In coronavirus disease 2019 (COVID-19) patients with acute respiratory distress syndrome refractory to optimal conventional management, we should consider the indication for veno-venous extracorporeal membrane oxygenation (V-V ECMO). Growing evidence indicates that COVID-19 frequently causes coagulopathy, presenting as hypercoagulation and incidental thrombosis. For these reasons, a multifactorial approach with several anticoagulant markers should be considered in the management of anticoagulation using heparin in COVID-19 patients on V-V ECMO.A 48-year-old man was infected with COVID-19 with a worsening condition manifesting as acute respiratory distress syndrome.He was refractory to conventional therapy, thus we decided to introduce V-V ECMO. We used heparin as an anticoagulant therapy for V-V ECMO and adjusted the doses of heparin by careful monitoring of the activated clotting time (ACT) and activated partial thromboplastin time (APTT) to avoid both hemorrhagic and thrombotic complications. We controlled the doses of heparin in the therapeutic ranges of ACT and APTT, but clinical hemorrhaging and profound elevation of coagulant marker became apparent.Using thromboelastography  in addition to ACT and APTT, we were able to clearly detect not only sufficient coagulability of COVID19 on V-V ECMO  but also an excessive effect of heparin .Given the TEG findings indicating an excessive heparin effect, the early withdrawal of ECMO was considered. After an evaluation of the patient's respiratory capacity, withdrawal from V-V ECMO was achieved and then anticoagulation was stopped. The hemorrhagic complications and elevated thrombotic marker levels dramatically decreased.TEG monitoring might be a useful option for managing anticoagulation in COVID-19 patients on V-V ECMO frequently showing a hypercoagulative state and requiring massive doses of heparin, to reduce both hemorrhagic and thrombotic complications. It should be noted that coagulopathies of diverse etiologies have been frequently described in severe COVID-19 patients.,5 For these reasons, there needs to be strict monitoring of the coagulation function during treatment with ECMO adjuvants. The activated clotting time (ACT) and activated partial thromboplastin time (APTT) are commonly used for monitoring on ECMO. However, a multifactorial approach is suggested due to the poor association between the heparin dose and APTT during V-V ECMO.,7Anticoagulation using heparin is recommended for patients on V-V ECMO,–10 Recently, Panigada et al. showed that TEG-guided anticoagulation in ARDS patients on V-V ECMO was associated with less heparin administration than a standard APTT-based protocol without increases in hemorrhagic or thrombotic complications, suggesting the potential utility of TEG in COVID-19 patients on V-V ECMO. To our knowledge, there have been no case reports describing effectiveness of TEG monitoring under anticoagulation in COVID-19 patients on V-V ECMO.Thromboelastography (TEG) is a fully established point-of-care viscoelastic test of hemostasis in whole blood that allows for the measurement of global clot formation and dissolution in real time Fig. . It is lWe herein report the excessive effect of heparin by TEG monitoring with no notable findings on an APTT evaluation.2Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal. Because of this, there is no need to conduct special ethic review and the ethical approval is not necessary.A 48-year-old man  had had symptoms of a fever, cough, and diarrhea since April 2 and was prescribed amoxicillin on April 6 at hospital A. Because of worsening symptoms of dyspnea, he was introduced to hospital B on April 9, and he was diagnosed with COVID-19 pneumonia. His past medical history included hypertension on medications and alcoholic liver disease, and active smoking. His hypoxemia progressively worsened, and he was finally intubated and placed on a ventilator on April 10. His respiratory status worsened, and the partial pressure of arterial oxygen/fraction of inspiratory oxygen ratio was < 100 on April 13, and then he was transferred to our hospital on April 14. Chest x ray and high resolution computed tomography scan on admission revealed bilateral diffuse alveolar infiltrates with normal cardiac size  was initially administered for anticoagulation of V-V ECMO, and the dose was adjusted based on the ACT (therapeutic range: 140–180 sec) and APTT (therapeutic range: 40–65 sec). On Day 3 after the initiation of ECMO, the ACT and APTT were 217 and 33.7 sec, respectively, under 14 U/kg/h of unfractionated heparin. We also assessed TEG (1st TEG) on the same day, and the results showed that the blood clot strength was markedly enhanced -MA 47.4 mm) due to an increased function of fibrinogen, while the effect of heparin was not sufficient   and APTT (37.4 sec) had almost reached the therapeutic range under 14 U/kg/h infusion of heparin. However, TEG (2nd TEG) showed that the blood clot strength was still strong , suggesting insufficient anticoagulation therapy  under 11 U/kg/h of heparin and 30 mg/h of nafamostat mesilate, clearly showing an excessing effect of heparin that had not been detected by the ACT/APTT evaluation along with a sustained strong blood clot function  on Day 10 and started continuous intravenous nafamostat mesilate (30 mg/h), which was relatively few bleeding complications. Under medication with these anticoagulants, the D-dimer/ fibrin/fibrinogen degradation products levels remained high, although the APTT and ACT were 46 and 140 seconds, respectively. Furthermore, there was no improvement in the oral, airway, or respiratory bleeding clinically. TEG was performed again on Day 13 , fibrinogen concentration, and platelet count, are utilized in many clinical settings; however, we often face difficulties understanding the discrepancy between clinical bleeding or thrombosis and the results of these tests. TEG is an established way of measuring clot viscoelasticity using the whole blood and is used to predict coagulopathy and the risk of bleeding in surgery and anesthesiology. hemodialysis, and deep vein thrombosis. The results of the TEG examinations, including CK-R/CKH-R in the present case, provided supportive evidence for the reduction or discontinuation of heparin in anticoagulation therapy for this patient on ECMO when conventional APTT and ACT evaluations failed to provide useful data. TEG might be useful for managing anticoagulation in COVID-19 pneumonia patients in an excessive hypercoagulable state on V-V ECMO.TEG on Day 13 in the present case revealed an excessive anticoagulant effect of heparin  although ACT and APTT were controlled within the optimal respective ranges during anticoagulant therapy with heparin. TEG makes it possible to assess the underlying coagulation with heparin by performing paired tests with and without heparinase, CKH and CK, respectively. Previous reports have shown that the TEG-guided anticoagulant therapy with heparin allowed the administration of lower heparin doses without an increase in either thrombotic or bleeding complications compared to the APTT protocol in patients with ECMO adjuvants, The incidence of thrombotic complications is higher in COVID-19 patients than in other ICU patients, and an elevated D-dimer is an independent predictor for mortality. In the present case, TEG showed that the patient had a hypercoagulable status, supporting the above findings. TEG (Fig. COVID-19 infection is reported to likely be associated with coagulopathy.4We herein report a case in which TEG-guided anticoagulation therapy was useful in a COVID-19 patient with severe ARDS on V-V ECMO. In the future management of anticoagulation therapy in such cases, TEG evaluations might reduce both hemorrhagic and thrombotic events.The authors would like to thank Taku Yokoyama for his cooperation in the introduction and withdrawal of V-V ECMO in the present case.RN, TI, and MN contributed to the initial conception of the study and drafted the manuscript. All authors have read and approved the final manuscript.Data curation: Ryosuke Nakashima, Masaaki Nishihara, Takeshi Iyonaga.Investigation: Ryosuke Nakashima, Masaaki Nishihara.Writing – original draft: Ryosuke Nakashima, Masaaki Nishihara, Takeshi Iyonaga.Writing – review & editing: Masaaki Nishihara, Sho Iwasaka, Yuzo Yamamoto, Yuji Shono, Jun Maki, Kentaro Tokuda, Tomohiko Akahoshi, Taiki Higo, Takanari Kitazono, Hiroyuki Tsutsui.


Coagulopathy and venous thromboembolism are common findings in coronavirus disease 2019 (COVID-19) and are associated with poor outcome. Timely initiation of anticoagulation after hospital admission was shown to be beneficial. In this study we aim to examine the association of pre-existing oral anticoagulation (OAC) with outcome among a cohort of SARS-CoV-2 infected patients.P = 0.013) as well as the secondary endpoints COVID-19-related death  and non-recovery . The combined endpoint death or thrombotic event tended to be less frequent in patients on OAC .We analysed the data from the large multi-national Lean European Open Survey on SARS-CoV-2 infected patients (LEOSS) from March to August 2020. Patients with SARS-CoV-2 infection were eligible for inclusion. We retrospectively analysed the association of pre-existing OAC with all-cause mortality. Secondary outcome measures included COVID-19-related mortality, recovery and composite endpoints combining death and/or thrombotic event and death and/or bleeding event. We restricted bleeding events to intracerebral bleeding in this analysis to ensure clinical relevance and to limit reporting errors. A total of 1 433 SARS-CoV-2 infected patients were analysed, while 334 patients (23.3%) had an existing premedication with OAC and 1 099 patients (79.7%) had no OAC. After risk adjustment for comorbidities, pre-existing OAC showed a protective influence on the endpoint death (OR 0.62, Pre-existing OAC is protective in COVID-19, irrespective of anticoagulation regime during hospital stay and independent of the stage and course of disease. The novel coronavirus disease 2019 (COVID-19) is currently spreading rapidly, causing significant morbidity and mortality worldwide. An infection with the underlying severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) predominantly causes respiratory symptoms of varying degrees, ranging from mild dyspnoea to acute respiratory distress syndrome . In addiAll these data and recommendations focus on anticoagulation during hospitalization; however, the association of pre-existing oral anticoagulation (OAC) with outcome parameters in COVID-19 is still unclear. Analysing relevant outcome parameters of patients pre-treated with OAC may provide essential information, because mainly older patients suffering from comorbidities such as chronic cardiovascular disease are at risk for fatal outcomes, a patient group also frequently pre-treated with OAC. Using the Lean European Open Survey on SARS-CoV-2 Infected Patients (LEOSS) registry , an exteWe here report data from the Lean European Open Survey on SARS-CoV-2 Infected Patients (LEOSS). LEOSS is a multi-centre, non-interventional registry study for the documentation of SARS-CoV-2 infected patients mandated by the Emerging Infections Task Force (EITaF) of the European Society for Clinical Microbiology and Infectious Diseases (ESCMID) and supported by the German Center for Infection Research (DZIF) and the German Infectious Disease Society (DGI).Since LEOSS was initiated in March 2020, more than 120 sites predominantly located in Germany, but also in Austria, Belgium, Bosnia, Canada, Ireland, Italy, Latvia, Spain, Switzerland, Turkey, United Kingdom and the USA have retrospectively reported data on hospitalized and outpatient SARS-CoV-2 infected patients at all different stages of disease severity (from asymptomatic to life threatening). LEOSS is registered at the German Clinical Trials Register  and was approved by the applicable local ethics committees of all participating centers.The primary outcome was all-cause mortality. Secondary outcome measures were COVID-19-related mortality, recovery  operated using the cohort platform ClinicalSurveys.net and software developed by Questback . The data entry was conducted in an anonymized manner. Moreover, the LEOSS study team performed further data anonymization and categorization of data to prevent the possibility to draw conclusions to a single hospital.t tests, respectively. Since our analysis was solely retrospective and patients were not randomized to the two treatment options (anticoagulation vs. no anticoagulation), multivariable logistic regression analyses were applied to verify the impact of anticoagulation. As potential confounders, a total of 10 baseline patient characteristics  were imputed using median imputation (median age = 70 years). For BMI and smoking status, missing values were more frequent and used as separate variables. For other pre-existing diseases, there were no codes to indicate that data were missing; thus if the patient’s electronic health record did not include information on a clinical characteristic, it was assumed that that characteristic was not present. No adjustment for multiple testing was carried out. Thus, p values may not be interpreted as confirmatory but are descriptive in nature and inferences drawn from the 95% confidence intervals may not be reproducible. All analyses were carried out using Stata 16.1 .Difference between categorical and continuous variables were analysed using Fisher's exact test and Students’ P < 0.001), tended to be more likely female  and had more comorbidities. They suffered significantly more frequently from solid tumours , coronary artery disease , prior myocardial infarction , atrial fibrillation , peripheral vascular disease  and cerebrovascular disease . Arterial hypertension was significantly more frequent in patients without OAC . The severity of disease at diagnosis was comparable in both groups, indicating similar grades of illness  and smoking status (53.6% in the group with OAC and 49.2% in the group without OAC).P = 0.382; COVID-19 related death: 22.8% vs. 20.7%, P = 0.444). A similar proportion of patients recovered from COVID-19 in both groups . Thrombotic events occurred only in a few cases in both groups, with 4.2% in patients with OAC and 3.7% in patients without OAC, respectively (P = 0.745). Intracerebral bleedings occurred in 1.2% of patient without OAC and in 0.9% of patients with OAC in similar proportions (P = 1.0). Death or thrombotic event as combined endpoint occurred numerically slightly more often without statistical significance in the group with OAC  as well as the combined endpoint death or intracerebral bleeding  as well on the secondary endpoint COVID-19 related death , non-recovery  and the combined endpoint death or intracerebral bleeding . Patients with pre-existing OAC tended to have a better outcome at the combined endpoint death or thrombotic event , whereas patients with coronary artery disease  or prior myocardial infarction did not . Also patients with peripheral vascular disease , cerebrovascular disease  or hypertension  did not have an increased risk of mortality. If patients had diabetes mellitus with organ damage, risk for mortality was significantly increased , whereas patients with diabetes mellitus without organ damage did not . Age and sex  irrespective of anticoagulation during hospital stay. In this real-world cohort, pre-existing OAC was associated with less mortality and increased recovery rate.The hypothesis that pre-existing OAC might have an effect on the outcome of COVID-19 was based on the recent findings on thrombotic events and anticoagulation during SARS-CoV-2 infection –19. ThroFew recent studies showed inconclusive and oppositional results of mortality in patients with SARS-CoV-2 infection on pre-existing oral anticoagulation. One study from Spain showed worse outcome in patients on oral anticoagulation with a surprisingly high mortality rate of 68.2% in this cohort. In contOur colleagues could show elevated markers of thrombo-inflammatory activation in patients with cardiovascular diseases and their prediction for a worse outcome in the population of the LEOSS registry , reinforWe aimed to evaluate the effects of pre-existing OAC on prognosis and outcome of COVID-19 of all stages of disease irrespective of anticoagulation regime during inpatient treatment and irrespective of the stage and course of SARS-CoV-2 infection. Patients pre-treated with OAC are more likely to suffer from cardiovascular comorbidities that make them susceptible for a more severe course of COVID-19 . The finApart from the limitations commonly associated with retrospective studies, the LEOSS registry has some specific limitations. Despite its multinational approach, most patients were documented in Germany and a generalization of our results could be biased. Furthermore, the data on the extent of underlying comorbidities or regarding substance, dose or duration of treatment with OAC were not incorporated in the LEOSS database, as both, comorbidities and medication intake, were collected as binary categories. Numerous patients had to be excluded due to missing data on anticoagulation.Furthermore the anticoagulation regime during hospitalization was not recorded systemically. The lack of knowledge how and if patients were anticoagulated during the hospital stay significantly limits the interpretation of the data, e.g. whether anticoagulation was reduced in prior anticoagulated patients or whether previously non-anticoagulated patients received "full" anticoagulation as a prevention measure. Anonymization and categorization of data made it impossible to consider parameters such as length of hospital stay or length of mechanical ventilation as outcome parameters. Furthermore, major bleeding events such as gastrointestinal bleedings have not been recorded systematically in the LEOSS registry, only intracerebral bleedings were considered systematically in the database. Furthermore the chosen endpoint "intracranial bleeding" occurred only 3 times the anticoagulated group, a number way too small to draw valuable conclusions.In this observational study evaluating real-world data on the pre-existing OAC on outcome in COVID-19, we investigated mortality, recovery, thrombotic events and intracerebral bleeding using data from the Lean European Open Survey on SARS-CoV-2 Infected Patients (LEOSS). After risk adjustment, a substantial decrease in all-cause and COVID-19-related mortality and an increased recovery rate in patients with pre-existing OAC compared to patients without pre-existing OAC was observed. The combined outcome measure “thrombotic event and/or death” indicated beneficial effects of pre-existing OAC. We did not evaluate anticoagulation regimes during potential hospital stays. While there may be patients benefitting from full-dose anticoagulation, in general prophylactic or moderate dose might be sufficient. Current studies are ongoing .Our results were independent of the clinical stage and course of COVID-19. Our findings need validation in other COVID-19 cohorts or larger registries that can confirm this hypothesis and should not inform directly on the management of patients with COVID-19. However, they support the observations made by many groups that anticoagulation may be beneficial for most patients with COVID-19.


Bacteria harboring ESBLs are currently the number one critical pathogens posing a major threat to human health.  The world prevalence of community and hospital-acquired extended-spectrum Enterobacteriaceae (ESBL-E) and associated genes at community and hospital settings in East, Central, and Southern African countries.  To provide a summary of molecular evidence on the prevalence of ESBL-producing  We conducted a systematic literature search on PubMed and Google Scholar databases for the available molecular studies on ESBL-E in hospitals and community settings in East, Central, and Sothern Africa (ECSA). Published studies in English language involving gene characterization of ESBLs from human samples in hospital and community settings were included in the review, inception to November 2019. A random effect meta-analysis was performed to estimate the prevalence of ESBL-E. E. coli as the dominant isolate among ESBL-E recovered from clinical samples and Klebsiella pneumoniae was reported dominant isolates in 33% of all studies. A random pooled prevalence of ESBL-E was 38% (95% CI = 24–53%), highest in Congo, 92% (95% CI = 90–94%), and lowest in Zimbabwe, 14% (95% CI = 9–20%). Prevalence was higher in hospital settings 41% (95% CI = 23–58%) compared to community settings 34% (95% CI = 8–60%). ESBL genes detected from clinical isolates with ESBL-E phenotypes in ECSA were those of Ambler molecular class A [1] that belongs to both functional groups 2be and 2d of Bush and Jacob classification of 2010 [2]. Majority of studies  reported predominance of blaCTX-M gene among isolates, particularly CTX-M-15. Predictors of ESBL-E included increased age, hospital admissions, previous use of antibiotics, and paramedical use of herbs.  A total of 27 studies involving molecular characterization of resistance genes from 20,225 ESBL-E isolates were included in the analysis. Seventy-four percent of all studies were hospital based, 15% were based in community settings, and others were done in both hospital and community settings. Of all the studies, 63% reported  Few studies have been conducted at a molecular level to understand the genetic basis of increased resistance among members of ESBL-E in ECSA. Limited molecular studies in the ECSA region leave a gap in estimating the burden and risk posed by the carriage of ESBL genes in these countries. We found a high prevalence of ESBL-E most carrying CTX-M enzyme in ECSA with a greater variation between countries. This could be an important call for combined  efforts to combat the problem of antimicrobial resistance (AMR) in the region. Antibiotic use and hospital admission increased the carriage of ESBL-E, while poor people contributed little to the increase of AMR due to lack of access and failure to meet the cost of healthcare compared to high income individuals. They are mostly effective against a range of β-lactam drugs including ceftazidime, ceftriaxone, cefotaxime, and aztreonam [Pathogenic bacteria evolve to resist the actions of antimicrobials through acquired and intrinsic mechanisms including production of ic value , 2. Exteztreonam –5. In maThe world prevalence of community and hospital-acquired ESBL-E is increasing tremendously. Bacteria harboring ESBL enzymes are currently the number one critical pathogens posing a major threat to human health . The sprE. coli commonly causing community acquired urinary tract infections (UTIs) [There has been a significant advancement in the understanding of ESBL-producing bacteria epidemic which was previously related to hospital-acquired infections , 13. Recs (UTIs) , indicats (UTIs) . HoweverEnterobacteriaceae [Enterobacteriaceae in the region [In most poor resource countries of East, Central, and Southern Africa, there is lack of routine surveillance systems that could estimate the magnitude and risk factors as well as clinical outcomes associated with ESBL eriaceae . The ovee region –22.Enterobacteriaceae in East, Central, and Sothern Africa, we sought to summarize molecular evidence on the prevalence of ESBL-E and associated genes at community and hospital settings.To better understand genetic determinants of resistance among ESBL-producing This review and meta-analysis of prevalence has been conducted in compliance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and checklist .The review provides information on published articles from East, Central, and Southern Africa (ECSA) countries in accordance with Africa Union Countries profile . We incl(extended-spectrum beta-lactamase OR extended-spectrum OR beta-lactamase OR ESBL beta-lactamases OR beta-lactamase OR Enterobacteriaceae) AND Community OR Hospital AND .Literature search of peer reviewed studies was conducted on PubMed and Google Scholar databases for the available molecular studies on ESBL-E in hospitals and community settings in ECSA. The search strategy included the following index terms and Boolean operators All available published molecular studies (involving genotypic characterization of ESBL) in English language on human subject reporting ESBL-E in hospitals and communities in ECSA were considered eligible. Unpublished studies, editorials, letters, studies on nonhuman subjects, studies published in other languages than English, and studies that did not utilize molecular tools were excluded. All studies available on the selected databases at the time of data extraction were examined (inception to November 2019).Data extraction checklist was developed to guide the acquisition of the information which included name of the author(s), year of publication, study setting , study design, subjects/target population, source of isolates/specimen, clinical samples, sample size, bacteriological methods for estimating ESBL's, molecular methods used, isolate species, number of isolates analysed, ESBL positive isolates, genes encoding for ESBL identified and risk factors associated with ESBL infection if studied.Metanprop) specific for pooling binomial data including methods of computation of the 95% confidence intervals (CI), continuity correct, and the Freeman–Tukey transformation was used [Acquired data were entered into Excel spreadsheet and statistical analysis was done using Stata version 12 . We performed a random effect meta-analysis to determine heterogeneity of ESBL-E prevalence in ECSA. Decision to perform random effect meta-analysis over fixed effect meta-analysis was made due to an assumption that the difference in ESBL-E prevalence among studies in ECSA is attributed to different factors such as study settings  and different laboratory methods used for detection of ESBL-E. A new program in STATA  59%); one study used both DDST and combination disk method (CD) . An auto%; one stThree molecular tools were used in all 27 studies to detect the presence of ESBL encoding genes among isolates. These included microarray, polymerase chain reaction (PCR), and sequencing. Seventeen studies (63%) used both PCR and sequencing, other studies either utilized PCR 22%) , 46–48 o% , 46–48Klebsiella pneumoniae (K. pneumoniae) and Escherichia coli (E. coli). Of the studies, 63% reported predominance of E. coli among isolates, Klebsiella pneumoniae was dominant in 33%, and 5% of the studies reported that Proteus spp. was dominant. Other Enterobacteriaceae isolated in a small proportion that could not dominate were Enterobacter spp., Citrobacter spp., Morganella spp., and Providencia spp. Prevalence of ESBL-E varied across the countries in ECSA; the highest prevalence was observed in DR Congo followed by Tanzania and Malawi at the rate of 92% (95% CI = 90–94%) [A total of 20,225 ESBL-producing isolates from various clinical samples were reported in 27 studies across Eastern, Central, and Southern Africa. Eighty-one percent of the studies isolated both  90–94%) , 89% (95 90–94%)  and 62%( 90–94%) , respect 90–94%)  . The pooled prevalence of ESBL-E in hospital settings was 41% (95% CI = 23–58%) and 34% (95% CI = 8–60%) in community settings. The variation in the prevalence of ESBL-E attributable to heterogeneity in ECSA was very high   .β-lactamases of subgroups 2b, 2be, and 2ber), and OXA like β-lactamases of subgroup 2d  reported predominance of blaCTX-M genes among isolates particularly CTX-M-15, predominance of SHV gene was reported in three studies  [β-lactamase coding genes including SHV, TEM, and OXA type were mostly detected in K. pneumoniae commonly recovered from blood samples [Majority of studies  , 37, 45, 3, 11%) . The det samples , 48, 49.Enterobacteriaceae in children [Five of 27 articles reviewed stressed out factors associated with ESBL-E infections to include increased age, hospital admissions, and previous use of antibiotic. A study in Gabon found that hospitalization and at least 5 years of age were the risks for the carriage of ESBL children . Higher children . In an achildren . Increaschildren –40.Enterobacteriaceae in Eastern, Central, and Southern Africa. Few studies have been conducted to determine ESBL genes in these countries. Tanzania did most of the genotypic characterization of ESBLs while in other ECSA countries there was no any molecular work on AMR due to ESBL production by members of Enterobacteriaceae. The overall pooled prevalence was high (38%), close to previous findings by Sonda et al., [In the present review, we present the summary of molecular determinants and the pooled prevalence of ESBL-producing  et al.,  but high et al.,  and Bula et al., .According to the data generated from the present review, there was low pooled prevalence of ESBL-E in Zimbabwe and higher in DR Congo, Tanzania, and Malawi. Comparing our study with previous findings, it is surprising to find the prevalence of ESBL-producing pathogens in Malawi has increased by 89% within 12 years since the introduction of third-generation cephalosporins. The rate of resistance due to ESBL production at the time of cephalosporins introduction in Malawi in 2005 was very low (0.07%); the reason for low prevalence at that time was tight restriction on the use of antibiotics . HoweverThe prevalence of ESBL-E was higher in the hospital settings than the community settings; this was similar to finding of others , 56. We E. coli and K. pneumoniae [β-lactamases in the studies. However, there could also be inadequate infection control in healthcare systems contributing to the increased spread of ESBL-E in these poor resource countries as previously suggested [β-lactam antibiotics as a first-line treatment of infections caused by Enterobacteriaceae has been described to increase the spread of resistance and hence could lead to high prevalence in ECSA [Aloe vera and other herbal extracts used for paramedical purposes [Higher prevalence of ESBL-E in ECSA according to this review could be attributed to some factors including the focus of the studies reviewed and resistant genes targeted. Many studies across these countries reporting ESBL-E from human either were focused on certain ESBL bacteria, mainly eumoniae , 42, 49,eumoniae , 40, 41.uggested . Selecti in ECSA , 42. Incpurposes . In mostThe fact that few molecular studies have been conducted in the ECSA region undermines the understanding of ESBL gene diversity implicated in hospital and community acquired infections caused by ESBL-E strains. Most studies done with regard to ESBL-E in the region looked at identifying the pathogens involved and phenotypic resistance patterns rather than the genes responsible for such resistance. Similar to other studies , 60, we The importance of genotypic detection of ESBL genes in bacteria over phenotypic screening cannot be ignored; this is because these genes are carried on plasmids permitting higher chances of horizontal transfer which cannot be detected phenotypically. Phenotypic screening for ESBL pathogens is useful for surveillance purposes but they can underestimate the burden of resistance posed by ESBL pathogens. Previous reports detected more resistant ESBL producers when molecular methods were used compared to phenotypic methods . For defOne of the strengths of this review is that we included studies published in English which is the official language of many countries in the study area. Searching Google Scholar database provided an advantage to retrieve articles that could have not been published in highly indexed journals. Institutional subscription also allowed retrieval of articles that were not available for free access. However, the study was limited by the challenge encountered in determining true prevalence because some studies were laboratory surveillance based and did not provide the actual sample size or number of participants from which the clinical samples were drawn.Few studies have been conducted at a molecular level to understand the genetic basis of increased resistance among members of ESBL-E in ECSA. Limited molecular studies in the ECSA region leave a gap in estimating the burden and risk posed by the carriage of ESBL genes in these countries. We found a high prevalence of ESBL-E most carrying CTX-M enzyme in ECSA with a greater variation between countries. This could be an important call for combined  efforts to combat the problem of AMR in the region. Antibiotic use and hospital admission increased the carriage of ESBL-E, while poor people contributed little to the increase of AMR due to lack of access and failure to meet the cost of healthcare compared to high income individuals.


Currently, there is little evidence about the outcome of two-stage exchange arthroplasty for the treatment of knee periprosthetic joint infection (PJI) in patients with chronic viral hepatitis. To evaluate it, we set the primary outcome as infection recurrence, and the secondary outcome as the difference between patients diagnosed with hepatitis B virus or hepatitis C virus.Between June, 2010 and December, 2016, 172 patients with knee PJIs were treated with two-stage exchange arthroplasty at our institute. Treatment success was defined using Delphi-based consensus. These patients were further divided into groups with or without chronic hepatitis. Variables were analyzed, including age, sex, comorbidities, microbiology, and operative methods. Minimum follow-up was 12 months .p = 0.017. However, there was no significant difference in the infection recurrence rates between patients with HBV  and HCV . Regarding the outcomes of patients with infection recurrence, 4 of the non-hepatitis patients were treated with the debridement, antibiotic treatment, irrigation, and retention of prosthesis (DAIR) procedure, with a success rate of 75%. The other 17 patients (7 with hepatitis and 10 without) were treated with repeated two-stage exchange arthroplasty with 100% infection elimination rate until the final follow-up.Of the 172 knee PJI patients, 25 were identified with chronic hepatitis. The infection recurrence rate in the hepatitis group  was significantly higher than that in the non-hepatitis group , Knee PJI patients with chronic hepatitis have higher infection recurrence rate after two-stage exchange arthroplasty (28%). Over the past decade, there has been an increase in the number of knee arthroplasties performed worldwide. Over a 10-year period the incidence of knee periprosthetic joint infection (PJI) is about 0.75% at 10 years in primary TKA, accounting for nearly one-fourth in revision cases . Post-opPatients can be more susceptible to PJI with specific risk factors, such as uncontrolled diabetes –6, malnuIn early acute PJI, debridement, antibiotic, and implant retention (DAIR) procedure showed satisfying treatment result . Two-staTo the best of our knowledge, the efficacy of two-stage exchange arthroplasty in knee PJI patients with chronic hepatitis has not been reported. Chronic viral hepatis has been considered to have poor immune function and a high risk of infection . This stWe retrospectively reviewed a joint database of arthroplasty to identify patients who were diagnosed with knee PJI and were treated with two-stage exchange arthroplasty at our institution between June, 2010 and December, 2016. Patients who previously received revision surgery in other institutions were excluded.PJI was defined by fulfilling one of the following three criteria: (1) a sinus tract communicating with the prosthesis; (2) isolated pathogens from two or more samples obtained from the infected prosthetic joint; (3) presence of purulence in the affected joint with elevated synovial white blood cell count and synovial neutrophil percentage (PMN%) combined with serum erythrocyte sedimentation rate and serum C-reactive protein concentration elevation .Eight surgeons were involved in these operations, all following the same protocol. Pre-operative joint aspiration for microbiology culture was performed in all the enrolled patients. After diagnosis of knee PJI, they were treated with protocol of two-stage exchange arthroplasty. In brief, medial para-patella approach, resection arthroplasty for PJI included radical debridement, removal of prosthesis, antibiotic-loaded bone cement implantation, and administration of systemic antimicrobial agents for controlling joint infection. Vancomycin and Ceftazidime were loaded in Simplex P, Stryker, providing broad-spectrum anti-bacterial capacity . All patTwo to 4 weeks of antibiotics were used after the implant removal (first stage). Partial weightbearing was recommended in this interim period. One to 3 days of antibiotics were used after re-implantation of prosthesis (second stage). Walking with full weightbearing was allowed immediately after the re-implantation of prosthesis. The choice of regiment was depended on the microbiology culture. The outcome was assessed according to the 2013 Delphi-based International Consensus definition (1) infection eradication, characterized by a healed wound without fistula, drainage, or pain, and no infection recurrence caused by the same organism strain; (2) no subsequent surgical intervention for infection after reimplantation surgery; and (3) no PJI-related mortality caused by sepsis or necrotizing fasciitis.We also identified patients who were diagnosed with chronic viral hepatitis, including hepatitis B virus (HBV) and hepatitis C virus (HCV). Patients were further divided into the hepatitis group and the non-hepatitis group (control group). Patients with liver cirrhosis were further identified within these cases, and liver cirrhosis was mainly diagnosed by histological findings. For those who had not undergone liver biopsy, the diagnosis of liver cirrhosis was made by at least two of the followings: (1) abnormal liver functional test ; (2) esophageal varices (EVs) on endoscope, and (3) portal hypertension suggested on imaging studies (ultrasonography or computed tomography) . HepaticWe reviewed patient characteristics , comorbidities, results of microbiologic studies, and final outcomes in all knee PJI patients with or without chronic hepatitis. Approval for this study was obtained from the Institutional Review Board.p < 0.05. Due to the small sample size in this study, univariate and two-sided analysis were performed in this study. Statistical analysis was carried out by SPSS 24.0 program for Windows .The survival analysis was evaluated using Kaplan-Meier survival curve with 95% confidence interval (CI). The Chi-square test or the Fisher’s exact test was used where appropriate to analyze categorical data. Independent t-test or nonparametric Mann-Whitney U-test was applied for between-group comparisons in numerical data. Kaplan-Meier and Cox regression were applied for survival analysis. Statistical significance was defined as Between June, 2010 and December, 2016, 172 knee PJI patients  with an average age of 68 years old  were treated with two-stage exchange arthroplasty protocol at our institute. The mean duration of follow-up was 35 months . Twenty-five patients were diagnosed with chronic viral hepatitis (16 HBV and 9 HCV), and 147 patients were hepatitis-free. The patients in both groups were homogeneous.p = 0.017. Kaplan-Meier and Cox regression survival analysis showed a significantly higher treatment failure rate in the hepatitis group than in the non-hepatitis group, p = 0.01 . Details of the patient characteristics are summarized in Table The infection recurrence rate in the hepatitis group  was significantly higher than that in the control group 9.5%, 14 in 147), 4 in 147,Regarding the 21 patients with infection recurrence, 4 patients  with infection signs/symptoms less than 3 weeks were treated with the DAIR procedure. One of them experienced treatment failure and took a second two stage exchange arthroplasty. The overall success rate of the first time DAIR in the non-hepatitis group was 75%. The other 17 patients (10 in the non-hepatitis group and 7 in the hepatitis group) with infection relapse sign/symptoms more than 3 weeks received repeated two-stage exchange arthroplasty, with 100% success rate.Staphylococcus aureus was the most common pathogen , followed by coagulase negative Staphylococcus , Enterococcus faecalis , and Pseudomonas aeruginosa . In sum, 93 cases (54.1%) were caused by Gram positive bacteria, 12 (7.0%) were Gram negative bacteria, 2 (1.7%) were Mycobacteria, and 6 (3.5%) were yeast infection. Fifty-nine cases (34.3%) were culture-negative. The result is listed in Table Regarding the microorganisms in the knee PJI, With the two-stage exchange arthroplasty treatment protocol, a significantly higher incidence of infection recurrence was noted in the hepatitis group compared to the non-hepatitis group (28% vs. 9.5%) in this study. For the hepatitis group, whether the pathogen is HBV or HCV does not affect the outcome.It has been well known that chronic liver disease is associated with higher surgical mortality and morbidity rates. HBV can suppress the production of primary cytokines involved in the innate immune response, disturbance in proliferation processes, and cytokine production . ChronicIn this study, all seven patients with chronic hepatitis who failed two-stage exchange arthroplasty underwent prosthesis removal and a second two-stage exchange arthroplasty. The patients were followed for at least 21 months in the outpatient department , and no sign of recurrent PJI was noticed.Liver cirrhosis has been recognized as a risk factor for hip PJI treatment failure with two-stage exchange arthroplasty , 35. In According to the Delphi-based International Consensus of PJI 2013, DAIR can be performed on PJI patients who had late hematogenous infection within 3 weeks of an inciting event or symptoms no longer than 3 weeks . In the There are several limitations in this study, including minimum length of one-year follow-up, small sample size, and retrospective study design. Larger prospective randomized controlled trials are needed to confirm whether the selection criteria for two-stage exchange arthroplasty after the first episode of PJI can improve prognosis and quality of life in patients with chronic hepatitis. This study suggests that surgeons can consider two-stage exchange arthroplasty when counseling knee PJI patients with chronic hepatitis, and provides a basis for future studies.Knee PJI patients with chronic hepatitis displayed a higher rate of treatment failure (28%) after two-stage exchange arthroplasty and needed further surgery for infection control.


Causes of early-onset inflammatory bowel disease (IBD) vary, and primary immunodeficiency diseases (PIDs) are associated with early-onset IBD as monogenic disorders.This review investigates the prevalence, clinical manifestation, genetic profile, and treatment of patients with early-onset IBD in Southeast and East Asia.A systemic review of articles reporting PID patients associated with early-onset IBD in Southeast and East Asia was conducted.XIAP, three with IL10RA, and two or one patient with other gene mutations. In addition, ten patients were reported as having IL-10 receptor alpha (IL-10RA) deficiency in China and Hong Kong. Allogeneic hematopoietic stem cell transplantation was performed in patients with X-linked inhibitor of apoptosis deficiency, IL-10RA deficiency, or other PID as a curative treatment, and the preferable outcome of reduced-intensity conditioning and complete resolution of IBD symptoms and dysbiosis were achieved.The prevalence of PID associated with IBD was higher than that reported in western nations, and the frequency of patients with bloody stools as an early symptom was relatively higher in monogenic diseases. A total 13 (12.0%) of 108 patients with early-onset IBD were diagnosed as PID by exome sequencing and targeted gene panel analysis in Japan, including four patients with Comprehensive molecular diagnosis has been widely applied to screen for patients with PID-associated IBD in Southeast and East Asia. These results contributed to the awareness of monogenic PID in early-onset IBD patients and their differences in clinical manifestations and genetic profiles compared to the patients in western counties. Inflammatory bowel disease (IBD) is caused by various factors, including genetic background, host-microbe interactions, dysbiosis, and environmental factors , 2. ReceXIAP; three in DOCK8; two each in FOXP3, LRBA and ARPC1B; and one each in IL10RB, CYBB, and other genes. Only 1% of the patients with variants were considered potential candidates for correction of variants by allogeneic hematopoietic stem cell transplantation (HSCT)  .In accordance with the worldwide recognition, multicenter studies for pediatric patients with IBD have been reported in Japan, China, Hong Kong, and Malaysia in recent years. This review of relevant published literatures in the Southeast and East Asia summarizes the prevalence, clinical manifestations, results of genetic analysis by exome sequencing and targeted gene panel analysis, and treatment options of allogeneic HSCT as a curative therapy focusing on IL-10RA deficiency, XIAP deficiency and other PID.http://pubmed.ncbi.nlm.gov). The following search terms or abbreviations were used: primary immunodeficiency, PID, inflammatory bowel disease, IBD, early-onset IBD, VEO-IBD, Asia.A comprehensive search of articles reporting PID patients associated with early-onset IBD in Southeast and East Asia was performed using PubMed  described the prevalence and clinical features of VEO-IBD in University Malaya Medical Center, Malaysia. Six patients  out of 48 pediatric patients  of IBD were infantile-onset IBD before 12 months of age. Compared with later-onset IBD patients, infantile-onset IBD patients were more likely to present with bloody diarrhea; however, no mutation in IL-10 or IL-10R was identified in enrolled patients . Ishige  describeXIAP, three with IL10RA, two with TNFAIP3, and one each with RELA, CTLA4, FOXP3, and CYBB gene mutations. All three patients with IL-10RA deficiency were under 1 year of age; all four patients with XIAP deficiency were over 6 years of age at onset. The patient with refractory diarrhea caused by heterozygous truncated RelA protein expression was the first identified case worldwide, and functional analysis revealed that the mutation affected nuclear factor-kappa b (NFκB) signaling. Genotypes were significantly associated with clinical and pathological findings in each patient. Yanagi et al.  out of 108 patients enrolled in the study were monogenic. A total of 13 (12.0%) patients were diagnosed as monogenic PID in Japan , 18, and.9% out oi et al.  and Ishii et al.  reportedi et al.  reportedi et al. .IL10RA gene in 2012  and Uhlig et al. (2021) proposed integrated diagnostic methods and clinical genomics for IBD-related PID patients based on their different implications in systemic immunity , 12. GenGenetic investigations provided us a new approach for better treatments other than immunosuppressive agents, nutritional supplement and surgical intervention. One of the curative treatments for PID with early-onset IBD is allogeneic HSCT, and RIC is a suitable treatment option for these nonmalignant diseases in terms of reduced long-term sequelae if engraftment and complete chimera are achieved after HSCT. Allogeneic HSCT can induce remission in patients with IL-10 and/or IL-10R deficiency , 26. In Allogeneic HSCT has also been applied for IBD in XIAP deficiency as a curative treatment option –31. YangFOXP3 gene mutation and the absence of regulatory T cells (Tregs). Horino et al. (2014) reported a selective expansion of donor-derived Tregs after allogeneic bone marrow transplantation in a mixed chimeric state in a patient with IPEX syndrome, thus suggesting a growth advantage of normal Tregs in the IPEX patient. He suffered from severe diarrhea and required parenteral nutrition and red blood cell transfusion because of severe bloody diarrhea. The gastrointestinal symptoms were ameliorated after engraftment and expansion of CD4+CD25+Foxp3+ Tregs. However, optimal conditioning regimens should be further discussed to achieve a complete chimeric state in the rare patients with IPEX syndrome (Other PID-associated IBDs included IPEX syndrome caused by syndrome .If the patients had no human leukocyte antigen (HLA)-identical donors or suitable cord blood for transplantation, an HLA haplo-identical related donor was another candidate for HSC sources. Osumi, et al. (2020) reported a retrospective study of allogeneic HSCT with post-transplantation cyclophosphamide and antithymocyte globulin from HLA-mismatched related donors for nonmalignant diseases, and XIAP deficiency, IL-10RA deficiency, WAS and CGD patients were included in the case series .In terms of treatments other than HSCT, the frequency of patients treated with gastrointestinal surgery was relatively higher in the monogenic patients than in non-monogenic IBD patients –18. The The genes responsible for PID play critical roles in normal immunity in the gastrointestinal tract. Using whole-exome sequencing and targeted gene panel analysis, they identified underlying gene mutations responsible for PID in pediatric patients with early-onset IBD in an East Asian population. We are aware of the evidence that normal IL-10 signaling, nucleotide-binding oligomerization domain-containing protein 2 (NOD2)-mediated signaling and Tregs play indispensable roles in keeping normal immune homeostasis in the gastrointestinal tract by determining immunological defects in patients with IL-10 signaling deficiency, XIAP deficiency and IPEX syndrome, respectively.Classical WAS patients also suffer from VEO-IBD , 39. A cWe recently reported that a pig model of X-lined severe combined immunodeficiency (X-SCID) completely lacked Peyer’s patches and IgA production in the small intestine. Allogeneic HSCT to X-SCID pigs did not facilitate the lymphoid organogenesis completely and created atypical intestinal immune and microbial environments in the animal model of X-SCID. We also showed that our patients with X-SCID in mixed chimera after current allogeneic HSCT showed lower IgA levels and dysbiosis in their stool samples compared to the patients in complete chimera or normal individuals, indicating that common γ chain had significant roles in intestinal lymphoid organogenesis .Comprehensive molecular diagnosis has been widely applied to screen monogenic PID with early-onset IBD patients in Southeast and East Asia. The findings of different studies and contrasting issues compared to western counties are relatively higher frequency of IBD patients associated with various PID in Japan and higher frequency of IL-10RA deficiency in China and Hong Kong. Identifying links between genetic mutations and clinicopathological and immunological parameters helped us understand the pathogenesis and select appropriate therapies, such as infliximab, immunosuppressive therapy, or allogeneic HSCT as a curative treatment for patients with IBD. Determining whether unidentified genes, a dysregulated immune response to intestinal microbiota, or dysbiosis are involved in the pathogenesis of these diseases may expand our understanding of normal immunity and host-microbe interactions in the gastrointestinal tract.All authors listed have made a substantial, direct, and intellectual contribution to this work and approved it for publication.This work was supported by grants from the Japanese Ministry of Health, Labour and Welfare ; the Japan Agency for Medical Research and Development (JP21gk01104h0003); and the Japan Blood Products Organization to YS.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.The handling editor declared a past collaboration with the authors YS, TU, and TS.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. 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Identification of markers predicting disease outcome is a major clinical issue for non-muscle invasive bladder cancer (NMIBC). The present study aimed to determine the role of the mitochondrial proteins Mitofusin-2 (Mfn2) and caseinolytic protease P (ClpP) in predicting the outcome of NMIBC. The study population consisted of patients scheduled for transurethral resection of bladder tumor upon the clinical diagnosis of bladder cancer (BC). Samples of the main bladder tumor and healthy-looking bladder wall from patients classified as NMIBC were tested for Mfn2 and ClpP. The expression levels of these proteins were correlated to disease recurrence, progression. Mfn2 and ClpP expression levels were significantly higher in lesional than in non-lesional tissue. Low-risk NMIBC had significantly higher Mfn2 expression levels and significantly lower ClpP expression levels than high-risk NMIBC; there were no differences in non-lesional levels of the two proteins. Lesional Mfn2 expression levels were significantly lower in patients who progressed whereas ClpP levels had no impact on any survival outcome. Multivariable analysis adjusting for the EORTC scores showed that Mfn2 downregulation was significantly associated with disease progression. In conclusion, Mfn2 and ClpP proteins were found to be overexpressed in BC as compared to non-lesional bladder tissue and Mfn2 expression predicted disease progression. Bladder cancer (BC) is the most common urinary system malignancy. The reported European age-standardized incidence rate is 16.3 . BC deveDysregulation of the energy metabolism has emerged as a hallmark of many cancers . One of As for BC, available evidence suggests that the main energy source sustaining proliferation may be glycolysis ,9, thus Recent reports highlight the role of mitochondrial proteins Mitofusin-2 (Mfn2) and caseinolytic protease P (ClpP) in cancer progression. Mfn2 is a mitochondrial protein involved in mitochondrial dynamics (fusion) as well as in the cell cycle , cell prClpP is a mitochondrial serine protease that plays an important role in maintaining the integrity of the mitochondrial respiratory chain and optimizing mitochondrial function by removing damaged mitochondrial proteins . ClpP isThe present study, therefore, aimed to determine the prognostic role of Mfn2 and ClpP proteins expression in patients diagnosed with BC.The study population consisted of patients with non-muscle invasive BC at first diagnosis scheduled for transurethral resection of bladder tumor (TURBT) at Foggia University Hospital, Italy. A total of 66 patients with NMIBC met the inclusion criteria; their median age was 72 years and the female gender accounted for 20% of cases . PatientA single senior pathologist with expertise in bladder pathology reviewed all specimens according to the latest WHO Classification of Tumors of the Urinary System and Male Genital Organs  and the Patients were followed up according to EAU guidelines for NMIBC . The lowThe study protocol was approved by the Ethical Committee of the University of Foggia  and carried out following the Helsinki Declaration recommendations. All patients signed an informed consent to be enrolled.g for 10 min. The mouse anti-Mfn2 monoclonal antibody  and the rabbit anti-ClpP monoclonal antibody  were used. Mfn2 and ClpP levels were referred to Actin content (loading control).Assessment of Mfn2 and ClpP was carried out using Western-blotting analysis as previously reported . The samContinuous variables were reported as medians and interquartile range (IQR) and analyzed by the Mann-Whitney test. Categorical variables were reported as frequencies and compared by the Chi-Square or the Fisher’s exact test, as appropriate. The expression levels of Mfn2 and ClpP were first compared in lesional and non-lesional tissue, and then across low-risk NIMBC, including low-grade Ta BC, and high-risk NMIBC, including all T1 tumors, high-grade Ta/T1 tumors, and carcinoma in situ (CIS) . The expSince Mfn2 was found to be a predictor of disease progression and to establish optimal cutoffs for the biomarker of interest, we performed receiver operating characteristic (ROC) analysis predicting disease progression at 24 months of follow-up. Youden’s index was then used in conjunction with ROC analysis to select the cutoffs of the mitochondrial proteins associated with the best combination of sensitivity and specificity. The index was defined for all points of the ROC curve, and the maximum value of the index was used as a criterion for selecting the optimum cut-off point. The sensitivity and specificity of the mitochondrial proteins were computed and graphically presented at each probability cutoff. Recurrence-free survival (RFS), progression-free survival (PFS), and cancer-specific survival (CSS) of patients with proteins downregulation (below the cut-off) and upregulation (above the cut-off) were estimated non-parametrically using the Kaplan-Meier method, with differences being tested for significance using the Log-rank test. Finally, the ability of these mitochondrial proteins in predicting the recurrence and progression of NMIBCs was tested by Cox regression analysis. Univariable semi-parametric Cox regression analysis was used to match them with the variables included in EAU guidelines , namely p < 0.05 and all tests were two-sided. Statistical analysis was carried out using the STATA SE 14  according to the following syntax: chi2, kwallis, lsens, stset, sts test, stcox.Significance was set at p < 0.0001) in lesional than in non-lesional tissue; such difference was even higher  for ClpP expression levels  whereas non-lesional levels were similar; conversely, lesional ClpP expression levels were significantly higher (p = 0.046) in high-risk NMIBC as compared to low-risk NMIBC; again, non-lesional levels were similar in the 2 categories , whereas those who experienced progression had significantly lower lesional Mfn2 expression levels . Mfn2 expression levels were also slightly lower in NMIBC patients who died of BC .Median follow-up was 33.0  months . Among tp = 0.6), progressed  and died of BC   .p = 0.0008) but did not impact on RFS and CSS  whereas presence of CIS , EORTC score  and Mfn2 down-regulation  all emerged as significant predictors of disease progression. At multivariable analysis adjusting for EORTC scores, however, Mfn2 downregulation was the only significant predictor of disease progression .Univariable Cox regression analysis  pointed The increasing interest in mitochondrial metabolism changes has been supported by the evidence of their involvement in cancer cell proliferation ,6,7,8,9 The mechanisms underlying the transition from mitochondrial OXPHOS to aerobic glycolysis in cancer cells are not yet fully understood. Mitochondrial dynamics (fusion and fission) may play a role in this transition. Indeed Mfn2, a key mediator of mitochondrial fusion, supports increased oxidative phosphorylation . The first study testing Mfn2 expression in BC pointed out that tumor compared to adjacent non-tumorous tissue was characterized by decreased Mfn2 protein levels and significantly higher Mfn2 mRNA levels . No corrA recent study  reportedClpP has been found to be increased in several cancers including BC ,27,28,29p = 0.046) in high-risk NMIBC as compared to low-risk NMIBC. Again, non-lesional levels remained stable through the 2 categories. Our study pointed out that BC displayed significantly higher expression levels of Mfn2 and ClpP than healthy bladder tissue. Interestingly, lesional Mfn2 expression levels significantly decreased by increasing disease stage/grade whereas non-lesional levels remained stable; conversely, lesional ClpP expression levels were significantly higher (Our data, in contrast with Pang et al. 2019 , showed It has been reported that mitochondrial fusion, along with an increase of stress-induced mitochondrial protease, protects cells from apoptosis and induces a metabolic shift from glycolysis to oxidative phosphorylation ,35,36,37Therefore, it is attractive to assume that the increase of Mfn2 and ClpP expression in lesional compared to non-lesional tissues may increase oxidative phosphorylation and promote energy production and proliferation in the first phase of carcinogenesis. On the contrary, the Mfn2 down-regulation in high-risk NMIBC and in patients who progress may be explained assuming a shift from oxidative phosphorylation to glycolysis that is a more favorable condition in a future hypoxic microenvironment.Supporting this hypothesis, previous studies have shown that HIF-1α significantly increases in high-grade, invasive, and metastatic bladder cancer tissues compared with low-grade tumors . TherefoConversely, despite its role in other cancers, ClpP expression was not found to be associated with BC outcomes.Given the unpredictable behavior of NMIBC, particularly in the high-risk group, the identification of novel molecular markers predicting disease outcome and representing potential therapeutic targets remains a major clinical issue. Our findings would suggest that Mfn2 expression may play such a role. It is worth mentioning that targeting cancer cells metabolism could be particularly relevant given the increasing interest in immune therapies. Indeed, the interplay between tumor and immune cells leads to metabolic competition in the tumor ecosystem, limiting nutrient availability and leading to microenvironmental acidosis, which hinders immune cell function ,40.The novelty of this study was to evaluate the role of Mfn2 and ClpP as molecular predictive markers in a specific set of patients, namely NMIBC. However, this study has some limitations. First, the study population is relatively small but we elected to design a prospective study focusing on a homogeneous population of NMIBCs with a reasonable follow-up. Second, it did not include in vitro functional tests onto cell lines, but this would have been outside the scope of the present study aiming to test the role of these markers as potential predictors of disease outcome. Larger multicenter studies should be performed to externally validate our findings.In conclusion, in patients with NMIBC, the neoplastic tissue displays significantly higher Mfn2 and ClpP expression levels than the non-neoplastic tissue. Mfn2 expression correlates with disease outcome since down-regulation predicts disease progression, whereas ClpP expression does not. These findings make Mfn2 an interesting marker and a potential therapeutic target.


Infection was not associated with undergraduate vs. graduate student status, Division I athlete status, or housing type . A multi-faceted public health approach was critical for reducing the impact of COVID-19 while carrying out the university’s educational mission.With limited COVID-19-guidelines for institutions of higher education (IHEs), colleges and universities began the 2020–2021 academic year with varying approaches. We present a comprehensive COVID-19 prevention and mitigation approach at a residential university during the 2020–2021 academic year, along with campus SARS-CoV-2 transmission during this time. Risk management of COVID-19 was facilitated through (1) a layered approach of primary, secondary, and tertiary prevention measures; (2) a robust committee structure leveraging institutional public health expertise; (3) partnerships with external health entities; and (4) an operations system providing both structure and flexibility to adapt to changes in disease activity, scientific evidence, and public health guidelines. These efforts collectively allowed the university to mitigate SARS-CoV-2 transmission on campus and complete the academic year offering in-person learning on a residential campus. We identified 36 cases of COVID-19 among the 2037 in-person learners during the fall semester, 125 cases in the inter-semester break, and 169 cases among 2095 in-person learners during the spring semester. SARS-CoV-2 infection during the academic year was associated with gender ( After rapid campus closures and near-universal pivots to remote instruction in Spring 2020 due to the COVID-19 pandemic, universities were forced to plan for the 2020–2021 academic year in the midst of emerging information and conflicting guidance. Additionally, enrollment declines of 5–20% were predicted for the upcoming fall semester, with greater economic impacts anticipated for private institutions . To dateWe describe the process and partnerships involved in implementing public health measures in response to COVID-19 at a small, residential liberal arts and sciences institution during the 2020–2021 academic year. We present outcomes, along with challenges and successes, identifying aspects of the response structure that could provide a model to ongoing and future public health efforts in university settings.The university is located in Greenville County, South Carolina, a geographic area that implemented minimal COVID-19 mitigation mandates. In summer 2020, Greenville County experienced its first wave of COVID-19 cases with two-week incidence rates peaking at 500 cases per 100,000 individuals (13 July 2020–27 July 2020) and percent positivity tests greater than 15% [n = 2095; spring semester, n = 2109) elected to participate in on-campus learning and/or housing. Students were majority undergraduates (98.5%) and female (60.6%) and resided on campus for at least one of the semesters (91.3%). Of reported races and ethnicities representing ≥5% of the student population, 78.1% were non-Hispanic white, 6.8% were non-Hispanic Black, and 5.0% were Hispanic. Fourteen percent of students were involved in Division I athletics, 46.0% were affiliated with a sorority or fraternity, and the mean age was 20.4 years (SD = 2.5). This report focuses on those students living or learning on campus. Of the 30 weeks of in-person learning, 23 weeks were in a period in which the county was defined as having high transmission, while the remaining 7 weeks had substantial transmission.In the 2020–2021 academic year, the university took a hybrid education approach, relaxing on-campus living requirements and allowing options for remote learning. In this dynamic student population, the majority of the 2310 enrolled students  relied on guidance from existing committee structures, actions at other universities, and consultations with public health faculty to pivot to remote learning following an extended spring break and to bring students home from study away programs. In early summer 2020, the university administration developed a tiered committee structure to assess and develop public health responses and operationalize COVID-19 mitigation measures for the coming academic year. The primary committees included the: (1) COVID Response Steering Committee; (2) Public Health and Safety Advisory Group (PHSAG); (3) COVID Operations Teams; and (4) Dashboard Data Group . More thCommittees and subcommittee membership represented diverse expertise and responsibilities across the university, with membership overlap across committees to facilitate consistency. Some subcommittees were eliminated or folded into existing committees over time as implementation of their work was completed or inefficiencies were identified. The streamlined committee structure was maintained throughout the spring semester with the addition of committees as needed, such as a vaccine committee. Recommendations from these committees advanced to the SAT, which worked with a Board of Trustees COVID-19 Oversight Task Force for final decision making.Throughout the process, university administration participated in weekly calls to collaborate with consortium institutions and other institutions of higher education within the state.The university collaborated with four external entities to facilitate campus operations. An existing partnership with a healthcare system provided early clinical guidance and diagnostic testing capabilities through the on-campus student health center. A private local laboratory performed reverse transcription–polymerase chain reaction (RT-PCR) tests on campus for asymptomatic testing, first for university athletics and later for university-wide surveillance. This collaboration enabled routine testing of large numbers with 24 h turnaround time for results. South Carolina Department of Health and Environmental Control (SCDHEC) provided contact tracing guidance prior to the reopening of campus. At the end of the fall semester, SCDHEC also provided on-campus testing for the university and local community prior to the close of in-person learning in anticipation of Thanksgiving weekend travel. Additionally, university faculty collaborated with content experts at SCDHEC to provide a panel discussion on COVID-19 vaccines to students and employees prior to an on-campus vaccine clinic. This one-day vaccine clinic for students and employees was accomplished in collaboration with another healthcare system.The academic year started one week earlier than usual, on 18 August 2020, to allow in-person instruction to end prior to Thanksgiving (20 November 2020), with end-of-semester coursework and exams conducted online to minimize travel between holidays. Additionally, a staggered start to the fall semester allowed for reduced population density on campus and facilitated a flexible operational response for the newly implemented policies and procedures. First- and fourth-year students, those least likely to share housing or academic spaces, returned first to campus for in-person learning; second- and third-year students returned three weeks later (7 September 2020).Due to a national spike in infection rates in late December and early January, the start of the spring semester was delayed one week to 19 January 2021, with virtual-only classes the first week. Single break days were scheduled throughout the spring semester, replacing the typical weeklong Spring Break, in order to discourage widespread travel.A layered prevention approach was implemented, following Centers for Disease Control and Prevention (CDC) and SCDHEC guidelines available at the time. Primary prevention strategies included required masking and physical distancing of six feet with minimal exceptions . Students were encouraged to reduce the number of social contacts. Class capacities were reduced. Indoor dining was limited to students, and table capacity was reduced. In-person engaged learning experiences  and large social gatherings were not permitted. Enhanced cleaning and ventilation were implemented. The campus was closed to visitors, and the on-campus fitness center was limited to students enrolled in a related academic class .Students and employees completed daily self-screening through a survey connected to an existing campus app.At the start of the fall semester, CDC and SCDHEC guidelines did not yet recommend widespread surveillance testing, given the limited availability of tests and potential impact on testing laboratories ,10; thusStudent health services provided in-person and remote health evaluations, diagnostic testing, and clinical care through the on-campus student health center.Approximately 90 housing spaces were designated for quarantine and isolation. Students were asked to make a COVID-19 contingency plan prior to the start of the fall semester and encouraged to plan for potential quarantine or isolation at home when feasible.Once a student tested positive for SARS-CoV-2, the on-campus student health services contacted the student for clinical care and notified the university employee who served as the university’s contact tracer. The tracer queried the student by phone about close contact (within 6 feet of someone for 15 consecutive minutes or more in one 24 h period) with other individuals at the university in the 48 h prior to receiving a positive SARS-CoV-2 test result. All individuals determined to be close contacts were then notified that they were required to enter quarantine, either off-campus or in designated campus housing. During the fall semester, per CDC guidelines, all students remained in quarantine for 14 days. In the spring semester, CDC guidance allowed individuals in quarantine to test 5–7 days after exposure and to exit quarantine with a negative result.n = 1258) later that week. Second- and third-year students were then required to submit a negative test completed within five days prior to arrival on campus.In the first weekend of the fall semester, two unsanctioned fraternity events occurred off campus, resulting in an outbreak of COVID-19 among students. Public health actions included immediate quarantine and testing of all known student attendees, with 34 of 58 students testing positive for SARS-CoV-2. Testing was required for all remaining students , epidemiologists within PHSAG developed a framework specific to our institutional context to guide campus operations based on on- and off-campus COVID-19 measures . The colRecognizing that full restrictions for a prolonged period were not sustainable, a harm-reduction approach  was adopAfter establishing a baseline of <1% weekly campus incidence during the first two weeks of the spring semester amid high county-level incidence, campus operations proceeded in Orange phase. Surveillance testing was subsequently reduced to 50% of students for the following two weeks. As elective procedures at regional hospitals resumed and on-campus disease transmission remained low, the campus moved to Yellow phase by mid-February and decreased surveillance testing to 25% of students, and subsequently to 20%, following testing of 200 students with 0 positive results. With low on-campus infection and improving community levels, the university entered Purple phase from the end of March to the end of the semester. On-campus student gathering restrictions were relaxed, and surveillance testing was reduced to 15% of students; restrictions remained in place for off-campus activities.The weekend before classes ended, at least 39 students attended an unauthorized on-campus gathering at which disease precautions were not followed. Public health actions included quarantine and testing for involved students. At the time of the event, 11 of the 39 student attendees were fully vaccinated, and eight were within 90 days of previous SARS-CoV-2 infection. The remaining students were tested, and no infections were identified associated with this event.University administration created and maintained a student database to support COVID-19-related actions and university functions. We analyzed the database for this report and present descriptive statistics and bivariate analyses of student characteristics and SARS-CoV-2 infection. Chi-squared tests compared SARS-CoV-2 infection across student groups; Fisher’s exact test was used for characteristics with small sample sizes. Risk ratios and 95% confidence intervals (CIs) were calculated to quantify the relative risk of COVID-19 across different student groups.p = 0.04), race/ethnicity (p = 0.01), and sorority/fraternity membership (p < 0.01). Differences were not observed across undergraduate/graduate student status (p = 0.08), Division I athlete status (p = 0.2), or housing type (p = 0.08)  . The relPercentage utilization of on-campus quarantine and isolation housing ranged from 0–20% over the academic year. During the fall semester, 18.9% (396/2037) of students were identified as a close contact and placed in quarantine. Twelve of these students became symptomatic during quarantine but tested negative for a SARS-CoV-2. An additional 18 students became symptomatic during quarantine and tested positive for SARS-CoV-2 infection. Eight of eighteen were roommates, significant others, or teammates of the initial individual who tested positive. During the spring semester, 18.4% (386/2095) students were identified as a close contact and placed in quarantine. Seven of these students became symptomatic during quarantine but tested negative for a SARS-CoV-2. An additional 24 students became symptomatic during quarantine and tested positive for SARS-CoV-2 infection. Eleven of eighteen were roommates, significant others, or teammates of the initial individual who tested positive.p = 0.03). No significant associations were observed between other student characteristics and infection among the 5.6% of the in-person student population infected during this period.Six percent of spring semester students reported infection with SARS-CoV-2 during the inter-semester 6-week break (125/2095). Infection during the winter break was associated with athlete status (8.0% of athletes (29/361), vs. 5.1% of non-athletes (96/1888), Weekly surveillance testing resulted in percent positivity ranging from 0% to 1.3% . In the This university developed and implemented a comprehensive risk management approach through a robust committee structure with public health expertise to fulfill the university’s core mission to provide in-person, engaged learning experiences amidst a pandemic. Uninterrupted in-person learning was possible with a layered disease prevention and mitigation approach with flexibility to respond rapidly to disease levels on- and off-campus. While the university experienced COVID-19 cases each semester, mitigation efforts minimized adverse consequences of COVID-19 to the campus population. The number of cases in a 15-week semester at a university with congregate living settings was nearly identical to that of the 5-week break between semesters (when students returned home) and weekly cases remained relatively low.Central to the ability to safely provide in-person learning were effective internal and external processes and partnerships to address the volume and changing nature of issues. The continual availability of a public health and safety advisory group to make recommendations for campus decision-making needs in light of dynamic data and emerging public health guidelines, combined with representation of senior leadership in the committee structure, facilitated the ability to enact recommendations quickly and ensure timely allocation of resources.Harm reduction provided a helpful framework for considering the potential unintended negative consequences of and tension between different possible actions, recognizing the physical and mental health needs of students.The formation of the PHSAG provided a structure specifically focused on public health goals, facilitating review of emerging public health guidelines, assessment of potential public health actions, and formulation of targeted recommendations to be assessed by other committees in the context of university operations. A liaison between this advisory group and the steering committee facilitated workflow and communication.Strengths of the committee structure included working groups of manageable size to maximize productivity, overlap of membership across committees to facilitate continuity of efforts, and the flexibility to respond to emerging needs as required. The breadth of expertise involved in committees—ranging from public health to housing to police—ensured the application and enforcement of disease prevention and mitigation measures in a way that functioned within existing university practices and structures. Student membership in committees provided an important student voice for decision-making.Reopening a university for in-person learning after a swift pivot to remote learning in spring 2020 semester presented significant challenges. Guidance for universities from public health agencies was still evolving and limited at critical times when university planning and operational decisions needed to be made for the Fall 2020 semester.The reallocation of human resources required to accomplish COVID-19-related decision-making, implementation, and enforcement was significant, and burnout was a concern. Students and employees faced COVID-19 fatigue, requiring the university to adjust key support services.The findings in this report include limitations. The university consists of a dynamic college population, with some students returning home for short times in the middle of the semester or permanently. Disease activity was analyzed from a database of students completing each semester of in-person learning and may not represent those who withdrew or switched to remote learning mid-semester. The university’s National Collegiate Athletic Association Division I athletics program followed a separate protocol for student athletes not described in this report. The results presented in this case study may not be generalizable to large or non-residential universities.Multiple layers of prevention mitigated the COVID-19 impact at a small university and allowed for in-person learning without interruption. As universities navigate operational decisions for the 2021–2022 academic year, they are again faced with changes that will necessitate further revision of the strategies developed. Universities are now faced with decisions regarding potential vaccine requirements, which would provide an additional layer of infection prevention to a campus setting but may be hindered by state legislation and cultural perceptions. Vaccination rates of students and employees must be factored into restrictions for the summer and leading into the next academic year. High vaccine coverage on university campuses will be an important element of robust risk management in educational settings, particularly in light of emerging and highly transmissible variants.


Since the outbreak of the new coronavirus, healthcare systems around the world have witnessed not only COVID-19 symptoms but also long-term complications of the aforementioned, including neurological problems. We report a clinical case of an adult patient with bilateral facial nerve palsy and progressive ascending paresis of the limbs after contracting the novel coronavirus (COVID-19). Additionally, the systematic review aimed to identify and summarize specific clinical features, outcomes and complications of the studies focusing on bilateral facial diplegia as a sequela of COVID-19 infection. The total number of analyzed patients was 15. Only one patient was diagnosed with isolated bilateral palsy; the rest had Guillain-Barré Syndrome (GBS). With one exception, all the presented cases had favorable outcomes, with facial palsy recovery from slight to almost complete. In patients with a confirmed COVID-19 diagnosis, bilateral facial palsy may be an isolated symptom as well as a variant of GBS. Symptoms of cranial nerve damage during a COVID-19 infection may explain the appearance of facial nerve damage. In order to clarify the spectrum of neurological manifestations and a causal relation between SARS-CoV-2, COVID-19 vaccination and neurological symptoms, direct attention towards the study of this virus is crucial. It seems reasonable to recognize human coronavirus as another potential GBS trigger. Since the outbreak of the new coronavirus, healthcare systems around the world have witnessed not only COVID-19 symptoms but also long-term complications of the aforementioned. New phenomenon might be overviewed or misdiagnosed due to its novelty or lack of knowledge about the connection to previous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, which might have serious consequences including death. There is a need to share knowledge and increase awareness among health care professionals for better management of the patients. The first reported patient with SARS-CoV-2 in Wuhan, China was reported in December 2019 .Neurological manifestation related to SARS-CoV-2 and other coronaviruses depends on the exact location of the lesion, and their symptoms range from mild to severe. Among peripheral nervous system (PNS) alterations, neuralgia, olfactory and gustatory disorders are mentioned. Assessing the changes in the central nervous system (CNS), symptoms such as headache, dizziness, altered consciousness and ischemic or hemorrhagic stroke were observed. Acute inflammation of the CNS  and PNS were also repeatedly reported ,5. A 70-year-old Caucasian male, a proper diction teacher with a medical history of hypertension and stable heart disease, was admitted to our neurological department in November 2020 with acute symmetric progressive ascending paresis of the limbs, impaired sensation and bilateral facial nerve palsy. One month earlier (on 20 October 2020) he was treated at home for suspected SARS-CoV-2 infection without serious complications. The infection manifested itself through fever, gastrointestinal symptoms, headaches and severe pain in the thoracic spine. Three weeks later, the patient had an antibody blood test for SARS-CoV-2 with immunoglobulin M (IgM) rate at 4.18 (negative result < 1.00) and immunoglobulin G (IgG) rate at 5.69 (negative result < 1.4). Seven days after the disease laboratory confirmation, he came to the GP because of paraesthesia of the distal parts of the limbs and burning of the tongue. A diagnosis of ulcers (aphthae) in the mouth and sensory disturbances due to changes in the cervical and lumbar spine were made. Then, two days later, bilateral paresis of the facial nerve appeared, and he was thus transported from the private neurological praxis by ambulance to our neurology department.The systemic examination was normal. In the neurological examination the patient presented the following: complete lower motor neuron facial weakness bilaterally, swallowing difficulties, jaw dropping and dysarthria, symmetrical flaccid quadriparesis, absent deep tendon reflexes and sensory disturbances from the thoracic spinal nerve 6 (T6) downwards. The patient complained of a lack of facial expressions and diplopia. Then, due to diaphragm and intercostal muscles paralysis, respiratory disorders of the “compression of the iron rim” type appeared. Brain computed tomography (CT) and magnetic resonance imaging (MRI) were performed without any acute pathological finding. In a thoracic MRI (scope of the study T6–L2) examination, due to striped, subtle contrast enhancement at T12–L1 level on the anterior and dorsal surface of the conus medullaris and the roots of the cauda equina, suspicion arose of Guillain-Barré Syndrome. A lumbar puncture was performed, and the CSF picture revealed normal glucose and cell count with 98 mg/dL protein level, albumin level at 56.8 mg/dL and positive oligoclonal bands type IV indicative of damage to the blood–brain barrier. Other laboratory tests were within normal range. A nerve conduction study showed sensorimotor polyneuropathy of a demyelinating-axonal character. The patient received intravenous treatment with immunoglobulins at a dose of 2 g per kilogram body weight; the course of treatment was uneventful and there was gradual improvement. For further recovery, the patient was transferred to the rehabilitation department.We report a clinical case of patient with acute symmetric progressive ascending paresis of the limbs and bilateral facial nerve palsy after COVID-19 infection. The primary outcome of literature analysis was to identify and summarize specific clinical features and outcomes in SARS-CoV-2 patients complicated by bilateral facial diplegia. Our review focuses on the disease entities that lead to the emergence of bilateral facial diplegia, their likely underestimation and the impact of SARS-CoV-2 infection and COVID-19 vaccinations on their appearance. To identify appropriate literature, a systematic literature search was conducted based on the PRISMA guidelines . The eleThis study reported a patient with progressive neurological manifestations in the form of ascending paresis of the limbs and impaired sensation that were initially misdiagnosed. The onset of the neurological symptoms appeared one month after COVID-19 infection, confirmed by the presence of IgG to SARS-CoV-2 in the patient’s blood. It was found that 100% patients reached positive virus-specific IgG after approximately 17–19 days after first symptoms [Fourteen clinical cases were included in this systemic review, with a total of 15 analyzed patients, including the above clinical case. The age of the patients ranged from 20 to 70 years old, the average age was 46.13 ± 14.61 and the group was predominantly male (66.7%). The time elapsed between first symptoms of infection and admission to hospital due to neurological signs ranged from 2 days to 6 weeks with an average of 18.36 ± 10.82 days. Most cases (9/14) had a time lapse between 10 and 21 days. Of the available data, three patients had no symptoms of COVID-19 infection prior to admission, while four patients had a positive RT-PCR SARS-CoV-2 test result. Out of 15 described patients, only one had no albumin-cytological dissociation (ACD) in CSF results and was diagnosed with isolated bilateral facial palsy (BFP) in the context of otherwise asymptomatic COVID-19. Among the other patients, four presented only bilateral facial paresis with no other deviations in the neurological examination. In 5 of the 15 cases, brain MRI showed bilateral contrast enhancement of the facial nerves. Neurophysiological studies results were available for 10 out of 15 patients. The most common finding was demyelinating polyneuropathy. In the treatment, the following were used: intravenous immunoglobulins (IVIG) in 60.00% (9/15) of patients, corticosteroids in 33.33% (5/15) and plasmapheresis in 6.67% (one case). Data are missing in one case. Fourteen out of fifteen cases reported an improvement from slight to almost complete; however, one patient died from severe autonomic dysfunction .The first clinical case of a patient with GBS and SARS-CoV-2 infection was presented in The Lancet Neurology Journal . On 23rdGuillain-Barré Syndrome, despite being a rare disease, is diagnosed at any age and is the most common cause of acute flaccid paresis . GBS incThe relationship between COVID-19 and GBS and the resulting symptoms continue to be investigated. The vast majority of studies were published as case reports or series of cases ,34,35. AOn the one hand, the number of registered GBS cases, while underestimated, has fallen during the COVID-19 pandemic; on the other hand, altered social conduct is observed. Due to changes in social behavior, such as social distancing and the use of personal protective equipment and hygienic procedures, the prevention of infectious diseases, known as triggers of GBS, has increased ,38. ReceCampylobacter jejuni (C. jejuni), cytomegalovirus, Epstein–Barr virus, influenza and Zika virus infection, or vaccination. After a bacterial or viral infection, a cross-reaction called molecular mimicry appears, in which antibodies and nerve ending antigens are involved [Campylobacter jejuni is mentioned. Its molecular similarity to ganglioside structures (GM1) on human spinal nerve roots drives immune-mediated nerve damage. As many as one-fourth or one-third of patients after this infection can develop GBS [Multiple potential “classical” triggers of GBS have been reported e.g., involved ,42. As oelop GBS . There aelop GBS . In COVID-19 and neurological damage, three pathogenic pathways are proposed: direct damage, dysregulated inflammatory response and antibody-mediated injury. Freire et al. suggest neuro-invasive ability by disrupting the blood–brain barrier (BBB). Pro-inflammatory cytokines increase BBB permeability and activate glial cells  or retroProbable aetiology of Bell’s palsy is also associated with viral and autoimmune diseases; however, congenital conditions, traumas and idiopathy are also mentioned. Bell’s palsy incidence is approximately 15–30 cases per 100,000 people annually  and it aBilateral facial weakness is one of the prognostic risk factors contributing to mechanical ventilation in GBS . The morAuthors are debating increasingly the possible effects of COVID-19 on the onset of peripheral facial nerve palsy. Opinions are divided: Özdemir Ö.  in his lRecently, Nasuelli et al. reported a patient who developed four-limb distal paraesthesia, bilateral facial diplegia and postural instability ten days after vaccination with Oxford–AstraZeneca chimpanzee adenovirus vectored vaccine ChAdOx1 nCoV-19 . PerhapsIn order to avoid complications of potential adverse events of COVID-19 vaccination, medical professionals should be aware of symptoms such as peripheral nerve palsy or suggestive of GBS . NeverthThe presence of uncommon characteristics or confounding factors  can This systemic review has several limitations. The included studies are mostly clinical reports and focus on specific neurological symptoms. The number of reports is limited and the studies are retrospective. Due to the ongoing pandemic, many related studies have not yet been published, which could influence the results. There is also a high risk of cross-infection, which limited the evidence of neurological involvement.In patients with a confirmed COVID-19 infection, bilateral facial palsy may be an isolated symptom as well as a variant of Guillain-Barré Syndrome. Except for one patient, the presented cases had favorable outcomes ranging from slight to almost complete recovery from facial palsy. Olfactory and gustatory dysfunctions, as well as the appearance of oculomotor palsies and trigeminal impairment in the course of this viral infection, are evidence of the involvement of the cranial nerves, which would explain also the observed facial nerve damage. GBS is reported as one of the more common neurological complications of SARS-CoV-2, especially since the connection between this disease entity and viral infections has already been proven. It seems reasonable to recognize and include human coronavirus as another GBS potential trigger. Medical professionals should be aware of potential adverse events of COVID-19 vaccinations, among which Bell’s palsy and symptoms suggestive of GBS may appear. Nevertheless, the vaccines’ benefits appear to outweigh the potential risks of developing either of these complications.The current epidemiological situation and extremely frequent neurological complications related to the COVID-19 infection pushed the researchers to a wide analysis of its pathogenic mechanisms and manifestations. The etiopathogenesis is still unknown and requires further research. It appears that, due to negative PCR SARS-CoV-2 results in CSF, immune/cell-mediated reaction against SARS-CoV-2 should be considered rather than direct viral origin pathology; however, a potential route of penetration through the intranasal trigeminal nerve endings is also suggested. In order to clarify the spectrum of neurological manifestations and a causal relationship between SARS-CoV-2, COVID-19 vaccination and neurological symptoms, direct attention towards the study of this virus is crucial.