Recent years have observed the increasing utilization of robotic-assisted and computer navigation techniques in total hip arthroplasty (THA), given the proposed benefits of enhanced consistency and precision in implant placement. The purpose of this study was to conduct a systematic review of randomized controlled trials (RCTs) to determine whether differences in surgical times, adverse events, and implant positioning existed between manual, robotic-assisted, and computer navigation THA.PubMed, OVID/MEDLINE, and Cochrane databases were queried for RCTs comparing robotic-assisted versus manual THA and computer navigation versus manual THA at a minimum 1-year follow-up. Frequentist model network meta-analyses with P-scores were conducted to compare revisions, complications, and surgical times among the three treatment groups. A random-effects meta-analysis between computer navigation and manual THAs was conducted to analyze cup positioning because no robotic-assisted THA studies reported this outcome.P < 0.001). No difference was observed in the incidence of all-cause complications  or revisions  among the three treatment groups based on the network meta-analysis. In three studies that reported acetabular implant positioning, computer navigation had a significantly higher percentage of acetabular cups placed in the Lewinnek “safe zone” compared with manual THA .Five RCTs compared robotic-assisted and manual THAs, while seven compared computer navigation and manual THAs. manual THA was associated with significantly reduced surgical time in comparison with computer navigation (mean difference: 23.3 minutes) and robotic-assisted THAs (mean difference: 8.6 minutes; manual THA results in markedly shorter surgical times and a similar incidence of complications and revisions compared with robotic-assisted and computer navigation THAs, given the sample sizes available for study. However, computer navigation THA led to increased precision in the placement of acetabular implants. The proposed benefits of robotic-assisted and computer navigation THAs include increased precision and accuracy of the acetabular cup version and inclination along with more consistent restoration of leg length and offset.Although previous literature has sought to investigate the influence of manual versus robotic-assisted and computer navigation THAs on patient outcomes, these studies have been limited by the level of evidence of included articles. The purpose of this study was to conduct a systematic review of only level 1 evidence to determine whether there are any differences in surgical time, adverse events, and implant positioning between manual, robotic-assisted, and computer-navigated THAs.14 The query for studies was done in August 2020 using the Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials, PubMed (2008 to 2019), and OVID/MEDLINE (2008 to 2019) databases using the Boolean search strategy “(((((Hip) AND (arthroplasty)) OR (THA)) AND (robotic))) OR (computer-nav*).”This systematic review and meta-analysis was conducted in accordance with the 2009 Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines.Inclusion criteria for the search mentioned earlier consisted of all studies published in the English language reporting information regarding the use of robotic-assisted or computer-navigated THAs. Exclusion criteria consisted of (1) nonrandomized controlled trials, (2) cadaveric studies, (3) animal studies, (4) preclinical articles, (5) editorial articles, (6) surveys or case reports, and (7) less than 1-year minimum follow-up. Two investigators independently reviewed the abstracts from all identified articles. Full-text articles were obtained for review to allow additional assessment of inclusion and exclusion criteria when necessary. Bibliographies of relevant systematic reviews and included articles were manually searched for additional references.15 was used to assess the methodological quality of all included randomized controlled trials (RCTs). The Jadad Scale consists of a five-point questionnaire used to critically evaluate the methodological quality of RCTs. The following questions are used to assess each study: (1) Was the study described as random? (2) Was the randomization scheme described and appropriate? (3) Was the study described as double-blind? (4) Was the method of double blinding appropriate? (5) Was there a description of dropouts and withdrawals? The scale is graded from 0 to 5 . The interobserver reliability for the two independent graders (blinded for review) was excellent at 0.95 .The Jadad ScaleCategories for data collection for each full article included (1) publication characteristics, (2) patient demographics, (3) patient-reported outcome measures, (4) adverse events, (5) inclusion and exclusion criteria; (6) and implant positioning data, including acetabular inclination and version, and proportion of acetabular cups placed within the safe zone. Means and standard deviations were extracted to calculate pooled values for patient demographics. Ranges were reported for all outcomes not amenable to meta-analysis to avoid improper pooling and misinterpretation bias. Owing to variability in the reporting of patient-reported outcome measures, these were not considered for the meta-analysis. The Fisher exact test was used to compare specific revision and complications among the three cohorts.16 The assumption of consistency from direct and indirect evidence under the random-effects model was assessed using the Q statistic.17 Competing treatments were ranked in the network meta-analysis by using point estimates and standard errors to calculate P-scores.18 P-scores represent a measure of certainty that a specific treatment is superior to other treatments in the network model for a given outcome. The higher the P-score for a given treatment, the more certainty the treatment is superior in comparison with the other treatments. We used the term “treatment ranking” to order the treatment arms by P-score from best to worst treatment for each outcome.A frequentist network meta-analysis model was used to compare the effect of robotic-assisted, computer navigation, and manual THAs on the outcomes of surgical time, revision surgeries, and postoperative complications.Given that a network meta-analysis compares multiple treatments, these models consider both direct (comparisons from studies that include both treatment arms) and indirect evidence (comparisons that did not include both treatment arms within a study). For example, if a study compared complications between manual and robotic THAs (direct evidence), the network model also considers manual THA complications in studies that compare manual and computer navigation THAs, although these contribute less weight to the overall effect because indirect evidence constitutes a smaller proportion of the total evidence. Therefore, although the cumulative number of an event (complications) may seem markedly greater in one treatment arm compared with another, the events in the subset of studies providing direct evidence in comparing two treatment arms may be similar and contribute more weight.19 Network meta-analysis could not be conducted for this outcome, given that none of the included studies concerning robotic-assisted THA assessed implant positioning. Therefore, only computer navigation–assisted and manual THAs were compared for this outcome. Forest plots were used to graphically depict the comparison of surgical time, implant positioning, and complication and revision surgery rates between competing treatments. Study heterogeneity was assessed using I-squared (I2) tests. All statistical analyses were conducted using R Project for Statistical Computing software .Precision of implant positioning was analyzed through a random effects meta-analysis of the pooled rate of acetabular cup placement in the Lewinnek safe zone.20212223242526 assessed the use of computer-navigated THA versus manual THA while the remaining five2728293031 assessed the use of robotic-assisted THA versus manual THA. The mean age  and BMI  did not differ between the three cohorts. The pooled mean follow-up was 4.3 years  among all 12 studies, and there was no difference in the mean follow-up between the groups . All robotic-assisted THA were done with the ROBODOC/ORTHODOC  system for femoral preparation and milling  (Table P < 0.001). Treatment rankings  based on the network meta-analysis were as follows: (1) manual (P-score = 1.00), (2) navigation-assisted (P-score = 0.50), and (3) robotic (P-score = 0.00).Of the 12 RCTs, six reported surgical time and were included in the network meta-analysis. Three studies (N = 346 patients) directly compared robotic and manual THAs, and three studies (N = 373 patients) compared navigation-assisted and manual THAs. Conducting manual THA (pooled mean: 86.6 minutes) was associated with a significantly reduced mean surgical time in comparison with both robotic-assisted (pooled mean: 110.7 minutes) and navigation-assisted THAs  directly comparing robotic-assisted THA with manual THA and seven studies (N = 598 patients) comparing navigation-assisted THA with manual THA. No significant differences were observed between treatments for all-cause postoperative revisions with the sample sizes available for study Table . TreatmeP = 0.002). Post hoc analysis revealed that robotic THA was associated with more revisions for instability compared with manual THA (P = 0.003) but not computer-navigated THA (P = 0.11). Furthermore, there was no significant difference between the rate of revision for instability between the manual and computer navigation cohorts (P = 0.34). No association was observed between the THA method and the head and liner exchange for polyethylene wear (P = 0.19), with three patients (1.1%) revised with a head and liner exchange in the robotic cohort, zero patients (0.0%) in the computer navigation cohort, and five patients (0.87%) in the manual cohort , while it was dislocation (n = 5) for the robotic-assisted cohort. The three revisions in the computer navigation cohort were for periprosthetic joint infection (n = 1), dislocation (n = 1), and periprosthetic fracture (n = 1). When comparing revisions for instability between the groups, five patients (1.8%) were revised in the robotic-assisted cohort, one 0.34%) was revised in the computer navigation cohort, and none were revised in the manual cohort (% was revP < 0.001). However, there was no significant difference is dislocation rates between the computer navigation and manual cohorts (P = 0.67).Postoperative complication rates were reported in a total of 11 studies. No significant differences were observed between the three groups for likelihood of all-cause postoperative complications Table  based onP = 0.02). Moderate heterogeneity was observed between pooled studies in the manual THA cohort (I2 = 68%), whereas the computer navigation THA cohort had no statistical heterogeneity (I2 = 0%). No studies comparing robotic-assisted and manual THAs reported on acetabular cup positioning.The number of acetabular cups placed in the Lewinnek safe zone relative to the total number of cups placed Figure  was repoP = 0.15).The mean Jadad score among all 12 studies was 3.6 ± 1.1 Table , indicatRobotic-assisted and computer-navigated THAs have become increasingly popular with a purported benefit of more precise implant positioning that could lead to a reduced risk of complications. However, with the emphasis on value-based care, questions remain whether the costs of these procedures outweigh these proposed benefits. The results from this study demonstrate that manual THA leads to reduced operating room time when compared with computer navigation–assisted and robotic THAs, with no significant differences in rates of all-cause postoperative complications or revisions. However, robotic-assisted THA was associated with a higher incidence of postoperative dislocations and revisions for instability, although the only robotic systems implicated in RCTs to date and subsequently identified in this systematic review used robotic assistance only for preparation of the femoral implant. The use of computer navigation led to more precise positioning of acetabular implants and trends toward fewer complications.32 conducted a systematic review of seven computer navigation versus manual THA studies and reported that surgical times were significantly increased for the computer navigation method . Other systematic reviews solely comparing computer navigation and manual THAs34 or robotic-assisted and manual THAs35 have also reported increased surgical times with these approaches compared with manual THA. The increased surgical time is likely because of the learning curve encountered when using these new technologies and the setup required, which is greater than that of manual THA. However, previous studies have indicated that over time with the continued use of robotics or computer-navigated THA, surgical times gradually decrease and may become comparable with manual THA.37 Future studies are warranted to determine which factors associated with these procedures contribute the most to the increased surgical times found in multiple studies.The increased surgical time with robotic-assisted and computer-navigated THAs found in our study corroborates findings found previously. Specifically, we found that manual THA resulted in a mean 8.6-minute shorter procedure compared with computer navigation THA and a 23.4-minute shorter procedure compared with robotic THA. Liu et al12 conducted a Medicare database analysis of 64,944 THA procedures  and reported that computer navigation THA and manual THA had comparable dislocation rates, but computer navigation resulted in markedly higher rates of revision THA at 30 days (1.0% versus 1.4%) and 90 days (1.2% versus 1.7%); however, these were 0.4% and 0.5% differences, respectively. However, our data are more consistent with those reported by Bohl et al.38 In a large claims database of claims database of 803,732 primary THA procedures, Bohl et al found that navigation-based THA was associated with reductions in rates of dislocation and aseptic acetabular revisions compared with manual THA. Furthermore, a recent nationwide database study of 309,252 THAs done by Gausden et al39 found that the use of computer-navigated THA resulted in a 12% reduced odds of 90-day complications and lower readmission rates for dislocation in comparison with manual THA. In this study, the complication rate for computer navigation THA was 0.7%, whereas manual THA had a complication rate of 1.4%. There were no acetabular implant revisions for loosening in either cohort, which may be a function of the follow-up period; however, only one dislocation was experienced in the computer navigation cohort, whereas four were experienced in the manual THA cohort. Furthermore, a total of five patients who underwent manual THA subsequently went on to have head and liner exchanges for excessive wear, while no patients in the computer navigation cohort had revisions for this reason. Although it is logical that navigation-based THA would result in fewer acetabular implant revisions because it is theorized to improve cup placement, we are limited in our ability to draw conclusions from these findings with these data, given that the head and liner exchanges came from one study in which patients underwent THA between 1994 and 1998 and therefore highly cross-linked polyethylene was not used. However, our findings remain supported by the previous literature discussed earlier.This study demonstrated that there are no differences in the incidence of all-cause complications or all-cause revision THA when comparing the three techniques. However, there was a trend toward an increased incidence of all-cause complications with manual THA when compared with computer-navigated THA. Montgomery et alP = 0.06).35 However, these authors also reported that (1) the rate of dislocations was higher in the robotic cohort than the manual cohort, (2) the rate of revision was slightly higher in robotic patients (two versus one) and was attributed to abductor insufficiency, and (3) one included study noted a significantly higher rate of Trendelenburg signs postoperatively in robotic patients . Although conflicting evidence exists among lower quality systematic reviews and trials, this study of RCTs indicates no difference in all-cause complication and revision rates among these treatments using a network approach; however, it seems that there is an association between the robotic-assisted THA approach and the resultant instability and dislocations when conducting direct comparisons that do not account for study variability because statistically significant differences were observed. In addition, the overall complication rate of robotic THA was high at 16.2%, the significance of which may not be clear using a network approach. Future RCTs are required to examine the short-term complications of systems that implicate robotic assistance for both acetabular and femoral implant placements and that focus on direct comparisons of these adverse events.The results from this study demonstrate that robotic-assisted THA was associated with a markedly higher rate of postoperative dislocations and revision for instability when compared directly. However, it should be noted that these robotic systems only used this technology for preparation and milling of the femoral canal. To our knowledge, there are currently no RCTs using more contemporary robotic systems. Therefore, this may have influenced the increased dislocation and revision rates observed among these studies. Despite the fact that the acetabular implant was placed manually, one may still expect to observe no significant differences in dislocations and revisions for instability when compared with the manual THA cohort. Interestingly, a recent meta-analysis of seven robotic-assisted versus manual THA studies reported that the odds ratio for postoperative complications for robotic-assisted THA compared with manual THA was 3.35 , although this did not reach statistical significance . Therefore, it is possible that the same benefits observed for computer navigation THA in this study are also applicable for robotic-assisted THA. Indeed, previous literature has suggested this equivalency, although it remains limited. Ando et al41 compared robotic-assisted THA with navigation-based THA for patients with osteoarthritis secondary to hip dysplasia and reported an advantage for robotic THA in reducing acetabular cup placement variation, although the clinical relevance of this finding was not clear. Shibanumaet al42 reported no statistically significant differences in postoperative radiographic inclination or anteversion between robotic-assisted versus navigation-assisted THA in a prospective study involving 60 patients. Overall, although meaningful comparisons between these two methods were not available given in the study data, comparison between computer navigation THA and manual THA demonstrated that computer navigation THA confers superior accuracy and precision of acetabular cup placement without jeopardizing safety as measured by complications and revisions as compared with manual THA. This finding may also have accounted for the absence of acetabular cup revisions in this cohort (Table Computer navigation THA resulted in markedly better acetabular cup precision and accuracy when compared with manual THA. Specifically, a total of 79% of the cups were placed in the Lewinnek safe zone with computer-assisted THA compared with 52% of the cups with manual THA. A recent systematic review also reported statistically significant improvements in precision and accuracy for computer navigation cup placement when compared with manual THA.43 Because these models depend on retrospectively collected data for recently available systems, studies included in this review may not reflect the cost-effectiveness associated with these findings. This review highlights the need for future RCTs to study a wider range of robotic systems that are currently available that assist with both acetabular and femoral preparation because the current data suggest that robotic preparation of solely the femoral implant may result in costly complications and revisions related to the acetabular preparation. Future studies are needed to compare the immediate and long-term cost differences between these three studies, if they exist, should the data become available.Recent literature, which has used Markov modeling for both robotic-assisted and computer-navigated THAs, has reported that potential reductions in revision rates, complications, and readmissions make these systems cost-effective compared with manual THA.The results of this study should be considered in the context of several limitations. First, as with all systematic reviews, publication bias may be present, which may influence our results because studies with equivocal findings may be less likely to be published and therefore would not be included in this review. Second, owing to variable reporting and outcome heterogeneity, we were unable to conduct a network meta-analysis of acetabular implant positioning and patient-reported outcome measures. Third, we used the Lewinnek safe zone as the benchmark for proper implant positioning. We recognize that this may not be the best position for an acetabular implant for all patients, particularly those with spinopelvic pathology such as a stiff lumbar spine. However, we do not think that this greatly limits our comparison of precision between the three techniques because most of the included studies were published before the emphasis on the spinopelvic relationship and acetabular implant positioning. Fourth, we recognize that the only published RCTs to date on robotic-assisted THA evaluate one system. This system only used robotic assistance for preparation and milling of the femoral canal, and the acetabular implant was placed manually, which limits our ability to draw conclusions on the influence of robotics on the placement of the acetabular implant. In addition, given that only one robotic system was used, we are thus unable to draw any conclusions regarding other robotic systems that may be in the market. Fifth, 10 different computer navigation systems were used in the included studies. We are unable to draw any conclusions regarding any one particular system based on the results from this study. To draw any conclusions regarding any particular computer navigation or robotic system requires multiple independently funded, bias-free, well-designed, prospective RCTs with long-term follow-up of both clinical and radiographic outcomes. Finally, we did not exclude studies based on the date of publication or when THA was done. This is relevant because several studies included THAs done before the adoption of highly cross-linked polyethylene. This in addition to the long follow-up likely explains why all the head and liner exchanges included in the manual cohort came from one study with a mean 14.2-year follow-up in which the patients underwent THA between 1994 and 1998.Based on currently available level 1 RCTs, manual THA results in significantly shorter surgical times and a similar incidence of complications and revisions compared with RA and CN THAs, given the sample sizes available for study. However, CN THA led to increased precision in the placement of acetabular implants in the “safe zone” compared with manual THA.


The ongoing Coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has imposed a huge threat to public health across the world. While vaccinations are essential for reducing virus transmission and attenuating disease severity, the nature of high mutation rate of SARS-CoV-2 renders vaccines less effective, urging quick development of effective therapies for COVID-19 disease. However, developing novel drugs remains extremely challenging due to the lengthy process and high cost. Alternatively, repurposing of existing drugs on the market represents a rapid and safe strategy for combating COVID-19 pandemic. Bronchodilators are first line drugs for inflammatory lung diseases, such as asthma and chronic obstructive pulmonary disease (COPD). Compared to other anti-inflammatory drugs repurposed for COVID-19, bronchodilators are unique in that they have both anti-inflammatory and bronchodilating properties. Whether the dual properties of bronchodilators empower them greater potential to be repurposed for COVID-19 is worth exploring. In fact, clinical and preclinical studies have recently emerged to investigate the benefits of bronchodilators such assalbutamol, formoterol and theophylline in treating COVID-19, and many of them have shown encouraging efficacy on attenuating disease severity of pneumonia and other associated symptoms. To comprehensively understand the latest progress on COVID-19 intervention with bronchodilators, this review will summarize recent findings in this area and highlight the promising clinical benefits and possible adverse effects of bronchodilators as therapeutic options for COVID-19 with a focus on β2 receptor agonists, anticholinergic drugs and theophylline. The emergence of SARS-CoV-2 was reported in December 2019 and could cause COVID-19. It gained its name due to its similarity to SARS-CoV given by the International Committee on Taxonomy of Viruses (ICTV) . ExternaThe symptoms of COVID-19 vary from asymptomatic, mild, moderate, to severe and critical. Severely and critically ill COVID-19 patients have a high risk of acute respiratory distress syndrome (ARDS), infiltrating pneumonia, sepsis, septic shock, and even death . Autopsyin vitro and in vivo that SARS-CoV-2 can infect the lung and multiple organs  released from virus-infected host cells, eliciting IL-1β- and pyroptotic cell death-dependent systemic inflammation . ClinicaThe immunopathology of COVID-19 strongly implies that targeting the overwhelmed inflammatory response and thus reversing respiratory dysfunction could be a viable strategy to reduce its morbidity and mortality.+ and CD8+ T cells during the acute phase. The number of CD4+ and CD8+ T cells is reduced in both mild and severe diseases, but in severe cases it is particularly lower , bronchospasm and other airflow restricted lung diseases . The freIt is verified by a clinical trial in COPD patients that using a combination of long-acting β2-adrenoceptor agonists and long-acting muscarinic acetylcholine receptor antagonists plays a synergistic role on the relaxation of airway smooth muscles (ASM) . For theDuring the pandemic of COVID-19, bronchodilators have been repurposed to treat COVID-19 patients and encouraging efficacy has been achieved, suggesting promising potential to be therapeutic options for COVID-19 .β2 adrenoceptor agonists are used to relieve asthma symptoms by stimulating β2 receptors on the surface of airway smooth muscle and mast cells, relaxing airway smooth muscle, inhibiting the release of inflammatory mediators from mast cells and basophils, reducing microvascular permeability, and increasing airway epithelial ciliary oscillation. Based on the acting duration time, they can be divided into short-acting (4–6 h of action) agonists, such as terbutaline and salbutamol, and long-acting (12 h of action) agonists, such as formoterol and salmeterol .β2 adrenoceptor agonists were used to treat the patients with moderate and severe COVID-19 , Salbutain vivo by inhibiting the activation of NLRP3 inflammasome -salte IL-10 . FurtherCholinergic receptor blockers can inhibit the downstream signaling pathways by competitive combination of these receptors with their ligands  on bronchial smooth muscle and exhibit the role of bronchial dilation. Ipratropium is a potent anticholinergic drug with high selectivity and affinity for bronchial smooth muscle M receptors, which has a strong effect on the relaxation of smooth muscle, but a weak effect on the relaxation of respiratory glands and cardiovascular system. By blocking the smooth muscle muscarinic M3 receptor subtype, the selective anticholinergic medication trotripum causes bronchiectasis. Ipratropium refers to short- and medium-acting cholinergic receptor blockers, while tiotropium refers to the long-acting cholinergic receptor blockers.Tiotropium was identified as a promising candidate for SARS-CoV-2 in a drug-target interaction-based prediction study of commercially available drugs using a deep learning algorithm . This fiin vitro assay conducted in human bronchial epithelial cells demonstrated that tiotropium was able to inhibit LPS-induced NF-κB activation, thereby reducing the production of chemokine IL-8  is an important drug used either alone or in combination with other drugs to treat COPD or asthma with a long history. As phosphodiesterase inhibitors, theophylline have a direct dilating effect on airway smooth muscles, albeit a slightly weaker than that of β2 receptor agonists. These drugs have a rapid onset of action but a relatively short duration, for example, aminophylline and sulpiride. Theophylline can also function as an adenosine receptor antagonist and responsible for its ability to relax pulmonary blood vessels .in silico study showed that among 5 methylxanthines tested, theophylline exhibited the best binding affinity for all three target proteins of SARS-CoV-2, the spike protein, main protease, and nucleocapsid protein. This lays the groundwork for future studies of theophylline as an antiviral drug for COVID-19  associated with COVID-19. A retrospective study to examine the potential efficacy and safety of theophylline and pentoxifylline in COVID-19 pneumonia patients demonstrated the associations of theophylline and pentoxifylline with an increase in ROX score and nominal decreases in C-reactive protein and mortality, laying the basis for further exploration of clinical benefits of these drugs for COVID-19 pneumonia . The undCOVID-19 .pP2A enzymatic activity to repress IL-8 secretion in airway smooth muscle cells   Ichiyam.The side effects of β2 agonists are mainly related to the activation of the sympathetic nervous system with the most common being shivering, tension, palpitation and muscle spasm. In severe conditions side effects can be extended to paradoxical bronchospasm, hypersensitivity reaction, hypokalemia and myocardial infarction. Patients who have been using short-acting β2 adrenergic receptor agonists for a long period of time may need an increasing dose to achieve the corresponding benefit due to the downregulation of its receptor. The main side effects of M receptor antagonists are symptoms caused by decreased vagal tone, such as dry mouth, urinary retention, tachycardia, constipation and stomach upset, etc. Since it can induce delirium in elderly patients, cautions needs to be taken when using M receptor antagonists . When asWhile most of these adverse effects of bronchodilators have not been documented in a limited number of clinical studies of COVID-19, attentions need to be paid to them in future investigations. In addition, montelukast (non-bronchodilator) may benefit COVID-19 patients by maintaining the inflammatory/anti-inflammatory balance, preventing respiratory failure through bronchodilator activity, and lowering mortality .Emerging evidences from preliminary clinical results reveal the potential benefits of bronchodilators as repurposed drugs for the treatment of pneumonia or bronchospasm associated with COVID-19. Drug repurposing suggests that attention should be paid to the potential benefits of bronchodilator drugs in the treatment of critically ill patients of COVID-19. It is required to increase the clinical application of bronchodilator drugs, which may bring benefits to critically ill patients. The emerging and reemerging respiratory viral infections will pose new threats to the world in the future. Repurposing use of bronchodilators for COVID-19 would also very likely benefit the therapy for future emerging respiratory infectious disease.


Follow-up care provides long-term support for cancer survivors. Little is known about follow-up care in hematologic malignancies.Our questionnaire-based study included blood cancer survivors diagnosed at the University Hospital of Essen before 2010, with a ≥ 3-year interval since the last intense treatment. The primary goal of the retrospective study was the identification and characterization of follow-up institutions.p < 0.0001). While allogeneic transplant recipients clustered at the university hospital, survivors with monoclonal gammopathy, multiple myeloma, myeloproliferative disorders, or indolent lymphomas were often seen by non-university oncologists, and survivors with a history of aggressive lymphoma or acute leukemia by non-oncological internists or general practitioners. Follow-up intervals mirrored published recommendations. Follow-up visits were dominated by conversations, physical examination, and blood tests. Imaging was more often performed outside than inside the university hospital. Satisfaction with follow-up care was high, and quality of life was similar in all follow-up institutions. A need for improvement was reported in psychosocial support and information about late effects.Of 2386 survivors meeting the inclusion criteria, 1551 (65.0%) consented to participate, with a follow-up duration > 10 years in 731. The university hospital provided care for 1045 participants (67.4%), non-university oncologists for 231 (14.9%), and non-oncological internists or general practitioners for 203 (13.1%). Seventy-two participants (4.6%) abstained from follow-up care. The disease spectrum differed among follow-up institutions (The naturally evolved patterns identified in the study resemble published care models: Follow-up clinics for complex needs, specialist-led care for unstable disease states, and general practitioner-led care for stable conditions.The online version contains supplementary material available at 10.1007/s00432-023-04889-7. One out of three individuals will be affected by cancer during their lifetime  study included blood cancer survivors who had been diagnosed at our institution before 2010, with an interval from the last intense treatment of at least three years. The retrospective part of the study was based on information provided by the survivors. Its major goal was to identify patterns in follow-up care and characterize the institutions that provide it. In the ensuing prospective part of the study, we compared these institutions with respect to health-related outcomes and resource use.This report summarizes recruitment of blood cancer survivors and patterns of follow-up care identified in the retrospective part of the ABC study.Patients 18 years or older diagnosed with and/or treated for a hematologic malignancy at the University Hospital of Essen were eligible for the study, provided that the interval between study inclusion and the date of diagnosis (for untreated patients) or the end of last treatment  was ≥ 3 years. In patients receiving continuous oral medication or low-dose maintenance therapy after intensive induction, eligibility started 3 years after treatment initiation or end of induction, respectively. Patients exclusively treated in childhood or adolescence were not eligible. Conditions included monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma (MM), indolent non-Hodgkin lymphoma including chronic lymphocytic leukemia (iNHL/CLL), myeloproliferative neoplasms including chronic myeloid leukemia (MPN/CML), myelodysplastic syndromes (MDS), aggressive non-Hodgkin or Hodgkin’s lymphoma (aNHL/HL), and acute myeloid or acute lymphoblastic leukemia (AML/ALL). Irrespective of the underlying disease, allogeneic transplant recipients were allocated to a separate group (AlloTx). Patients were categorized according to diagnostic group, treatment, follow-up institution, and year of follow-up .The ABC study was an observational study. It was performed from October 2013 to December 2016, comprising a 6-month retrospective and an 18-month prospective part. The study was approved by the ethics committee of the University of Duisburg-Essen (no. 14-5692-BO).In the retrospective part, eligible patients were identified by the hospital information system, tumor board reports, and discharge letters of the Department of Hematology spanning the period from 1999 to 2010. Patients were informed by mail about the purpose of the study and invited to complete a 118-item questionnaire specifically designed for the study. Eleven questions pertained to general aspects of follow-up care . Quality of life was assessed by the German versions of the EORTC QLQ C-30 and Hospital Anxiety and Depression Scale (HADS) questionnaires. Patients not responding within 4–6 weeks were contacted by mail again, and patients failing to respond to the second invitation were reminded by phone . They are compared using the Kruskal–Wallis test and graphically displayed as box whisker plots, diamonds representing means. All analyses are exploratory assuming statistical significance at p ≤ 0.05.Frequencies are presented as numbers and compared using the chiThe patients’ response behavior was analyzed by logistic regression with stepwise selection of variables (inclusion and exclusion). Two binary variables served as dependent variables: 1. participating patients versus eligible non-participants, and 2. patients refusing participation versus patients disregarding the invitation to participate. The independent variables included age, sex, disease group, time from diagnosis, time from last treatment, relapse, and place of residence.The quality-of-life scales were normalized to attain maximum power. The following transformations from the log-transform family were found to yield well normalized scales suitable for analysis of variance (ANOVA) and co-variance (ANCOVA):XY also increases. The transformed scales and the nominal factor ‘follow-up institution’ were used to calculate general linear models adjusting for age and sex. P values corrected for multiple testing pertain to any group difference as well as pointwise deviation from the common least-squares mean.Note that the sense of direction is maintained, i.e., with increasing Of 19461 blood cancer patients identified in the hospital files, 2555 patients that fulfilled the eligibility criteria according to the data available at the University Hospital of Essen were asked to participate in the study. Eleven patients had to be excluded because of previously unrecognized exclusive treatment in adolescence, 69 were deceased, 82 had experienced a relapse within the last 3 years, and 7 had developed a second cancer within the last 3 years, leaving 2386 living patients meeting the inclusion criteria , most frequently in survivors with a history of MDS , AML/ALL , or MPN/CML  (Table p = 0.0316) and affiliation to the AlloTx  or iNHL/CLL groups . It was negatively correlated with the interval from last treatment . Active refusal (versus disregard of the invitation to participate) was positively correlated with age  and relapse , and negatively correlated with male sex .Baseline characteristics of study participants and eligible non-participants are provided in Table The survivors named 1070 physicians involved in follow-up care. Of these, 223 were hematologists and medical oncologists , 366 non-oncological internists, 386 general practitioners, and 95 represented other disciplines. The majority  worked in private practice, but a substantial proportion of oncologists  was hospital-based.The study participants were asked to indicate their major follow-up institution. The answers revealed three groups: first, the university hospital ; second, oncologists outside the university hospital  working at non-university hospitals (67 patients) or in private practice (164 patients); and third, other physicians in private practice  trained as non-oncological internists (99 patients), general practitioners (94 patients), or in other disciplines (10 patients), collectively referred to as ‘internists/practitioners’. Seventy-two blood cancer survivors (4.6%) did not undergo follow-up care, including 49 who had never made use of it, and 23 who had terminated it. Over time the number of patients cared for at the university hospital decreased from 78.8 to 60.5%, and the number of patients seen by internists/practitioners increased from 4.8 to 19.2% (Table p  <  0.0001). Although most survivors  were followed up at the university hospital, patients with MGUS and MDS were most often seen by external oncologists who also cared for a substantial proportion of patients with multiple myeloma, myeloproliferative disorders, or indolent lymphomas (Table There were significant differences in the spectrum of blood cancer survivors seen by different follow-up institutions (as Table . Interni1241 of 1551 responding blood cancer survivors (80.0%) reported to have regular intervals between follow-up visits, and 485 of 1442 (33.6%) were reminded of the scheduled date by their physician. The proportion of survivors with regular intervals was the highest in MDS  and MPN/CML , and the lowest in AML/ALL  and MGUS . The reported intervals became significantly longer with increasing follow-up time, with 3-month intervals prevailing in years 1 and 2, 6-month intervals in years 3 to 5, and yearly intervals thereafter . During most visits, the physicians took the patient history, most consistently at the university hospital Table . Specialp < 0.0001), other physicians and therapists , religious caregivers , and advocacy groups  than disease management without transplantation.789 blood cancer survivors (50.9%) reported that they did not require help beyond the follow-up visits. Sources of further help were family and friends for 506 (32.6%), other physicians or therapists for 321 (20.7%), religious caregivers for 80 (5.2%), and advocacy groups for 62 survivors (4.0%). There were no statistically significant differences between follow-up institutions except for help from family and friends that was the least often sought by survivors treated by internists/practitioners , and ‘symptoms’ of the EORTC QLQ C-30 questionnaire, and ‘anxiety’ and ‘depression’ of the HADS questionnaire. Quality of life was the best in survivors not undergoing follow-up care. There were no significant differences between follow-up institutions , had received curative treatments (AlloTx), or suffered from incurable diseases with good prognosis . Prognostically unfavorable diseases such as MM or MDS  were disproportionately often seen by non-university oncologists. By contrast, survivors with curable diseases in stable remission (AML/ALL and aNHL/HL) were frequently followed up by internists/practitioners. Although the patterns of follow-up care observed in the ABC study evolved naturally, they resemble published care models: long-term follow-up clinics  for survivors with complex needs and a high risk of late effects, specialist-led care for unstable disease states, and general practitioner-led care for stable conditions . In that study, participation in group activities was perceived as a benefit by most blood cancer survivors . Patients alive at the time of the survey are a selection of individuals with a favorable disease course. Whether the information provided by them is representative of the entire population remains uncertain. A further limitation is the fact that any comparison of institutions is confounded by differences in disease spectrum and follow-up duration. A strength of our study is its large size with a high proportion of participants in late periods of follow-up care.Almost all blood cancer survivors participating in the ABC study received follow-up care. There were three major follow-up institutions that exhibited significant differences with respect to disease groups and diagnostic procedures. The naturally evolved patterns observed in the study resemble published care models: follow-up clinics for complex needs, specialist-led care for unstable disease states, and general practitioner-led care for stable conditions. Irrespective of institution, the survivors’ satisfaction with follow-up care was high, but there was room for improvement in psychosocial support and information about late effects.Supplementary file1 (PDF 181 KB)Below is the link to the electronic supplementary material.


The Evaluation of the Methods and Management of Acute Coronary Events (EMMACE)longitudinal cohort study aims to investigate health trajectories of individualsfollowing hospitalization for myocardial infarction (MI).EMMACE is a linked multicentre prospective cohort study of 14 899 patients with MIadmitted to 77 hospitals in England who participated in the EMMACE-3 and -4 studiesbetween 1st November 2011 and 24th June 2015. Long-term follow-up of the EMMACE cohortswas conducted through the EMMACE-XL (27th September 2020 to 31st March 2022) andEMMACE-XXL (1st July 2021 to 1st July 2023) studies. EMMACE collected individualparticipant data for health-related quality of life (HRQoL) measured by three-levelEuroQol five-dimension and visual analogy scale at admission, 1 month, 6 months, 12months, and 10 years follow-up, as well as medications, medication adherence, beliefsabout medicines, Satisfaction with Information about Medicines Scale, and illnessperceptions. Participant data were deterministically linked to the Myocardial InfarctionNational Audit Project (MINAP) for information on baseline treatments and comorbidities,Hospital Episode Statistics Admitted Patient Care , and the Office for National Statistics  up to 2020.EMMACE is a nationwide prospective cohort that will provide unique insights into fataland non-fatal outcomes, medication adherence, and HRQoL following MI.ClinicalTrials.gov NCT01808027 and NCT01819103Trial registration:  What is already knownHealth-related quality of life (HRQoL) is a key outcome in cardiovascular diseases.Researchers have focused mostly on objective measures of health, such as mortality andmorbidity, but HRQoL may impact negatively on patient outcomes.What this study addsThis is the largest nationwide patient-level cohort to date that provides a holisticview on health states of myocardial infarction (MI) survivors capturing HRQoL andclinical outcome trends up to 10 years following hospitalization with MI. The use of alongitudinal study design allows the capture of temporal trends in changes of HRQoLover time and associations with patient outcomes.This cohort profile data can be used to determine the associations of HRQoL withfatal and non-fatal outcomes following MI identifying precisely in whom worse (orbetter) outcomes may occur to permit the design and testing of novel interventions toreduce premature death from MI and its complications.1 contributing to a third of all deaths and reduced quality oflife.2 Despite a substantial declinein mortality rates from cardiovascular disease,3–5 myocardial infarction (MI) remains unnecessarilycommon and, in addition to its death toll and economic burden, is associated with a legacyof recurrent cardiovascular events, including heart failure, cerebrovascular disease, andMI.6Cardiovascular disease is the leading cause of death globally,7–9 This suggests aneed for prolonged surveillance of individuals with MI and a refreshed perspective on theoutcomes from MI and their management. This paper provides a cohort profile of theEvaluation of the Methods and Management of Acute Coronary Events (EMMACE) longitudinalcohort study containing long-term survey and EHRs follow-up data for individuals with MIacross 77 hospitals in England. The EMMACE-3 and -4 studies10 and the EMMACE-XL and EMMACE-XXL follow-up studies weredesigned to collect individual participant data about a wide range of clinical outcomesfollowing admission with MI.Information about the health outcomes of people with MI is required to determine individualhealth needs, enable earlier detection and treatment of new onset disease, and inform healthservice planning. However, there is a limited literature about health outcomes of peoplewith MI that is nationally representative, includes patient survey data as well asinformation systematically collected through electronic health records (EHRs), and extendsmany years from the index admission MI. In some geographies, fatal and non-fatalcardiovascular events after MI have now reached a plateau, yet remain elevated beyond thefirst year.The aim of the EMMACE longitudinal cohort is to collect and study longitudinal healthoutcomes in individuals admitted with MI, providing unique insights into patient healthtrajectories after MI, including healthcare utilization, health-related (HRQoL), and howthey may change over time.11–21 Individual patient data were collected across healthcareutilization, HRQoL, and how they changed over time. As the registry aims to capturereal-world outcomes for patients who had experienced an MI, management and/or treatmentmanagement strategies were not pre-specified by the study protocol.The EMMACE longitudinal cohort builds on the successes of EMMACE-1 and -2, which wereused for translational and cardiovascular outcomes research.A total of 77 National Health Service (NHS) hospitals in England (n = 5556) participants were recruited between 1st November2011 and 17th September 2013 and EMMACE-4 (n = 9343) participants wererecruited between 1st October 2013 and 24th June 2015. Long-term follow-up of the EMMACEcohorts was conducted through the EMMACE-XL (27th September 2020 to 31st March 2022) andEMMACE-XXL (1st July 2021 to 1st July 2023).EMMACE-3  Research Ethics Committee . The EMMACE-XL and EMMACE-XXL studies were granted ethicsapproval by the London Bridge Research Ethics Committee  and byLondon-Hampstead Research ethics committee . Permissions for thelinked Hospital Episode Statistics Admitted Patient Care (HES APC) data and ONS mortalitydata were obtained through NHS Digital (DARS-NIC-332338-X1N2G-v0.9).The EMMACE studies included patients aged 18 years or older who had been admitted with anacute coronary syndrome at one of the participating hospitals. Patients at a terminalstage of any illness, and those for whom follow-up would be inappropriate or impractical(e.g. patients requiring emergency treatment), were excluded from the study.22 EQ visualanalogue scale [EQ-VAS]), treatments, medication beliefs questionnaire,23 Single Question Medicine Adherence,Satisfaction with Information about Medicines Scale [SIMS],24 Care Quality Commission Pickering Inpatientquestionnaire,25 and Brief IllnessPerception.26 Baselineco-morbidities and quality-of-care data were obtained from the Myocardial InfarctionNational Audit Project (MINAP) registry.27Baseline data included patient demographics and socioeconomic status, patient-reporteddata at the time of admission with MI concerning HRQoL , the EMMACE cohortparticipants were contacted and consented to complete a further quality-of-lifequestionnaire , supply their current medication data, and answer aquestion relating to their perceived adherence to their current medication as well as toanswer lifestyle questions about their smoking habits. An additional follow-up of theEMMACE cohort was through the EMMACE- XXL(2021–22) study that collected furtherquality-of-life data , information about frailty (using the Program ofResearch on Integration of Services for the Maintenance of Autonomy [PRISMA-7] frailtyquestionnaire),n = 14 899) were linked to theMINAP registry27 with a furtherdeterministic linkage with HES-APC29data and the Office for National Statistics for the years 2010/11 to 2020/21 by NHSDigital acting as the trusted third party (DARS-NIC-332338-X1N2G-v0.9). Each participant'sNHS number, date of birth, and sex along with their EMMACE study identification number wassecurely transmitted to NHS Digital whereby returned data included  corresponding HES records, cause of death, anddate of death for patients who have died. NHS Digital publishes how their databases areregularly checked to ensure accuracy of the recorded data, and their methods of datacleaning and quality assurance.30Details of the EMMACE data flow are shown in Consented EMMACE-3 and -4 participants  within the University of Leeds. LASER isa Leeds Institute for Data Analytics purpose-built cloud-based platform for hostingsensitive data compliant with ISO 27001 standards and the NHS Data security and protectiontoolkit. Pseudonymized data are accessible for analysis with approval from the local datacontroller (CPG) in a dedicated secure LASER Virtual Research Environment. All individualswith access to these data are required to undergo the University of Leeds informationsecurity training and to sign an information security policy before accessing the data.The University of Leeds Information Security Policy is implemented and drawn up in linewith ISO 27 001.Access to the EMMACE longitudinal cohort data may be requested by contacting the ChiefInvestigator (CPG).The EMMACE longitudinal cohort is a nationwide individual participant-level database thatprovides a holistic view of the states of health of people with MI, capturing HRQoL,medications, all hospitalized events, and all deaths during 10 years of follow-up. Thereal-world origin and robustness of the data sources provide a strong basis for thegeneralizability of the study results, which can be translated into novel post-MI healthcaresystem goals. Phenotyping MI survivors based on longitudinal changes in HRQoL and subsequentoutcomes may allow healthcare providers to identify high-risk group of patients who maybenefit from timely targeted interventions to achieve sustained improvements in healthstatus.qcad040_Supplemental_FileClick here for additional data file.


Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can lead to multiorgan insufficiency and death, particularly among the older adults. Statins have been suggested as potentially protective drugs due to their pleotropic effects, but the actual benefit of statin use among the older population in this setting is not clear. This study aimed to evaluate the association between preadmission statin use and the presentation and clinical outcomes of hospitalized COVID-19 patients older than 70 years of age.A historical cohort study of all patients above 70 years of age who were hospitalized with COVID-19 infection in a large academic hospital between March and August 2020 was performed. The association between preadmission statin use and patients’ presentation and adverse outcome was studied. Adverse outcome was defined as any of the following: shock, invasive or non-invasive ventilation, organ insufficiency, myocardial infarction, cerebrovascular accident, in-hospital or 30-day post-admission mortality, hospital stay longer than the median length of stay of all COVID-19 patients, referral to nursing home or rehabilitation center.p = 0.028) and cardiovascular disease . Seventy two percent of the STP had adverse outcome, compared to 86% of the non-STP (p = 0.033). After adjustment for potential confounders, prior statin use was associated with decreased risk for an adverse outcome .Seventy-two (44%) of the 163 studied patients  had been preadmission treated with statins. The statin-treated patients (STP) had a higher prevalence of diabetes (40% vs 24%, The preadmission use of statins was associated with a lower risk of adverse outcome in older adults hospitalized with COVID-19. Continuation of statin treatment might be implemented for risk reduction of adverse outcomes in the older population in the era of new SARS-CoV-2 variants and less effective vaccines. As of March 2022, coronavirus disease-2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected over 470,000,000 people and caused more than 6,100,000 deaths worldwide , and theA beneficial role of statins was shown in the patients with pneumonia, other infection diseases and sepsis based upon their well-established pleotropic properties –10. The A historical cohort study of all patients above 70 years of age who were hospitalized with COVID-19 infection during the first wave of the pandemic and who received the same pharmacological treatments, which included steroids, was performed between March and August 2020 at the Tel Aviv Sourasky Medical Center (TASMC). TASMC is a tertiary university-affiliated 1500-bed medical center located in central Israel. Only patients with laboratory-confirmed COVID-19 infections were included in the study. Excluded from the study were patients whose data could not be accessed, as well as subjects who had end-stage/advanced malignancy, liver cirrhosis, past single or multiple organ transplantations, and those who continued care at another acute medical center. Also excluded were patients with nosocomial COVID-19 according to European Centre for Disease Prevention and Control (CDC) , women who were admitted to hospital to give birth and pregnant women. The study was approved by the local ethics committee (TLV-0341–20).All of the analyzed data were retrieved from the hospital database. Data on demographic parameters (age and gender), anthropometric measurements (weight and body mass index), first vital signs on emergency department admission , comorbidities, first blood test findings on emergency room admission and chronically used medications  were collected. Information on hypertension (HTN), diabetes mellitus (DM), cardiac disease, cerebrovascular disease (CVA/TIA), chronic renal failure (CRF), chronic obstructive pulmonary disease (COPD) or asthma, chronic liver disease and hypothyroidism was also recorded. Disease severity was determined using the NIH classification criteria .Blood tests results included complete blood count, C-reactive protein (CRP), creatinine, and liver enzymes . The estimated glomerular filtration rate was calculated with the CKD-EPI equation . Shock, Blood cell counts were performed with the Beckman Coulter UniCel. Blood chemistry tests were measured by ADVIA  as described previously . Viral rSample size was calculated using a significance level of 5% and a power of 80%. We assumed that approximately 30% of the STP would have an adverse outcome compared to 55% of non-STP. In addition, a ratio of 1:1 between STP and non-STP groups was assumed, whereupon 136 individuals would be needed.Categorical variables were described as frequency and percentage. Continuous variables were evaluated for normal distribution using histograms and Q-Q plots and reported as median and interquartile range (IQR) for readers’ ease. The Chi-square test and Fisher’s exact test were used to compare categorical variables and independents samples, and the T-test and Mann–Whitney test were applied to compare continuous variables. Due to the limited sample size and the variety of medications, the associations between medication and adverse event were included only in the univariate analysis. A multivariable logistic regression was used to identify the independent association between routine statin use and adverse outcome. The multivariable analysis included only pre-admission variables, since vital signs and blood tests at admission may represent the acute phase rather than the patient's background status. Due to the restrictions imposed by the pandemic setting, anthropometric measurements were estimated rather than precisely measured in some patients, and those parameters were not included in the multivariable analysis.p value > 0.1. All statistical tests were two-tailed, and p < 0.05 was considered statistically significant. All statistical analyses were performed with SPSS The regression included two blocks: routine statin use was entered in the first block while age, gender and all comorbidities were entered in the second block followed by the application of a backward method with the Wald test to remove variables with a n = 104, 64%), followed by cardiac disease , DM  and COPD/asthma . The prevalence of other studied comorbidities was less than 20%. Forty one (25%) patients had an estimated glomerular filtration rate less than 45 mL/min/1.73m2 on admission, and the group’s median CRP was 57 mg/L. Seventy two (44%) patients used statins regularly before being admitted to the hospital, 55 (34%) used aspirin, 60 (37%) used beta blockers, 51 (31%) used calcium channel blockers and 47 (29%) used diuretics. Table A total of 163 patients met the inclusion criteria during the study period. The group's median age was 82 years and 73 (45%) were males. HTN was the most common comorbidity (Age and gender distribution of patients who were taking statins regularly (STP) were not significantly different from those who did not use statins (NSTP), while DM and cardiovascular disease were more common among the STP . Vital signs, blood test results and the severity of COVID-19 at emergency department admission were not statistically different between the two groups. Angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, calcium channel blockers, beta blockers, diuretics and aspirin were more commonly used by patients who also used statins on a regular basis. Table p = 0.033). The patients who sustained adverse events were older , had lower hemoglobin levels  and higher inflammatory biomarkers on admission . Comorbidities and chronic treatments with medications other than statins were not significantly different between the patients with and those without an adverse outcome. Table p = 0.03), while older age  was associated with an increased risk , 54 with organ insufficiency and 6 with myocardial infarction or a cerebrovascular accident. Forty-seven patients died in the hospital and another 2 patients died during 30 days post-admission. In addition, 111 were hospitalized longer than the median length of stay of all-age COVID-19 patients (5 days), 7 were referred to nursing homes and 7 were referred to rehabilitation centers. Taken together, these findings revealed that 72% of the STP had an adverse outcome compared to 86% of NSTP .The results of this retrospective study suggest that although there were no significant clinical differences between the STP group and the NSTP group with regard to the severity of COVID-19 at presentation, preadmission statin use was associated with a decreased risk for an adverse outcome  and had higher rates of HTN, DM, cardiac diseases, and chronic kidney disease [As expected, more STP presented with DM compared to NSTP  as well as with cardiovascular disease (58% vs 34%). Memel et al. described higher rates of HTN, DM, coronary artery disease, heart failure, and chronic kidney disease among 43.1% of their STP who were > 65 years of age . El-Solh disease . De Spie disease . Those aThere are several explanations for the positive effect of statins on clinical outcome after COVID-19 infection. First, they show immune modulation and counteraction against the inflammatory response and the cytokine storm leading to the acute respiratory distress syndrome often present in viral infections. Second, stabilization by statins of the product of the MYD88 gene that regularly activates NF-κB resulting in mitigation of the inflammatory response has been reported in animal models –33. ThirThe major strength of this study is the use of systematic electronic medical records of preadmission STP older than 70 years of age at the time of admission for COVID-19. The study was designed to include all consecutive patients that met the inclusion and exclusion criteria, thus, making selection bias unlikely to occur. All studied outcomes were fully recorded in the patients' records, and disease severity was based upon updated NIH classification .Our study has a several limitations that bear mention. First, it includes a retrospective cohort of patients treated in a single medical center. Second, there is the possibility that some of the same patients were later readmitted to a different hospital, resulting in the loss of final follow-up of the patients in our database. Since the number of those latter patients is negligible, however, the influence of that caveat on the study results is likely to be small. Finally, our cohort of patients was recruited from the beginning of the pandemic period, before drugs intended to directly treat the COVID-19 patients were offered and before vaccines were available. However, those drawbacks did not prevent this cohort of patients to enable us to evaluate the association between statin use and COVID-19 severity among the older population.In conclusion, the results of this retrospective study showed significant protective effects of statin use on adverse outcomes among older adult patients hospitalized for COVID-19, and demonstrated the importance of continuing chronic statin therapy.


As the prevalence of patients with left ventricular assist devices (LVAD) presenting to the emergency department (ED) increases, clinicians must be aware of LVAD-associated infections.A well-appearing, 41-year-old male with history of heart failure status post prior-LVAD placement presented to the ED for swelling of his chest. What appeared initially as a superficial infection was further assessed with point-of-care ultrasound and found to represent a chest wall abscess involving the driveline, ultimately resulting in sternal osteomyelitis and bacteremia.Point-of-care ultrasound should be considered an important tool in the initial assessment of potential LVAD-associated infection. Continuous-flow left ventricular assist devices (LVAD) have improved the survival of patients with end-stage systolic heart failure.2According to the International Society for Heart and Lung Transplantation, LVAD infections are broken up into LVAD-specific infections, LVAD-related infections, and non-LVAD infections.5It is difficult to discern the extent of the infection with only radiographic imaging. Computed tomography (CT) images are limited by artifact from the device. Point-of-care ultrasound (POCUS) can detect pockets of concern but cannot effectively inform whether deeper structures are involved.4A 41-year-old Hispanic male with a history of American College of Cardiology/American Heart Association Stage D chronic systolic heart failure secondary to prior anabolic steroid use, status post HeartMate 3 LVAD placement three years prior to presentation, on warfarin, presented to the emergency department (ED) due to concern for midsternal chest wall swelling that developed spontaneously two days prior. The patient denied any trauma to the chest, fever, chills, or rash. The patient reported a small amount of pain to the area with palpation only, and no active drainage. Initial vital signs were significant for a mean arterial pressure of 62 millimeters of mercury, heart rate of 78 beats per minute, respiratory rate of 20 breaths per minute, oxygen saturation of 98% on room air, and oral temperature of 37.2 degrees Celsius (98.9° Fahrenheit). Physical examination revealed a 2 centimeter (cm) × 2 cm, elevated, mildly tender, midsternal collection without overlying erythema or crepitus. Laboratory results found a white blood cell count of 8.94 thousand per microliter (K/uL) (reference range: 3.8–10.5 K/uL), hemoglobin of 7.6 grams per deciliter (g/dL) (13–17 g/dL), platelet count of 279 (K/uL) (150–400 K/uL), and an international normalized ratio of 2.53 (0.88–1.16). Serum electrolytes were within normal limits.A point-of-care ultrasound was performed to further evaluate the fluid collection. The POCUS revealed a complex, mixed echogenic, collection that extended deep to chest wall and appeared contiguous with the driveline wire .Swirling of complex material was evident with compression. Use of color flow Doppler demonstrated an avascular heterogeneous structure, concerning for a deep space infection with driveline involvement .After POCUS was performed, a CT of the chest with intravenous contrast was ordered, and blood cultures were drawn due to concern for acute infection. The patient was given 2000 milligrams (mg) of cefepime and 1000 mg of vancomycin for antibiotic coverage. Computed tomography of the chest revealed a fluid-attenuating midline chest-wall lesion extending to the anterior sternal border measuring 2 cm × 1.9 cm × 3.4 cm with mild peripheral enhancement suggestive of a chest wall abscess.CPC-EM CapsuleWhat do we already know about this clinical entity?Left ventricular assist device (LVAD) infections are a significant cause of morbidity and mortality; computed tomography diagnosis can be limited by artifact.What makes this presentation of disease reportable?To date, there have been no reports on the use of ultrasound to diagnose LVAD driveline infections.What is the major learning point?Point-of-care ultrasound should be considered an important tool in the initial assessment of potential LVAD driveline infections.How might this improve emergency medicine practice?Point-of-care ultrasound can allow for rapid detection of LVAD driveline infections, leading to earlier identification and management.Staphylococcus epidermidis, and the first set of blood cultures grew Streptococcus mitis/oralis. The patient went to the operating room (OR) for irrigation and debridement of the sternal wound, removal of sternal wires except the inferior-most wire, and application of a wound vacuum-assisted closure device. Intraoperative transesophageal echocardiogram did not reveal valvular vegetations, and a wound culture obtained during debridement grew rare Propionibacterium acnes. The patient returned to the OR later in his hospital stay for further wound exploration and debridement. He was discharged on hospital day 17 on long-term antibiotic therapy with ceftriaxone 2000 mg via a peripherally inserted central catheter line.While in the ED the patient developed a fever of 38.3° Celsius and became tachycardic. He was admitted to the cardiothoracic surgery service for definitive management. On admission, the fluid collection opened spontaneously and drained purulent material. A culture was sent and grew In this case, POCUS was essential for making the diagnosis of a deep space infection. What appeared on physical exam to be only a superficial pustule, was discovered on POCUS to be a deep soft tissue infection involving the driveline. Point-of-care ultrasound is a safe, quick, and accurate way for emergency clinicians to differentiate between cellulitis and abscess.9In this patient, a complex-appearing fluid collection was visualized extending deep into the chest wall and communicating with the driveline wires concerning for a driveline infection. The results of this POCUS exam allowed for rapid diagnosis and early antibiotic administration. Although CT is typically preferred to assess for deep LVAD infections, the sensitivity and specificity of CT for the detection of these LVAD infections are not well-defined given the lack of a gold standard test for comparison.10Point-of-care ultrasound allows for the rapid and accurate evaluation of skin and soft tissue infections at the bedside, and although there have been no reports to date on the use of POCUS to detect LVAD infections, prior research has shown that ultrasound is more sensitive than CT for diagnosing certain soft tissue abscesses and provides more details regarding the contents of the abscess cavity. 10This patient, who presented with superficial swelling of the chest wall, suffered from several infectious complications associated with his LVAD, including a DLI with associated chest wall abscess, sternal osteomyelitis, and LVAD-associated bloodstream infection (BSI). Driveline infections are the most frequent LVAD infection overall and occur most often within the first year of LVAD implantation13Overall, the rate of LVAD implantation has increased greatly in recent years, and as the prevalence of LVADs increases, so too will the prevalence of LVAD patients in the ED.This case presents an LVAD recipient with a DLI associated with a chest wall abscess, sternal osteomyelitis, and bloodstream infection. Point-of-care ultrasound provides a fast, portable, and accurate method of detecting soft tissue infections that may be missed on physical exam, and in this case detection of a fluid collection on ultrasound ultimately led to the diagnosis of serious infectious complications in an LVAD recipient.


First-line treatment for restoring and maintaining sinus rhythm in patients with symptomatic atrial fibrillation (AF) involves the use of antiarrhythmic drugs. However, these are associated with significant side effects and have limited success rates in terminating AF episodes. In contrast, catheter ablation has been shown to be superior in maintaining sinus rhythm and improving the quality of life of AF patients. These procedures can also be performed via a hybrid set-up involving a minimally invasive surgical approach. These options have shown promise in restoring and maintaining sinus rhythm but are not without risks. Therefore, further studies investigating different ablative strategies are needed.Catheter ablation has been shown to be more effective at maintaining sinus rhythm and improving quality of life when compared to antiarrhythmic drugs. Radiofrequency and cryoablation are two effective methods. However, catheter-only ablation strategies have not consistently produced high success rates in treating longstanding and persistent AF patients. The emerging treatment of choice for such cases is hybrid ablation, which involves a multidisciplinary and minimally invasive approach to achieve surgical ablation of the direct posterior left atrial wall in combination with endocardial catheter ablation. Studies have shown promising results for the hybrid approach when compared with catheter ablation alone, but it is not without risks. Large and randomised studies are necessary to further evaluate these strategies for managing AF. Antiarrhythmic drugs (AADs) are the first-line treatment of choice for restoring and maintaining sinus rhythm in patients with symptomatic atrial fibrillation (AF). In patients for whom rhythm control is not appropriate, rate control can be used instead by exerting a negative chronotropic effect to reduce the ventricular rate in combination with anticoagulation for stroke prevention. AADs have demonstrated debatable results with class 1 and 3A agents terminating 50% of AF episodes, whilst amiodarone is able to terminate only 70% of AF episodes .AF catheter ablation has become established as the superior alternative to maintaining sinus rhythm and achieving an improvement in quality of life. Catheter ablation also offers curative treatment in contrast to AADs, through electrical isolation of the pulmonary veins. Current guidelines recommend AF ablation in the event of AAD failure; however, the role of AF ablation as the first-line treatment option for AF is surfacing. At present, the European Society of Cardiology and American College of Cardiology guidelines provide a restricted recommendation for AF ablation as first-line therapy, limiting it to a highly selected patient group with symptomatic paroxysmal (class IIa) or persistent AF (class IIb) without major risk factors for AF recurrence such as left atrial size, AF duration, and renal dysfunction as well as consideration of patient preference ,4. OveraThis review will examine current ablation management strategies in paroxysmal AF, heart failure in concomitant AF and persistent AF, and the evidence base behind these.The first catheter ablation in humans was performed in 1981 by Scheinman through the delivery of DC shocks to an electrode catheter . This prp < 0.001). In addition, PV antrum isolation was associated with a significantly lower rate of hospitalisation  and improved quality of life.Three key trials have addressed the relative differences in ablation and pharmacological therapy as first-line interventions in paroxysmal AF (PAF). The Radiofrequency Ablation versus Antiarrhythmic Drugs as First-line Treatment of Symptomatic Atrial Fibrillation (RAAFT-1) trial was the first to suggest the merits of catheter ablation as a first-line therapy for AF. In this trial, 70 patients with symptomatic PAF  were randomised to either catheter ablation or AAD therapy . The ablIt is crucial to highlight that the benefits of catheter ablation as shown in the study may have been underestimated, given the high rate of crossover to catheter ablation in patients initially assigned to AAD (51%). Complications were also comparable between the two treatment groups (12.5% in the catheter ablation arm versus 11.5% in the AAD group).Given the results of the RAAFT trial, two further large multicentre randomised trials assessed radiofrequency ablation (RFA) as first-line therapy over AAD: the Medical Antiarrhythmic Treatment or Radiofrequency Ablation in Paroxysmal Atrial Fibrillation (MANTRA-PAF) trial and the Radiofrequency Ablation versus Antiarrhythmic Drugs as First-Line Treatment of Paroxysmal Atrial Fibrillation (RAAFT-2) trial.p = 0.004).MANTRA-PAF randomised 294 patients with symptomatic PAF to either RFA or AADs. In contrast with the RAAFT trial, the ablation methods used were heterogeneous and varied from PV isolation guided by circular mapping catheter to circumferential PV ablation guided by a three-dimensional electroanatomic mapping system . The utilisation of different ablation methods was at the discretion of the enrolling cardiologist. The primary study endpoint was cumulative AF burden (symptomatic and asymptomatic) during 7-day Holter recordings after 3, 6, 12, 18, and 24 months of follow-up. Freedom from any AF after 24 months, quality of life, and burden of symptomatic AF were included among the secondary endpoints. The trial failed to meet its primary endpoint of a reduction in the cumulative burden of AF >2 years; however, it still demonstrated that CA was associated with a lower rate of AF recurrence compared with AAD  at follow-up. The RAAFT-2 trial also had a substantial number of patients crossing over from AAD to RFA (26%).The RAAFT-2 trial utilised similar inclusion criteria, endpoints, and ablation techniques as RAAFT; however, it had a significant exception with the utilisation of irrigated-tip ablation catheters. A total of 127 patients with symptomatic PAF were randomised to either RFA or AAD. After 2 years, AF/atrial tachycardia recurred in 54.5% of the RFA group compared with 72.1% of the AAD group  was the first cryoballoon technology used for ablation. This involved the use of the double-walled 10.5Fr cryoballoon catheter, which would inflate and fill with coolant (nitrous oxide) to deliver ablation lesions between the PVs and the LA. The 15Fr FlexCath Steerable Sheath was a deflectable delivery sheath that would allow introduction of the cryoballoon into the LA. The CryoConsole was the third component of the cryoballoon technology, which contained the coolant and mechanical components. The nitrous oxide would then be delivered to the double-walled balloon where it would undergo a liquid-to-gas transformation, delivering cooling temperatures of approximately −80 °C.There were three major randomised trials comparing cryoballoon ablation to AADs as first-line therapy of AF. These include the Catheter Cryoablation Versus Antiarrhythmic Drug as First-Line Therapy of Paroxysmal Atrial Fibrillation (Cryo-FIRST) trial , the Earp < 0.0001). Class Ic AADs were the initial AAD of choice used in the antiarrhythmic drug group . In EARLY-AF, 30% of the AAD group needed several antiarrhythmic drug trials to achieve suppression of AF on implantable monitoring. Subtherapeutic antiarrhythmic drug dosing was observed in 7% in Cryo-FIRST, 0% in EARLY-AF, and 21% in STOP-AF First, with 18%, 0%, and 12% permanently discontinuing the study drug, respectively.These three studies included a total of 724 patients in their intention-to-treat. Across them, the mean ages were 60 years (STOP-AF First), 60 years (EARLY-AF), and 52 years (CRYO-First). Most patients were male  and the majority of patients had normal left ventricular function and left atrial size. Although the patients had been enrolled at an early stage of diagnosis (median time from first AF diagnosis of 12 months), patients were mostly high symptomatic from their arrhythmia on the basis of their Atrial Fibrillation Effect on QualiTy-of-life (AFEQT) scores (mean score 60.1). Three-minute freezes were standardised in EARLY-AF, while they were recommended in STOP-AF First and Cryo-FIRST. Procedure duration was shortest in Cryo-FIRST (84 ± 29 min), moderate in EARLY-AF (106 min (IQR: 89–131 min)), and longest in STOP-AF First  and STOP-AF First (15%). STOP-AF and CRYO-FIRST assessed tachyarrhythmia occurrence with 12-lead electrocardiography at scheduled time points and 24 h Holter monitoring during months 6 to 12. Meanwhile, EARLY-AF monitored atrial tachyarrhythmias with continuous cardiac rhythm monitoring with an implantable cardiac device.p < 0.001). Cryoballoon ablation was also associated with lower recurrence of symptomatic atrial tachyarrhythmia (11.0% versus 26.2%) and a significant reduction in AF burden. The rate of serious adverse events was similar in the two groups (3.2% versus 4.0%). STOP-AF showed that initial success of the ablation procedure was achieved in 97% of patients, and procedure-related serious adverse events were uncommon. The percentage of patients with treatment success at 12 months  was higher with ablation than with drug therapy . CRYO-FIRST showed freedom from atrial arrhythmias was higher in patients who underwent cryoablation compared to the AAD treatment arm . The incidence rate of symptomatic palpitations was notably reduced in the cryoballoon compared to the AAD arm .In contrast to the results of previous studies of first-line RFA, first-line cryoablation consistently demonstrated significant reductions in arrythmia recurrence . EARLY-AIt is important to note that each study employed different rhythm monitoring protocols, which could impact clinical outcomes. Intermittent non-invasive cardiac rhythm monitoring was used in Cryo-FIRST and STOP-AF, whereas EARLY-AF used implantable cardiac monitoring. Non-invasive monitoring is less sensitive in the detection of paroxysmal arrhythmias and can exaggerate the approximations of arrhythmia-free survival. EARLY-AF was the only study to provide AF burden data as it employed implantable cardiac monitoring, where it demonstrated a significant reduction in AF burden with ablation. However, the cardiac monitor was implanted when treatment was initiated so it did not evaluate change in AF burden from baseline. Additionally, continuous monitoring captured a higher AF recurrence.These substantial randomised trials offer definitive evidence that AF ablation is superior to AADs as first-line treatment of patients with paroxysmal AF. The outcomes from the pivotal STOP-AF trial also formed the basis for the U.S Food and Drug Administration (FDA) approval for the Arctic Front CryoAblation Catheter system for the treatment of drug refractory PAF in 2010.Two randomised studies directly compared both cryoablation and RFA for the treatment of drug-refractory PAF. These include FIRE AND ICE and CIRCA-DOSE. Both showed that these two approaches are comparable in terms of efficacy and safety.In the FIRE AND ICE trial, a total of 762 patients were randomised to each arm with an average follow-up of 18 months . The stuThe cryoballoon was also shown to be more cost-effective due to lower resource utility post-ablation and lower payer cost than the RF arm. In summary the FIRE AND ICE trial confirmed the non-inferiority of the cryoballoon to RF ablation in patients with PAF. It also demonstrated a similar safety profile. Prior to this study, the European Society of Cardiology and the Heart Rhythm Society recommended radiofrequency energy as the leading ablation energy source. Following the trial, both societies updated their consensus documents to advocate for both cryoablation and RFA as a safe and efficient modality for the treatment of AF.The CIRCA-DOSE also directly compared both ablation modalities and its findings were in support of the FIRE AND ICE trial. However, there were two main differences. First, both RF and cryoablation were performed with the latest-generation catheter . CIRCA-DOSE further compared two cryoablation regimens (4 min versus 2 min freezes) to the use of contact-force-guided RF to isolate the PVs in patients with PAF. Secondly, all patients underwent implantation of a loop recorder. There were no significant differences between the two different ablation approaches in terms of recurrent atrial arrhythmias’ occurrence in the first year. However, it did show an overall >98% reduction in arrhythmic load, but with no significant difference between the different ablation methods in the intention-to-treat analysis.Furthermore, no significant difference in 1-year efficacy was seen between the 2 min and the 4 min freeze procedures; however, procedure duration was significantly reduced with the 2 min freeze protocol. Overall, the CIRCA-DOSE trial demonstrated that PVI completed either by cryoballoon or contact-force-guided RFA resulted in comparable freedom from atrial arrhythmias, as observed by implantable cardiac monitoring.p < 0.05) and a 40% increased risk of death in patients included in randomised clinical trials (p < 0.0001) . It. It17]. MacDonald et al. randomised 41 patients with severe LVSD and persistent AF to rate control or PVI catheter ablation, and they measured changes in the LVEF as the primary endpoint . In the p = 0.018).The ARC-HF  trial  and CAMTp < 0.0001). The catheter ablation treatment arm also noted a reduction in fibrosis on CMR at 6 months in those who were restored to sinus rhythm.The CAMERA-MRI study  included 66 patients with persistent AF and idiopathic cardiomyopathy with an EF < 45% . After ep = 0.001). The study noted, at 4.0 ± 0.9 years of follow-up in the catheter ablation group, the absence of ventricular LGE on CMR correlated with LVEF normalisation in 19 patients (58%) versus 4 patients  who exhibited late gadolinium enhancement on their CMR.There are now data available on the long-term outcomes of this trial with 4 years of follow-up . At 6 mop < 0.001) after a follow-up of 24 months . Th. Th62]. r cohort . Kress eIn 2020, the landmark trial CONVERGE  was performed . This waDeLurgio et al. introduced the contemporary epicardial lesion pattern, consisting of posterior wall homogenisation through the creation of parallel, overlapping rows of contiguous lesions using the most recent generation of unipolar RF catheter  in a linear configuration. Similar to Maclean et al., the primary access technique also changed to a subxiphoid incision for cannula insertion. This avoided the potential for transdiaphragmatic hernias developing post-procedure.p = 0.036). These results were sustained off AADs, too . Furthermore, at 18 months using 7-day Holter, 74% of patients in the hybrid convergent arm achieved over 90% AF burden reduction when compared to 55% with endocardial catheter ablation only .Patients were randomised in 2:1 to hybrid convergent ablation versus endocardial catheter ablation, this was performed to obtain data for safety outcomes. In the catheter ablation group, PVI, roofline, and cavotricuspid isthmus ablation were performed. If AF persisted, then additional complex fractionated atrial electrogram ablation was performed as per physician discretion. At 12 months, the convergent ablation arm showed superiority with freedom from atrial arrhythmias on AADs as compared to catheter ablation alone  multicentre study has shown PFA is effective in arrhythmia-free survival, with rates comparable to current ablation technologies with a low rate of primary safety adverse outcomes (0.7%) . Further