomenon is to strengthen the vaccination campaign, with the goal of covering the greatest number of people possible in the face of growing disinformation. Dermatologists who are directly involved in assisting patients with moderate to severe psoriasis with immunosuppressive or immunomodulatory medications should be regarded active participants in this chess game.Patients with moderate to severe psoriasis, particularly those on biologics, should be regarded vulnerable and at a high risk of developing severe forms of COVID, and hence should adhere to the vaccine campaign completely. However, these patients’ perceptions of being at high risk vary, and this should be viewed as a significant potential hazard for individuals who underestimate the crucial importance of vaccination in preventing evocation of a serious form of COVID-19.The levers for increasing vaccination compliance and tactics for avoiding vaccine resistance might be numerous and interconnected. To begin, dermatologists should raise awareness among patients with moderate to severe psoriasis that they are at an increased risk of developing a severe form of COVID-19, as compared to the general population matched for other well-known risk factors .Dermatologists should discuss vaccination adverse events with their patients, reminding them that these effects are reversible and investigating ways to manage and reduce them. They should avoid using so-called “crisis language” while presenting the mechanism of action of vaccinations to minimize selfish or competitive behaviors and to prevent undermining people’s sense of social support and caring ,96. By cTrust in presently available vaccinations should be created and strengthened by open communication that focuses on key points such as “what is known”, “what is unknown”, and most importantly, “what efforts are being made to learn more”. Generally, the pandemic has endangered temporal, geographical, and normative security. Additionally, SARS-CoV-2 vaccines have been approved by the European Medicines Agency for emergency use in Europe and are currently undergoing post-marketing surveillance. In this setting, as data on the effectiveness and safety of vaccinations continue to accumulate and are swiftly recorded and shared, vaccination strategies must be adjusted to specific circumstances and new issues. To ensure that these issues are easily accessible to patients, strategic involvement with patient associations may be necessary.National psoriasis patient associations could alleviate negative pressure on both hesitant and opposed patients by demonstrating that their voices are heard and that their perspectives are considered not only by clinicians, but also by other decision-makers involved in vaccination campaigns, thereby increasing trust in vaccination ,98.Additional steps to be taken include anticipating and managing disinformation. The WHO acknowledged the presence of a parallel “infodemic” to the pandemic. The term “infodemic” refers to the abundance of information available, which can make it difficult to determine whether sources are trustworthy .Pre- and post-debunking strategies  are critical, as misinformation concerning this subject is increasing .The outbreak of the SARS-CoV-2 pandemic has promoted the use of telemedicine, so dermatologists have been encouraged to use it in an outpatient setting.Among dermatological patients, those with chronic, plaque type, and stable disease on systemic/topical maintenance therapy may be considered as ideal candidates for telemedicine, and several authors have demonstrated both the effectiveness and feasibility of this care approach ,101,102.Preference for telemedicine among psoriasis patients has been investigated by Gisondi et al. who investigated the preference for telemedicine over in-person visit among psoriasis patients receiving biologics and the reasons behind their preferences.A positive attitude toward telemedicine was found in almost half of the patients affected by psoriasis in maintenance therapy with biological drugs .Main reasons for preferring telemedicine were saving time, feasibility, and safety issues related to the COVID-19 pandemic.The preference for telemedicine was found to correlate directly with the age of the patients, with disease benignity, and grade of severity .The remaining half part of the patients preferred the in-person visit owing to the need of directly interacting with the clinicians without any “technological barriers”. However, providing patients with training related to “telecommunication” technologies might increase patients’ adherence to telemedicine.The most limiting barriers associated with telemedicine have been identified as follows: recruitment of technically skilled staff; resistance to change; costs for technical equipment; implementation of simple procedures to obtain reimbursement of visits; attitude of patients to use technology daily depending on age, educational level, and personal predisposition; written and verbal communication impairment ,106.A strength point connected to the use of teledermatology for the assistance of psoriasis patients is the reduction of indirect costs related to health care and the opportunity of offering assistance to patients unable to reach the care centers for fragility, geographical reasons, difficulty in moving.Considering all the opportunity and limitations, data from literature highlight teledermatology as an effective tool to counter limitations during COVID-19 pandemic, they also recommend the need to continuously examine our operative models to understand patient preferences, overcome practice-driven barriers, and ensure the sound allocation of limited health care resources .In the context of the current COVID-19 pandemic, physicians treating patients with psoriasis are tasked with challenging decisions when initiating immunosuppressive therapy or altering the existing regimens for their patients. Moreover, they must be ready to understand the needs of patients undergoing vaccination and be aware of the reciprocal effects of psoriasis and SARS-CoV-2 infection.-Most of the existing evidence is based on spontaneous case series, and although data from literature globally indicate no significant increase of the risk for severe COVID-19 evolution in psoriasis patients, it is hard to evaluate which biological agent is safer for COVID-19. However, from the current unclassified research, biologics do not seem to have a significant impact on the COVID-19 course. Regardless of which biological agents have been used, patients in biologics treatment seem to be not at higher risk for severe COVID complications.-According to the recommendations of the major global dermatological associations ,109,110,-For all candidates undergoing biological treatment, it is advisable to carefully assess the balance between benefits and risks of treatment for each patient.-The National Psoriasis Foundation COVID-19 Task Force, in the last version of guidance for the management of psoriatic disease during the pandemic has reported that patients not infected with SARS-CoV-2 should continue biologics for psoriasis in most cases. Shared decision-making process between clinician and patient is recommended to guide discussions about the use of systemic therapies during the pandemic .Relationships between COVID and psoriasis can be synthesized as follows:-Conversely, as the impact of MTX or CsA on COVID-19 infection is still to be cleared, despite they are commonly used immunosuppressive agent for psoriasis, studies focusing on these drugs on SARS-CoV-2 infection or COVID-19 evolution in psoriasis patients under treatment are few and inconclusive. Further research in this field is warranted and needed, before giving specific recommendation on continuation of their use in psoriatic patients affected by COVID-19.-Although psoriatic patients have no increased risk of evolving toward severe forms of COVID-19 compared to the general population, they are frail subjects with respect to SARS-COV-2 infection which can favor the release of psoriasis clinically in remission, or favor its onset in predisposed patients or condition the appearance of different psoriasis phenotypes .-Vaccination still represents the most effective measure to prevent the development of serious form of COVID-19 in psoriasis patients who should be advised to be vaccinated without discontinuing their biological treatment. In case the patient is starting a biological treatment, he should be vaccinated in advance, as current evidence suggests that the use of immunosuppressive agents may reduce the vaccine immune response to a certain extent .-Dermatologists should be aware that vaccination of psoriasis patients is mandatory. They should consider the opportunity to be prompted to manage vaccination hesitancy in all patients, reassuring patients, with a clear and communicative language and informing them about the risks associated with vaccination, which are low in terms of the risk-benefit ratio .-Although from the beginning of the pandemic, more and more information has been collected, and dermatologists globally improved their knowledge on managing psoriasis patients, the current evidence has still certain limitations. Therefore, it is necessary to be cautious when making clinical decisions. More prospective studies with higher levels of evidence are needed to support clinical decision-making.Scientific dermatological associations recommend that psoriasis patients with asymptomatic SARS-CoV-2 infection and at low risk for severe COVID-19 evolution  should continue their biological therapy. For high-risk patients , the decision of discontinuing the treatment should be made case on case, through the balancing of benefits and risks, and the risk of disease relapse and retreatment failure should be taken into consideration too . Similar


Since countries commenced COVID-19 vaccination around the world, many vaccine-related adverse effects have been reported. Among them, short-term memory loss with autoimmune encephalitis (AE) was reported as a rare adverse effect. Since case numbers are limited, this brief report may draw the attention of the medical community to this uncommon adverse effect and serve as a reference for future vaccine improvement. However, given the high risk of adverse outcomes when infected with SARS-CoV-2 and the clearly favorable safety/tolerability profile of existing vaccines, vaccination is still recommended. Coronavirus disease 2019 (COVID-19) is a new public health crisis affecting populations worldwide. Since the outbreak of COVID-19 in late December 2019, more than 539.8 million cases and more than 6.3 million deaths have been reported worldwide . ImmunizSince large-scale global vaccination began, different adverse effects and complications have been reported. Although important post-immunization surveillance of vaccines is ongoing, SARS-CoV-2 vaccines are currently considered highly effective and safe, even with neurological adverse events following immunization (AEFI) . These tThis is a new issue related to the COVID-19 pandemic and, in this paper, we explore autoimmune enthesopathy on COVID-19 vaccination. Although cases are rare, we searched for published articles that mention and discuss the issue of AE. To determine the mechanism of AE caused by COVID-19 vaccination, further study is needed.A literature review was performed on studies up to 25 June 2022 by searching in the electronic databases PubMed and Web of Science. We used the following search strings: “COVID-19 vaccination” with “forgetfulness or memory impairment or anterograde amnesia or transient amnesia or memory lose”. Variations of these terms were also searched. We also used the “related articles” option on the PubMed Web search homepage as well as manually searching through references listed in retrieved articles. Articles were limited to those with titles and abstracts available in English published in peer-reviewed journals. After deduplication, the identified full-text articles were examined for original data, and we also retrieved and checked for related references for further studies. Articles with the following criteria were included: (1) full-text articles that can be obtained from electronic databases; (2) patients enrolled in the studies were all laboratory confirmed for COVID-19 vaccination; and (3) articles included case reports.From 2019 to the present, the rapid spread of COVID-19 has resulted in a global pandemic for which a vaccine was quickly developed. As the safety of COVID-19 vaccines continues to be monitored, cases of autoimmune encephalitis following vaccination with short-term memory loss have been reported. Short-term memory loss is a clinical syndrome characterized by the sudden onset of anterograde amnesia with autoimmune disorders, which are characterized by inflammation. Patients may develop cognitive impairment, which is referred to as autoimmune dementia. Autoimmunity can be caused by the following processes in patients: (1) molecular mimicry between infectious antigens and self-antigens, (2) the acceleration of the autoimmune process by antigen-presenting cells and antigens induced by foreign antigens, and (3) increased cytokine production and induced autoreactive T-cell expansion by B lymphocytes or bystander activation [The long-term sequelae of SARS-CoV-2 infection are being increasingly recognized. These include cardiovascular disease, chronic lung disease, and proinflammatory-related neurological dysfunction that may lead to neurocognitive and psychological impairments. A major component of cognitive impairment is operationally classified as “brain fog”, which includes forgetfulness, difficulty concentrating, depression, fatigue and confusion. Short-term memory loss caused by autoimmunity after vaccination is somewhat like “vaccine brain fog” but the symptoms subside faster and the impact is smaller.In this study, the literature search commenced in 2021, and the last day of the search was 24 June 2022. Generally, vaccination elicits strong proinflammatory cytokine expression and the response of T cells ,21. The It is worth noting that in the early stage of adverse reactions on COVID-19 vaccination, patients’ MRIs were normal. Cerebral fissures, cerebral cisterns and sulci were normal in appearance, without mid-line structure deviation and evidence of intracranial hemorrhage. In addition to memory loss, more attention should be paid to autoimmune encephalitis cases, which were characterized by onset of symptoms of encephalitis within 7 to 30 days, followed by recurrent seizures and progressive cognitive decline over a 4-week period after COVID-19 vaccination. Lymphocytic pleocytosis, elevated protein and glucose levels were also found on CSF examination ,13. As aAlthough the adverse effect of transient amnesia is uncommon after COVID-19 vaccination, these reports all showed unexpected onset of autoimmune encephalitis. These cases describe hyperactive acute encephalopathy following vaccination. Antiphospholipid syndrome may be associated with viral infections or vaccinations, including COVID-19 vaccine ,30,31,32Neurological adverse effects have been reported in various SARS-CoV-2 vaccinations. Previous studies regarded the neurological disorder of memory loss and clinical diagnostics in patients after COVID-19 vaccination. Most patients presented with amnesia and other disorders that were diagnosed post-vaccinal encephalitis by imaging modalities or laboratory surveillance. In such cases, there was no definitive evidence to support the relationship between the COVID-19 vaccine and short-term memory loss with autoimmune encephalitis. Despite this, there are recognized rare adverse events that have been causally linked to SARS-CoV-2 vaccines; it might be useful to point out more than with the currently available data to address the relationship between the COVID-19 vaccine and short-term memory loss with autoimmune encephalitis. However, the current advice is that the benefits of the vaccination outweigh the risk. This appears to be accurate from a neurological standpoint. Currently, population worldwide are receiving COVID-19 booster doses. We believe that this may resulting in an increasing number of cases and more articles to determine the mechanism of AE caused by COVID-19 vaccination. Although our study could not provide and establish a possible causality of encephalitis by COVID-19 vaccination, further study is needed in the future.Since billions of people worldwide have been vaccinated, some cases of neurological conditions may occur post-vaccination simply by chance. Such cases included in our report should increase awareness of possible rare autoimmune reactions following this novel vaccination. In summary, short-term memory loss with autoimmune encephalitis is rare and its causes are still mostly unknown and are only now being determined. Autoimmune encephalitis is an under-recognized condition and has a favorable prognosis if treated promptly. Furthermore, we still believe that the benefits of COVID-19 vaccination outweigh the risks of ongoing vaccination programs.


To assess whether fear of coronavirus disease 2019 (COVID-19) is associated with depression, anxiety, and psychosis and to evaluate if these variables are correlated with the interaction between spirituality and fear of COVID-19.Between September and November 2020, this cross-sectional study enrolled 118 chronic schizophrenia patients. The interview with patients included Fear of COVID-19 Scale, Lebanese Anxiety Scale-10, Montgomery-Asberg Depression Rating Scale, Positive and Negative Syndrome Scale (PANSS), and Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being-12. The results were analyzed by using linear regressions (Enter method), with anxiety, depression, total PANSS score, positive PANSS, negative PANSS, and general psychopathology PANSS subscales as dependent variables. Spirituality, fear of COVID-19, and the interaction of spirituality with fear of COVID-19 were independents variables.P = 0.030). Higher spirituality was significantly associated with lower anxiety , lower depression , lower total PANSS score , lower negative PANSS score , and lower general psychopathology PANSS score . In patients with high fear of COVID-19, having low spirituality was significantly associated with higher anxiety, depression, and psychotic symptoms.Fear of COVID-19 was positively correlated with increased total PANSS scores (Beta = 0.90, This study suggests a positive correlation between fear of COVID-19 and higher psychosis among inpatients with schizophrenia. The interaction of spirituality with fear of COVID-19 was correlated with reduced anxiety, depression, and psychosis. The impact of the SARS-CoV-2 on the central nervous system and the associated neuropsychiatric consequences have not been widely studied. Various types of neuropsychiatric symptoms can emerge during or after an acute infection with a respiratory virus -5.An effect of having a psychiatric condition on the vulnerability to coronavirus disease 2019 (COVID-19) has also been reported. Patients who already had a psychiatric disorder had 65% higher incidence of COVID-19 -IV . SpirituThis cross-sectional study was performed between September and November 2020. The inclusion criteria were chronic schizophrenia, age above 18 years, and hospital stay for more than one year in Psychiatric Hospital of the Cross, Jal el Dib, Lebanon. Schizophrenia was diagnosed by a clinician according to the DSM-5. The exclusion criteria were clinical conditions preventing the patients from participating in the interviews (at the physician's discretion), schizoaffective disorder (based on the DSM-5 criteria), cognitive impairment , delusional disorder (patients unable to answer correctly), and refusal to answer the questions . The finThe study was approved by Psychiatric Hospital of the Cross Ethics and Research Committee and it complied with the Hospital's Regulatory Research Protocol. A written informed consent was obtained from each patient.The questionnaire was in Arabic, with the response time from 30 to 45 minutes. The data were collected by a trained person through a personal interview. The first section of the questionnaire inquired about socio-demographic variables. The second section included questions inquired about medical history and medications used.Fear of COVID-19 was assessed with the seven-item Fear of COVID-19 Scale (FCV-19S). In this scale, the questions are graded from one to five, with higher scores indicating more fear of COVID-19 . The CroAnxiety level was assessed with the 10-item Lebanese Anxiety Scale-10 (LAS-10). It is a scale measuring the severity of anxiety symptoms among Lebanese adults  and adolDepression level was assessed with the Montgomery-Asberg Depression Rating Scale (MADRS). The 10-item scale, with each item presenting a group of symptoms , is an iSpiritual well-being was assessed with the self-rated, 12-item Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being-12 (FACIT-SP12). All items in this scale are graded from zero to four according to their occurrence during the previous seven days. The responses are summed up to create a total FACIT-SP-12 score. Higher scores reflect higher spiritual well-being . The CroPositive and negative symptoms of psychotic disorder were evaluated with the 30-item Positive and Negative Syndrome Scale (PANSS) . The AraUsing the G-power version 3.1.9.4 software, we calculated a minimum required sample of 82 participants, according to a hypothetical correlation effect size  of 0.3, an alpha error of 5%, and a power of 80%.Cronbach’s alpha values were calculated for all the scales and subscales. Missing data were not replaced as they represented less than 5% of the database. The normality of distribution of depression, anxiety, and PANSS total scale and subscale scores was confirmed by visual inspection of the histogram and calculation of the skewness and kurtosis. Values for skewness and kurtosis between -2 and +2 indicated normal univariate distribution . The nort test or ANOVA, respectively. The correlation was assessed with a Pearson correlation test. Six linear regressions were conducted by using the Enter method with the following dependent variables: anxiety, depression, total PANSS score, positive PANSS, negative PANSS, general psychopathology PANSS subscales. Two models were used. In the first model, the independent variables were spirituality and fear of COVID-19 scales. In the second model , the interaction between spirituality and fear of COVID-19 was added. The variables showing a significant P value in the bivariate analysis were entered as adjusted variables. P < 0.05 was considered significant. Statistical data analysis was performed with the SPSS version 25 .Differences between two or three groups were assessed with a The average age was 51.78 ± 14.61 years . There wP < 0.001). Respondents with intermediate education level had higher anxiety compared with respondents with other education levels. Fear of COVID-19 was significantly positively correlated with anxiety , whereas spirituality was inversely correlated with anxiety .Married participants had higher anxiety compared with single patients  and respondents living in rural areas had higher depression than those living in urban areas . Spirituality was significantly inversely correlated with depression . Married respondents compared with single respondents, respondents living in rural areas compared with those living in urban areas, and respondents who had an elementary education level compared with respondents with other educational levels had significantly higher mean total PANSS, negative PANSS, and general psychopathology PANSS scores. Spirituality was significantly inversely correlated with total, positive, negative, and general psychopathology PANSS scores. However, fear of COVID-19 was significantly positively correlated with total PANSS scale and subscales scores.Married patients had significantly higher depression compared with single respondents ; however anxiety was not associated with fear of COVID-19 (2 = 42%) than the model 1 (R2 = 39%); in patients with high fear of COVID-19, having low spirituality was significantly associated with higher anxiety ; however, depression was not associated with fear of COVID-19 (2 = 33.0%) than model 1 (R2 = 30%); in patients with high fear of COVID-19, having low spirituality was significantly associated with higher depression  (P = 0.03). The model to which the interaction between fear of COVID-19 and spirituality was added explained the variation in the total PANSS score better (R2 = 49%) than model 1 (R2 = 44%); in patients with high fear of COVID-19, having low spirituality was significantly associated with a higher total PANSS score  . IncreasSS score .P = 0.010).No significant association was found between positive PANSS subscale, spirituality, and fear of COVID-19 . The modP = 0.01); however negative PANSS was not significantly associated with fear of COVID-19 (2 = 46%) than model 1 (R2 = 43%); the interaction between spirituality and fear of COVID-19 was significantly associated with lower negative PANSS score .Lower negative PANSS score was significantly associated with higher spirituality . Increased general psychopathology PANSS score was significantly associated with higher fear of COVID-19  (2 = 52%) than model 1 (R2 = 47%); the interaction between spirituality and fear of COVID-19 was significantly associated with lower general psychopathology PANSS score .Lower general psychopathology PANSS score was significantly associated with higher spirituality  . The modThis study highlighted that spiritual beliefs in patients with schizophrenia directly affected representations of illness and psychopathology. Spirituality was significantly inversely correlated with depression, anxiety, and psychosis. In patients with high fear of COVID-19, having low spirituality was significantly associated with higher depression, anxiety, and psychosis.In line with recent studies ,37, our The inverse correlation of spirituality and depression observed in this study agrees with the results of previous studies ,18. In aIn addition, fear of COVID-19 positively correlated with increased total and general psychopathology PANSS scores. This was expected since previous studies confirmed an association between SARS-CoV-2 and psychosis ,39. ManyIn our study, spirituality was inversely correlated with total PANSS scores, which agrees with previous findings . In agreThere is a need to further evaluate the link between spiritual beliefs and symptoms of schizophrenia. A proper definition of spirituality in nursing mental health care practice and training will help nurses respond to patients’ mental and spiritual needs. This can help in the treatment of psychotic symptoms and pathological distortions related to spirituality. Specifically, during stressful conditions such as the COVID-19 pandemic and the economic and political crisis in Lebanon, clinicians should be more aware of the importance of spirituality in patient care procedures.This study is subject to several limitations. First, the cross-sectional design prevents us from identifying causal relationships. Furthermore, the COVID-19 pandemic and related restrictions limited us from collecting data from all patients with schizophrenia admitted to the hospital; the sample size was relatively small although enough statistical power was reached for the bivariate and multivariable analyses. The Arabic versions of FACIT-SP12 and FCV-19 have not been previously validated in Lebanon. In addition, patients were chosen from a single hospital, which predisposes the study to selection bias. As patients may have overestimated or underestimated some questions, an information bias might also have been present. Because not all factors correlated with depression, anxiety, and psychosis were included in the questionnaire, such as treatment duration or treatment type, a residual confounding bias is expected. However, our study was the first to assess fear of COVID-19 and its association with psychopathology among patients with schizophrenia using different validated scales . It was also the first to evaluate the interaction between fear of COVID-19 and spirituality among inpatients with schizophrenia.Research is warranted to evaluate the effect of including spiritual therapy in the treatment of patients with schizophrenia. A challenge remains for clinicians to find a strategy how to encourage patients' spiritual behavior as part of patients' treatment.


Malignant melanoma is one of the most common cancers in the world. In the disease’s early stages, treatment involves surgery, in advanced stages however, treatment options were once scarce. There has been a paradigm shift in advanced melanoma treatment with the introduction of immunotherapy and targeted therapies. Understanding the molecular pathways and their pathologic counterparts helped identifying specific biomarkers that lead to the development of specific targeted therapies. In this review we briefly present some of these markers and their relevance to melanoma treatment. Malignant melanoma is one of the most common cancers in the world, ranking fifth for the highest number of estimated new cases in 2022 according to Cancer Statistics Cases . In the Many patients, however, develop either primary or even secondary resistance to current systemic treatment options. Resistance is due to multiple complex mechanisms driven by a set of rewiring processes that involve cancer metabolism, epigenetics, gene expression and interactions in the tumour microenvironment.There are several molecular pathways that, when unregulated, may become pathological and influence the onset, proliferation and invasion of melanoma. The Mitogen-activated Protein Kinase (MAPK) pathway, where serine/threonine-protein kinase BRAF (BRAF) is involved ;The phosphatidylinositol-3-kinases (PI3K)-AKT pathway ;The gene suppressor Cyclin-Dependent Kinase Inhibitor 2A (CDKN2A) and tumour suppressors pathway ;The microphthalmia-associated transcription factor (MITF) pathway ;The nuclear factor-kappa B (NFκB) pathway .The five main pathways are: .Understanding these molecular pathways and their pathologic counterparts helps identify specific biomarkers that lead to the development of specific targeted therapiesWe briefly review some of these markers and their relevance to melanoma treatment.The classical prognostic markers regarded as the “Gold Standard” for melanoma treatment are histological: Breslow thickness, Clark level ulceration and mitotic rate . By utilSpecific mutations may correlate with sun exposure. BRAF mutation expression, for example, is associated with intermittent skin solar exposure . Other oBased on this understanding, in 2018 the WHO proposed a more comprehensive classification for melanoma  that incType I Superficial spreading melanoma with low cumulative sun damage (CSD);Type II Lentigo maligna melanoma;Type III desmoplastic melanoma;Type IV Spitz melanoma;Type V Acral melanoma-related with high CSD;Type VI Mucosal melanoma;Type VII Melanoma in congenital nevus;Type VIII Melanoma in blue nevus;Type IX uveal melanoma, with low or non-CSD.Each category has a specific set of key molecular genes with particular gene mutation amplification or rearrangement of the RNA sequencing.This classification consists of nine categories based on sun exposure:It is well known that the presence or absence of estrogen and progesterone receptors and the HER2 protein are used in the basic classification of breast cancer and for predicting treatment and prognosis . In contHerein we present select molecules involved in melanoma cell transformation, invasion and metastasis, followed by the suggested role of these molecules in determining patient prognosis.The BRAF gene is a proto-oncogene that belongs to the signal transduction protein kinases and affects cell proliferation, differentiation and migration. Mutations in this gene have been found in several cancer types, while its association with malignant melanoma is one of the most studied. Oncogenic mutations in BRAF are found in approximately 40–60% of patients with cutaneous melanoma  and actiAnalysis of BRAF mutation status is already standard procedure in diagnosing melanoma. A large meta-analysis  showed pThough most patients have homogeneous BRAF, heterogeneity has been established; however, its impact on therapeutic response to BRAF/MEK inhibitors or on patient survival has not been elucidated .The NRAS gene encodes the NRAS protein, which is involved primarily in regulating cell division. Similar to the BRAF gene, the NRAS gene is a proto-oncogene, for which gene mutation may contribute to cancer formation in humans. The NRAS mutation is found in 15–20% of melanomas tested  and is aThe c-KIT gene is another proto-oncogene; it directs the formation of transmembrane Recetyrosine kinase. KIT signalling plays a role in cell survival, proliferation and differentiation. KIT mutations are identified in 3% of all melanomas, specifically in about 35% of acral and mucosal melanomas . MutatioThe NF1 gene encodes for neurofibromin, which is one of the primary negative regulatory factors of the RAS protein through GTPase activity. NF1 is a tumour suppressor gene. Mutations in this gene lead to a common genetic syndrome characterised by café-au-lait macules, neurofibromas and more. Individuals with NF1 mutations have an increased risk of developing desmoplastic melanoma . NF1-mutThe prognosis of all patients with NF1-mutated melanoma has been reported to be significantly worse than patients with other mutation patterns .PMCA4 is an enzyme encoded by the AATP2B4 gene in humans . This enIn the context of melanoma, pre-clinical investigations have demonstrated that the plasma membrane calcium ATPase PMCA4 inhibits the migration and metastatic activity of BRAF-mutant melanoma cells . TherefoA recently published study  analysedBefore the introduction of checkpoint inhibitors in 2011, the median overall survival (OS) of patients with disseminated melanoma was about nine months. According to current data, the median OS is more than two years . ImmunotWith an arsenal of proven efficient treatments, it is now time to take a step forward and offer each patient the treatment he/she needs according to the specific disease profile. The main biologically targeted treatment given today is a combination of BRAF and MEK inhibitors, with the main immunotherapy treatment being anti-PD1/CTLA-4. We review recent studies showing the effects of these treatments based on the molecular profile of melanoma.As previously mentioned, the BRAF mutation is found in approximately 40–60% of melanomas. For patients with non-resectable, metastatic, BRAF-mutant melanomas, BRAF/MEK inhibitor treatment can prolong progression-free survival and overall survival . The comThe NRAS-mutant melanoma is refractory to BRAF inhibitors ; still, Data are lacking for c-KIT mutations since the mutation pathways are different and the potential for significant efficacy is low.p = 0.0095) [PD1-inhibitor monotherapy has already been proven as an efficient treatment for unresectable melanoma  and as a 0.0095) .The effectiveness of anti-PD1/CTLA-4 for BRAF-mutant melanoma patients is similar to that of other subtypes of melanoma, even though immunotherapy is not targeted for specific mutations. Immunotherapy appears to have a comparable or even greater effect in NRAS-mutant melanoma patients compared to other subtypes .Anti-PD1 efficiency was proven in NF1-mutated melanoma patients, with a better median OS observed in mutated tumours as compared to the wild type .Oncological treatment strategies are moving toward targeted therapy based on the grouping of tumour subtypes, and in the near future, grouping will be on an individual basis.Currently, data are lacking regarding individual genome-adapted therapy; however, the impressive outcomes of targeted therapy have accelerated discoveries in the field. While treatments are not based on individuals, patients grouped together based on tumour mutation type may be offered different treatment options. In addition to mutation type, patient gender is also considered in groupings, as this is an important prognostic factor in melanoma and affects treatment choice . Moving Female patents have a survival advantage in the case of melanoma, regardless of other tumour characteristics such as Breslow thickness or ulceration . This leSix hundred and thirty-five biomarkers are associated with malignant melanoma . There aTargeted therapy for c-KIT-mutated melanoma: The c-KIT gene mutation has been observed in gastrointestinal stromal tumours. Imatinib blocks the receptor tyrosine kinase activity of c-KIT and is a first-line therapy for gastrointestinal stromal tumours (GIST) [s (GIST) . Inhibits (GIST) ,57,58. IMEK inhibitors for NF1-mutation melanoma: Although NF1-mutant melanoma patients do not usually express NRAS or BRAF mutations, inhibition of the BRAF, MEK and mTOR pathways may be therapeutic since the NF1 mutation increases RAS/MAPK pathway signalling [gnalling . The gregnalling ,60. Althgnalling . ImmunotThe field of targeted therapy is continuously evolving, with existing agents being investigated for new combinations and indications. Immunotherapy is also making continuous progress, and new standards of treatment are determined frequently.Immunotherapy as a neoadjuvant therapy: Currently there are no standardized neo-adjuvant treatment regimens; however, there are several trials showing good pathological response rates, ranging from 50–80%, including OpACIN-neo studies and the PRADO trial, which are both phase II studies. These trials have confirmed the safety and high pathologic response rate (approximately 60%) of neoadjuvant Ipilimumab and Nivolumab. Patients with resectable BRAF-mutant stage III melanoma who received concurrent treatment with Dabrafenib+Trametinib+Pembrolizumab triple combination therapy in a new phase II trial had a high pathological response rate (80%) and a pathological complete response of 50% [e of 50% . Adjuvant therapy: Anti-PD-1 monotherapy is an adjuvant treatment option for stage III melanoma and stage IV resectable patients. Standardized treatment options include adjuvant nivolumab treatment, which has shown significantly longer relapse-free survival (RFS) than adjuvant Ipilimumab in patients with resected stage IIIB, IIIC and IV resectable melanoma. In the KEYNOTE-054 study [54 study  assessin54 study  trial of54 study , patientImmunotherapy is discussed as a neoadjuvant and adjuvant therapy in the current standards of treatment in melanoma, while surgery is still an essential part of the treatment when possible. The new immunotherapy drugs and the development of targeted therapy, with a face towards personalised therapy, bring up the question of the place of surgical treatment in the rapidly changing medical field. Surgical treatment is the gold standard for resectable cases and takes an important part in staging determination, but despite its values, it may lead to complications and morbidity. Therefore, a question about the potential of advanced medical treatments to replace surgical treatment has to be asked, at least for cases of mutilating resection surgeries. Triple therapy for BRAF-mutant patients: the standard of care for BRAF-mutant melanoma patients is either BRAF/MEK inhibitor therapy or immunotherapy. There are three studies that have assessed anti-PD1+BRAF inhibitors + MEK inhibitors. Firstly, IMspire 150 [pire 150  was the pire 150 , showed pire 150 , also shpire 150  assessinNew immunotherapy combinations: A new study, RELATIVITY-047, suggested using combined immunotherapy for unresectable or metastatic melanoma with anti-PD-1 and anti-lymphocyte-activation gene 3 (LAG-3) as active agents [e agents . While ae agents . RELATIVe agents  comparede agents . There ae agents . A phasee agents . There ie agents . Lastly,e agents . In a vee agents .An additional study assessed a TOLL-like receptor (TLR)-9 agonist: vidutolimod. This drug has shown promise in patients as a monotherapy as well as in combination with anti-PD-1 therapy, with a response rate of approximately 20% in both regimens; however, it is more durable when combined with anti-PD-1 therapy .. Current treatment options, however, are subpar, and new therapeutic targets and therapies are critical to optimize treatment outcomes and allow for personalized therapeutic approaches for the best patient care.Understanding the molecular pathways involved in malignant melanoma pathogenesis leads to the development of specific targeted therapies and improves the prognosis of melanoma patients


It is well known that the presence of comorbidities and age-related health issues may hide biochemical and metabolic features triggered by SARS-CoV-2 infection and other diseases associated to hypoxia, as they are by themselves chronic inflammatory conditions that may potentially disturb metabolic homeostasis and thereby negatively impact on COVID-19 progression. To unveil the metabolic abnormalities inherent to hypoxemia caused by COVID-19, we here applied gas chromatography coupled to mass spectrometry to analyze the main metabolic changes exhibited by a population of male patients less than 50 years of age with mild/moderate and severe COVID-19 without pre-existing comorbidities known to predispose to life-threatening complications from this infection. Several differences in serum levels of particular metabolites between normal controls and patients with COVID-19 as well as between mild/moderate and severe COVID-19 were identified. These included increased glutamic acid and reduced glutamine, cystine, threonic acid, and proline levels. In particular, using the entire metabolomic fingerprint obtained, we observed that glutamine/glutamate metabolism was associated with disease severity as patients in the severe COVID-19 group presented the lowest and higher serum levels of these amino acids, respectively. These data highlight the hypoxia-derived metabolic alterations provoked by SARS-CoV-2 infection in the absence of pre-existing co-morbidities as well as the value of amino acid metabolism in determining reactive oxygen species recycling pathways, which when impaired may lead to increased oxidation of proteins and cell damage. They also provide insights on new supportive therapies for COVID-19 and other disorders that involve altered redox homeostasis and lower oxygen levels that may lead to better outcomes of disease severity. Efforts to unravel novel therapies to treat COVID-19 and post-COVID-19 manifestations are crucial due to the emergence of novel SARS-CoV-2 variants with augmented infectivity and/or pathogenicity. Clinical tests combining integral snapshots from the metabolic status of patients with COVID-19, have provided important information on the metabolic abnormalities provoked by SARS-CoV-2 infection , which mIt is well known that decreased oxygen supply, incremented glycolysis, and activation of immune responses promote an altered redox state in COVID-19 and several malignancies –8. Thesee.g. metabolic syndrome, obesity, diabetes, and hypertension, among others) and age-related issues may hide important biochemical and metabolic characteristics derived from SARS-CoV-2 infection  and received in-hospital treatment. In subjects that met the inclusion criteria, blood samples were collected from an antecubital vein and placed in tubes containing clot-activating gel . Tubes were inverted five times and the mixed blood was allowed to clot for 30 minutes at room temperature, centrifuged at 1300 x g for 15 minutes, and the resulting serum was then collected with a sterile disposable Pasteur pipette, aliquoted in cryogenic vials, and stored at -80°C until GC/MS analysis. All included samples were drawn upon admission to the triage area at the emergency department for the patients or at the epidemiology unit for the controls, where hospital staff members attended for randomized nasopharyngeal PCR testing during the morning shift and in a fasting state (minimum 8 h). The study was approved by the institutional ethics and research committees of our institute (Ref. RAI3688/21/22/1). Written informed consent to participate in the study was obtained from all participants. All analytical methods were carried out in accordance with relevant and updated guidelines and regulations.To minimize the influence of gender, age and/or comorbidities on the metabolomics analysis performed –26,30,31al tests ) were seal tests   spectral library. Only those metabolites with a matching value >70% were included in the final analysis. The raw data has been submitted to MetaboLights data base with the accession number MTBLS5011.Raw GC/MS data was transformed using the Agilent Chemstation software (Agilent), and the chromatogram deconvolution and alignment were processed with the Mzmine 2 software  using thp<0.05 was considered statistically significant. Spearman´s rank correlation analysis, heatmaps with hierarchical clustering, and fold change analysis were performed in Metaboanalyst 5.0 and R project software [To analyze for differences among control and patients groups, the U-Mann-Whitney test or Kruskal-Wallis test were applied using Graphpad Prism software 8.0  and adjusted by False Discovery Rate analysis. A probability value of software ,38 usingThe main characteristics of the cohort studied are listed in Our untargeted metabolomic approach consistently identified 33 different metabolites . To ensuTo identify potential associations between the metabolites and disease severity, we performed Spearman correlation analysis, which revealed that glutamic acid correlated negatively with cystine, threonic acid, and glutamine . LikewisTo further discriminate between disease severity, PLS-DA was applied to the data, showing a good performance  . The var2, and HCO3, and negatively with PaFi. On the other hand, glutamic acid showed negative associations with prothrombin time (PT), International Normalized Ratio (INR), and FiO2. Moreover, cystine and threonic acid showed a positive correlation with alanine aminotransferase (ALT) and aspartate aminotransferase (AST), both markers of hepatic function. Conversely, cystine and threonic acid showed negative associations with sodium levels. Phenylalanine correlated negatively with SpO2, albumin, pH, and anion gap markers. The main changes observed in several amino acids and other metabolites are shown in Metabolite association (VIP>1.2) with the clinical features in the severe group is depicted in The main complications derived from SARS-CoV-2 infection are related to systemic oxygen shortage due to lung tissue damage as a result of exacerbated immune activation and virus replication, which lead to metabolic changes that prepare target organs and tissues to reduced oxygen supply . LeavingIn the present study, we identified several differences in serum levels of particular metabolites among healthy controls and patients with mild/moderate or severe forms of COVID-19, which presumably were not related to any co-morbidity associated to a negative prognosis . Immune-The endogenous source of glutamic acid derives from glutaminase activity, an enzyme that produces glutamic acid from glutamine in a process called glutaminolysis. A different source of glutamic acid is the gamma-glutamyl cycle, which is the synthetic pathway of GSH, an important tripeptide with antioxidant activity. Dysregulation of this cycle promotes the increment of glutamic and pyroglutamic acid . IndividCysteine or cystine imbalance has been reported in other COVID-19 cohorts with variable changes according to disease severity, immune activity and presence of comorbidities ,51,68–70On the other hand, it was previously shown that reduced cystine levels correlated positively with threonic acid, a catabolite of ascorbic acid, the primary antioxidant obtained from food . This rein vitro studies with cardiomyocytes expressing higher levels of proline dehydrogenase revealed that enhanced proline metabolism reduced apoptosis and decreased hypoxia derived from ROS [In agreement with findings from other studies ,2,79–81,from ROS . In thisfrom ROS . This refrom ROS .Finally, we observed a modest, but significant increase  in levels of serine in patients with mild/moderate and severe COVID-19, albeit to a lower extent in the latter group. Altered levels of serine associated with variable outcomes have been documented in other metabolomic analyses ,86,87. IWe recognize that the number of patients included in this metabolomic analysis was limited, given that the study design did not consider subjects with co-morbidities associated with high COVID-19 mortality and which may potentially confound the metabolomic analysis –26,31. FIn conclusion, this study documents the existence of altered levels of several metabolites in COVID-19 patients in the absence of frequently associated co-morbidities. Assessing the magnitude of these alterations in both mild/moderate and severe COVID-19 patients is important as they seem to play a pivotal role in immune response and ROS scavenging. Our data emphasize the potential importance of amino acid supplementation in COVID-19 patients to prevent not only further progression of the disease but also probably the development of the chronic form of this infection.S1 FigPooled samples (blue intense) were used as a quality control and shows a compact well-defined cluster, ensuring a good reproducibility of our GC/MS analysis.(DOCX)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.