Previous studies have shown that increased neutrophils, as a manifestation of oxidative stress, may be involved in the progression of kidney disease. To our knowledge, little is known about the relationship between neutrophils and renal impairment in rheumatoid arthritis (RA). Therefore, we aim to investigate whether neutrophil is associated with renal impairment in RA patients.We retrospectively investigated the renal function of 602 RA patients in the First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine by estimated glomerular filtration rate (eGFR) from September 2018 and September 2019. The exposure variable was neutrophils, and the main outcome was eGFR. General data , whole blood markers, lipid indexes, and inflammatory indexes were collected as much as possible. We used multivariable logistic regression analysis to evaluate the association between neutrophils and renal impairment in RA participants.2, and 75 cases (84.3%) were female. Subgroup analysis showed that female , neutrophils greater thsn 7.5 × 109/L , NLR > 3.53 , hemoglobin less than 120 g/L , and UA > 360 μmol/L  was related to renal damage in RA. Adjusted for several confounders, the multivariable analysis indicated that neutrophils greater than 7.5 × 109/L  was independently associated with an increased risk of renal impairment in RA.A total of 89 cases (14.8%) had renal impairment with eGFR < 60 ml/min/1.73 m9/L was associated with a high risk of renal impairment in RA, suggesting that neutrophil may be a biomarker for renal impairment in RA.Our study demonstrated that neutrophils greater than 7.5 × 10 9/L may be associated with a high risk of renal impairment in RA. We also found that UA > 360 μmol/L and hemoglobin less than 120 g/L independently associated with a higher risk of renal impairment in RA patients. Although more prospective studies are needed to verify our results, based on the above data, we believe that continuous monitoring of these risk factors in RA patients is necessary and it could be used for early detection and identification of changes in GFR, allowing doctors to treat patients with potential kidney damage promptly.In this present study, neutrophil greater than 7.5 × 10 As a result, 602 samples were available for investigation. The inclusion process was shown in Figure A total of 685 data from the original database of the First Affiliated Hospital of Guangzhou University of Chinese Medicine between September 2018 and September 2019, were screened in our cross‐sectional analysis. Patients in this data set should meet the classification criteria of the American College of Rheumatology for RA 20102.2Written informed consent was acquired from all participants. We followed the principles of the Declaration of Helsinki and received approval from the Ethics Committee of the First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine (No. ZYYECK [2019]040).2.3General demographics included sex, age (years), durations, current alcohol, cigarette use, and medication history . Laboratory indicators, such as neutrophil, neutrophil to lymphocyte ratio (NLR), white blood cell (WBC), lymphocyte, red blood cells (RBC), hemoglobin levels, total cholesterol (TC), triglycerides (TG), high‐density lipoproteins (HDL), low‐density lipoproteins (LDL), ESR, C‐reactive protein levels (CRP), UA levels, rheumatoid factor, and anti‐cyclic citrullinated peptide.2.42 were identified as having renal impairment regardless of kidney markers.The main outcome was eGFR. Following the 2013 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines, the Chronic Kidney Disease—Epidemiology Collaboration (CKD‐EPI) equation involving SCr and CysC levels was used to calculate eGFR. Patients with eGFR<60 ml/min1.73m2.5SD or median (Interquartile range [IQR]), and qualitative data as number and percentage. Categorical data were assessed by the χ2 test or Fisher exact test, while continuous data were appraised by the Mann–Whitney test or Student t test. We performed subgroup analyses of eGFR on RA participants including age, gender, duration, hypertension, diabetes, current drinking, current smoking, steroid, bDMARDs, NSAIDs, neutrophils, NLR, hemoglobin, TC, LDL, HDL, TG, ESR, CRP, and UA. To further analyzed factors independently associated with the RA patients with renal impairment, we employed multivariable logistic regression analysis by establishing two models: unadjusted, adjusted I . Features with significant significance and clinical relevance in subgroup analysis were introduced into the multivariate logistic model. Results were presented as the odds ratio (OR) and their 95% confidence interval (95% CI). All analyses in our study used Stata (version 15.0) and the threshold for statistical significance was set to 0.05.The normality of the data was evaluated by the Shapiro–Wilk test.33.12, and 513 (85.2%) had normal renal function with eGFR > 60 ml/min/1.73 m2. Among renal damage group, 75 (84.3%) were female, and 31 (34.8%) suffered from Hypertension and 12(13.5%) had diabetes mellitus. Compared to RA patients with normal renal function, RA patients in the renal impairment group had a relatively older age , lower RBC count  and hemoglobin level . WBC count , ESR , CRP , UA levels , Scr , and CysC  significantly increased compared with that of RA participants with normal renal function.Table 3.2p = .011), neutrophils greatert than 7.5 × 109/L , NLR > 3.53 , hemoglobin less than 120 g/L , and UA > 360 μmol/L  were significantly associated with renal impairment in RA patients.The results of the subgroup analysis were shown in Table 3.39/L  is an independent indicator of an increased risk of renal damage in RA patients. We also found that UA > 360 μmol/L , hemoglobin less than 120 g/L  were independently associated with a high risk of renal impairment in RA patients. The result of multivariable logistic regression analysis was presented in Table Variables  with significant significance in subgroup analysis were incorporated in the multivariable logistic model. We employed an unadjusted and adjusted I model  to assess the independent effects of neutrophils on eGFR by multivariable logistic regression analysis. Adjusted I model analysis showed that neutrophil count greater than 7.5 × 1042, estimated by the Modification of Diet in Renal Disease equation.2) in 17.48% of the patients with RA.2.In this retrospective cohort study, 14.8% of patients with RA had an eGFR<60 ml/min/1.73m2, evaluated using the CKD‐EPI formula. Our data are roughly consistent with findings in previous studies. In a cohort of 400 subjects with RA in England, 13% had an eGFR < 60 ml/min/1.73 m9/L was associated with an increased risk of renal damage in RA patients. To our knowledge, this was the first survey to report the relationship between neutrophils and renal damage in RA patients. Previous reports suggested that oxidative stress induced by increased neutrophil count was associated with adverse renal outcomes.In this investigation, we found that neutrophil count greater than 7.5 × 10Another finding of our present study showed that UA > 360 μmol/L and hemoglobin less than 120 g/L were significantly associated with a higher risk of renal impairment in RA patients. Similarly, Daoussis et al. also indicated that an elevated UA level was a strong predictor of renal damage in RA patients.Chiu et al followed more than 12,000 RA patients for five years in a cohort study, and they observed that diabetes, hypertension, hyperlipidemia, and cardiovascular disease were related to renal damage,Several limitations in this study should be discussed. eGFR, estimated by various quantitative equations, has been determined to be the optimal indicator of renal function in recent years. The CKD‐EPI SCr/CysC equation recommended as a GRF equation by the KDIGO guidelines,5In this present study, neutrophils greater than 7.5 × 109/L may be an independent risk factor for renal impairment in RA. Although more prospective studies are needed to verify our results, based on the above data. we believe that continuous monitoring of neutrophils in RA patients is necessary and it could be used for early detection and identification of changes in eGFR, allowing doctors to treat patients with potential kidney damage promptly.The authors declare that there are no conflict of interests.Pei‐Dan Yang, Si‐Min Lin, and Zhi‐Xin Chen completed collecting, analyzing the data, and drafting the manuscript. Kai‐Jun Zhu helped revise the manuscript. Min‐Ying Liu, Qing‐Ping Liu, and Chang‐Song Lin helped collect the data. Cong‐Qiu Chu and Qiang Xu conceived of the study, and participated in its design and coordination, and revised this manuscript.


Angiotensin‐converting enzyme 2 (ACE2) acts as a functional receptor for the entry of severe acute respiratory syndrome coronavirus 2 into host cells. Angiotensin (1–7) (Ang (1–7)) obtained from the function of ACE2 improves heart and lung function. We investigated the relationship between Ang (1–7) level and disease severity in patients with coronavirus disease 2019 (COVID‐19).This cohort study was carried out at Masih Daneshvari Hospital in Tehran, Iran from September 2020 to October 2020. To do so, the Ang (1–7) levels of 331 hospitalized COVID‐19 patients with and without underlying disease were measured by ELISA kit. The need for oxygen, intubation, and mechanical ventilation were recorded for all the patients.p = 0.002), patients who needed intubation and mechanical ventilation versus those who did not (9.80 (62) vs. 68.70 (102), p < 0.000) and patients hospitalized in an intensive care unit (ICU) than people hospitalized in other wards. We also found that the older patients were more in need of ICU and mechanical ventilation than younger patients.Results showed a significant inverse relationship between the levels of Ang 1–7 and the severity of the disease . According to the results, median (interquartile range) of Ang (1–7) levels was significantly lower in patients who needed oxygen versus those who needed no oxygen (44.50 (91) vs. 82.25 (68), Higher levels of Ang (1–7) have been associated with decreased disease severity. Besides this, we perceived that synthetic Ang 1–7 peptides may be useful to treat and reduce the complications of COVID‐19. The renin–angiotensin–aldosterone system plays a critical role in COVID‐ 19 pathogenesis.Recent studies have shown a crucial role of angiotensin‐converting enzyme 2 (ACE2) in the pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection, which causes COVID‐19. ACE2 acts as a functional receptor for the entry of SARS‐CoV‐2 into host cells. ACE2 as a membrane‐bound aminopeptidase converts angiotensin I (Ang I) and Ang II into Ang (1–9) and (Ang 1–7), respectively, and is expressed in various human organs.On the one hand, ACE2 is overexpressed in heart failure, arterial hypertension, and diabetes mellitus. So, people with these underlying diseases are more likely to get infected by COVID‐19. On the other hand, SARS‐CoV‐2 downregulates ACE2 and reduces Ang (1–7) after infection. As a result, the high severity and high mortality rate among these patients could be due to reasons, such as vasoconstriction, vascular damage, fibrosis, proliferation, and inflammation due to reduction of Ang (1–7).Given the key role of ACE2 in infection of the virus and the protective roles of Ang (1–7) as its product, we hypothesized that there was an indirect relationship between Ang (1–7) level and disease severity in patients with COVID‐19.However, no reports are available regarding Ang (1–7) levels in the COVID‐19 patients with various disease severities. Therefore, in this study, we evaluated the relationship between Ang (1–7) levels and disease severity in the COVID‐19 patients with and without the underlying diseases, such as cardiovascular diseases and diabetes.2α) = 0.05, z score (z) = 1.96, and expected range (d) =  0.93, and (q) = 1 − p, where p is the expected prevalence of intensive care unit (ICU) admission in COVID‐19 patients according to the study of Mehta et al.This cohort study was carried out at Masih Daneshvari Hospital in Tehran, Iran from September 1, 2020 to October 30, 2020. In this study, the Ang (1–7) levels in patients with the COVID‐19 disease with different severity were measured and compared. We calculated the sample size according to the following formula:To decrease the selection bias, due to the specific conditions of this emerging disease and the existence of little information about this disease, we considered all the people who were referred to the hospital and were hospitalized for this disease for a period of time  as the prototype sample size. About 1853 people with the COVID‐19 disease were hospitalized during this period. For all patients, questionnaires were completed by nurses. The questionnaire contained all inclusion and exclusion criteria except noticeably changed in lifestyle in terms of nutrition, especially the use of antioxidants and vitamin D and physical activity during the 6 months before this disease. The blood samples were taken from all patients after admission before starting any additional treatment  to evaluate clinical trials. For all patients, excess serums  were stored at −80°C for further research on this emerging disease. The patients' clinical symptoms, including ICU admission, the use of mechanical ventilation, oxygen need, fever, and gastrointestinal disorders were drawn out from the patient's medical record after being discharged from the hospital. At the end of the study period, after reviewing the questionnaires, 645 patients were selected based on the inclusion and exclusion criteria in this study. Of these patients, those who had significantly changed their diet or lifestyle during the 6 months before illness or were not satisfied with participating in the study were excluded, and the remaining 331 patients were considered as the final sample volume for Ang (1–7) level assay.Inclusion criteria were infection with COVID‐19 approved by real‐time PCR test and hospitalization, while exclusion criteria included patients with COVID‐19 being reluctant to participate in the study, with several underlying diseases simultaneously, have died during this period, smokers, and drug users, as well as patients who had noticeably changed their lifestyle in terms of nutrition, especially the use of antioxidants and vitamin D and physical activity during the 6 months before the disease.2.1The blood samples of all the subjects were first taken immediately after the patients were admitted to the hospital when it was confirmed that the patient had COVID‐19. Next, aliquot samples of serums were saved following centrifugation  at −80°C. Then, the samples' levels of Ang (1–7) were measured by ELISA kit , on the basis of the biotin double antibody sandwich technology, with assay range 40–1280 ng/L, sensitivity 5 ng/L, intra‐assay (coefficient of variation [CV] < 10%), and interassay (CV < 12%).Finally, the patients' clinical symptoms, including ICU admission, the use of mechanical ventilation, oxygen need, fever, and gastrointestinal disorders were drawn out from the patient's medical record after being discharged from the hospital2.2χ2 test, while continuous variables were compared with the Mann–Whitney U test. A χ2 test was performed to examine the correlation between fever, gastrointestinal symptoms, an underlying disease with ICU admission, and oxygen need. Mann–Whitney U test was performed to compare Ang (1–7) levels according to severity outcome (ICU admission and Oxygen need) with 95% confidence intervals (CIs). All the significance tests were two‐tailed. The significance level of the p value was set at a  <0.05.Statistical analyses were performed using the IBM Statistical Package for Social Sciences . Continuous quantitative variables were reported as medians and interquartile ranges (IQRs) if they had nonparametric distribution and categorical variables were described as numbers (percentages). Kolmogorov–Smirnov test was used to assess normality of Ang (1–7). The median and IQR have been used to describe the Ang (1–7). Categorical variables were compared with the use of the 3This cohort study was carried out from September 2020 to October 2020 Three hundred and thirty‐one patients with COVID‐19 participated in this study.2  of patients was 28.23 ± 10.99 kg/mTable p < 0.001), and patients who needed oxygen and those who needed no oxygen (44.50 (91) vs. 82.25 (68) pg/ml, p value = 0.002). Finally, there is a significant indirect relationship between the severity of the disease and Ang (1‐7) levels.Table 4In this study, we evaluated the relationship between Ang (1–7) level with disease severity in COVID‐19 patients hospitalized in Hospital. Also, we studied the association of underlying diseases and disease severity in COVID‐19 patients. We observed the disease was more severe in COVID‐19 patients with underlying diseases, such as cardiovascular, respiratory, and diabetes than patients without such underlying diseases. Also, Ang 1–7 levels in both groups of patients with and without underlying diseases hospitalized in ICU were lower than patients hospitalized in other wards. In agreement with the results of our study, Huang et al.As far as we know, no study has been so far conducted regarding Ang (1–7) level in COVID‐19 patients. In this study, levels of this peptide were found to be lower in patients with higher severity, although the severity of the disease was higher in the elderly, the levels of this peptide did not differ at different ages. Despite the fact that no age‐dependent ACE2 levels have been observed in human studies, one of the reasons for the severity of this disease in elderly patients could be higher Ang II and lower MasR expression (as the putative receptor for Ang1–7) in older patients compared to younger ones.In this study, moreover, disease severity and Ang 1–7 levels were not different between male and female patients. In an investigation on 99 patients infected with SARS‐CoV‐2, Chen et al.One of the limitations of this study was the nonparticipation of non‐COVID‐19 volunteers and COVID‐19 patients who did not need to be hospitalized, as well as those who unfortunately died of this disease. The other limitation was the lack of peptide assay by gold‐standard methods such as liquid chromatography‐tandem mass spectrometry. The lack of matching of factors such as age, sex, and BMI was another limitation of this study; however, the amount of Ang (1–7) in different groups of age, sex, and BMI in this study was not different.5In the current research, we firstly found that there is a significant and indirect relationship between Ang (1–7) levels and the severity of COVID‐19 disease, both in patients with and without underlying diseases. Therefore, further studies, especially randomized controlled clinical trials are needed to clearly delineate the benefits of Ang (1–7) actions in COVID 19 patients.The authors declare no conflicts of interest.This study was approved by the human research ethics committee at Arak University of Medical Sciences, Arak, Iran (IR. ARAKMU. REC.1399.3691) and the human research ethics committee at Shahid Beheshti University of Medical Sciences, Tehran, Iran (IR. SBMU. NRITLD. REC.1399.153). We confirm that consent was obtained from all patients before participating in this study.Seyed Mohammad Seyedmehdi: Conceptualization; funding acquisition; investigation; resources; visualization; writing—original draft. Fatemeh Imanparast: Conceptualization; data curation; funding acquisition; validation; visualization; writing—original draft; writing—review and editing. Pegah Mohaghegh: Validation; writing—review and editing. Saeed Mahmoudian: Investigation, methodology, project administration, writing—review and editing. Mona Karimi Dehlaqi: Investigation, methodology, project administration, writing—review and editing. Fatemeh Mehvari: Methodology, project administration, resources, software, writing—review and editing. Mihan Pourabdollah: Investigation, methodology, project administration, writing—review and editing.


We aim at examining the long‐term clinical outcome after Xience everolimus‐eluting stent (X‐EES) implantation.Long‐term clinical outcomes beyond 5 years after X‐EES implantation remain unclear.This retrospective study has collected data from 1184 consecutive patients, corresponding to 1463 lesions, who were treated with X‐EES alone in the Nagoya Heart Center between January 2010 and December 2013. The primary endpoint was the 10‐year cumulative incidence of target lesion failure (TLF), defined as cardiac death, target vessel myocardial infarction (MI), and clinically indicated target lesion revascularization (TLR). Definite/probable stent thrombosis (ST) was evaluated as a secondary outcome.P = .02), left ventricular dysfunction , hemodialysis , prior percutaneous coronary intervention , peripheral vascular disease , severe calcification , and in‐stent restenosis .At 10 years, the cumulative incidence of TLF was recorded to be 12.4%, whereas that of cardiac death, target vessel MI, and clinically indicated TLR was at 4.4%, 4.1%, and 7.8%, respectively. The cumulative rate of definite/probable ST was observed to remain low . In the multivariate analysis, the risk factors of TLF were insulin‐treated diabetes (hazard ratio (HR), 1.93; 95% confidence interval (CI), 1.13‐3.29; The incidence rates of the long‐term adverse effects after X‐EES implantation, such as late TLR and ST, were determined to be low in this study; however, they increased over time until 10 years after stent implantation. All patients gave their written informed consent for the procedure and the follow‐up protocol, and the study has also received approval from the ethics committee of our hospital.2.2The PCI strategy was left to the discretion of the operating surgeon. Patients who were scheduled for PCI received daily oral aspirin (≥81 mg/day) and P2Y12 inhibitor (75 mg/day clopidogrel), while ticlopidine (200 mg/day) was administered only in those who cannot tolerate clopidogrel. Patients with acute coronary syndromes, namely, STEMI  and NSTE‐ACS (non‐ST elevation acute coronary syndrome), received loading doses of aspirin (200 mg) and P2Y12 inhibitor (300 mg clopidogrel). During the procedure, unfractionated heparin (100 U/kg) was administered to all the patients who reached an activated clotting time of 250 seconds. After the procedure, all patients were prescribed with optimal pharmacologic therapy based on the current guidelines, including statins, beta‐blockers, or renin‐angiotensin system blockers. Moreover, the duration of dual antiplatelet therapy (DAPT) was also dependent on the surgeon's discretion.2.3All the patients were followed up at 1, 3, 6, and 12 months after their index procedure and annually thereafter. Additional information was obtained by telephone communication or medical records, as needed, and follow‐up angiography was recommended in patients based on clinical symptoms and findings of noninvasive tests.2.4The primary endpoint of this study was the target lesion failure (TLF) up to 10 years after the index procedure, which is defined as a composite of cardiac death, target vessel myocardial infarction (MI), and clinically indicated TLR. The secondary endpoint included individual components of the composite primary endpoints and definite/probable stent thrombosis (ST) at various time points. Risk factors of clinically indicated TLR and definite/probable ST rate in the cases of acute MI (AMI) were also evaluated.Death was, by default, considered as cardiac unless an unequivocal noncardiac cause could be established. MI and ST were defined as per the Academic Research Consortium.2.5P < .10) after univariate analysis were subjected to multivariable modeling, and adjusted hazard ratios and their 95% confidence intervals were then calculated; a P‐value of <.05 was considered significant. Statistical analyses were performed using JMP version 14.0 .Categorical variables are presented as numbers and percentages, whereas the continuous variables are expressed as mean ± SD or median with inter‐quartile range. Cumulative incidence was estimated using the Kaplan‐Meier method, and differences were assessed. For TLF and clinically indicated TLR, we used landmark analysis with 1‐year intervals to examine the late events after the first year. Patients with individual endpoint events before 1 year were excluded in the landmark analysis. A Cox proportional hazards model was used to identify the independent risk factors for clinically indicated TLR during the follow‐up period of 10 years. Continuous variables were based on clinically meaningful reference values. To determine the independent risk factors, variables that were significant  at 1 year, in 91 patients (8.2%) at 5 years, and in 127 patients (12.4%) at 10 years Table . The cumFor secondary endpoints, the cumulative 10‐year incidence of definite/probable ST was determined to be at 0.3% at 1 year, 0.6% at 5 years, and 1.1% at 10 years Table . There w3.3P = .02), left ventricular dysfunction , hemodialysis , prior percutaneous coronary intervention , peripheral vascular disease , severe calcification , and in‐stent restenosis  were considered significant throughout the follow‐up , 1.93; 95% confidence interval (CI), 1.13‐3.29; 3.4P = .04), hemodialysis , peripheral vascular disease , and in‐stent restenosis  as they are considered significant throughout the follow‐up  While the rate of incidence of late adverse events after X‐EES implantation was low, it continued to increase gradually over time up to 10 years after stent implantation; and (b) insulin‐treated diabetes, left ventricular dysfunction (LVEF <35%), hemodialysis, peripheral vascular disease, and in‐stent restenosis were independent risk factors of clinically indicated TLF.Widespread use of second‐generation DES has resolved several clinical issues related to major adverse cardiac events.2) is decided using IVUS imaging and is based on evidence from previous studies.To date, several large‐scale registries of first‐generation DES have recorded annual VLST incidence rates of 0.21% to 0.53%.5There are several important limitations to our study. First, this was a retrospective, single‐center study, which might have significantly affected some results, especially because confounding factors were not controlled for. Therefore, these results, which represent the post‐hoc analysis of a trial, should be used only for hypothesis generation. Next, no information on bleeding complications during the follow‐up period was available, and this outcome was, therefore, not analyzed.6In conclusion, the incidence rates of long‐term outcomes such as late TLR and definite/probable ST after X‐EES implantation were very low in this study; however, they gradually increased during the follow‐up period of 10 years. Larger trials based on clinical follow‐up are needed to confirm the use of X‐EES as an optimal long‐term strategy.The authors have no conflicts of interest to declare.Conceptualization: Hiroaki MatsudaData curation: Hiroaki MatsudaFormal analysis: Hiroaki MatsudaInvestigation: Hiroaki MatsudaMethodology: Hiroaki MatsudaProject administration; Hiroaki Matsuda, Yoriyasu SuzukiWriting – original draft preparation: Hiroaki MatsudaWriting – review and editing: Hiroaki Matsuda, Yoriyasu SuzukiAll authors have read and approved the final version of the manuscript.The corresponding author or manuscript guarantor will have to confirm that he/she had full access to all of the data in the study and takes complete responsibility for the integrity of the data and the accuracy of the data analysis.The lead author, Hiroaki Matsuda, affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned  have been explained.


Comprehensive, nationwide data regarding Parkinson's disease (PD) hospitalizations, coronavirus disease 2019 (COVID‐19) in‐hospital frequency, and COVID‐19‐associated inpatient mortality during the first wave of the COVID‐19 pandemic are not available.To provide a nationwide analysis on hospitalized PD patients in Germany and evaluate the impact of the COVID‐19 pandemic.+ cases between January 16 and May 15, 2020.We conducted a cross‐sectional study using an administrative claims database covering 1468 hospitals and 5,210,432 patient hospitalizations including a total of 30,872 COVID‐19+) than in non‐PD patients , especially in subjects with advanced age (≥ 65 years). Regarding established COVID‐19 risk comorbidities, COVID‐19+ inpatients with PD showed higher incidences than non‐PD COVID‐19+ subjects, particularly hypertension and chronic kidney disease. Advanced age and male sex were significantly more frequent in COVID‐19+ than in COVID‐19− PD patients. The COVID‐19 inpatient mortality rate was much higher in PD patients than in non‐PD patients , especially in patients aged 75–79 years. Of note, overall inpatient mortality of PD patients was significantly higher in 2020 than in 2019 .Compared to 2019, hospitalizations for PD transiently decreased by up to 72.7% in 2020. COVID‐19 frequency was significantly higher in the population of 64,434 PD patients (693 being COVID‐19Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder SocietyPD inpatients are more frequently affected by COVID‐19 and suffer from increased COVID‐19‐associated mortality in comparison to non‐PD patients. More comprehensive studies are needed to assess the significance of associated comorbidities for COVID‐19 risk and mortality in PD. © 2021 The Authors.  As of February 18, 2021, approximately 110 million confirmed COVID‐19 cases and 2.4 million deaths have been reported globally.The first wave of the COVID‐19 pandemic in the first half of 2020 has indirectly and directly affected patients with Parkinson's disease (PD). Indirect effects comprise a large impact on health care provision including a reduction in overall hospitalizations. As of March 2020, Germany was one of the most severely affected countries worldwide, and because of the need for more COVID‐19 treatment capacities, (semi‐)elective hospital treatments were postponed or even cancelled. However, chronic illnesses require an extensive service of care including hospitalizations in cases of exacerbation of primary neurologic disease or because of worsened comorbidities. The numbers of patients who had to be hospitalized for treatment of PD or concomitant disease has strongly risen in the last year as we have shown in our own recent analysis of the entire German population.+) PD patients similarly more frequently present comorbidities such as hypertension,−) PD patients. Use of advanced therapies, long disease duration, and older age were common,Risk factors for a severe course of COVID‐19 and mortality are known for the general population. They include general features such as older age+ PD patients range from 5.7%+ non‐survivors with PD had longer disease duration, concomitant dementia, and often arterial hypertension.Mortality rates in COVID‐19In Germany, the first COVID‐19 case was reported on January 28, 2020− PD patients, and provide data on the inpatient mortality of COVID‐19+ and COVID‐19− PD patients, we performed a nationwide study using an administrative database for the 4‐month period between January 16 and May 15, 2020. We focused our analysis on three principal questions: How did hospitalizations of PD develop during the pandemic? Are PD patients particularly affected by COVID‐19 and what are the characteristics of PD patients diagnosed with COVID‐19? Are PD patients more at risk of COVID‐19‐associated death?In order to thoroughly assess the situation of hospitalized PD patients during the COVID‐19 first pandemic wave, evaluate disease profiles in comparison to non‐PD and COVID‐1922.1To describe hospitalization numbers of patients with PD during the first wave of the COVID‐19 pandemic in Germany and to calculate COVID‐19 frequency and inpatient mortality in PD, we conducted a cross‐sectional observational study based on comprehensive nationwide administrative data in Germany between January 16 and May 15, 2020 and 2019, respectively.2.2www.g-drg.de). In Germany, all inpatient cases are encoded according to the International Classification of Diseases 10th revision, German Modification (ICD‐10‐GM). Within the DRG coding system, main diagnoses  and secondary diagnoses (comorbidities) are shown. The database covers 1468 hospitals and almost 100% of inpatient cases. As of March 31, 2020, the number of inhabitants of the covered area was 83,157,201.We analyzed case numbers of hospital admissions during the first wave of the COVID‐19 pandemic in 2020 on a nationwide level using a high‐quality and validated administrative diagnosis‐related group (DRG) database  scale. The unit of analysis for frequency analyses is “case”. Multiple counting was avoided using key “06” . We consider case numbers as patient numbers, since the number of potentially readmitted patients in the examined period is regarded as negligible. As the PD inpatient population is selective due to hospitalization, we report COVID‐19 frequency rather than prevalence, a term used for more defined populations.We calculated the change in case numbers in the first 4 months of 2020 versus 2019 , thereby including the date of the first reported COVID‐19 case in Germany, and the beginning and end of a lockdown period. Additionally, we determined relative differences in case numbers between the first and the second half of March and April 2020, respectively. Here, we determined the number of hospitalizations using the main diagnosis codes for PD and additionally for all further ICD diagnoses, and using the secondary diagnosis codes for laboratory‐confirmed COVID‐19 (U07.1) Table . The dat+” and “COVID‐19−”, respectively.For the analysis of COVID‐19 frequencies and inpatient mortality, we assessed main and secondary diagnosis codes regardless of the reason for hospitalization. Within the inpatient population, we compared the COVID‐19 frequencies of PD and non‐PD patients in distinct age groups and calculated odds ratios (ORs) for COVID‐19 diagnosis. To improve readability, patients with or without laboratory‐confirmed COVID‐19 are termed “COVID‐19Inpatient mortality analyses were performed applying discharge key “07” . Cases with key “07” were termed “non‐survivors”, whereas cases without key “07” were termed “survivors”. We calculated the COVID‐19‐associated inpatient mortality rate in PD and non‐PD patients as the proportion of deaths among the respective population.2.4For descriptive analyses of the study population, values were calculated as mean and standard deviation (SD) for continuous variables and as absolute (n) and relative (%) frequencies for categorical variables. Differences were assessed by unpaired t‐test and chi‐squared test for continuous and categorical variables, respectively. In order to describe COVID‐19 diagnosis odds and inpatient mortality risk, ORs with 95% confidence intervals (95% CIs) were determined. Due to the short‐term supply of the COVID‐19 data by the German administration and due to database structure, which gives frequencies only and no individual data, adjustment was calculable for age only. Individual data to perform a multivariate analysis accounting for comorbidities as possible confounders were not available. Age as a confounder variable was controlled for by using age group stratification. Significance level was set at 0.05. Data were analyzed using Microsoft Excel for Windows.33.1Overall numbers of hospitalized patients substantially decreased from 6,254,091 to 5,210,432 (−16.7%) in 2020 as compared to 2019 in the period under study between January 16 and May 15 Fig. . PatientIn the more detailed analysis of semi‐monthly hospitalization numbers, these changed differentially between mid‐January and mid‐May 2020 for PD and for COVID‐19 if compared to 2019 Fig. . The mos3.2P < 0.001). The total inpatient frequency of PD was 1.2%, whereas PD patients represented a total of 2.2% of all COVID‐19 cases.Between January 16 and May 15, 2020, a total of 30,872 COVID‐19 inpatient cases were documented in 1468 hospitals in Germany, of which 693 also had PD. COVID‐19 was significantly more frequent in patients with PD than in non‐PD inpatients  and chronic kidney disease  than COVID‐19− PD patients. COVID‐19+ PD patients were slightly less frequently affected by vitamin D deficiency, cardio‐ and cerebrovascular disease, diabetes type 2, and COPD (Table + PD patients were older (more often aged ≥80 years) and more frequently male than PD inpatients from the same time period in 2019.In order to identify typical characteristics of COVID‐19+ PD and COVID‐19+ non‐PD patients (Table + PD patients were significantly older (more often aged ≥75 years), more frequently male, and showed even higher frequencies of COVID‐19 risk factors than COVID‐19+ non‐PD patients. More specifically, they more frequently suffered from hypertension, cardio‐ and cerebrovascular disease, chronic kidney disease, and vitamin D deficiency, whereas type 2 diabetes and COPD were similarly frequent in COVID‐19+ PD and non‐PD patients . For patients aged 75–79 years, the odds to die were approximately 1.5‐fold higher in PD patients . Correspondingly, this age group showed the greatest mortality difference between PD and non‐PD patients. Due to the database structure, adjustment for comorbidities was not calculable.In order to evaluate COVID‐19‐associated inpatient mortality, we calculated the COVID‐19 inpatient mortality rate and compared it between PD and non‐PD patients Fig. . Overall+ PD non‐survivors, we compared their demographic and PD features as well as comorbidity rates with COVID‐19+ PD survivors .Furthermore, we compared overall PD inpatient mortality between 2020 and 2019, independent of COVID‐19 status. Overall mortality of PD inpatients was significantly higher in 2020  than non‐PD patients. More specifically, they more frequently suffered from hypertension, cardio‐ and cerebrovascular disease, and chronic kidney disease, whereas type 2 diabetes and COPD were similarly frequent in COVID‐19+ and COVID‐19− PD patients in terms of age or severity of disease,+ and 63,741 COVID‐19− PD patients.Smaller studies with double‐digit case numbers did not detect differences between COVID‐19+ PD non‐survivors were of older age, suffered more frequently from chronic kidney disease, and exhibited more frequently advanced disease stage (HY 5) when compared to PD survivors. These negative outcome parameters are in line with known risk factors for COVID‐19 mortality.+ PD patients showed an increased mortality rate of 19.7% in PD patients with COVID‐19, and identified dementia, hypertension, and PD duration as risk factors for severe outcome.+ PD patients of older age and with longer disease duration.+ PD patients  independent of age, sex, and race were demonstrated in a large USOverall COVID‐19‐associated inpatient mortality was significantly higher in PD patients than in non‐PD patients in our study. COVID‐19+ PD patients, especially if based on large administrative claims data. To what extent distinct comorbidity patterns in PD patients or PD per se could be responsible for this finding remains an open question that can only be answered when individualized patient data are made available.epidemiological study.There is currently no definitive answer as to whether PD per se predisposes for SARS‐CoV‐2 infection. It has been suggested that amantadine and alpha‐synuclein may be protective against COVID‐19,4.1Certain limitations of this cross‐sectional study need to be acknowledged. It focused on hospitalized patients, which may present with more significant overall disease burden. Thus, there is a risk of selection bias that limits the generalizability of results for the general PD population in Germany. However, the study warrants an accurate analysis of a defined population at risk for comparison. With regard to the quality of documentation of comorbidities, the resulting administrative claims are very carefully controlled for validity by board‐certified physicians of the medical service of Germany's National Association of Statutory Health Insurance Funds in order to ensure a high level of quality.Large‐scale datasets of COVID‐19 infection rates and clinical profiles of the general PD population are not yet available as a comparison. The currently available data for stationary care treatment do not comprise detailed individualized information and therefore do not permit full appreciation of confounding factors such as comorbid diseases. Thus, higher ORs of COVID‐19 diagnosis or associated death in PD could possibly be related to comorbidities or higher frailty. No analytic inference can be drawn of an independent risk of PD patients for COVID‐19 with the existing data.To our knowledge, this is the first nationwide analysis of PD inpatient care during the COVID‐19 pandemic. By means of the DRG coding system, full coverage of all hospitalized patients with laboratory‐confirmed COVID‐19 is warranted and has permitted us to perform a very thorough analysis of the PD inpatient population throughout Germany.4.2The COVID‐19 pandemic strongly affects healthcare provision for PD patients. We here demonstrate that during the first wave of the pandemic in 2020, PD hospitalization numbers decreased substantially. COVID‐19 frequency and COVID‐19‐associated inpatient mortality were higher in older PD patients than in non‐PD subjects of the same age. Therefore, PD inpatients are particularly affected by COVID‐19, even if the higher risk of morbidity or inpatient mortality is probably mediated by higher prevalences of certain COVID‐19 risk comorbidities. It is of special importance that overall inpatient mortality of PD patients was increased too, independent of COVID‐19 status. Care must be taken to ensure that optimal treatment for hospitalized PD patients is always guaranteed, and that potentially competing priorities do not have a negative impact on PD care in these pandemic times.(1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing the First Draft, B. Review and Critique.R.S.: 1B, 1C, 2A, 2B, 3A, 3BE.H.K.: 2B, 3A, 3BD.R.: 2C, 3BD.B.: 1A, 1B, 1C, 2C, 3BR.G.: 3BC.K.: 2C, 3BL.T.:1A, 1B, 1C, 2C, 3A, 3BThe authors have nothing to disclose. Raphael Scherbaum reports no disclosures. Eun Hae Kwon reports no disclosures. Daniel Richter receives FoRUM grant (K136‐20) of the Ruhr‐University of Bochum. Dirk Bartig has received orders for analysis of the German Diagnosis‐Related Groups system from Boehringer Ingelheim and Sanofi Aventis. Ralf Gold received consultation fees and speaker's honoraria from Bayer Schering, Biogen Idec, MerckSerono, Novartis, Sanofi‐Aventis, and TEVA. He also acknowledges grant support from Bayer Schering, Biogen Idec, MerckSerono, Sanofi‐Aventis, and TEVA. Christos Krogias has received speaker honoraria or travel grants for scientific meetings from Bayer Vital, and Daichii Sankyo. Lars Tönges has received travel funding and/or speaker honoraria from AbbVie, Bayer, Bial, Desitin, GE, UCB, and Zambon and consulted for AbbVie, Bayer, Bial, Desitin, UCB, and Zambon.Table S1 Diagnoses used in the study with corresponding codes according to the International Classification of Diseases 10th revision, German modification (ICD‐10‐GM).Table S2: Case numbers of Parkinson's disease (PD) inpatients (admissions) including disease severity between January 16 and May 15, 2020 vs. 2019.Table S3: Semi‐monthly case numbers of Parkinson's disease (PD) and COVID‐19 between January 16 and May 15, 2020 vs. 2019 and relative difference between the first and the second half of March 2020 and April 2020, respectively.Table S4: COVID‐19 frequencies in Parkinson's disease (PD) inpatients with different disease severity stages between January 16 and May 15, 2020Table S5: COVID‐19‐associated inpatient mortality in age groups of Parkinson's disease (PD) and non‐PD inpatients between January 16 and May 15, 2020.Table S6: Inpatient mortality in Parkinson's disease (PD) inpatients between January 16 and May 15, 2020 vs. 2019Click here for additional data file.


Lipoprotein(a) (Lp[a]) is a causal risk factor for atherosclerotic cardiovascular disease (ASCVD). Proprotein convertase subtilisin/kexin‐9 monoclonal antibodies (PCSK9mAbs) can lower Lp(a) levels in clinical trials, but their effects in patients with elevated Lp(a) in clinical practice remain unclear.To investigate the effectiveness and safety of PCSK9mAbs in lowering plasma Lp(a) in patients with elevated Lp(a) concentrations in a lipid clinic.This was an open‐label study of 53 adult patients with elevated Lp(a) concentration (≥0.5 g/L). Clinical, biochemical, and safety data were collected before and on treatment with evolocumab or alirocumab over a mean period of 11 months.Treatment with a PCSK9mAb resulted in a significant reduction of 0.29 g/L (−22%) in plasma Lp(a) concentration (p<.001). There were also significant reductions in low‐density lipoprotein‐cholesterol (LDL‐C) (−53%), remnant‐cholesterol (−12%) and apolipoprotein B (−43%) concentrations. The change in Lp(a) concentration was significantly different from a comparable group of 35 patients with elevated Lp(a) who were not treated with a PCSK9mAb . The reduction in Lp(a) concentration was not associated with the corresponding changes in LDL‐C, remnant‐cholesterol, and apolipoprotein B . 7.5% and 47% of the patients attained a target concentration of Lp(a) <0.5 g/L and LDL‐C <1.8 mmol/L, respectively. PCSK9mAbs were well tolerated, the common adverse effects being pharyngitis (9.4%), nasal congestion (7.6%), myalgia (9.4%), diarrhoea (7.6%), arthralgia (9.4%) and injection site reactions (11%).PCSK9mAbs can effectively and safely lower plasma Lp(a) concentrations in patients with elevated Lp(a) in clinical practice; the impact of the fall in Lp(a) on ASCVD outcomes requires further investigation. Patients were selected for having a plasma Lp(a) concentrations ≥0.5 g/L.2.2n = 44), monthly (n = 2) or six‐weekly (n = 1) and three on 420 mg monthly subcutaneous injections of evolocumab; two received 150 mg fortnightly and one 75 mg monthly injections of alirocumab. Patients attended regular clinic visits, where they were reviewed by a nurse specialist and/or a consultant physician and received best standard of care; clinical and biochemical data were collected and compared before and on treatment with evolocumab or alirocumab. For comparison, 35 patients with elevated Lp(a), attending the clinic and did not receive evolocumab or alirocumab, were also studied as a control group. At the time of recruitment, the 35 patients had plasma LDL‐cholesterol levels above guideline recommended target of <1.8 mmol/L but were not eligible for receiving a PCSK9mAb according to the PBS criteria in Australia. Clinical audit approval was granted by the Royal Perth Hospital .The study was a sequential, open‐label study of the effect of PCSK9mAbs in patients with elevated Lp(a), carried out over a period from 2015 to 2020. Forty‐seven patients were on 140 mg fortnightly  using the modification of diet in renal disease (MDRD) equation. Similar information to the above was collected in the 35 clinic patients with elevated Lp(a) who were not treated with PCSK9mAb.The following clinical data were recorded: Age, gender, ethnicity, body mass index (BMI), blood pressure; personal history of coronary artery disease (CAD), cerebrovascular event (a stroke or transient ischemic attack), peripheral artery disease (PAD), hypertension, diabetes, or kidney disease; family history of ASCVD; current medications. CAD was defined as a history of either; (i) myocardial infarction, (ii) angioplasty, or (iii) coronary artery bypass grafting.2.4LDLR, APOB, and PCSK9 genes.FH was defined according to the Dutch lipid clinic network (DLCN) criteria and/or the presence of a pathogenic mutation in the 2.5Statin intolerance was defined as the inability  to tolerate at least two different statins (one statin at the lowest starting daily dose and another statin at any daily dose) due to clinically important adverse effects, such as musculoskeletal symptoms and markedly elevated plasma creatinine kinase and/or hepatic aminotransferase.2.6Adverse events (AEs) during PCSK9mAb therapy were defined as general systemic symptoms and injection site reactions. General systemic symptoms were flu‐like , musculoskeletal , gastrointestinal , and other (headache and fatigue). Injection site reactions were defined as a cluster of erythema, pain, bruising, swelling, induration, rash, or pruritus around the injection sites. The severity of the above was assessed by the numerical rating scale on a 0–10 scale, any score of >4 defined as the presence of a clinically significant AE.2.7Patients first attended a nurse‐managed clinic for education and training on the administration, dosage, and frequency of the subcutaneous injections, as well as on the storage requirements of the injectate and potential AEs. Typically, follow‐up reviews were done via telephone, or with intermittent clinic visits as required. Patients were telephoned by the specialist nurse every fortnightly or monthly, based on the injection schedules to elicit and discuss clinical progress and AEs. The first post‐treatment fasting blood test for lipids, lipoproteins, and other biochemical analytes were carried out 6 weeks after the first injection, followed by blood tests at 3–4 monthly intervals; blood tests were not done during acute illness.2.8Plasma glucose, liver  and muscle (creatine kinase) enzymes, total cholesterol (TC), triglyceride and high‐density lipoprotein‐cholesterol (HDL‐C) concentrations were determined by standard enzymatic methods . LDL‐C was calculated by the Friedewald equation or measured by a direct assay with plasma triglycerides >4.5 mmol/L. Non‐HDL‐C was calculated by subtracting HDL‐C from TC, whereas remnant‐cholesterol (REM‐C) was calculated by subtracting HDL‐C and LDL‐C from TC. LDL‐C was adjusted for Lp(a)‐cholesterol by subtracting 30% of the individual's Lp(a) total mass from the plasma LDL‐cholesterol concentration.2.9t‐test. Treatment effects were analyzed using paired t‐tests. Change in plasma Lp(a) concentration between the PCSK9mAb treated and the non‐PCSK9 treated group were compared using general linear modeling with baseline as a covariate. Absolute changes in Lp(a) levels with PCSK9mAb treatment according to quartiles for Lp(a) were compared using ANOVA with multiple comparisons. The proportion of patients attaining LDL‐C and Lp(a) targets after PCSK9mAb treatment were calculated with reference to recommendations in current guidelines.Statistical analyses were carried out using the SPSS Statistics . Data were presented as mean ± SD unless otherwise specified. The Shapiro–Wilk test was used to determine whether variables were normally distributed. Skewed variables, including plasma triglyceride, REM‐C, and Lp(a) concentrations were log‐transformed. Gender differences in plasma levels of pre‐treatment and post‐treatment Lp(a) were compared using independent 33.1LDLR gene (n = 20). More than half the patients were current or ex‐smokers and hypertensive, 13% had diabetes, 42% were obese and 38% were statin intolerant. Approximately one‐third of the patients were on statin monotherapy, ezetimibe monotherapy or the combination of a statin and ezetimibe; 15% of patients were on a mean dose of 65 mg/day atorvastatin, 20% were on 28 mg/day rosuvastatin, 8% were on 65 mg/day simvastatin, and 2% were on 20 mg/day pravastatin. There were no statistically significant differences in age, gender, BMI, blood pressures, plasma lipid and lipoproteins concentration  between the intervention group and the control group of 35 clinic patients with elevated Lp(a) who were not on PCSK9mAb (Supplementary Table Table 3.2Table When stratifying patients into quartiles on the basis of pre‐treatment Lp(a) levels Table , PCSK9mAThe absolute change in Lp(a) concentration was not significantly correlated  with the corresponding changes in LDL‐C, REM‐C and apoB concentrations Figure . Likewis3.3In univariate regression, pre‐treatment Lp(a) concentration was significantly and inversely associated with the absolute reduction, but not with percentage reduction, of Lp(a) in response to PCSK9mAb treatment . In a multiple linear regression model including age, gender, BMI, baseline LDL‐cholesterol concentration and treatment duration, only the baseline Lp(a) concentration was independently and significantly correlated with the absolute reduction in Lp(a) concentration .3.4The common adverse effects reported by the patients treated with PCSK9mAbs are shown in Supplementary Table 44.1Our principal finding was that in patients with elevated Lp(a) attending a lipid clinic, PCSK9 inhibition with a mAb resulted in a significant reduction in Lp(a) concentration and was well tolerated over a mean period of 11 months. We also demonstrate that the reduction in Lp(a) with PCSK9mAb was significantly and inversely correlated with pre‐treatment Lp(a) concentration, but not with the changes in LDL‐cholesterol, remnant‐cholesterol or apoB concentration.4.2Few studies have reported the real‐world effectiveness of PCSKmAb on Lp(a) concentration in a clinical setting.4.3Several large clinical trials of PCSK9mAb treatment have consistently demonstrated a significant reduction in Lp(a) concentration.4.4PCSK9 is a key regulator of LDL and other hepatic receptor involved in the metabolism of apoB‐100 containing lipoproteins.4.5Recent randomized controlled trials (RCTs) and meta‐analyses have favorable safety and good tolerability profile of PCSK9mAbs.4.6Our sample size was relatively small, but the findings were comparable to previous studies in real‐world settings of PCSK9mAb.4.7Several clinical practice guidelines recommend measuring plasma Lp(a) concentration in patients with high‐risk of ASCVD.Patients with elevated Lp(a) who also have CAD and FH, as in our sample population, remain at high residual risk of ASCVD despite statin treatment.5In clinic patients with elevated Lp(a), most of whom had CAD and FH, PCSK9mAb treatment safely and significantly lowered the plasma concentration of Lp(a), with a greater reduction in LDL‐C and apoB. Whether the incremental reduction in Lp(a) translates into a decrease in ASCVD events remains unclear. The aggregate fall in atherogenic apoB‐containing lipoproteins, including Lp(a), with PCSK9mAb, is likely due to increased hepatic clearance of these lipoproteinsGerald F. Watts has received honoraria for lectures and advisory boards or research grants from Amgen Inc., Arrowhead, AstraZeneca, Esperion, Kowa, Novartis, Regeneron, and Sanofi. Anindita Chakraborty, Jing Pang, Dick C. Chan, Wendy Barnett, Ann Marie Woodward, and Mary Vorster have no disclosures.Appendix S1: Supporting InformationClick here for additional data file.


The aim of this analysis is to determine geo–economic variations in epidemiology, ventilator settings and outcome in patients receiving general anesthesia for surgery.Posthoc analysis of a worldwide study in 29 countries. Lower and upper middle–income countries (LMIC and UMIC), and high–income countries (HIC) were compared. The coprimary endpoint was the risk for and incidence of postoperative pulmonary complications (PPC); secondary endpoints were intraoperative ventilator settings, intraoperative complications, hospital stay and mortality.P = .003). The incidence of PPC was 9.0% in LMIC, 3.2% in UMIC and 2.5% in HIC (P < .001). Median tidal volume in ml kg− 1 predicted bodyweight (PBW) was 8.6 [7.7–9.7] in LMIC, 8.4 [7.6–9.5] in UMIC and 8.1 [7.2–9.1] in HIC (P < .001). Median positive end–expiratory pressure in cmH2O was 3.3 [2.0–5.0]) in LMIC, 4.0 [3.0–5.0] in UMIC and 5.0 [3.0–5.0] in HIC (P < .001). Median driving pressure in cmH2O was 14.0 [11.5–18.0] in LMIC, 13.5 [11.0–16.0] in UMIC and 12.0 [10.0–15.0] in HIC (P < .001). Median fraction of inspired oxygen in % was 75 [50–80] in LMIC, 50 [50–63] in UMIC and 53 [45–70] in HIC (P < .001). Intraoperative complications occurred in 25.9% in LMIC, in 18.7% in UMIC and in 37.1% in HIC (P < .001). Hospital mortality was 0.0% in LMIC, 1.3% in UMIC and 0.6% in HIC (P = .009).Of 9864 patients, 4% originated from LMIC, 11% from UMIC and 85% from HIC. The ARISCAT score was 17.5 [15.0–26.0] in LMIC, 16.0 [3.0–27.0] in UMIC and 15.0 [3.0–26.0] in HIC (The risk for and incidence of PPC is higher in LMIC than in UMIC and HIC. Ventilation management could be improved in LMIC and UMIC.Clinicaltrials.gov, identifier: NCT01601223.The online version contains supplementary material available at 10.1186/s12871-021-01560-x. T) with appropriate positive end–expiratory pressure (PEEP) resulting in a low driving pressure (ΔP), has been shown to prevent PPC , VT, PBW = VT/PBW [kg]. For females, PBW = 45.5 + 0.91 * (height [cm] – 152.4), and for males, PBW = 50.0 + 0.91 * (height [cm] – 152.4). Low VT ventilation was defined as a VT < 8 ml/kg PBW. ΔP was calculated by subtracting PEEP from the plateau pressure.VIntraoperative complications were similar to those used in the parent study and were defined as follows . No assumptions for missing data were made. Histograms are used to assess for normality. Depending on data distribution, an ANOVA, Kruskal Wallis test or chi–square test was performed to determine differences among geo–economic regions. If appropriate, a posthoc Dunn test was performed, in which the Bonferroni method was used to adjust for multiplicity. Effect sizes were determined with estimated median differences and Cramér’s V. Length of hospital stay and in–hospital mortality was censored at postoperative day 28.T, PBW, ΔP, need for a blood transfusion, need for vasoactive drugs, and desaturation were considered as clinically relevant possible effect modifiers  cm in LMIC vs 168 [162 to 175] in UMIC and 168 [162 to 175] cm in HIC (P = .015). The proportion of patients with and ASA score ≥ 3 was higher in patients in HIC. Urgent or emergency surgery happened more often in the UMIC and LMIC than in HIC.Of 9864 patients included in the current analysis, 405 patients (4%) originated from LMIC, 1076 patients (11%) from UMIC, and 8383 patients (85%) from HIC . The proportions of patients with a low, an intermediate and a high risk for PPC, however, was not different across the geo–economic regions (Table P < .001) (Table P < .001) and HIC (OR 0.035 (0.020 to 0.062), P < .001)  in HIC . Median PEEP increased from LMIC to UMIC and HIC (P < .001). Median ΔP and FiO2 decreased from LMIC to UMIC and HIC (P < .001).Key ventilator variables and parameters are shown in Table P < .001) (Table P < .001), and all–cause hospital mortality was higher in UMIC than HIC (P = .009) (Table Intraoperative complications occurred more often in HIC and LMIC than in UMIC (1) Table . Length 9) Table .Table 4IThis posthoc analysis of the conveniently sized LAS VEGAS study shows that the risk for and actual incidence of PPC decreases from LMIC to UMIC and HIC. The analysis also shows significant geo–economic differences in ventilation management, as well as in the incidence of intraoperative complications, length of in–hospital stay and mortality.To our best knowledge, this is the first study examining whether geo–economic variation in the risk for and actual incidence of PPC in surgical patients exist. We used the database of a prospective study that included surgical patients requiring intraoperative ventilation for various types of surgery, that included centers worldwide. The LAS VEGAS study was performed in both community and teaching hospitals, increasing the generalizability of the findings. Another strength is that data were collected within 1 week, preventing against the risk of temporal changes in risks for and incidences of PPC, intraoperative ventilation management and outcomes.T or a high ΔP to have an association with the development of PPC [T and ΔP were higher in LMIC compared to that in UMIC and HIC.Our analysis rejects the null hypothesis that there are no geo–economic variations in the risk for and incidence of PPC. While the higher incidence of PPC in LMIC might partly be explained by a higher ARISCAT score in patients in these regions, the fraction of patients at an increased or high risk for PPC in LMIC was comparable to UMIC and HIC. The fraction of patients undergoing upper abdominal surgery was higher in LMIC, which is important as especially this type of surgery has a strong association with occurrence of pulmonary complications after surgery . An altet of PPC , 16. We In the LAS VEGAS study, we used strict definitions for PPC to minimize regional variations in terminology. Each PPC was easy to score; additional tests were not required by the study protocol and follow–up of PPC ended at patient’s discharge. To ensure accurate data collection, standard operating procedures for data entry were present for all investigators. The Case Report Form of the LAS VEGAS study was developed with the assistance of the European Society of Anesthesiology––Clinical Trial Network, resulting in a straightforward and easy–to–use form. Furthermore, national coordinators were delegated to assist, train and monitor local data collectors , 12. HowRespiratory failure was the most frequently diagnosed component of PPC in all three geo–economic groups. The incidence of respiratory failure was significantly higher in LMIC compared to its incidence in UMIC and HIC. It is unknown if the occurrence of residual curarization, a possible cause of respiratory failure, differed between the geo–economic groups. Of note, we did find the use of neuromuscular blocking agents and antagonists to be higher in LMIC compared to UMIC and HIC.Length of hospital stay in LMIC was 4 times higher than in UMIC and even 8 times higher than in HIC. This could, at least in part, be explained by the difference in the incidence of PPC. PPC occurred significantly more often in LMIC compared to UMIC and HIC. Indeed, earlier studies showed the development of PPC to be associated with an increased length of in-hospital stay . RegionaSeveral studies described the development of PPC to be associated with increased mortality , 8. In oIntraoperative complications, specifically hypotension and the use of vasoactive drugs, occurred more often in HIC compared to UMIC and LMIC. Patients from HIC were ventilated with a higher PEEP and received more frequently an epidural catheter than patients from UMIC and LMIC, both known to be risk factors for hypotension –23. It iWe found small differences in preoperative saturation and intraoperative respiratory rate. These differences reached statistical significance but were probably of no clinical meaning. This interpretation is supported by the between–group comparable median, interquartile ranges, and estimated median differences.Our study has limitations. One limitation is the unequal distribution of patients between the geo–economic groups. Indeed, the number of patients in HIC was 8 times higher than in UMIC, and even 20 times higher than in LMIC. This increases the risk of type II errors. Furthermore, it is uncertain if the small number of patients in the LMIC gives an adequate representation of this latter geo–economic group. Patients from LMIC were median 2 cm taller compared to patients from UMIC and HIC which is not to be expected. The mortality rate of zero in LMIC was unexpected as well. These findings could be the result of the small group size since another plausible explanation is lacking. We also did not have patients that received surgery in a low–income country, the fourth group of the 2020 World Bank country classifications. One additional limitation is that the LAS VEGAS study was conducted in 2013. Perioperative care is not expected to have been changed dramatically over the last two decades, but is uncertain if our findings are completely generalizable to the present.It should be stressed that the findings of this posthoc analysis serve as hypothesis–generating evidence. A posthoc analysis has a lower positive predictive value by design, which increases the risk for a type I error . HoweverThe increased incidence of PPC and the decreased use of lung–protective ventilation in LMIC should concern us. An association between gross national income per capita and clinical outcomes has been found in other cohorts as well. Several studies showed lower income to be associated with worse survival in ICU patients diagnosed with ARDS or with sepsis , 25, 26.T and ΔP, higher FiO2 but lower PEEP compared to patients from UMIC and HIC. These findings raise the awareness of geo–economic differences in clinical outcome and ventilation management of surgical patients.In this worldwide study of intraoperative ventilation under general anesthesia for surgery, the risk for and actual incidence of PPC was higher in LMIC compared to UMIC and HIC. During intraoperative ventilation, patients in LMIC were ventilated with higher VAdditional file 1. Full list of LAS VEGAS collaborators. A list of all LAS VEGAS researchers and their affiliations.Additional file 2. ARISAT score. The ARISCAT risk score is used to calculate the risk for developing postoperative pulmonary complications.Additional file 3. Definitions of postoperative pulmonary complications. A description of the definitions of postoperative pulmonary complications used in this analysis.Additional file 4. Definitions of intraoperative complications. A description of the definitions of intraoperative complications used in this analysis.Additional file 5. CONSORT flow chart of the study population. Flowchart with information on how the study population was obtained.Additional file 6. Posthoc pairwise analysis for numerical data. Posthoc Dunn’s test for pairwise multiple comparison of the ranked data.Additional file 7. Posthoc pairwise analysis for categorical data. Chi-square test for pairwise comparison.Additional file 8. Multivariate model of factors associated with the development of PPC. HIC and UMIC were compared to LMIC and centers were entered as random effect.


Flecainide is a class 1C antiarrhythmic with a narrow therapeutic window and thereby a high-risk medication for causing acute toxicity. Dysrhythmias secondary to flecainide ingestion are often refractory to antiarrhythmics and cardioversion, and patients commonly require extracorporeal support. We review the successful resuscitation of two brothers aged 2 and 4 who presented two years apart with unstable wide-complex tachyarrhythmia suspicious for severe flecainide toxicity. Each patient received sodium bicarbonate and 20% intravenous lipid emulsion with a full recovery. While extracorporeal support is often required following flecainide ingestion, we present two cases where it was avoided due to aggressive multimodal management with sodium bicarbonate, electrolyte repletion, and 20% intravenous lipid emulsion. In addition, avoidance of agitation-induced tachycardia may be beneficial. Maximum% [2/day . Althoug% [2/day . AlternaInformed parental consent was obtained to report the following cases.2 of 71 mmHg and a serum bicarbonate level of 23 mmol/L. Flecainide trough level on arrival was 5.6 μg/mL (therapeutic range 0.2 μg/mL to 1 μg/mL). Synchronized cardioversion was performed three times , and 1-2 mEq/kg 8.4% sodium bicarbonate boluses were given three times, resulting in conversion to sinus rhythm with widened QRS  on flecainide maintenance therapy (30 mg every 8 hours). He presented to the emergency department three hours after an unwitnessed ingestion of approximately 2 g of flecainide with alternating bradycardia and wide complex tachyarrhythmia , alteredened QRS . The patμg/mL, and his home dose of flecainide restarted. He was discharged home on the same maintenance dose of 30 mg every 8 hours.On admission to the PICU, the patient's heart rate was 160 BPM with no other changes to his physical exam or vital signs. He was intubated and mechanically ventilated with extracorporeal support and a pediatric cardiac electrophysiology consultant immediately available. The patient's serum potassium was 2.5 mEq/L; ionized calcium was 0.9 mmol/L with otherwise normal electrolytes. Sodium bicarbonate boluses were given in 1-2 mEq/kg increments for QRS > 100 ms to maintain a goal pH of 7.5. He was initiated on a sodium bicarbonate infusion at a rate of 1 mEq/kg/hr which continued until the following morning. Serum calcium and potassium were replaced and magnesium given for treatment of the wide complex arrhythmia. Due to continued dysrhythmia and hemodynamic instability despite the above treatments, the child received 1.5 mL/kg 20% ILE bolus followed by a 0.25 mL/kg/min infusion. Following, the child had successful conversion to a sinus rhythm at a rate of 80 BPM with a wide QRS, blood pressure of 90/60 mmHg, and improved perfusion and mental status. The ILE infusion was weaned and completely discontinued after two hours. The child continued to have intermittent runs of pleomorphic ventricular tachycardia with agitation while mechanically ventilated. These episodes of agitation-induced tachycardia were successfully treated with an appropriate sedative dose. Following hemodynamic stability, the child was extubated after 36 hours, at which time the QRS had completely normalized. The patient's serum flecainide level had decreased to 0.3 2 of 63 mmHg and a serum bicarbonate level of 24 mmol/L. After receiving 1 mg/kg lidocaine bolus with no effect, he was given three 0.5 mEq/kg sodium bicarbonate boluses resulting in wide complex tachycardia , presented to the emergency department with seizure-like activity, altered mental status, bradycardia, and hypotension. Although serum flecainide concentrations were not obtained, the patient's mother reported finding the child near his brother's (child 1) empty flecainide bottle, estimating approximately a 400 mg ingestion 45 minutes prior to presentation. This occurred two years following his brother's hospitalization. On arrival to the hospital, his heart rate was 70 BPM, blood pressure 70/30 mmHg with faint central pulses, and capillary refill time of 4 seconds. He was breathing spontaneously with an oxygen saturation of 100% on a nonrebreather mask. He was responsive only to pain. Presenting pH was 7.2 with a pCOhycardia . He was On admission to the PICU, the patient's heart rate was 150 BPM with a blood pressure of 64/40 mmHg but otherwise no change in his physical exam or vital signs. The child was intubated and mechanically ventilated with extracorporeal support and a pediatric cardiac electrophysiologist immediately available, as above. Sodium bicarbonate boluses were given in 1-2 mEq/kg increments for QRS > 100 ms to maintain a goal pH of 7.5. Serum potassium was 3.3 mEq/L, and ionized calcium was 0.91 mmol/L, both of which were repleted. All other electrolytes were normal. A 50 mg/kg intravenous dose of magnesium sulfate was given for the wide complex tachyarrhythmia with brief conversion to sinus rhythm .An isoproterenol infusion was initiated in an attempt to suppress recurrent ventricular tachycardia at 0.1 mcg/kg/min, resulting in persistent widening of the QRS, so the infusion was stopped. He also received 1 mEq/kg 3% hypertonic saline. Due to continued dysrhythmia and hemodynamic instability despite the above interventions, the child received 1.5 mL/kg 20% ILE bolus followed by a 0.25 mL/kg/min infusion. He required a second bolus of 1.5 mL/kg 20% ILE due to persistent hypotension, followed by an increase in the infusion rate to 0.5 mL/kg/min. With the above interventions, the child had successful conversion to a sinus rhythm at a rate of 90 BPM with a wide QRS, blood pressure of 100/50 mmHg, strong pulses, and capillary refill time of 2 seconds. The ILE infusion was weaned and completely discontinued after two hours. Similar to his brother, the patient continued to have intermittent runs of pleomorphic ventricular tachycardia with agitation while mechanically ventilated, which resolved with appropriate sedative dosing. Following hemodynamic stability, child 2 was extubated after 24 hours of mechanical ventilation with no remaining sedative requirement. Complete normalization of the QRS took approximately 36 hours. Child protective services was notified in both cases, and a safety plan for discharge was determined.Management of flecainide toxicity can be challenging. We described the presentation and successful treatment of two children, which precluded the need for extracorporeal support. In cases of severe intoxication and hemodynamic instability, we recommend an integrated approach with sodium bicarbonate, normalization of electrolytes, ILE, avoidance of agitation, mechanical ventilatory support, and immediate availability of extracorporeal support.Sodium bicarbonate can be used as monotherapy and is commonly given as the first line treatment for QRS > 100 ms in increments of 1-2 mEq/kg –9. It inThe rationale for using intravenous lipid emulsion (ILE) in flecainide toxicity is extrapolated from its use in the treatment for regional anesthetic drug toxicity , 16. SimRhythm response to normalization of electrolytes has been reported, and as per pediatric advanced life support recommendations, magnesium should be administered for polymorphic ventricular tachycardia , 25, 26.Both children had progressive widening of the QRS complex with tachycardia in the setting of agitation during the first 12 hours postingestion. This association of tachycardia and QRS prolongation has been described in both human and animal models with maintenance flecainide doses, even in the absence of toxicity –32. At aFlecainide ingestions can cause wide complex tachyarrhythmias and hemodynamic collapse refractory to typical management, often requiring extracorporeal support. While we cannot conclude with certainty if one treatment was solely responsible for the improvement observed in our patients, we do provide validation for a multimodal treatment approach to flecainide toxicity, preventing the need for extracorporeal support. Flecainide toxicity should be treated with sodium bicarbonate boluses; electrolyte repletion, with particular attention to magnesium: intravenous lipid emulsion; judicious administration of sedatives to avoid tachycardia from agitation; and if needed extracorporeal support.


Botulinum toxin (BoNT) injections were shown to improve muscle tone of limbs in patients with spasticity. However, limited data are available regarding the effects of repeated BoNT injections on walking ability.To assess changes in walking velocity (WV), step length, and cadence under different test conditions after repeated treatment with abobotulinumtoxinA  in spastic lower limb muscles.Secondary analysis of an open‐label, multiple‐cycle extension  to a phase III, double‐blind, randomized, placebo‐controlled, single‐treatment cycle study, in adults with chronic hemiparesis (NCT01249404).Fifty‐two centers across Australia, Belgium, the Czech Republic, France, Hungary, Italy, Poland, Portugal, Russia, Slovakia, and the United States.352 Ambulatory adults (18‐80 years) with spastic hemiparesis and gait dysfunction caused by stroke or traumatic brain injury, with a comfortable barefoot WV of 0.1 to 0.8 m/s.Up to four aboBoNT‐A treatment cycles, administered to spastic lower limb muscles.Changes from baseline in comfortable and maximal barefoot and with shoes WV (m/s), step length (m/step), and cadence (steps/minutes).P < .0001 to .0003 vs baseline). More patients (7% to 17%) became unlimited community ambulators (WV ≥0.8 m/s) across test conditions compared with baseline, with 39% of 151 patients classified as unlimited community ambulators in at least one test condition and 17% in all four test conditions.At Week 12 after four injections, WV improved by 0.08 to 0.10 m/s, step length by 0.03 to 0.04 m/step, and cadence by 3.9 to 6.2 steps/minutes depending on test condition (all Clinically meaningful and statistically significant improvements in WV, step length, and cadence under all four test conditions were observed in patients with spastic hemiparesis after each aboBoNT‐A treatment cycle. Walking velocity (WV) in patients with chronic hemiparesis following stroke or traumatic brain injury is typically limited, stabilizing at a level that leaves many patients unable to functionally ambulate in the community.Gait velocity is used as an outcome to assess community ambulation potential in patients who have experienced a stroke.Spastic hemiparesis may contribute to gait dysfunction as a result of impaired motor control, abnormal muscle activation, muscle weakness, and muscle extensibility loss.A secondary outcome of this study was 10‐m comfortable barefoot WV without walking aids, a common test for assessing gait in hemiparesis.Along with comfortable barefoot WV analyses, there were other assessments of WV performed in the adult lower limb study, including comfortable WV with shoes, maximal barefoot WV, and maximal WV with shoes, with change in functional ambulatory category (according to WV) also examined over treatment cycles. In addition, changes in step length and cadence were assessed to determine if the changes in WV were achieved by increasing step length, cadence, or both.Ambulation improvement provides value in terms of life participation, quality of life, and reduction of medical complications and is an important treatment goal for many patients.Details of the adult lower limb double‐blind (NCT01249404) and open‐label (NCT01251367) studies have been previously published.The double‐blind study primary objective was to demonstrate single aboBoNT‐A injection efficacy  versus placebo in the lower extremity; safety was a secondary objective. The open‐label study primary objective was to assess long‐term safety of repeated aboBoNT‐A injections; long‐term efficacy was a secondary objective. The research protocol and all study documents were approved by an independent ethics committee and the study was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonisation Consolidated Guidelines on Good Clinical Practice.In each injection cycle, aboBoNT‐A injections were administered to the gastrocnemius‐soleus muscle complex, with additional injections to the tibialis posterior, flexor digitorum longus, flexor digitorum brevis, flexor hallucis longus, flexor hallucis brevis, rectus femoris, hamstrings, adductor magnus, gracilis, or gluteus maximus based on the investigator's clinical judgment. Injections could also be administered to the affected upper limb based on the investigator's clinical judgment from the beginning of open‐label Cycle 3. Patients were not required to meet the initial study inclusion criteria in order to receive injection at each cycle. The need for retreatment was considered at each study visit after Week 12 of each treatment, with optional follow‐up visits at Week 16, 20, and 24 of each cycle. Retreatment decisions were based on the following reinjection criteria: a MAS score within 1 grade of the double‐blind study baseline value, a physician's global assessment score that showed no improvement (≤0) compared with double‐blind study baseline, and no unacceptable safety risk based on investigators' clinical judgment. The maximum study duration was 18 months , during which patients could receive a maximum of five injections (including double‐blind cycle). If patients did not require reinjection at the Week 24 visit of open‐label Cycle 1 or 2, they attended follow‐up visits every 4 weeks until they either met the retreatment criteria and entered the next treatment cycle or completed at least 12 months of follow‐up.As per the study protocol, no standardized physiotherapy was administered and could not be initiated 4 weeks prior to study entry or during the first 4 weeks of the study.Ambulatory patients aged between 18 and 80 years with spastic hemiparesis causing gait dysfunction; comfortable barefoot WV between 0.1 and 0.8 m/s, measured with a 10‐m WV test (WVT) without walking aids; and only one clinically defined stroke episodeHere we report a detailed statistical analysis of changes in WVTs, step length, and cadence of the patients treated with aboBoNT‐A over the first four injections (one double‐blind and the first three open‐label injections) assessed at Week 12 of each cycle relative to preinjection baseline of the double‐blind study. Some patients received five injections (open‐label Cycle 4), but the last mandatory study visit was at Week 4 of this cycle; therefore, Week 12 data were not available (n = 0). As such, the fifth injection cycle was not included for these analyses. Walking ability was assessed through measurement of comfortable barefoot WV, maximal barefoot WV, comfortable WV with shoes, and maximal WV with shoes. In all WV tests, patients were asked to walk for 10 m on the same flat floor at all visits, without obstacles or turns. Duration was measured with a stopwatch from the time the first foot crossed the starting mark to when a foot crossed the arrival mark. The evaluator walked beside the patient and measured the time and the number of steps taken during the 10 m. Space for acceleration and deceleration was provided. A 1‐minute resting period was scheduled between each of the walking tests.Data are provided at Week 12 post injection up to the fourth injection (open‐label Cycle 3). Patients were also categorized and grouped based on Perry et al's classification for WVNumerical differences between baseline and Week 12 post‐injection results are presented  in the four walking test conditions, alongside percentage improvement values . An intragroup analysis was performed after each injection to compare the Week 12 values with the initial baseline values.In addition, a statistical model was used to analyze the change from baseline to Week 12 following each injection. Considering the context of multiple walking assessments, a mixed model for repeated measures (MMRM) has been used, including the fixed categorical effects of test condition, visit, test condition‐by‐visit interaction, test condition‐by‐baseline interaction, and baseline value as a fixed continuous covariates. Least squares (LS) mean changes from baseline as well as 95% confidence intervals (CIs) are provided at Week 12 of each cycle, under each test condition for walking velocity, step length, and cadence.Patient demographics, patient disposition, and BoNT‐A dose administered to each muscle group across cycles have been previously reported.Depending on the number of injections received, mean comfortable barefoot WV (SD) at baseline ranged between 0.43 (0.20) and 0.45 (0.22) m/s. In other test conditions, baseline values were between 0.56 (0.30) and 0.60 (0.33) m/s for maximal barefoot WV; 0.48 (0.22) and 0.49 (0.23) m/s for comfortable WV with shoes; and 0.64 (0.33) and 0.66 (0.33) m/s for maximal WV with shoes Table .P < .0001; Table Improvements in WV were observed in the comfortable barefoot walking test across the four injections with a mean (SD) improvement from baseline to Week 12 (mean percentage improvement) of +0.09 (0.14) m/s (+23.6%) at Week 12 after the fourth injection. Improvements observed at Week 12 after each injection for comfortable barefoot WV were statistically significant compared with baseline values  and 53% as limited ambulators (WV 0.4 to 0.8 m/s) at baseline . After fGlobally, 39% (n = 59/151) of the patients who had received four injections achieved unlimited community ambulation in at least one test condition, 31% (n = 47/151) in two or more conditions, 22% (n = 33/151) in three or more conditions, and 17% (n = 26/151) in all four conditions.P < .0001). Similar statistically significant improvements were also seen across the three other walking test conditions  of +0.04 (0.08) m/step +13.8%) with an improvement in cadence of +5.0 12.3) steps/minutes (+8.4%) at Week 12 after the fourth injection  hemiparesis.Step length improved by 0.03 to 0.04 m/step (10% to 14%) across all test conditions after four injections, and cadence improved by 3.9 to 6.2 steps/minutes (7% to 10%). Along with a mean improvement in comfortable barefoot WV of around 0.09 m/s (20%) and improvement in ambulatory capacity, this represents a clinically meaningful achievement in chronic hemiparesis.Other studies have reported improvements in walking ability following BoNT‐A injections of the lower limb using a number of assessment techniques, including timed walking tests, Fugl‐Meyer assessments, use of video technology to measure temporospatial parameters, or instrumented insoles,In the primary study, comfortable barefoot WV improvement was consistently greater at Week 12 compared with Week 4,Patients with hemiparesis have previously reported improved quality of life with increased WV following repeated aboBoNT‐A treatments but not after a single BoNT‐A treatment.Patients with a comfortable barefoot WV of more than 0.8 m/s at baseline were excluded from the study, which represents a potential study bias. Additionally, improvements in walking velocity were not the primary endpoint of the studies from which these data were obtained, and analyses by ambulatory category, for the MMRM and statistical analyses of changes from baseline were not planned, but post hoc analyses.Repeated aboBoNT‐A injections to the lower limb were associated with sustained and statistically significant improvements in WV, step length, and cadence in patients with chronic spastic hemiparesis after stroke or traumatic brain injury. Improvements were progressive and greater after several treatment cycles. These improvements in WV were also shown to have a positive impact on community ambulation achievement in some patients.Where patient data can be anonymized, Ipsen will share all individual participant data that underlie the results reported in this article with qualified researchers who provide a valid research question. Study documents, such as the study protocol and clinical study report, are not always available. Proposals should be submitted to datasharing@ipsen.com and will be assessed by a scientific review board. Data are available beginning 6 months and ending 5 years after publication; after this time, only raw data may be available.Appendix S1 Supporting InformationClick here for additional data file.


Drosophila, the pigmentation genes ebony and tan have pleiotropic effects on flies' response to light, creating the potential for correlated evolution of pigmentation and vision. Here, we investigate differences in light preference within and between two sister species, Drosophila americana and D. novamexicana, which differ in pigmentation in part because of evolution at ebony and tan and occupy environments that differ in many variables including solar radiation. We hypothesized that lighter pigmentation would be correlated with a greater preference for environmental light and tested this hypothesis using a habitat choice experiment. In a first set of experiments, using males of D. novamexicana line N14 and D. americana line A00, the light‐bodied D. novamexicana was found slightly but significantly more often than D. americana in the light habitat. A second experiment, which included additional lines and females as well as males, failed to find any significant difference between D. novamexicana‐N14 and D. americana‐A00. Additionally, the other dark line of D. americana (A04) was found in the light habitat more often than the light‐bodied D. novamexicana‐N14, in contrast to our predictions. However, the lightest line of D. americana, A01, was found substantially and significantly more often in the light habitat than the two darker lines of D. americana, thus providing partial support for our hypothesis. Finally, across all four lines, females were found more often in the light habitat than their more darkly pigmented male counterparts. Additional replication is needed to corroborate these findings and evaluate conflicting results, with the consistent effect of sex within and between species providing an especially intriguing avenue for further research.Environmental adaptation and species divergence often involve suites of co‐evolving traits. Pigmentation in insects presents a variable, adaptive, and well‐characterized class of phenotypes for which correlations with multiple other traits have been demonstrated. In  Drosophila novamexicana and in three lines of the dark‐bodied Drosophila americana. In both species, female flies are more lightly pigmented than male flies and also show a stronger tendency to select a more brightly lit habitat. Patterns of habitat choice within and between species were mixed, but showed some trends of lighter bodied flies preferring more brightly lit habitats.Light preference was examined in the light‐bodied  In 2019, a second observation period at 4 p.m. was added.Each trial was run for six consecutive days. At 12 p.m. every day, the number and species of flies in the light side of each cage were recorded. In the mixed‐species experiments, this was done by looking for the number of dark‐bodied flies  were placed in both the light and dark sides of two empty cages. We recorded the temperature reading of each side of each cage, at noon and 4 p.m. daily for 6 days.2.7To test for differences in fly light preference, a generalized linear model was fitted using the glm command in RStudio 1.3.1093, “Apricot Nasturtium,” within the lme4 package. We assumed a Poisson distribution for the dependent variable, which was the number of flies on the light side of the cage. Independent variables included a fixed effect of taxon; a fixed effect of sex in experiments that included both male and female flies; a fixed effect of time of day for comparisons between 12 p.m. and 4 p.m.; a random effect of cage, to account for the repeated measurements made on each cage; and a random effect of experiment to account for the fact that multiple rounds of data collection were performed, at different times and by different groups of experimenters.t test in R was used to determine whether there was a significant temperature difference between the light and dark sides of the cages.A paired 2.8tan and ebony genes. DNA was extracted using the Omega E.Z.N.A. Tissue DNA Kit  and eluted in 50 μl of water. Partial sequence was amplified from the tan gene using primers 5′‐ CCGATGCCTGTTCCATTAAC‐3′ and 5′‐ GGCGGCTTGTATTTACCAAA‐3′, and from the ebony gene using primers 5′‐AGCCCGAGGTGGACATCA‐3′ and 5′‐GTATGGGTCCCTCGCAGAA‐3′, with G‐Biosciences Taq DNA Polymerase . Thirty cycles of PCR were performed with a 54℃ annealing temperature and a 30‐s extension time. PCR product purity and concentration were estimated from a 1% agarose gel.At the end of the 2020 experiments, the flies were visually inspected to verify homogeneity of pigmentation within each line. To further confirm that the lines had not interbred over the course of the experiments, one female fly of each line was sequenced at both D. americana and D. novamexicana obtained from GenBank and from Cooley et al. (https://www.geneious.com).Samples were sequenced, using both forward and reverse primers, by Eton Biosciences . Manually trimmed sequences were compared to sequences of y et al. . Alignme33.1D. novamexicana than D. americana were observed on the light sides of the fly cages , more total s Figure . The efft = 0.848, df = 3, p = .405). Time of day had a significant effect on total numbers of flies in the light habitat  was found in the light habitat more often than either of the darker lines .In experiments with one taxon per cage, in contrast to the mixed‐species experiments, no significant difference was observed between 14 Table . The prea Figure . Within In the 2020 experiments, a consistent and significant effect of sex was observed Table .3.3tan and ebony , male flies of D. americana line A00 and D. novamexicana line N14 were placed together in behavioral choice cages. These experiments revealed a consistent and highly significant effect of species, with the lighter bodied D. novamexicana found slightly but significantly more often in the “light” habitat compared to D. americana, for data collected at both mid‐day and afternoon times. In contrast, a second set of experiments with only a single type of fly per cage (the 2020 datasets) did not reveal any difference between D. americana‐A00 and D. novamexicana‐N14.Correlations between melanin pigmentation and a variety of other phenotypic traits are commonly observed, across vertebrates and insects  was found significantly more often in the light habitat than the two dark lines (A04 and A00). Line A01 has a functionally D. novamexicana‐like (“light”) allele at tan, but not ebony, whereas line A00 has non‐novamexicana‐like (“dark”) alleles at both genomic regions ; funding acquisition (lead); methodology ; project administration (lead); supervision (lead); visualization (lead); writing–review and editing (lead). Suzanne Schmitz: Investigation (lead); writing–original draft (supporting). Eduardo J. Cabrera: Investigation ; writing–original draft (supporting). Mitchell Cutter: Conceptualization ; methodology . Maxwell Sheffield: Conceptualization ; methodology . Ian Gingerich: Investigation ; writing–original draft (supporting). Gabriella Thomas: Investigation ; writing–original draft (supporting). Calvin N. M. Lincoln: Investigation ; writing–original draft (supporting). Virginia H. Moore: Investigation ; writing–original draft (supporting). Alexandra E. Moore: Investigation ; writing–original draft (supporting). Sarah A. Davidson: Investigation ; writing–original draft (supporting). Nikhil Lonberg: Investigation ; writing–original draft (supporting). Eli B. Fournier: Investigation ; writing–original draft (supporting). Sophia M. Love: Investigation (lead); writing–original draft (supporting). Galen Posch: Investigation ; writing–original draft (supporting). Matthew B. Bihrle: Investigation ; writing–original draft (supporting). Spencer D. Mayer: Investigation ; writing–original draft (supporting). Kuenzang Om: Conceptualization ; methodology . Lauren Wilson: Investigation ; writing–original draft (supporting). Casey Q. Doe: Investigation ; writing–original draft (supporting). Chantalle E. Vincent: Investigation (lead); writing–original draft (supporting). Elizabeth R. T. Wong: Investigation ; writing–original draft (supporting). Ilona Wall: Investigation . Jarred Wicks: Investigation (lead); writing–original draft (supporting). Stephon Roberts: Investigation (lead); writing–original draft (supporting).https://doi.org/10.5061/dryad.dv41ns1xz.This article has earned an Open Data Badge for making publicly available the digitally‐shareable data necessary to reproduce the reported results. The data are available at