Future goals that are already under consideration in PAH include stronger integration of pathobiological characteristics when considering the use of specific drugs, or the development of novel therapies, toward precision medicine-based clinical pharmacology.Pulmonary arterial hypertension (PAH) is defined by a heterogenous pathobiology that corresponds to variable clinical presentation, treatment response, and prognosis across affected patients. The approach to pharmacotherapeutics in PAH has evolved since the introduction of the first prostacyclin replacement drug, which was trialed in patients with end-stage disease as a strategy by which to delay or prevent mortality. Subsequently, the aim of care in PAH has shifted toward minimizing symptoms, improving functional capacity, delaying disease progression, and prolonging life. Thus, treatments are now implemented earlier and according to the evidence base, which spans more than twenty years and includes patients at various stages of disease. Overall, the evidence supports multidrug therapy rather than monotherapy in the majority of PAH patients. Among incident patients, up-front combination therapy with ambrisentan and tadalafil or other comparable agents within these drug classes is recommended based on strong clinical trial data. In the near future, up-front triple therapy may be emerge as  These mechanistic underpinnings are integrated, and likely vary to some degree between patients and within the lung of individual patients.2,3 As a result, the PAH histopathophenotype and clinical presentation is heterogenous, adding an important measure of complexity to subclassifying patients and determining the optimal medical strategy for treatment.The proximate defining characteristic of pulmonary arterial hypertension (PAH) is a complex plexigenic arteriopathy that results in sub-total obliteration of distal arterioles.4 This gave rise to one paradigm that emphasized monotherapy to treat PAH. In addition, the first wave of randomized trials included patients with end-stage PAH.5 This, in turn, focused attention on a subgroup of PAH that is particularly frail with marginal cardiopulmonary reserve and for whom the safety of expanding medical therapy was not known or viewed by many as laden with risk.Indeed, the initial treatment era of PAH focused on calcium channel antagonism, which improved symptoms (and in some cases could be considered curative) for subpopulations characterized by increased vasoreactivity as a central pathophysiology observed at point of care.6 The current work reviews the rationale for using single vs. multiple drug therapy to treat PAH, which was the central topic of that presentation.Thus, reconciling the heterogeneous and integrated pathobiological basis of PAH with lingering concern regarding efficacy and safety of multidrug therapeutic approaches emerged as an early, but defining dilemma in the field. An overview of this topic was presented recently at the Sir Magdi Yacoub Aswan Heart Center Science and Practice Series , as part of the Pulmonary Vascular Research Institute’s commitment to global education.7A strong precedent exists in support of diversifying drug therapy to manage a wide spectrum of diseases, including highly prevalent cardiopulmonary disorders such as systemic hypertension, atrial fibrillation, myocardial infarction and others .78 Since this approach may be associated with adverse clinical events, it is important to confine decision-making to evidence-based strategies.In forms of pulmonary hypertension (PH) other than PAH , there is an unfortunate trend toward including unproven medical therapies for the routine management of patients.1,5 It is, in fact, by virtue of persistent effort among the clinical trialist community that has steadily improved PAH outcome compared to the original era in which disease-specific therapies were lacking. Comparative analysis of epidemiological data suggest that outcome in PAH is now more favorable than for patients with other, far more common cardiovascular disorders including various forms of left heart failure , and the prostacyclin pathways (prostaglandin-I2 replacement or counter-receptor agonism).1 Thus, the totality of data on multi-drug therapy centers is around the implementation of these therapies used in combination sequentially or combined up-front in the management of patients.The pathobiological framework of PAH is wide, implicating numerous different molecular mechanisms that regulate pathogenic vascular remodeling or modulate right ventricular dysfunction directly through afterload-independent pathways. It follows that new potential drug therapies continue to emerge frequently and are being tested in Phase I-III clinical trials at an expeditious rate (as reviewed in Ref. ). At pre2), reserved in practice today as an initial treatment for use in patients with particularly elevated clinical risk, was the only available pharmacotherapy in PAH from 1995 until access to the non-selective ETA∕B receptor antagonist bosentan became available in 2001.Intravenous epoprostenol (PGI11 Patients were started on epoprostenol (2 ng/kg/min to maximum 14 ng/kg/min at week 16) and then randomized to receive bosentan 62.5 mg b.i.d. for 4 weeks followed by 125 mg po b.i.d. or placebo. Compared to placebo, the median decrease in pulmonary vascular resistance in the bosentan arm was significantly greater than placebo (-8.1 WU vs. -2.4 WU). Later, it was determined that the addition of the inhaled prostacyclin analogue, iloprost, to stable monotherapy with bosentan was similarly effective in patients with New York Heart Association Functional Class (NYHA-FC) III symptoms but in whom parenteral epoprostenol was not indicated or was contraindicated.12In 2004, Humbert and colleagues completed the first double-blind, placebo-controlled study testing the effect of add-on therapy to prostacyclin.13 A placebo-adjusted increase in the 6-minute walk distance (6-MWD) by +28.8 m was observed in patients randomized to sildenafil (titrated to a maximum does of 80 mg t.i.d.) compared to +1.0 m for placebo. The benefit of add-on therapy was particularly notable among patients entering the study with a higher 6-MWD, implying that earlier intervention may be associated with an optimal treatment response. The salutary benefit of add-on therapy in this study also included improvement in central cardiopulmonary hemodynamics as well as longer time to clinical worsening.The wider availability and favorable safety profile of PDE-Vi drugs made add-on treatment with this class an important consideration, and one that could be tested in a larger patient population than preceding studies. Simonneau and colleagues completed a multinational study including 41 centers in 11 countries over 3 years and enrolling N=267 patients with idiopathic, associated anorexigen use or connective tissue disease, or congenital PAH.14Clinical trials in PAH have greatly improved patient outcome and should be a benchmark for aptitude in the advancement of other uncommon diseases. However, trial enrollment criteria is particularly stringent in PAH owing to clinical and pathobiological heterogeneity, and, therefore, it is imperative to understand the extent to which treatment paradigms affect patients in the ‘real world’ setting.vice versa on key clinical metrics was studied in a cohort of N=93 consecutive idiopathic or hereditary PAH patients evaluated at the National Referral Center in Bologna, Italy.15 The investigators included patients for whom sequential therapy was implemented due to failure for patients to meet pre-specified treatment goals on monotherapy . An assessment including 6-MWD, right heart catheterization, and NYHA-FC recording was performed at the time of treatment change and 3-4 months thereafter. Compared to baseline, data collected at the end of the follow-up period showed that significant fewer idiopathic or hereditary PAH patients (N=93) had NYHA-FC III/IV (51 vs. 32), increased 6-MWD by a median of +48 m, and improved cardiopulmonary hemodynamics including cardiac index +0.4 L/min/m2 and PVR -2.0 WU.In one retrospective study, the effect of sildenafil add-on to bosentan or 16 in patients with mild or moderate symptom burden for macitentan (non-selective ETA∕B antagonist) added to sildenafil; riociguat (sGC stimulator) added to bosentan; selexipag (prostacyclin receptor agonist) added to any endothelin receptor antagonist or PDE-Vi therapy  European Respiratory Society/European Society of Cardiology (ERS/ESC) Guideline recommendation therapy . A compr17 To that end, the Ambrisentan and Tadalafil in Patients with Pulmonary Arterial Hypertension (AMBITION) trial was a landmark multi-center international study that enrolled N=500 treatment-naïve PAH patients within about 10 days of diagnosis.18The concept of combination up-front, as opposed to sequential add-on therapy in PAH was modeled conceptually after such a strategy was implemented successfully in other complex diseases, such as human immunodeficiency virus.This study was innovative on many levels, including the end-point itself, which definitively transitioned away from single dimensional assessments in favor of comprehensive yet disease-specific measures. Specifically, the primary end-point was based on a time-to-event analysis driven by the first event of clinical failure, which was defined as the first occurrence of a composite of death, hospitalization for worsening pulmonary arterial hypertension, disease progression, or unsatisfactory long-term clinical response.A antagonist) vs. monotherapy with tadalafil vs. monotherapy with ambrisentan. The hazard ratio of the primary end-point for the patients randomized to the combination treatment arm vs. monotherapy with either tadalafil or ambrisentan was 0.50 , and at week 24 of the study there was a greater reduction in biochemical evidence of heart failure measured using N-terminal pro-brain natriuretic peptide (NT-BNP) level  and a higher rate of satisfactory clinic response (39% vs. 29%).Patients were randomized using a 2:1:1 strategy to receive combination tadalafil (PDE-Vi) and ambrisentan , major side effects were not observed at a prohibitive rate in the combination therapy group. Furthermore, the clinical benefits was internally consistent across nearly all subgroups. To avoid overemphasizing the utility of this specific drug therapy combination, the ERS/ESC Guidelines categorize the use of any ERA plus PDE-Vi as a Class IIb (Level of Evidence C) indication for up-front treatment of incident PAH patients .16 Alter19 and French20 registries prior to mainstream utilization of combination therapy were 85% and 87%, respectively, and 68% and 67%, respectively. However, in a contemporary analysis including 97 patients with newly diagnosed PAH treated with initial dual oral treatment of various combinations (86% had NYHA FC III/IV), Sitbon and colleagues21 reported 1- and 3-year survival rates that were substantially higher: 97% and 94%, respectively. Emerging data in carefully selected PAH patients suggests that up-front triple therapy with an ERA, PDE-Vi, and prostacyclin modulator is highly effective, and this topic is reviewed in greater detail elsewhere in this issue of the journal by Professor Simonneau.Escalation in the approach to PAH medical therapy would seem to drive gains in mortality reported observed in large and validated registries. For example, the 1- and 3-year mortality rate in the Registry to Evaluate Early And Long-term PAH Disease Management (REVAL)22 Taken together, a strong incentive remains to improve knowledge on pathophysiology, clinical trial design and rationale drug therapy selection in PAH patients. Specifically, there is increasing attention on using Mendelian randomization,23 biomarker-driven,24 and network medicine-based approaches to optimize the pathobiology-drug target relationship for clinical trial participants.25 It may be the case the future of clinical trial enrollment in the era of precision medicine includes alternative study designs, such as N-of-1 trials,9 to allow better insight into strategies that tailor drug selection based on the unique and individualized pathobiological profile.Notwithstanding these favorable trends in populations, many individual patients remain treatment non-responders, and the burden on patient quality of life and healthcare economics remains staggering.26 The selection an agent could be based on in silico screening tools, or empiric evidence. For example, the mineralocorticoid hormone aldosterone (ALDO) is increased in PAH and associates positively with NYHA FC status.27,28 We have demonstrated that increased ALDO oxidizes the ETB receptor in pulmonary endothelial cells to limit ETB-dependent nitric oxide synthesis and promote vascular fibrosis.29 Based on these empiric data, we hypothesized that ALDO antagonism with spironolactone in combination with ambrisentan would be an potential favorable drug combination by leveraging the anti-fibrotic effect of spironolactone with the anti-contractile and anti-mitogenic effect of ETA-receptor antagonism in vascular smooth muscle cells  as part of their standard of care medical regimen had a trend toward improved 6-MWD by 94% at week 12, improved plasma BNP concentration by 1.7-fold, and improved WHO FC status compared to patients not taking spironolactone (N=10). These data were limited by low patient volume among other reasons, but nonetheless provides one example by which drug repurposing may be validated through experimental and existing datasets. Other examples of repurposing with promising intermediate data include histamine receptor antagonists, angiotensin converting enzyme (ACE) axis modulators, and metformin.32,33Retrospective analysis of the ARIES-1 and -2 trials,34,35 is likely to widen the range of patients for whom clinical trial enrollment is a consideration. Overall, the trajectory of progress in PAH clinically is exemplar among cardiopulmonary diseases, and ongoing efforts continuing this line of progress appear well-suited to address important knowledge gaps that persist in order to meet patient’s expectations of treatment efficacy and improve outcome further.There is now ample evidence to support a multi-drug approach to the treatment of PAH, which includes up-front combination therapy in treatment-naïve patients using ambrisentan and tadalafil or other ERA and PDE-Vi. The evolution in treatment strategy from monotherapy in the prior generation parallels an emphasis on earlier detection of patients in advance of end-stage disease. In this way, patients are generally characterized by more favorable cardiopulmonary reserve, less fragility, and wider tolerance of side effects that allows for maximal clinical benefit of therapeutic intervention. Up-front triple therapy is on the horizon, as more data using this approach becomes available. Cutting-edge clinical trial enrollment methods that integrate pathobiological measures will continue to drive the field toward precision medicine, while mounting clarity on the cardiopulmonary hemodynamic spectrum of riskDr. Maron is a consultant for Actelion Pharmaceuticals, and is an inventor on a US patent 9,605,047 and US provisional patent applications 24622 and 61/99,754.


How often do commercially insured patients obtain follow-up treatment for opioid use disorder after a nonfatal opioid overdose?In this cohort study of national commercial insurance claims for 6451 patients, 16.6% of patients obtained follow-up treatment after a nonfatal opioid overdose. Among those who had not received treatment for opioid use disorder before the overdose, patients of older age, female sex, black race, and Hispanic ethnicity were less likely to obtain follow-up.Timely treatment for opioid use disorder following overdose appears to be low among commercially insured patients, with race/ethnicity, sex, and age disparities. Timely initiation and referral to treatment for patients with opioid use disorder seen in the emergency department is associated with reduced mortality. It is not known how often commercially insured adults obtain follow-up treatment after nonfatal opioid overdose.To investigate the incidence of follow-up treatment following emergency department discharge after nonfatal opioid overdose and patient characteristics associated with receipt of follow-up treatment.A retrospective cohort study was conducted using an administrative claims database for a large US commercial insurer, from October 1, 2011, to September 30, 2016. Data analysis was performed from May 1, 2019, to September 26, 2019. Adult patients discharged from the emergency department after an index opioid overdose (no overdose in the preceding 90 days) were included. Patients with cancer and without continuous insurance enrollment were excluded.The primary outcome was follow-up treatment in the 90 days following overdose, defined as a combined outcome of claims for treatment encounters or medications for opioid use disorder . Analysis was stratified by whether patients received treatment for opioid use disorder in the 90 days before the overdose. Logistic regression models were used to identify patient characteristics associated with receipt of follow-up treatment. Marginal effects were used to report the average adjusted probability and absolute risk differences (ARDs) in follow-up for different patient characteristics.A total of 6451 patients were identified with nonfatal opioid overdose; the mean (SD) age was 45.0 (19.3) years, 3267 were women (50.6%), and 4676 patients (72.5%) reported their race as non-Hispanic white. A total of 1069 patients  obtained follow-up treatment within 90 days after the overdose. In adjusted analysis of patients who did not receive treatment before the overdose, black patients were half as likely to obtain follow-up compared with non-Hispanic white patients . Women  and Hispanic patients  were also less likely to obtain follow-up. For each additional year of age, patients were 0.2% less likely to obtain follow-up .Efforts to improve the low rate of timely follow-up treatment following opioid overdose may seek to address sex, race/ethnicity, and age disparities. This cohort study examines the use of follow-up treatment by patients who experience heroin or prescription opioid overdose. Previous studies have focused on single states, the Medicaid population, and MOUD treatment.37 We hypothesized that these treatment disparities by race and sex would persist within a commercially insured population.We also sought to examine patient-level characteristics associated with timely receipt of follow-up care. Evidence suggests that significant treatment disparities on the basis of race, sex, and geography have emerged as the opioid epidemic has evolved, possibly owing to differences in health insurance coverage.39 The Optum database includes all inpatient, ED, outpatient, and pharmacy claims from a large national health insurance company that enrolled between 15 million and 18 million unique patients each year during the study period. Data analysis was performed from May 1, 2019, to September 26, 2019. The institutional review board at the University of Pennsylvania determined that this study was exempt from review because data are deidentified. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for cohort studies.40We conducted a retrospective cohort study of adult patients who were discharged from the ED following treatment for opioid overdose between October 1, 2011, and September 30, 2016. We used an administrative claims database, the Optum Clinformatics Data Mart (Optum).International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) and International Statistical Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) diagnosis codes before and after October 1, 2015, respectively  based on diagnosis codes.41 Prescription opioid refers to medications available by prescription but does not mean that the patient received a prescription for the medication.We examined patient-level characteristics as covariates that we hypothesized could be associated with access to follow-up treatment, including patient age, sex, and race/ethnicity. Optum uses data on race/ethnicity that is self-reported or derived from administrative data sources. We also included geographic location, according to 4 United States Census Regions .ICD-9-CM or ICD-10-CM diagnosis codes , with 95% CIs.In addition to the primary analysis, we investigated potential interactions between race/ethnicity and overdose type by including an interaction term in the logistic regression model. Also, we used multivariable logistic regression models to examine the association between patient characteristics and the secondary outcome of MOUD treatment alone. In addition, we used Kaplan-Meier failure analysis to examine days to receipt of follow-up treatment, stratified by overdose type. Data analysis was conducted from June 1, 2019, to September 1, 2019. Analyses were performed using Stata software, version 15.1 (StataCorp LP).The total cohort consisted of 6451 patients, of whom 1896 (29.4%) overdosed from heroin and 4555 (70.6%) overdosed from prescription opioids . FurtherFor all patients in the study cohort, 1069 individuals  obtained follow-up treatment in the 90 days following overdose . Among tIn the adjusted analysis for patients who did not receive treatment before the overdose, patients with prescription opioid overdose were less likely to obtain follow-up compared with heroin overdose  ARD, −8.These associations were not present for patients who received treatment in the 90 days before overdose, apart from a decreased rate of follow-up for patients in the South , compared with the Northeast  had a claim for MOUD following the overdose. In adjusted analyses, patients who were older, women, black race, and experienced a prescription opioid overdose were less likely to obtain MOUD treatment, while patients with a prescription for a benzodiazepine or treatment encounters for OUD were more likely , sex, and age. Research is needed to better understand the mechanisms behind these disparities. As health professionals adopt evidence-based practices for initiating medications for treatment of OUD and linking patients to sustained treatment, payers and policy makers should implement strategies to overcome systemic barriers to ensure that patients are given the best opportunity to access timely treatment. These interventions must account for disparities to ensure expanded and equitable access to life-saving treatment following overdose.


Results revealed that colistin-resistant Enterobacteriaceae were absent at birth. Some pigs at both farms had diarrhea and received colistin treatment during days 2–27. Colistin-resistant Enterobacteriaceae were detected in 13.3–50.0% of sick and healthy pigs. No sick pigs were observed during days 28–60, and colistin was not used during that period. Colistin-resistant Enterobacteriaceae were detected in 2.8–10.0% of healthy pigs on day 28, and in 0–3.4% of healthy pigs on day 60. The mcr-1 gene was detected in 57.6% of colistin-resistant Enterobacteriaceae isolates. Short-term treatment with colistin was found to be associated with the emergence of colistin-resistant Enterobacteriaceae in swine. Colistin-resistant Enterobacteriaceae rapidly emerged after colistin use, and rapidly decreased or disappeared after its discontinuation.Long-term use of colistin for preventing Gram-negative bacterial infections in food animals was prohibited in Thailand in 2017, but it is permitted for short-term treatment. This study aimed to investigate association between the use of colistin for short-term treatment of infection and the emergence of colistin-resistant Enterobacteriaceae in swine. The current study was conducted at 2 selected swine farms in Thailand. Neither farm has used colistin to prevent infection for longer than 1 year. Rectal swabs were collected from the same 66 pigs at birth, and on days 7, 14, 21, 28, and 60. Colistin was used to treat sick pigs for up to 3 days. Additional rectal swabs were collected during colistin treatment. Rectal swabs were analyzed for colistin-resistant Enterobacteriaceae and the  If this transfer of colistin resistance were to occur, the resulting spread of infection would likely result in human infections caused by colistin-resistant Enterobacteriaceae.Colistin has been one of the last-resort antibiotics for treatment of human infection caused by carbapenemt decade . Colistit decade , 3. Use t decade –16. Mecht decade . However in 2015 . Since the world . The emeIn Thailand, all antibiotics have been prohibited for use as a growth promoter in food-producing animals by the Ministry of Agriculture and Cooperatives since 2015. Colistin has been prohibited for use to prevent infection in food-producing animals by the Department of Livestock Development, Ministry of Agriculture and Cooperatives since 2017. The aforementioned regulations are based on the observation that antibiotic-resistant bacteria on farms that used antibiotics as a growth promoter and colistin-resistant bacteria on farms that used colistin to prevent infection were much more prevalent than on farms that did not use antibiotics to promote growth and on farms that did not use colistin to prevent infection in food-producing animals, respectively. However, colistin is still permitted for use as the last option therapy for short-term treatment of infection in food-producing animals under the supervision of a qualified veterinarian.mcr-1 in colistin-resistant Enterobacteriaceae isolated from pigs after receiving colistin for treatment of infection.The objective of the current study was to determine the occurrence of colistin-resistant Enterobacteriaceae in pigs raised on swine farms that received colistin for short-term treatment of infection, and the frequency of The Animal Care and Use Committee for Scientific Research of Kasetsart University (ACKU59-VET-002) approved this study. Formal approval was given by the owners of the 2 study farms for sample collection from study swine. This study was conducted at 2 large swine farms in Thailand and the microbiology laboratory of the Division of Infectious Diseases and Tropical Medicine, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand during October 2017 to April 2018.Two swine farms with more than 500 breeders each that are located in the Northeastern region of Thailand were included in this study. Neither of these two farms have used colistin to prevent infection for longer than one year. Halquinol and/or other antibiotics, such as ampicillin, tetracycline, tiamulin, and tilmicosin, was/were used to prophylactically prevent infection.Sick pigs, especially pigs with post-weaning diarrhea, were treated with colistin sulphate 50,000 IU per pig via oral administration two times per day for up to 3 days. If a sick pig did not respond to colistin, other antibiotics, such as ampicillin, ceftriaxone, or enrofloxacin, would be given.mcr-1 gene detection in colistin-resistant Enterobacteriaceae at the Division of Infectious Diseases and Tropical Medicine, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University.Rectal swabs were collected from 12 pregnant sows on Farm A, and from 6 pregnant sows on Farm B within 30 days prior to parturition. Rectal swabs were also collected from 3 to 5 pigs born to each sow at birth, and on days 7, 14, 21, 28, and 60. Additional rectal swab samples were collected from sick pigs that were treated with colistin. All rectal swabs taken were maintained in Cary Blair transport medium and subjected to bacterial culture, antibiotic susceptibility testing, and Escherichia coli, Klebsiella pneumoniae, Enterobacter spp., Citrobacter freundii, and Edwardsiella tarda) by conventional biochemical testing. Antibiotic susceptibility of the isolated Enterobacteriaceae to ceftriaxone and meropenem was performed by disk diffusion test according to the Clinical and Laboratory Standards Institute (CLSI) [mcr-1 gene in colistin-resistant Enterobacteriaceae isolates was performed by polymerase chain reaction (PCR) amplification using the commercial primer with the same sequence as the mcr-1 gene, as previously described by the researchers who discovered the mcr-1 gene [Each rectal swab sample was streaked on MacConkey agar supplemented with ceftriaxone 4 mg/L. The bacteria grown on the agar were identified up to the species level for Enterobacteriaceae (e (CLSI) . Determie (CLSI) . Enterobr-1 gene .mcr-1 gene in colistin-resistant Enterobacteriaceae isolates were described as number and percentage. Comparison of the prevalence of the mcr-1 gene in Enterobacteriaceae isolates was performed using chi-square statistics or Fisher’s exact test. A p-value less than or equal to 0.05 was considered statistically significantSPSS Statistics  was used to perform all statistical analyses. Data specific to antibiotic resistance, the presence of ESBL in isolated Enterobacteriaceae, and the presence of the E. coli, and some were K. pneumoniae or Citrobacter freundii. The prevalence of resistance to ceftriaxone, meropenem, or colistin; of ESBL production; and, of the presence of the mcr-1 gene in Enterobacteriaceae isolated from rectal swabs collected from 2 pregnant sows on Farm A, and from 6 pregnant sows on Farm B within 30 days before parturition is shown in Among the Enterobacteriaceae isolates that were detected from 18 pregnant sows within 30 days before parturition, most (70%) were E. coli, and some were K. pneumoniae, Enterobacter spp., Citrobacter freundii, or Edwardsiella tarda. mcr-1 gene in Enterobacteriaceae isolated from pigs born to study sows on Farm A and Farm B from birth to day 60 after birth. At least one Enterobacteriaceae isolate from all study pigs from birth to day 60 after birth on both farms was resistant to ceftriaxone in 91.2% to 100%. At least one Enterobacteriaceae isolate from all study pigs from birth to day 60 after birth on both farms was an ESBL-producer in 86.1% to 100%. None of the Enterobacteriaceae isolates from any of the study pigs on either farm was resistant to meropenem. Colistin-resistant Enterobacteriaceae isolates were not detected in any study pig at birth on either farm. At least one colistin-resistant Enterobacteriaceae isolate from study pigs aged 2 days to 27 days on Farm A (during which 69.4% of pigs had diarrhea and received colistin treatment) was detected in 16.7% to 50%. At least one colistin-resistant Enterobacteriaceae isolate from study pigs aged 3 days to 21 days on Farm B (during which 76.7% of pigs had diarrhea and received colistin treatment) was detected in 13.3% to 33%. Colistin-resistant Enterobacteriaceae were isolated from one pig (2.8%) aged 28 days on Farm A, and from 3 pigs (10%) aged 28 days on Farm B when all study pigs on both farms were not sick and they were not receiving colistin. Colistin-resistant Enterobacteriaceae were isolated from no pigs aged 60 days on Farm A, and from one pig (3.4%) aged 60 days on Farm B when all study pigs on both farms were not sick and they were not receiving colistin. None of the study pigs born to study sows were sick at birth. However, 25 pigs (69.4%) on Farm A had diarrhea and received colistin treatment during days 2–27 after birth, and 23 (76.7%) on Farm B had diarrhea and received colistin treatment during days 3–21 after birth. Among the Enterobacteriaceae isolates detected from all study pigs from birth to day 60 after birth most (54.1% to 100%) were E. coli and K. pneumoniae, respectively. Nearly all isolates of colistin-resistant Enterobacteriaceae were ESBL-producers. The MIC50, MIC90, and MIC range of colistin for all colistin-resistant Enterobacteriaceae isolates was 8, >128, and 4 to >128 mg/L, respectively. The overall prevalence of mcr-1 gene in colistin-resistant Enterobacteriaceae isolates was 57.6%. The prevalence of mcr-1 gene in colistin-resistant E. coli isolates was significantly higher than the prevalence of mcr-1 gene in colistin-resistant K. pneumoniae isolates .in vitro study that will expose colistin to colistin-susceptible Enterobacteriaceae and determine when and how often the study colistin-susceptible Enterobacteriaceae become resistant to colistin. Then, we will grow colistin-resistant Enterobacteriaceae in media without colistin for many rounds to determine when and how often the study colistin-resistant Enterobacteriaceae will revert to colistin-susceptible Enterobacteriaceae. The colistin-susceptible Enterobacteriaceae and colistin-resistant Enterobacteriaceae isolates will be studied by whole genome sequencing to determine the relevant mechanisms of this phenomenon. The presence of the mcr-1 gene was far more prevalent in colistin-resistant E. coli than in colistin-resistant K. pneumoniae isolated from pigs in this study. This finding is similar to the previously reported detection rate of the mcr-1 gene in colistin-resistant E. coli (84.6%) and colistin-resistant K. pneumoniae (1.9%) isolated from patients [mcr-1 gene was found to be more prevalent in E. coli than in K. pneumoniae in this study, and in the study in humans. We are collaborating with several genome centers to perform whole genome sequencing of colistin-resistant E. coli and K. pneumoniae. Those investigations may reveal additional mechanisms of colistin resistance in E. coli and K. pneumoniae other than mcr-1 that could be mediated by other new plasmids [This study was conducted on two large swine farms in Thailand that had not used colistin to prevent infection for at least one year to ensure that the outcomes of the study would not be adversely influenced by its recent use. However, these farms still used other antibiotics, including ampicillin, tetracyclines, tiamulin, tilmicosin, and/or halquinol, to prevent infection in their respective swine populations. Rectal swabs from pregnant sows and study piglets at birth revealed no isolates of colistin-resistant Enterobacteriaceae. Therefore, 13.3% to 50.0% of sick and healthy pigs with colistin-resistant Enterobacteriaceae isolated from their rectal swabs were associated with colistin use for treatment of sick pigs during day 2 to day 27. The prevalence of colistin-resistant Enterobacteriaceae isolated from pigs during the period that colistin was used to treat sick pigs in this study was higher than the previously reported prevalence , but it patients . We do nplasmids , 25, chrmcr-1. However, other resistant genes in plasmid  and chromosomal-mediated colistin resistance could also be a mechanism of colistin resistance in bacteria residing in the gastrointestinal tract of pigs that are exposed to colistin. Unabsorbed colistin in a pig is excreted from the pig’s gastrointestinal tract into the environment, and this could induce colistin resistance among bacteria that reside in the environment by various colistin resistance mechanisms similar to the bacteria in the gastrointestinal tracts of pigs that received colistin. Colistin-resistant Enterobacteriaceae that emerge in pigs receiving colistin can be transmitted to other pigs that do not receive colistin, and this would contaminate pork that is consumed by human beings, and potentially contaminate the environment [mcr-1 gene could potentially be transferred horizontally from colistin-resistant Enterobacteriaceae to other species of bacteria and become resistant to colistin [Although colistin resistance can disappear from Enterobacteriaceae after cessation of colistin, the short-term use of colistin is still worrisome since it poses several risks related to the emergence, transfer, and transmission of colistin-resistant bacteria. Colistin sulfate is poorly absorbed through a pig’s gastrointestinal tract . Thus, cironment –30. Morecolistin . TherefoIt should be noted that Enterobacteriaceae isolated from all pigs in this study were generally resistant to ceftriaxone and were ESBL-producers because many antibiotics in addition to colistin were still given to the pigs on these two farms to prevent and treat bacterial infections. Fortunately, no carbapenem-resistant Enterobacteriaceae (CRE) were detected among all of the samples obtained from pigs in this study. Our finding is in contrast to previous studies that reported the isolation of CRE from pigs. CRE is one of the most important antibiotic-resistant bacteria linked to high mortality in human beings , 32.mcr-1 and other types of mcr genes since we do not have the primers for these genes. Therefore, the prevalence of colistin resistance mediated by mcr genes in colistin-resistant Enterobacteriaceae isolates in this study could be more than the prevalence of the mcr-1 gene alone that was observed in this study.Although this study clearly demonstrates association between the use of colistin for short-term treatment of infections and the emergence of colistin-resistant Enterobacteriaceae in swine, our study also has some mentionable limitations. First, our study data was collected from only 2 farms, and both of those farms are located in the same region of Thailand; therefore, the magnitude of the prevalence of colistin-resistant Enterobacteriaceae in swine observed from this study may not be generalizable to other farms since the data obtained from these 2 study farms were also different between farms. Second, the prevalence of colistin-resistant Enterobacteriaceae in swine observed from this study should be considered as minimum prevalence because we used MacConkey agar supplemented with ceftriaxone 4 mg/L for culture of the samples collected from pigs, and some colistin-resistant isolates of Enterobacteriaceae might be missed if such isolates were susceptible to ceftriaxone. However, the aforementioned phenomenon is unlikely since colistin resistance was not detected in any ceftriaxone-susceptible Enterobacteriaceae in our laboratory. Third, we did not attempt to detect variants of Short-term treatment of sick pigs with colistin was found to be associated with emergence of colistin-resistant Enterobacteriaceae in swine raised on two large swine farms in Thailand. Colistin-resistant Enterobacteriaceae rapidly emerged after colistin administration, and colistin-resistant Enterobacteriaceae rapidly decreased or disappeared after colistin use was discontinued.S1 File(DOC)Click here for additional data file.


Phonetic (vowel and duration) changes elicited left-lateralized MMFs in the auditory cortices. Contrary to our hypothesis, MMF source strengths or lateralization did not differ between groups. However, better verbal working memory was associated with stronger left-hemispheric MMFs to duration changes across groups, and better reading was associated with stronger right-hemispheric late MMFs across speech-sound changes in dyslexic readers. This suggests a link between neural speech processing and reading-related skills, in line with previous work. Furthermore, our findings suggest a right-hemispheric compensatory mechanism for language processing in dyslexia. The results obtained promote the use of MMFs in investigating reading-related brain processes.Poor neural speech discrimination has been connected to dyslexia, and may represent phonological processing deficits that are hypothesized to be the main cause for reading impairments. Thus far, neural speech discrimination impairments have rarely been investigated in adult dyslexics, and even less by examining sources of neuromagnetic responses. We compared neuromagnetic speech discrimination in dyslexic and typical readers with mismatch fields (MMF) and determined the associations between MMFs and reading-related skills. We expected weak and atypically lateralized MMFs in dyslexic readers, and positive associations between reading-related skills and MMF strength. MMFs were recorded to a repeating pseudoword / Dyslexia; Magnetoencephalography (MEG), Speech processing, Mismatch field (MMF), Reading skills, Verbal working memory, Behavioral neuroscience, Cognitive neuroscience, Applied linguistics, Clinical psychology, Cognitive psychology Furthermore, we used an extensive neuropsychological test battery tapping reading and related skills  as well as intelligence quotient (IQ) of the participants. Since earlier studies have shown diminished and delayed MMN amplitudes in dyslexia .Forty-three healthy Finnish participants  aged 19–45 years without history of neurological diseases participated in the study. The inclusion criteria for the dyslexic group were a diagnostic dyslexia statement , or a history of reading difficulties in childhood , vowel identity , or syllable frequency (shifting the f0 of the second syllable from 175 to 225 Hz) in the second syllable . The duration of the vowel identity and syllable frequency deviants was identical to the duration of the standard stimulus. The intensity level of all deviants was root-mean-square normalized to match the average intensity level of the standard stimulus. The onset of change was at 180 ms from stimulus onset for the frequency and vowel deviants, and at 225 ms from stimulus onset for the duration deviant. Stimuli were presented pseudo-randomly  in two ≈12.6 min recording blocks, each containing 946 stimuli and starting with five standard stimuli. Standards were presented with a probability of approximately 75.3% and each deviant type with a probability of 8.3%. The stimulus-onset asynchrony (SOA) was 800 ± 50 ms .The repetitive “standard” stimulus was a naturally recorded Finnish 300-ms-long pseudoword /syllable . OccasioThe stimuli were presented during MEG/EEG recordings with Presentation Software  binaurally via plastic tubes and silicon earphones at a comfortable level (≈70–80 dB SPL). During stimulation, participants were sitting, instructed to keep the head still and to attend to a self-selected, subtitled, and silenced movie projected  to a back-projection screen  located 150 cm from the participant's head.2.4MEG/EEG was recorded using a 306-channel Elekta Neuromag TRIUX  whole-head MEG system (sampling rate 1 kHz and pass-band 0.03–330 Hz) in a magnetically shielded room  in BioMag Laboratory in Helsinki University Central Hospital (duration 2–3 h). Prior to the measurement, the positions of five head position indicator (HPI) coils and additional head surface points (EEG electrodes) were determined in relation to the nasion and both preauricular points with an Isotrak 3D-digitizer . The head position with respect to the MEG sensor array was continuously monitored. Vertical and horizontal electro-oculograms (EOG) were recorded.The anatomical T1-weighted images (MPRAGE) were acquired on a 3T MAGNETOM Skyra whole-body MRI scanner  with a 32-channel head coil at AMI centre of Aalto Neuroimaging (duration 30 min), Aalto University . The images were checked for incidental findings by a physician.2.5https://github.com/athiede13/neural_sources. Temporal signal space separation  version 5.3 and 6.0 following the standard procedure , the generators of individual MMFs were estimated in a cortically-constrained source space; the MEG forward solution was calculated for 4098 source points per hemisphere. The minimum-norm source estimate (MNE) was computed for the MMFs using depth-weighting (0.8), fixed-orientation constraint, and the 100-ms-pre-stimulus-baseline regularized noise covariance of pooled deviant and standard waveforms of each participant. The MNE source estimates were morphed to Freesurfer's average subject (fsaverage) cortical space and averaged for each group.After MRI–MEG coregistration (a priori chosen as regions of interest (ROI) based on previous research  to represent the area with the most consistent activity across participants. The source time course at the functional ROI were extracted with source signs flipped depending on the source orientation (pca_flip) to avoid cancellation.Auditory cortices  and a 200-ms wide window for the second peak . Individual maximum amplitudes and the corresponding latencies were extracted within the determined time windows and ROI for statistical analysis in both hemispheres.2.7t-tests against zero separately in each group. Group and laterality effects and their interactions on MMF source amplitudes (difference waveforms) were analyzed with three-way repeated-measures analysis of variance (ANOVA) with group  as between-subjects factor and laterality , deviant , and time  as within-subjects factors. Group and laterality effects and their interactions on MMF source latencies were analyzed with two-way repeated-measures ANOVAs with group as between-subjects factor and laterality and deviant as within-subjects factors. In the ANOVAs, main effects of deviant or time were not investigated. Significant three-way interactions were further investigated with separate follow-up ANOVAs. Greenhouse-Geisser correction was applied when the sphericity assumption was violated. Bonferroni correction was used to account for multiple comparisons in all post-hoc tests and only corrected p-values are reported. Although performance IQ differed between the groups, an analysis of covariance with performance IQ as a covariate was not performed, following the recommendations of N = 37, 19 in control group, 18 in dyslexic group). The profile of the matched groups did not otherwise differ from the original sample.SPSS version 25.0.0.1 , R  and RStuPartial Pearson correlations were computed between MMF source amplitudes and neuropsychological test scores, controlling for the effect of performance IQ. In order to reduce the amount of tests, correlations were analyzed in three steps both separately for the two groups and across groups; (1) for MMF source amplitudes at two hemispheres averaged across all deviants with the three neuropsychological composite scores, if significant, then (2) separately for MMFs to each deviant, if significant, then (3) separately for each subcomponent of the neuropsychological composite scores. Despite a potential risk of circular inference , this st3The MMF source waveform (difference waveform) indicated two responses , referrepost-hoc analyses are reported in Post-hoc analysis of that interaction indicated larger left- than right-hemispheric MMFs to the vowel deviant. A follow-up ANOVA for the late MMF time window revealed a significant main effect of laterality, indicating larger left- than right-hemispheric responses.Full statistics of significant effects in all ANOVAs and For the late MMF source latencies, a significant interaction effect between laterality and group was found, indicating slower late MMFs in the left than right hemisphere in the control group only. The reported ANOVA results remained similar when repeating the analyses for performance-IQ-matched subsamples of control and dyslexic groups; only the latter effect on late MMF latencies disappeared .Table 4SSource amplitudes of MMF and late MMF correlated with neuropsychological test scores , Table 54Our goals were to determine whether neural speech-sound discrimination is deficient or abnormally lateralized in adult dyslexic readers, and whether the speech-elicited neural responses correlate with reading-related skills. To improve spatial accuracy from previous EEG studies we recorded MMFs with MEG, and utilized individual MRIs for source localization. We found MMFs and late MMFs from bilateral auditory cortices to all three speech-sound changes. Furthermore, the MMFs and late MMFs were left-lateralized to all three deviants. For the MMFs, the effect was driven by the vowel deviant. Contrary to our expectations, MMFs and late MMFs did not differ in source amplitudes, latencies, or lateralization between dyslexic and typical readers. However, the MMFs were associated with skills pertinent for reading that are known to be affected by dyslexia . Correla4.1Two response components were found: The MMF peaked at around 125–170 ms after change onset with a clear and narrow peak. This latency is well within the established time range of the MMN/MMF . An addiThe MMFs and late MMFs in both groups originated from primary and secondary auditory cortices , confirming the findings of previous MMN localization studies applying other types of source modeling . Further4.2ba/ vs. /da/) also failed to find group differences , and University of Helsinki MRI measurement support. Anja Thiede was supported by the University of Helsinki Research Foundation and Arvo and Lea Ylppö foundation.This work was supported by The authors declare no conflict of interest.ClinicalTrials.gov under the registration number NCT02622360.The clinical trial described in this paper was registered at


For recipients of allogeneic hematopoietic stem cell transplant (HSCT), mycophenolate mofetil (MMF) plus tacrolimus combination is mostly used in reduced-intensity (RIC), and nonmyeloablative conditioning (NMAC) whereas methotrexate and tacrolimus combination is preferred in myeloablative conditioning (MAC). We present single institution outcomes in patients undergoing allogeneic HSCT with both MAC and NMAC/RIC regimen using MMF and tacrolimus for graft-versus-host disease (GVHD) prophylaxis. Data from all adult patients who underwent allogeneic HSCT from 2007 to 2017 was collected from Data Back to Centers web-based application of Center for International Blood and Marrow Transplant Research (CIBMTR). A total of 150 patients were included with the mean age of 46.9 years. For the patients who received MAC (n=109), the cumulative incidence of grade II-IV acute GVHD at day 100 was 37%, grade II-IV acute GVHD at one year was 51%, and chronic GVHD at one year was 38%. For the patients who received NMAC/RIC (n=41), the cumulative incidence of grade II-IV acute GVHD at day 100 was 31%, grade II-IV acute GVHD at one year was 28%, and chronic GVHD at one year was 36%. This institutional analysis shows that the combination of MMF and tacrolimus yields acceptable outcomes for the prevention of acute and chronic GVHD. Graft-versus-host disease (GVHD) is a serious and challenging complication of allogeneic hematopoietic stem cell transplant (HSCT). The risk of mortality with acute GVHD is approximately 10-20% [Mycophenolate mofetil (MMF) has been utilized to improve GVHD prophylaxis and reduce toxicity. MMF is an ester prodrug of the immunosuppressant mycophenolic acid, which inhibits inosine monophosphate dehydrogenase resulting in blockade of de novo purine synthesis, thereby limiting the proliferation of lymphocytes . Based oTacrolimus and MMF have been found to be synergistic in preclinical models . In addiPatients and data collectionCenter for International Blood and Marrow Transplant Research (CIBMTR) has a web-based application called Data Back to Centers that allows centers to access their own previously submitted data. Using this application, we downloaded de-identified data on patients who underwent allogeneic HSCT from 2007 to 2017 at the University of Louisville Hospital. All adults above the age of 18 years who received MMF with tacrolimus for GVHD prophylaxis were included.Data collected included age, gender, ethnicity, disease, conditioning regimen, donor type, stem cell source, the incidence of acute GVHD at day 100 and at one-year, chronic GVHD at one year, and survival status. Patients with missing survival status at one year were excluded. This study included only de-identified patient information; therefore, it was exempt from the institutional review board.Statistical analysisThe simple and multiple logistic regression analyses were used to evaluate predictors for grade II-IV acute GVHD at day 100, where the potential predictors included age, gender, race, disease, conditioning regimen, donor type, and stem cell source. The estimates of the odds ratio and 95% confidence interval (CI) are reported. Survival curves were generated using the Kaplan-Meier method. Statistical significance was considered for p < 0.05. Data analysis was performed by means of SAS v9.4 software . A total of 150 patients were included in the analysis. Patients’ demographic and transplant characteristics are shown in Table For the entire cohort, the cumulative incidence of grade II-IV acute GVHD at day 100 was 35%, grade II-IV acute GVHD at one year was 43%, and chronic GVHD at one year was 37%. In simple and multiple logistic regression analyses, none of the factors evaluated were related to the development of grade II-IV acute GVHD at day 100 , 47%  and 68% , respectively Figure  and 3. F%, 47%  conditioning and peripheral blood as the sole source of stem cells . The recThere are several aspects of our study that have significant clinical relevance. The role of tacrolimus + MMF combination as an effective regimen for GVHD prophylaxis in NMAC/RIC HSCT is well established . HoweverThe primary outcomes reported in our study were similar to those reported in other historical data. For patients receiving MAC, the incidence of grade II-IV acute GVHD at day 100 was 37% in our study. Incidence of grade II-IV GVHD was reported as high as 78% with MTX + tacrolimus arm and 79% with MMF + tacrolimus arm by Perkins et al. Similarly, for the MAC group, the incidence of one-year extensive chronic graft-versus-host disease was 38% in our study versus 62% in MMF + tacrolimus arm and 73% in MTX + tacrolimus arm in the study by Perkins et al. [Based on our results, MMF and tacrolimus combination had reasonable efficacy as a prophylactic regimen for GVHD. Historical data has shown that MMF and tacrolimus combination is associated with a lower incidence of mucositis, delayed platelet recovery, and the need for narcotic analgesia , 6, 12. Although this is a small study that represents outcomes from a single institution, it helps eliminate bias from variation in institutional practices related to the intensity of conditioning regimen, infectious prophylaxis, and supportive measures. Due it is a retrospective nature where de-identified data was downloaded from CIBMTR application called Data Back to Centers, it lacks information on important safety and efficacy endpoints evaluated in other studies, including the incidence of mucositis, renal impairment, T-cell recovery and timing of engraftment. No data could be extracted for the incidence of relapse, non-relapse mortality, grade III-IV acute GVHD, or GVHD relapse-free survival. The role of anti-thymocyte globulin (ATG) for acute GVHD prophylaxis has been well established in the literature, and ATG has been used at our institution; none of the patients in our study population from 2007-2017 received ATG . As therIn conclusion, this institutional analysis shows that for patients undergoing HSCT with MAC, combination of MMF and tacrolimus yields acceptable outcomes for prevention of acute and chronic GVHD as well as one-year OS. The results of this study need to be validated in a large, multicenter randomized controlled trial.


Infection with the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to a previously unknown clinical picture, which is known as COVID-19 (COrona VIrus Disease-2019) and was first described in the Hubei region of China. The SARS-CoV-2 pandemic has implications for all areas of medicine. It directly and indirectly affects the care of neurological diseases. SARS-CoV-2 infection may be associated with an increased incidence of neurological manifestations such as encephalopathy and encephalomyelitis, ischemic stroke and intracerebral hemorrhage, anosmia and neuromuscular diseases.In October 2020, the German Society of Neurology  published the first guideline on the neurological manifestations of the new infection. This S1 guideline provides guidance for the care of patients with SARS-CoV-2 infection regarding neurological manifestations, patients with neurological disease with and without SARS-CoV-2 infection, and for the protection of healthcare workers.This is an abbreviated version of the guideline issued by the German Neurological society and published in the Guideline repository of the AWMF . Infection with the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to a previously unknown clinical picture, which is known as COVID-19 (COrona VIrus Disease-2019) and was first described in the Hubei region of China. The infection was declared a pandemic by the WHO on 11.03.2020. SARS-CoV-2 belongs to the community acquired respiratory viruses (CARV), which can cause upper and lower respiratory tract infections. The pathogen belongs to the group of coronaviruses, which can cause illnesses ranging from a normal cold to severe disease progression. Related to the SARS-CoV-2 virus are the viruses that cause the clinical picture of SARS (Severe Acute Respiratory Syndrome) and MERS (Middle East Respiratory Syndrome) and for which neurotropy has been demonstrated.The SARS-CoV-2 pandemic has implications for all areas of medicine. It also directly and indirectly affects the care of neurological diseases. It is discussed that SARS-CoV-2 infection could be associated with the increased occurrence of neurological manifestations such as encephalopathy and encephalomyelitis, ischemic stroke and intracerebral hemorrhage, anosmia and neuromuscular diseases.Many reports suggest a deterioration in the care of patients with neurological disorders due to the special demands on health care systems during the pandemic. Impacts on care can be seen directly and indirectly through the redistribution of resources in favor of SARS CoV-2 patients and protective measures for patients and caregivers. They affect the actions of laypersons , transport to hospital and intrahospital emergency care up to and including rehabilitation.Encephalopathies are quite common in COVID-19, especially in severe cases.Symptoms and clinical course are highly heterogeneous.For encephalopathies triggered by SARS-CoV-2 are discussed as pathomechanisms: hypoxia, sepsis, severe systemic inflammation, renal failure and cytokine storm.Biomarkers found in this context in patients with severe COVID-19 were IL-2, IL-6, IL-7, GCSF, TNF-alpha1.A solid basis for specific therapeutic measures does not yet exist.In the case of newly occurring central neurological symptoms, especially in the case of disturbances of consciousness, acute cognitive deficits and epileptic seizures, further diagnosis with cerebral imaging (MRI), EEG examination and cerebrospinal fluid diagnostics is necessary.The use of corticosteroids in high doses may be attempted if symptoms persist.It is advisable to continue immunotherapy. Individual risk factors such as patient age, morbidity and regional prevalence of COVID-19 should be taken into account to assess the individual patient risk and in individual cases de-escalation strategies such as a change of therapy or an extension of the interval should be evaluated.In case of COVID-19 disease, aspects such as disease activity of the underlying neurological disease as well as the previous course of therapy should be considered and the immune therapy should be paused if necessary.An increased risk of COVID-19 disease under immunotherapy cannot be deduced from existing reports.Guillain-Barré syndrome (GBS) is a serious complication of COVID-19 disease and can occur within days of the first respiratory symptoms.Clinically, mild courses up to severe tetraparesis and cranial nerve involvement are possible.Electroneurographically, a demyelinating pattern of damage usually dominates, although axonal processes are also reported.CSF diagnosis is necessary to exclude an infectious etiology. In most cases a cytoalbuminous dissociation appears.Serological testing of ganglioside antibodies is recommended.Intravenous immunoglobulins as well as plasma exchange procedures are to be regarded as equivalent and should be initiated promptly.Newly occurring multifocal neurological symptoms suggest acute disseminated encephalomyelitis (ADEM), so that rapid diagnosis including MRI and CSF analysis should be initiated.MRI imaging with contrast agent administration is essential for the detection of inflammatory lesions. A complementary hemorrhage-sensitive sequence helps to detect a hemorrhagic component.A normal CSF finding does not exclude the diagnosis of ADEM.A 3–5-day cycle with methylprednisolone 1 g/day should be administered intravenously. If symptoms persist intravenous immunoglobulins should be administered.Worldwide, the number of patients hospitalized for stroke has fallen under the COVID 19 pandemic. In the pandemic, it is important for all physicians involved in stroke care to maintain the best possible quality of care for cerebrovascular diseases even under the current difficult conditions.Ischemic strokes and, more rarely, intracerebral hemorrhage (ICH) occur in patients with COVID-19 disease and are associated with a more severe course of the disease.When treating COVID-19 patients, it is important to detect possible cerebrovascular complications and immediately initiate the necessary diagnostic procedures.A confirmed or presumed infection with SARS-CoV-2 in patients with acute stroke should not lead to different treatment than for other stroke patients. They should receive the same acute diagnostics and acute treatment as all stroke patients, provided that appropriate hygiene measures are observed.If epileptic seizures or a status epilepticus (SE) occur in patients with COVID-19 disease, it should be clarified whether it is a first-time seizure or a recurrence of previously known epilepsy.In case of unclear disturbance of consciousness, an EEG should be performed to detect and localize activity typical for epilepsy and to detect or exclude a non-convulsive SE.The treatment of seizures or SE should be performed according to the respective guidelines.Contraindications and interactions of anticonvulsants with substances used for COVID-19 disease should be taken into account.In patients with known fever-associated seizures, an NSAID (e.g. paracetamol) should be given.Infection with SARS-CoV-2 can lead to chemosensory disorders, with hyposmia and often anosmia.During the pandemic, a suddenly appearing olfactory disorder (anosmia) during free nasal breathing is very likely an expression of an infection with SARS-CoV-2.Olfactory disturbances can precede other disease symptoms and are therefore epidemiologically relevant (early identification of new “hot spots”).The olfactory disorder in COVID-19 seems to be mostly temporary. Whether or not a complete restitution is regularly achieved cannot yet be conclusively assessed.-Should the olfactory function does not return to normal within 3–4 weeks, a neurological and ENT presentation with further diagnostics is recommended.Myalgia, fatigue and hyper-CK-emia are the most common triad forms (40–70%) of skeletal muscle affection in COVID-19 cohorts.A COVID-19 disease requiring intensive care with invasive ventilation can lead to ICUAW (“ICU-acquired weakness” [ICU: intensive care unit]), a clinical picture in which CIP  and CIM  intertwine.There seems to be no massively increased risk for neuromuscular patients suffering from SARS-CoV-2 infection.Neurological manifestations of COVID-19 can easily remain masked in the severe, pulmonally dominated intensive care setting. Therefore, an active search for involvement of the central or peripheral nervous system is necessary.Invasive ventilation with PEEP (Positive End-Exspiratory Pressure), a permissive hypercapnia or in abdominal position can lead to an increase of the intracranial pressure, but still be necessary.If cerebral or spinal involvement by COVID-19 is suspected, a CT or MRI should be performed. In some patients who cannot be reliably examined clinically due to severe intensive care and/or analgosedation, this may also be indicated prophylactically .To date there are only a few case reports about the occurrence of a (meningo-)encephalitis in the context of COVID-19 . It is uIn most cases, (sub-)acute cognitive deficits and impaired consciousness are dominating. (Non-)convulsive seizures or akinetic mutism may also be the initial symptom. Delayed weaning or persistent delirium after extubation should suggest a neurological involvement.There are no specific MRI findings. Cortical hyperdensities with partial contrast uptake as well as extensive bilateral subcortical hyperdensities have been observed.EEG-studies reveal unspecific changes, focal findings and epileptic discharges.CSF findings range from normal cell findings to lymphocytic pleocytosis of > 100 cells/μl. A blood-cerebrospinal fluid barrier disturbance may be present. The direct detection of viral material by PCR is rarely successful. Standard pathogen diagnostics, especially for herpes viruses, should always be performed. In addition, autoantibody diagnosis from serum and cerebrospinal fluid is useful to exclude autoimmune encephalitis.In case of negative pathogen diagnostics and persistence of symptoms, high-dose therapy with methylprednisolone (1 g/day) may be attempted over a period of 3–5 days. There are also case reports for the subsequent use of plasma exchange procedures, although in these cases no infectious or inflammatory pattern could be detected by CSF diagnostics.There are several reports of Guillain-Barré Syndrome (GBS) in COVID-19 disease , 7–19. AThe neurological symptoms usually appear within 5–10 days after a COVID-19 diagnosis, although GBS may develop even weeks after infection. Due to the risk of cardiovascular complications, in particular respiratory insufficiency and cardiac arrhythmias, a rapid diagnosis and immediate therapy including critical care admission is recommended.The symptoms range from mild sensitive deficits to severe tetraparesis. Cranial nerve involvement with bilateral facial nerve palsy, ocular muscle palsy or Miller Fisher syndrome are also reported. Often the rapidly progressive course leads to respiratory insufficiency and need of ventilation.To date, no association between the severity of COVID-19 disease and the occurrence or course of GBS has been demonstrated. In some cases, the diagnosis of COVID-19 infection was made retrospectively. Consequently, a corresponding SARS-CoV-2 test is recommended with every new GBS diagnosis.In CSF a “cytoalbuminary dissociation” with a total protein increase and normal or slightly increased cell count (0–10 cells/μl) is usually detectable. Intrathecal immunoglobulin synthesis and isolated oligoclonal bands are atypical. In addition, a serological test for ganglioside antibodies should be performed, particularly in cases of cranial nerve involvement.The therapy does not differ from the usual treatment for GBS. Up to now, the primary use of intravenous immunoglobulins (0.4 g/kg bw) is preferred, but plasma exchange is considered equivalent. Corticosteroids should be avoided.ADEM occurs as a rare complication following an infection or vaccination and is usually characterized by a monophasic course. To date, there are few case reports of ADEM-like manifestations in the context of COVID-19 disease , 20–22. The clinical symptoms of ADEM vary significantly. Severe focal neurological deficits  and a subacute encephalopathic syndrome may occur.In MRI, large lesions in the medullary canal and basal ganglia, some of which absorb contrast medium, are typical. In addition, a blood-sensitive MRI sequence (T2* or SWI) should be performed to detect acute hemorrhagic leukoencephalitis , 22.CSF testing usually reveals pleocytosis of < 100 cells/μl and sometimes a slight blood-brain barrier disturbance. Isolated oligoclonal bands in CSF are uncommon. Testing for aquaporin-4 or myelin oligodendrocyte glycoprotein (MOG) antibodies should be performed in order to identify the initial manifestation of a neuromyelitis optica spectrum disorder (NMOSD) or MOG encephalomyelitis.Therapeutically, the administration of high-dose corticosteroids (1–2 g/day) intravenously over 3–5 days with or without oral tapering is recommended. In case of an insufficient response to steroids, the administration of immunoglobulins (0.4 g/kg bw intravenously) is recommended.Based on the few case reports of COVID-19 disease under immunotherapy, it is currently impossible to conclude whether immunotherapies are associated with an increased risk for COVID-19 or a poorer prognosis of the infection –28. For Encephalopathy is a vaguely defined, mostly reversible diffuse brain dysfunction without structural or direct infectious cause. Systemic infections can trigger septic encephalopathy or, in case of multi-organ failure, other types of metabolic encephalopathy.Pathomechanisms for encephalopathies triggered by SARS-CoV-2 include sepsis, severe systemic inflammation, renal failure and cytokine storm.Acute encephalitis may be caused by the direct infection of brain tissue with the virus. The virus may either directly damage brain cells through lytic replication cycles or through the cytotoxic immune response of the host organism. Often the meninges are also involved, which is why meningoencephalitis is usually a more appropriate term .The symptoms of encephalopathy and encephalitis include neuropsychological abnormalities, agitation and delirium, extrapyramidal-motor movement disorders, coordination disturbances, impairment of consciousness, epileptic seizures and focal neurological deficits.COVID-19 cases with symptoms suggestive of encephalitis showed (sudden) olfactory and gustatory disturbances (10–70%), headaches (13%), dizziness (17%), hallucinations, confusion, dysexecutive disorders (after intensive care 36%), agitation (during intensive care 69%), vigilance reduction (8–15%), neuralgia (2%), epileptic seizures (1%), ataxia (1%), sudden neurological deficits (3%) or pyramidal tract signs (67%). Most cases were reported without CSF analysis, so that the presence of acute viral encephalitis cannot be assessed with certainty , 32.Biomarkers found in patients with severe COVID-19 include IL-2, IL-6, IL-7, GSSF, TNF-alpha ), a syndrome in which CIP  and CIM  intertwine , 89. TheIn outpatients, the standard diagnostics of neuromuscular diseases  and immunomodulatory therapy (eculizumab) may be continued in consideration of the individual benefit-risk profile. The administration of rituximab or the initiation of oral long-term immunosuppression should be delayed depending on the clinical condition of the patient and the patient’s medical history , 91.Vaccination recommendation for healthy individuals in the same age groups  apply also for neuromuscular patients.In case of respiratory decompensation of ventilated patients or in case of newly occurring respiratory impairment after exposure to COVID-19, telephone or telemedicine contact with the treating physician and the respiratory care provider is recommended.In Germany, neuromuscular patients are managed in neuromuscular centers, by telephone and video or as outpatients and inpatients while maintaining the necessary distance. There is a close exchange with patient organizations such as the German Society for Muscle Patients and the World Muscle Society (WMS). Specific prevention and therapy recommendations have been published , 92. SpeSo far, due to the adherence to general hygiene regulations with self-isolation measures, only very few neuromuscular patients in Germany have been infected with SARS-CoV-2. Thus, there does not seem to be a massively increased risk for neuromuscular patients undergoing COVID-19 infection.Reports of severe neurological involvement such as encephalitis, encephalopathy, status epilepticus, ischemic and hemorrhagic strokes and severe neuropathies (Guillain-Barré syndrome) in COVID-19 are increasing, which makes this problem particularly relevant to neurological critical care therapy.The nervous system can be directly or, more frequently, indirectly be involved. This distinction is important for diagnostic and therapeutic decisions, and the prognosis of COVID-19 patients. The knowledge of neurological involvement may also play a role in the strategy of supportive intensive care therapy. For example, some forms of therapy such as ECMO could be unfavorable in the presence of extensive brain infarctions. Neurological manifestations of COVID-19 can easily remain masked in the severe, pulmonary dominated intensive care situation. Therefore, an active search for involvement of the central or peripheral nervous system is necessary.The general principles of intensive care for COVID-19, are summarized in the guideline “Recommendations for intensive care therapy of patients with COVID-19” of the DGIN and DIVI , 94.Neurological manifestations of great importance for intensive care medicine are encephalopathies, meningoencephalitis, severe ischemic or hemorrhagic strokes, rapidly progressing polyneuropathies and intensive care unit-acquired weakness.In addition to the usual diagnostics for SARS-CoV-2, a RT-PCR test from CSF should also be performed if clinical suspicion of encephalitis, delirium or polyneuritis exists and there are no contraindications against lumbar puncture.An EEG should be performed if the wake-up reaction is unclear, a delirium exists, or if there are indications of convulsive or nonconvulsive status epilepticus.In the case of focal neurological symptoms cerebral and/or spinal MRI imaging should be performed. In some patients who cannot be reliably examined clinically due the intensive care situation and/or analgosedation, this may also be indicated prophylactically  , 95.Optimization of ventilation parameters can influence intracranial pressure. Invasive ventilation with PEEP (Positive End-Exspiratory Pressure), permissive hypercapnia or in prone position can lead to an increase of intracranial pressure. However, the data on this is inconsistent. Therefore, the procedure always requires an individual risk-benefit assessment –98.Multimodal neuromonitoring  can facilitate the therapeutic procedure in patients with increased intracranial pressure .


Background. Coronary artery disease (CAD) is a common finding among patients undergoing trans-catheter aortic valve implantation (TAVI), who often present severely calcified coronary lesions. Evidence is scarce about the use of rotational atherectomy (RA) in this setting, in particular regarding long-term outcome. Methods. RA was performed on severely calcified coronary lesions concomitant with TAVI in a consecutive series of patients treated between 2010 and 2020. Immediate and long-term clinical outcomes are reported. Results. A concomitant CAD  was observed in 402/845 (47.6%) consecutive patients undergoing TAVI at the University Hospital of Verona. Angioplasty was performed in 104 patients (12.3%). Among these, 19 patients , were treated with RA after TAVI: 10 after implantation of a balloon-expandable trans-catheter valve and 9 after a self-expandable valve. All procedures were successful. Hypotension occurred in 3 patients (15.8%), with rapid recovery after the procedure; CI-AKI (contrast-induced acute kidney injury) in 3 patients (15.8%), of which two recovered within discharge. At a median follow-up of 21.5 months (Q1–3: 6–36) event free survival was 83.3%. Only one patient suffered a target vessel failure >2 years after RA. Neither stroke nor peri-procedural infarctions were detected. Conclusions. RA concomitant with TAVI was feasible and safe in patients treated with implantation of either self-expandable, or balloon-expandable trans-catheter aortic valves. Long-term clinical events related to the coronary procedure were extremely infrequent and the survival rate at median follow-up of 21.5 months was 83.3%. Coronary artery disease (CAD) is a common finding among patients with severe aortic valve stenosis (AVS) candidate to Transcatheter Aortic Valve Implantation (TAVI) ,2.This population often present severely calcified CAD with an increased risk of intra-procedural complications and mid-term clinical events related to stent restenosis and stent thrombosis due to sub-optimal lesion preparation.Rotational atherectomy (RA) could represent a valid aid for plaque debulking, in order to optimize the revascularization results in such cases.Nevertheless, the implementation of RA to support percutaneous coronary intervention (PCI) after TAVI is uncommon, mostly due to apparent technical issues.In a previous report  we demonThe aim of the present study was to investigate the clinical efficacy at long-term follow up of RA-assisted PCI after TAVI. Moreover, the study sought to enhance the analysis of RA feasibility in this scenario, presenting a larger single-centre series.This is a retrospective analysis of prospectively collected data of patients presenting symptomatic severe AVS undergoing TAVI and RA-assisted PCI at the University Hospital of Verona, Italy, from March 2010 to August 2020.Patients were addressed to TAVI when presenting increased surgical risk as predicted by STS score >4, and in all cases after Heart Team discussion [n = 1918), approved by the ethical review board of the University of Verona.All patients provided their written informed consent to be enrolled in the local registry , the Medtronic CoreValve, Evolut-R or Pro  were used, according to the anatomic characteristics of the valve morphology as analysed at the CT-scan.PCI were performed in case of critical stenosis according to angiographic evaluation. Critical stenosis was defined by % Diameter Stenosis (DS) > 50 for LM and > 70 otherwise. For borderline lesions, functional evaluation was performed through Fractional Flow Reserve (FFR).-Ostial and heavily calcified lesions that cannot be dilated by using balloon angioplasty;-Severe calcified stenosis where a stent cannot be delivered to its target.The presence of the following lesion characteristics indicated RA use:In addition, in several patients, other than the angiographic evaluation of the coronary calcification, the coronary analysis of the pre-TAVI CT scan has added important information regarding the extension of the vessel calcification .Before coronary interventions, all patients were pre-treated with a loading dose of aspirin (300 mg) and clopidogrel (300 mg).Percutaneous radial or femoral arterial accesses were used, using either a 6Fr  or 7–8 Fr  sheath. Conventional Judkins right or EBU left 6Fr guiding catheters were used.®, Teleflex, Morrisville, NY, USA) was adopted in some cases. As for pharmacologic support, Noradrenalin, Dobutamine or Dopamine could be used according to operators’ and anesthesiologists’ evaluation of the case.Mechanical and pharmacologic support could be planned as an upfront strategy according to operator preferences based on a case-by-case evaluation, or as a bailout strategy, in case of abrupt hemodynamic impairment. As for mechanical support (MCS) Intra-aortic Balloon Pump .The protocol for RA used in our Institution follows the recommendations of the European RA expert group .Accordingly, a single-curve guiding catheter is preferred in most cases, due to the strong support offered (Judkins Right 4 or EBU). Then, a floppy rotawire is advanced across the lesion. In case of challenging advancement, a regular wire can be placed distally to the lesion and then switched with the rotawire using a microcatheter. Plaque debulking starts with small burs (1.25 to 1.5 mm) as an initial strategy, followed by a step-up approach to limit debris size and complications, maintaining a burr-artery ratio of <0.6. Low speeds  are usually sufficient to obtain adequate plaque modification. No special rotablation cocktail was used in the flush solution, just composed of saline and heparin.Routine use of temporary PM is not recommended. However, having most of these procedures been performed immediately after the TAVI  a temporary pacemaker catheter was already inserted in most cases. In the 3 cases (15.8%) of RA performed after the TAVI procedure, a temporary pacemaker was not preventively implanted.In our series, nitrates were used during PCI as in any routine coronary intervention. Please note that, performing the procedure after TAVI allows a safe use of nitrates since the aortic stenosis has been already removed.No particular technique was used in the presence of balloon-expandable valves, which are commonly recognized as “intra-annular” and for this reason not hindering access to coronary ostia.Conversely, the frames of self-expandable valves always interpose in front of the coronary origins. They allow however catheters >10Fr through the struts . Of note, the passage of the catheter through the diamond-shaped valve struts provides, itself, a good support to the guiding catheter even if not deeply or selectively engaged into the coronary.In some cases, the difficulty in the advancement of Rotawire across the lesion was overcome by using a microcatheter for wires switching.In all the cases, RA was performed after TAVI because it was assumed that any eventual ischemic complication related to the PCI  would have been better tolerated after the complete release of the left ventricle pressure overload.Moreover, the ischemia related to the rapid ventricular pacing during balloon-expandable valve implantation is very short and unlikely to create irreversible hemodynamic impairment, even before myocardial revascularization.In addition, for patients with an estimated large ischemic burden (unprotected left main (ULM) stenosis, proximal left anterior descending (LAD) and ostial stenosis of very large dominant right coronary arteries (RCA) with impaired left ventricular function), self-expandable valves were generally preferred so that rapid ventricular pacing was not even needed.In most cases of TF-TAVI, the femoral vascular access used to implant the valve was used to perform the RA-assisted PCI.Among the TA-TAVI patients, RA-assisted PCI was performed through the right or left radial access in most cases.The occurrence of procedural-related complications was prospectively evaluated, as well as in-hospital adverse events and long-term clinical follow-up.All adverse clinical events were defined according to VARC-2 recommendations .Procedural complications included: death, major stroke, side branch occlusion, peri-procedural hypotension, need for inotropic (drug-based) or circulatory  support, cardiac tamponade, life-threatening arrhythmias, conversion to cardiac surgery or major vascular complications.The assessed in-hospital adverse events included: death, any troponin rise, peri-procedural (type 4a) myocardial infarction (MI) defined as the occurrence of new ischemic symptoms or signs in addition to elevation of cardiac biomarkers  ≤ 72 h after the index procedure, contrast-induced acute kidney injury  and need for dialysis.After discharge, clinical follow-up assessment was conducted during outpatients’ clinic visits at 1, 6, 12 and 24 months. In particular, data about occurrence of death, cardiovascular death, major stroke, acute coronary syndrome (ACS), need for urgent revascularization, target lesion failure (TLF), renal function, need for permanent pacemaker implantation and left ventricular ejection fraction we carefully assessed.Longer term follow-up was thereafter collected yearly through telephonic interviews or clinical evaluation.The composite event of major adverse cardiovascular and cerebrovascular events (MACCE) was defined as the occurrence of cardiac death, major stroke, ACS and TLF.The primary endpoint was defined as the occurrence of MACCE at long-term follow-up.The secondary endpoint was defined as the occurrence of any procedural complication related either to TAVI or RA-assisted PCI.Categorical data are presented as numbers and percentages. Continuous data are presented as means and standard deviations (SD) for normally distributed variables and as median and interquartile range (IQR) otherwise.All the statistical analysis was performed with the use of SPSS 24.0 software .Between March 2010 and August 2020, 845 patients underwent TAVI at the University Hospital of Verona. Among these, 402 patients (47.6%) presented CAD defined as a coronary stenosis >50% as to visual estimation in at least one of the main coronary arteries. In 104 (25.9%) patients. CAD was treated with PCI either as a staged procedure before or after TAVI or as a concomitant procedure.In 19 cases  RA was performed as debulking technique on severe calcific lesions.2 respectively, 42.1% were women. Mean STS score was 5.3 ± 5.0.The high-risk nature of the patients population was mainly driven by the advanced age (medium age was 81.4 ± 7.2) and medium-high SYNTAX score. Mean LV function and mean eGFR were 51.4 ± 14.5% and 54.7 ± 17.8 mL/min/1.73 mThree patients (15.8%) were treated under critical conditions: one with signs of extensive ongoing myocardial ischemia, and two with refractory heart failure evolving into cardiogenic shock. All the other patients were treated under stable hemodynamic conditions.All baseline characteristics are described in In 10 out of 19 (52.6%) patients included in the present study a balloon-expandable valve was implanted, while the remaining 9 patients (47.4%) received a self-expandable valve.Most patients underwent TAVI via trans-femoral route . In 5 caIn two patients the RA-assisted PCI were performed by the radial access after TA-TAVI.RA was performed after TAVI in all cases; concomitant with TAVI after valve deployment in 16 cases (84.2%), while in 3 cases (15.8%) it was performed as a staged procedure within one month after TAVI . In one of the staged procedures, hemodynamic instability occurred during TAVI, so that the operator preferred performing RA after patient stabilization. In the other two cases, the complex coronary scenario revealed by the coronary angiography during TAVI led the operators to postpone PCI to heart team discussion and case preparation.All procedures were performed successfully and with implantation of DES after plaque debulking with RA and balloon dilatation before stenting.IVUS was used in all cases of left main PCI, both for pre-PCI assessment and for stent optimization.Mean amount contrast medium used, considering the sum of TAVI and RA procedure in case of staged approach, was 210.7 ± 92.4 mL. Mean procedural time was 164.0 ± 51.1 min.Inotropic support was used as upfront strategy in two cases , that experienced significant procedural hypotension (10.5%) restored with vasoactive drugs. Another patient (5.3%) presented unexpected hemodynamic worsening, requiring bailout inotropes infusion. In all these patients a rapid hemodynamic recovery was observed after the end of the PCI. No cases of major ventricular arrhythmias and cardiac tamponade were observed, and no patient required vascular surgery or conversion to cardiac surgery.Complete procedural characteristics and outcomes are reported in In-hospital stay mean length was 9.4 ± 10.5 days; of these 2.7 ± 5.7 in the intensive care unit.Serum creatinine levels did rise significantly in three patients (15.8%) with two of them (10.5%) treated with TAVI and PCI in emergency conditions (cardiogenic shock and hypotension with refractory ventricular tachycardia), requiring a short cycle of renal replacement therapy. However, their renal function returned to baseline after hemodynamic stabilization.None of the remaining patients had a significant rise of creatinine after TAVI and RA-assisted PCI, and no permanent pace-maker implantation was needed at the time of hospital discharge.A non-significant troponin release as detected by ultra-sensitivity method (any elevation >15 ng/L) was observed in all cases between 6 and 48 h after procedure. However, no peri-procedural myocardial infarction occurred.In Hospital complications are reported in Long term follow-up was available for a total of 18 out of 19 patients, who were discharged since one patient died before discharge for acute intestinal ischemia.Median follow-up length was 21.5 months (interquartile range Q1–Q3 = 6–36 months).Six patients (33.3%) died at long-term follow-up: three (16.7%) for cardiac causes and 3 (16.7%) for extra-cardiac causes.One patient (5.6%), who underwent RA on ostial RCA with stenting of proximal RCA was admitted two years after TAVI for an inferior NSTEMI with angiographic documentation of in-stent restenosis . The same patient died for heart failure at the age of 93, 49 months after the index procedure. Of note, no further TLF were reported.Three patients (16.7%) required a permanent pace-maker implantation during follow up, which occurred respectively after a period of three months, sixteen months and twenty-four months from the discharge date.Mean eGFR and LVEF values at follow-up did not show a significant variation when compared to baseline values before the procedure.Long-term follow-up events are reported in The main findings of this study are the feasibility, the safety and the long-term clinical efficacy of RA-assisted PCI in patients with complex CAD undergoing TAVI.To our best knowledge, this is the first study reporting the long-term outcome of combined RA and TAVI. These results support our previously reported data .CAD is often observed during the pre-TAVI diagnostic examinations, in most cases as an incidental finding, and the management of coronary stenosis in this setting is not standardized.Coronary artery bypass surgery concomitant with SAVR improve long-term survival compared to SAVR alone in patients with CAD  and is tEvidences in favor of percutaneous revascularization in TAVI patients are instead contradictory ,10 and cHowever, the rapid expansion of TAVI indications in younger patients as an alternative to SAVR is likely to expand also the indications for the treatment of the bystander CAD with a combined approach of TAVI and percutaneous myocardial revascularization. Nevertheless, patients undergoing TAVI usually present complex CAD which may need aggressive plaque debulking techniques in some cases. In these setting, RA can facilitate stent delivery and adequate stent expansion with the consequent reduction of the risk of procedural failure, stent under-expansion and potentially stent thrombosis and restenosis. Following these considerations, the number of TAVI patients needing RA is likely to increase in the next years.In our series, RA was used in 18.3% of all the PCI procedures performed in TAVI patients, a five to ten-fold higher percentage compared to that reported in clinical practice among non-TAVI patients .However, available data about RA in TAVI focuses on feasibility and short-term outcome ,13, withRegarding the feasibility, a series of 25 patients from a Japanese multi-centre registry (OCEAN Registry) has been published: in almost all cases RA and PCI were performed in a staged fashion before TAVI .We believe that such approach may lead to more potential ischemic complications related to the PCI in case of slow flow or vessel occlusion, due to the still present aortic stenosis and the related left ventricular increased oxygen demand as demonstrated by the routinely use of balloon pump, inotropic support and intra-vascular ultrasound as preventive measures in the OCEAN Registry  .Similarly, Lippmann et al. demonstrated the feasibility of RA-facilitated PCI in a series of 29 patients with severe AS patients under consideration for TAVI. A significant pressure and heart rate drop in 24 patients (82.8%) was observed and up to 1/3 of the cases needed for inotropic support and/or temporary pacing during the procedure .The potential risk of sustained hemodynamic instability during RA observed in severe aortic stenosis patients may support our strategy of undertaking complex PCI after the valve deployment. Moreover, concerns about performing TAVI in patients with underlying ischemia seems no more justifiable, since recent evidence from meta-analysis data has shown that PCI before TAVI does not improve MACE-free survival and can actually increase the risk of complications .In support of this position is the observation that even in the higher risk patients with TA-TAVI, and with severe calcified CAD of the left main or the proximal LAD, balloon-expandable valves were implanted under rapid pacing before treating the CAD without relevant hemodynamic issues, and the RA-assisted PCI was performed after the TAVI without complications.Our very first experience obtained in 2 patients showed the feasibility of performing urgent RA during the same TAVI procedure after the valve deployment , and a tAvailable data does not allow to tell whether RA would rather be done during the same TAVI session or as a deferred procedure; however, in the absence of complications related to the TAVI procedure, the concomitant strategy is feasible and appears reasonable since it lowers the risk for vascular complications and reduces in-hospital stay and costs in both, TF and TA-TAVI.Regarding the possible impact of a concomitant versus staged procedure on renal function, some concerns may rise among clinicians about the safety of exposing patients to higher contrast medium dose potentially used in such complex procedures. However, our experience supports the choice of a concomitant strategy as safer in term of CI-AKI risk. Indeed, severe aortic stenosis patients undergoing staged coronary procedures before TAVI are likely to be more exposed to contrast medium damage, since cardiac output before aortic valve substitution is compromised and consequently peripheric and renal perfusion is lower than after valve replacement.In the present manuscript, we analysed the impact of RA combined with TAVI on short-term and long-term renal function. In our series, we found an incidence of CI-AKI of 15.8%, in line with previous reports about TAVI alone procedures . In two Finally, our series provide, for the first time, information about the long-term clinical outcomes after RA-assisted PCI in TAVI. The MACCE-free survival rate at a mean follow-up of 24 months was 83.3%, comparable with that of TAVI patients without CAD . Of noteAt long-term follow-up, coronary adverse events consisted only in one target lesion failure.Our data should be interpreted with caution given the large experience of our group in performing RA ,5 and thThe number of patients reported is still limited because of their high complexity and the single centre nature of the observation. RA is a technically demanding procedure: the results obtained may widely vary depending on centres’ experience.RA concomitant with TAVI after valve deployment is feasible and safe in patients presenting AVS associated with calcified CAD, leading to satisfactory immediate and long-term clinical outcomes.