To examine whether vigorous-intensity physical activity confers additional reductions on all-cause and cause-specific mortality compared with moderate-intensity physical activity.A systematic review (registered in PROSPERO CRD42019138995) and meta-analysis.Three electronic databases up to April 14 2020.Inclusion criteria were prospective studies that contained information about (1) moderate-intensity ) and vigorous-intensity (≥6 METs) physical activities and (2) all-cause and/or cause-specific mortality. Exclusion criteria were prospective studies that (1) exclusively recruited diseased patients  or (2) did not account for total physical activity in their multivariable models (3) or did not adjust or exclude individuals with comorbidities at baseline or (4) used physically inactive participants as reference group.Five studies (seven cohorts using sex-specific results) were pooled into a meta-analysis. For all-cause mortality and controlling by total physical activity, vigorous-intensity physical activity (vs moderate) was not associated with a larger reduction in mortality . After the exclusion of one study judged with critical risk of bias  from meta-analysis, results remained similar . Due to the limited number of studies, meta-analyses for cancer and cardiovascular mortality were not performed.Prospective studies suggest that, for the same total physical activity, both vigorous-intensity and moderate-intensity physical activities reduce all-cause mortality to the same extent. However, absence of evidence must not be interpreted as evidence of absence due to the existing methodological flaws in the literature. Motorised transportation, sedentary jobs, increased urbanisation and wide use of technology during leisure time divert from the physically active lifestyles, which were required for human survival in the past.1 However, there is a limited knowledge of the role of specific components of physical activity  on different health outcomes across adulthood. The inconsistent findings obtained in prospective studies have led to conflicting views surrounding the importance of physical activity intensity for health.Low physical activity in adult populations of industrialised nations is recognised as one of the main drivers of poor health.4 the UK,5 Australia6 or from the WHO7 recommend that adults should accumulate at least 150 min of moderate-intensity activity  or 75 min of vigorous-intensity activity (≥6 METs) per week or a combination of both intensities, where 1 min of vigorous-intensity activity counts as 2 min of moderate-intensity activity. This implies that, when the overall activity energy expenditure is held constant, both moderate-intensity and vigorous-intensity activities may yield similar benefits for health. On the other hand, during the last decade, there has been a growing scientific interest among exercise physiologists into the potential of high-intensity vigorous training programmes as a time-efficient strategy to improve health.8 Compared with activities of lower intensity , some scientists claim that vigorous-intensity activities (often of shorter duration) elicit comparable or superior health benefits to lower-intensity activities due to, among other reasons, larger improvements in cardiorespiratory fitness.8–19 Nonetheless, to date, few observational studies have studied the effect of vigorous-intensity activities on mortality compared with moderate intensity, after controlling for total physical activity.20–25 While some prospective studies reported larger risk reductions on all-cause23–25 and cardiovascular disease (CVD) mortality in participants with higher vigorous-intensity activity,21 another study observed inconsistent associations (of vigorous-intensity vs moderate-intensity activities) on CVD mortality between sexes and a lower all-cause mortality in men.22On one hand, physical activity guidelines for health developed by expert groups in the USA,The aim of this systematic review was to compare vigorous-intensity versus moderate-intensity physical activities in relation to all-cause and cause-specific mortality, after adjusting for total physical activity.26 and the review protocol was registered in PROSPERO (CRD42019138995).This systematic review was conducted and reported based on the Preferred Reporting Items for Systematic Reviews and Meta-analysis statement,Two authors (AS and JPRL) in collaboration with a professional librarian developed the search strategy. A comprehensive electronic database search was conducted in Scopus, Web of Science and EMBASE via Ovid, for studies published from inception until April 14, 2020  and comparing vigorous-intensity (≥6 METs) to moderate-intensity  physical activities for all-cause and cause-specific (cardiovascular or cancer) mortality. Prospective studies were excluded when they were exclusive if conducted in diseased patients  or did not account for total physical activity in the multivariable models. Representative, population-based cohort studies  were considered eligible only if their effect sizes were adjusted for comorbidities or diseased individuals at baseline .To be included in the meta-analysis, we only selected those studies that compared mortality between participants reporting vigorous-intensity versus moderate-intensity physical activities .Two reviewers (AS and MMJ) independently screened the titles and abstracts to remove irrelevant studies. During the selection stage, a pair of reviewers (AS and MMJ) independently read the full-text articles and made the selection based on the eligibility criteria. Discrepancies during the screening or selection stages were resolved by a third author (JPRL).Information on the characteristics of the included studies were extracted independently by two reviewers (MMJ and JPRL): (1) authors and year of publication; (2) country, sample size, sex and age at baseline; (3) follow-up time; (4) measurement of physical activity; (5) outcome variables; (6) covariates included in the maximally adjusted model; (7) exposure reference group; (8) main results .27 This approach for evaluating risk of bias in observational studies covers seven domains through which bias might be introduced into interventions (or exposure groups) of studies that did not use randomisation to allocate participants to comparison groups. The tool includes a list of signalling questions for the following domains: (1) bias due to confounding, (2) bias in selection of participants into the study, (3) bias in classification of interventions, (4) bias due to deviations from intended interventions, (5) bias due to missing data, (6) bias in measurement of outcomes and (7) bias in selection of the reported result. Domain level judgements about risk of bias are conceived hierarchically: (1) low risk of bias , (2) moderate risk of bias , (3) serious risk of bias (the study has some important problems in that domain), (4) critical risk of bias (the study is too problematic in that domain to provide any useful evidence on the effects of the intervention) and (5) no information on which to base a judgement about risk of bias for that domain. Any disagreement was discussed between the two authors and, in case of further disagreement, a third author (MP-V) was recruited for a final judgement.Risk of bias of included studies was appraised by two authors (LFMR and JPRL) using the ROBINS-I tool (‘Risk Of Bias In Non-randomised Studies of Interventions’).metan package) to estimate the overall summary HR for all-cause and cause-specific mortality comparing vigorous-intensity versus moderate-intensity physical activity. In addition, to assess the impact of heterogeneity on the summary effect (under the random effect model), prediction intervals were calculated. When results of the original studies reported several multivariable models, only the data from the maximally adjustment model was considered. When authors reported several categories of vigorous intensity in their statistical analyses, only the group with the highest proportion of vigorous-intensity physical activity to total physical activity was extracted. Studies that reported results for men and women were included in the analysis as two separate cohorts. Heterogeneity was quantified using the I2 statistic and the χ² Cochran Q-test.28 The CI for the I2 measure was derived using the Q statistic and the corresponding degrees of freedom. Publication bias was examined using the asymmetry tests  and by the contour-enhanced funnel plots (using the confunnel package).29 Sensitivity analyses to determine whether a particular study largely accounted for heterogeneity were explored by removing one by one study from the meta-analysis. All analyses were performed using Stata, version 15 .Data from individual studies were pooled  using a random effects model . Of the 34 full-text articles retrieved, 29 studies were excluded from the systematic review  because 10.1136/bmjsem-2020-000775.supp2Supplementary data22–25 33 All studies were carried out in high-income countries: Germany,31 Finland,33 the UK,25 Australia,23 Japan24 and the USA.22 30 32Participant characteristics from eight studies meeting the eligibility criteria of the systematic review are summarised in 30 most studies reported information on leisure time physical activity only. Reference groups of exposure were defined as follows: a physically inactive group (two studies),30 31 a combination of both physically inactive and active group,32 a low moderate-intensity group,33 0% vigorous-intensity physical activity to total MVPA performed at vigorous intensity (three studies)23–25 and ≤10% of vigorous intensity to MVPA performed at vigorous intensity (one study).22 Regarding the outcome, all studies included all-cause mortality, five CVD mortality22 25 30–32 and four cancer mortality.25 30–32The sample size of the studies ranged between 4672 and 204 542 participants. All studies included both men and women. Age of participants at the baseline ranged between 40 and 85 years. Average follow-up time varied from 6.52 years to 17.8 years. All studies measured participants’ physical activity through questionnaires. A total of five studies measured habitual physical activity . Although one study provided detailed information on physical activity in several domains,In stage one, ROBINS-I requires the reviewers to specify the review question in order to emulate a hypothetical pragmatical randomised trial. Accordingly, healthy adults were defined as participants. The experimental intervention was vigorous-intensity physical activity and the comparator was moderate-intensity physical activity. Outcomes included all-cause mortality, cardiovascular mortality or cancer mortality. Confounders were age, sex, smoking, adiposity, alcohol consumption, dietary factors and individual-level socioeconomic factors. 10.1136/bmjsem-2020-000775.supp3Supplementary data22–25 33 (seven cohorts after using the sex-specific data) evaluated the association between vigorous-intensity physical activity (vs moderate-intensity) and all-cause mortality. Compared to moderate-intensity physical activity, vigorous-intensity physical activity was not associated with all-cause mortality   ; prediction interval 0.57–1.66) (oFive prospective studies60–1.51) . The exc61–1.51) . The exc7–1.66) o.10.1136/bmjsem-2020-000775.supp5Supplementary data10.1136/bmjsem-2020-000775.supp4Supplementary data22 25 (three cohorts after using the results available by sex) evaluated the association between vigorous-intensity physical activity and CVD mortality. Compared to moderate-intensity physical activity, women who reported the highest proportion of vigorous to total physical activity had 15% higher risk of CVD mortality .22 In men, the highest proportion of vigorous-intensity physical activity to total physical activity was associated with lower CVD mortality .22 Similarly, in 64 913 men and women from England and Scotland, the HR for CVD mortality in participants engaged in the highest proportion of vigorous-intensity physical activity was 0.88 (95% CI 0.69 to 1.11).25Two studieset al32 found a HR for CVD mortality of 0.66 (95% 0.40 to 1.07) when comparing participants with the highest proportion of vigorous-intensity activity to total physical activity vs 0% vigorous-intensity activity group .Zhao 25 Compared to moderate-intensity (but not vigorous-intensity) physical activity, the HR for cancer mortality in the group engaged in the highest proportion of vigorous-intensity physical activity was 0.88 (95% CI 0.73 to 1.07).One study examined the association between vigorous-intensity physical activity (vs moderate) and cancer mortality.et al (2007),30 in a sample of 252 925 middle-aged participants, found a HR of 0.95 (95% CI 0.85 to 1.07) when comparing vigorous group with moderate group. Another study conducted in 4672 middle-age adults during 17.8 years of follow-up showed a lower risk of cancer mortality in participants reporting vigorous-intensity versus moderate-intensity physical activities during leisure time (HR 0.36 95% CI 0.23 to 0.59).31 Finally, in a recent study from Zhao et al,32 a lower cancer mortality rate was observed in participants with the highest amount of vigorous-intensity activity (HR 0.61 95% 0.42 to 0.89) versus 0% vigorous-intensity activity. Nonetheless, the reference group used included both physically inactive and active participants.Two additional prospective studies compared the association of vigorous-intensity physical activity  and cancer mortality. Leitzmann As shown in 33 vigorous-intensity activity was associated with a 2% lower all-cause mortality (Results from five prospective studies (seven different cohorts) suggest that, for the same volume of physical activity, vigorous-intensity and moderate-intensity physical activities reduce mortality to the same extent. There was a 5% lower all-cause mortality among adults reporting regular vigorous-intensity physical activity compared with those reporting moderate-intensity physical activity. When we excluded one study judged as critical risk of bias ,ortality . On the 8 Given that high-intensity training studies have been conducted in laboratory settings during a short period of time, it is unknown whether vigorous-intensity activities maintained throughout life may offer larger health benefits compared with energy-matched physical activity of lower intensity. We found five prospective studies that aimed to close this gap of knowledge; yet, the existence of biases inherent to epidemiological studies challenges their interpretation. As depicted in Our findings are in agreement with the current physical recommendations for health in adults developed in countries such as the USA, Australia and the UK as well as the WHO. Remarkably, all the above-mentioned recommendations do not prioritise vigorous over moderate intensity to maximise the health benefits. Nonetheless, during the last decade programmes of short duration, vigorous-intensity activities have received considerable scientific attention among clinical researchers interested in the cardiometabolic benefits of exercise.et al,23 participants diagnosed with cardiometabolic diseases at baseline were included in the analysis. Therefore, we only included in the meta-analysis estimates obtained from participants without cardiometabolic diseases at baseline.23 Regarding other domains included in ROBINS-I, it is remarkable that most studies did not provide information about missing data. Missing data may occur among other reasons through loss to follow-up, incomplete data collection and exclusion from analysis by investigators. Bias  may arise if the reason for and/or the proportion of missing data differs according to groups being compared.A well-known limitation of epidemiological studies involving physical activity and mortality is reverse causation. To minimise this problem, we pooled prospective studies that accounted for the diagnosis of any disease in the multivariable model and/or excluded those with diseased participants. Nevertheless, some studies in the literature failed to account for reverse causation. For example, in the main results reported by Gebel 29 Furthermore, problems with the design of some prospective studies identified in the systematic review forced us to exclude them from the meta-analysis. For example, three studies (included in the narrative review) evaluated moderate-intensity and vigorous-intensity physical activities but employed as counterfactual reference groups: people with no physical activity30 31 or participants with no physical activity and some amount of non-vigorous-intensity physical activity.32 These analytical decisions may overestimate the benefits of vigorous-intensity physical activity on mortality. Evidence of the latter may be found in the analyses of Kikuchi et al,24 where a significant protective effect was reported using the physically inactive group (450 MET min/week) while no association was found using 0% of vigorous intensity to MVPA.Although we observed some asymmetry in the funnel plot, the results obtained in the contour-enhanced funnel plot suggest that causes of the observed asymmetry were likely due to other factors rather than publication bias .Homo sapiens.34 This opinion was, however, drawn on a narrative review of physiological and anatomical bases of endurance running capabilities of humans versus other primates. An observational study in modern hunter-gatherers  showed that adults tend to accumulate (per day) over 135 min of moderate-intensity to vigorous-intensity physical activities (measured by accelerometry), mostly at moderate intensity.1 In a recent study that compared cardiovascular adaptations induced by different types of exercise among humans, gorillas and chimpanzees, authors claimed that humans have evolved multisystem capabilities mainly matched for regular moderate-intensity endurance physical activity.35 Low volume strength and power physical activities (which can be categorised as vigorous-intensity activities) were an occasional form of physical activity in our ancestors. Interestingly, cardiological adaptations induced by strength and power exercise seem less cardioprotective  compared with programmes of moderate-intensity physical activity.35From an evolutionary perspective, it has been suggested that endurance running was instrumental in the survival of 3 The finding that either moderate-intensity activity or vigorous-intensity activity may provide similar reductions on mortality  is, if confirmed, good news because physical inactive population groups can find it difficult to attain and maintain intensities of vigorous intensity.Although our data indicates that both vigorous-intensity and moderate-intensity physical activities in adulthood may reduce mortality to the same extent, this finding should not downplay the key role of physical activity to improve individual and population health. Some estimates suggest that, worldwide, physical inactivity causes 6% of coronary heart disease, 7% of type 2 diabetes, 10% of breast cancer and 10% of colon cancer.36 we performed risk of bias assessments of the selected literature using ROBINS-I.To our knowledge, this is the first systematic review and meta-analysis designed to evaluate whether vigorous-intensity activities (vs moderate-intensity) may provide additional reductions on mortality after controlling for total physical activity. As the results of meta-analysis are only as valid as the quality of the studies included,37 Future epidemiological studies will undoubtedly benefit new technological developments to evaluate objectively physical activity level in large populations. In this sense, a recent prospective study conducted in 16 741 women evaluated the association of number and intensity of steps (by accelerometry) and mortality.38 Authors concluded that stepping higher in the intensity level was not related to lower mortality rates after accounting for total steps for a day.38 Second, only one measurement of physical activity was collected in all epidemiological studies identified (at baseline), which may have led to regression dilution bias. Physical activity levels tend to decrease with age, which in theory could attenuate a protective effect on mortality of vigorous intensity due to transitions toward inactive lifestyles. Further information on physical activity changes during adulthood will increase the quality of the available epidemiological evidence. Third, a low number of studies met our strict eligibility criteria. A reason for additional concern is the lack of epidemiological data about CVD or cancer mortality. Our review, therefore, highlights the urgent need to evaluate cause-specific mortality in future well-designed epidemiological studies. Finally, a small number of cohorts were identified and pooled into the meta-analysis and subgroup or meta-regression analyses were discarded  to explore the sources of heterogeneity.We acknowledge several limitations. First, the exposure variable  was assessed by questionnaires, which are less accurate than objective methods of physical activity measurement.The epidemiological evidence available indicates that vigorous-intensity and moderate-intensity physical activity may reduce mortality to the same extent, after controlling by the volume of physical activity. However, the absence of the evidence must not be interpreted as evidence of absence. This systematic review, indeed, shows that there are still very few prospective studies specifically designed to examine the role of intensity of physical activity on mortality, and important methodological flaws were observed in the literature .Low physical activity level in adult populations is recognised as one of the main drivers of poor population health. However, it is currently unclear whether vigorous-intensity physical activity may lead to larger reductions in mortality compared with moderate-intensity physical activity.The best synthesis of the epidemiological evidence shows similar risk reductions on all-cause mortality in participants that reported the highest proportion of vigorous-intensity activity versus moderate-intensity activity.A lower number of prospective studies have evaluated the impact of physical activity intensity on cause-specific mortality (CVD and cancer), and their findings do not convincingly support the hypothesis that vigorous intensity may produce larger benefits on mortality over moderate intensity.Future epidemiological studies on intensity of physical activity and mortality will require better study designs. For example, the use of objective tools to assess physical activity includes dietary variables as covariates, evaluates cause-specific mortality and informs about the proportion of missing data from participants.


Introduction: Myelin oligodendrocyte glycoprotein-immunoglobulin G (MOG-IgG)-related disease was initially described as a subtype of neuromyelitis optica spectrum disorder (NMOSD) with antibodies against MOG. However, it has recently been described as a separate disease entity with clinical and radiological features that overlap those of multiple sclerosis (MS) and NMOSD; the clinical features of this disease phenotype remain undetermined. We herein report the clinical presentation of nine MOG-IgG-positive patients, not all of whom fulfill the NMOSD criteria, in order to highlight the features and challenges of this condition.Method: We retrospectively reviewed the records of the London (Ontario) MS clinic to identify patients diagnosed with positive MOG antibodies based on the 2015 NMOSD consensus criteria.Result: Nine patients were identified, all Caucasian. Seven (78%) were female, and the median age of onset was 41 years ; the median Expanded Disability Status Scale score at onset was 3.0 . A monophasic course was noted in two (22.2%) patients, while the median number of relapse events was 3 (range 2–5) in 77.8% of the patients. Optic neuritis and transverse myelitis contributed equally as initial manifestations in three individuals (33%), while brainstem relapse was reported in two individuals (22%). The brain magnetic resonance imaging findings were compatible with McDonald's 2010 dissemination in space criteria in three cases (33%). Short myelitis and an (H)-sign were each documented in one patient.Conclusion: The phenotypes of MOG Ab-positive cases exhibited overlapping features with MS and NMOSD. This finding highlights the importance of screening for anti-MOG in individuals with demyelinating symptoms, in consideration of the possibility of false-positive MOG Ab results. Myelin oligodendrocyte glycoprotein (MOG) is a component of central nervous system (CNS) myelin. Antibodies against MOG have recently been recognized in a clinical syndrome that is likely a CNS demyelinating disorder separate from multiple sclerosis (MS), acute demyelinating encephalomyelitis (ADEM), and neuromyelitis optica spectrum disorder (NMOSD). Although MOG antibodies have been mentioned in the literature for the last 30 years, their role in demyelinating disease has not been fully elucidated and, to date, remains controversial , 2. In eMOG antibodies have recently been linked to seronegative cases of NMOSD. Recent cohort studies have demonstrated that 15–35% of seronegative NMOSD patients will test positive for MOG antibodies ; indeed,This study was approved by the University of Western Ontario's (Western) Health Science Research Ethics Board and written informed consent was obtained from all patients.All individuals who tested positive for anti-MOG at the London (Ontario) MS clinic were retrospectively reviewed. Data were obtained for age at onset, sex, first clinical presentation, number of relapses, disease course, and duration. The neurological examination data included the Expanded Disability Status Scale (EDSS) score at the initial and final follow-up and brain and spine magnetic resonance imaging (MRI). In addition, data on serological testing and cerebrospinal fluid (CSF) analysis including oligoclonal bands (OCB) were collected if available. Data on current and disease-modifying therapies (DMTs) were also included. Nine MOG-IgG-positive cases were identified .A 52-year-old male patient was referred due to suspected MS. In 2008, he presented with an episode of vertigo and gait instability, which resolved over a period of 2 months following corticosteroid and plasmapheresis treatment. He remained quiescent until 2017, when he presented with right facio-brachial weakness for 3 weeks. The EDSS score was 1.0 at the final follow-up at the clinic in 2019; brain MRI confirmed McDonald's 2010 dissemination in space (DIS) criteria . CSF anaA 29-year-old female patient presented in 2008 with double vision, ataxia, nausea, and vomiting. She was presumptively diagnosed with Miller Fisher syndrome or possibly thiamine deficiency; she was treated with intravenous immunoglobulin and thiamine, and her condition returned to normal within 3 months. All serology at that time was unremarkable. CSF analysis was unremarkable without albumin-cytological dissociation during hospitalization.In 2017, she developed decreased vision and color perception in her left eye; her visual acuity (VA) was 20/20 in the right eye and 20/50 in the left, with left relative afferent pupillary defect (RAPD). She scored 12/16 on the Ishihara color plate on the left eye, and the EDSS score was 2.0. She partially responded to 5 days of intravenous (IV) methylprednisolone treatment. Her brain MRI revealed an enhanced lesion at the anterior aspect of the left optic nerve sheath with unremarkable brain and spine findings. Her CSF examination was negative for OCB, and she had a normal IgG index. She was maintained on mycophenolic acid with no further relapse or new MRI brain lesions to date. At her final follow-up in 2019, her EDSS score was 2.0.A 31-year-old female patient was referred to our clinic with a diagnosis of MS following a diagnosis of transverse myelitis in 2014. Her spine MRI revealed short and long myelitis in the cervical and thoracic spinal cord . She wasA 19-year-old male patient presented in 2008 with right optic neuritis with residual peripheral visual field defect. In 2017, he presented with another episode of severe right optic neuritis; his VA in that eye was finger counting only. The EDSS score at this time was 4.0. Fundoscopic examination revealed bilateral optic pallor. There was no RAPD. He was treated with a 5-day course of IV methylprednisolone with good recovery; his uncorrected VA was 20/20 on the left and 20/40 on the right. His brain MRI revealed increased signal in his right optic nerve reaching the optic chiasm with mild gadolinium enhancement, with no brain or spinal cord lesions. His CSF examination was negative for OCB, and he had a normal IgG index. He was maintained on mycophenolic acid with no further relapses or imaging activity. At the final follow-up in 2018, the EDSS score was 2.0.A 43-year-old female patient presented with right optic neuritis since September 2014, with recurrent attacks in July 2015, December 2015, and June 2016. Her VA during each attack was 20/100 in the right eye and 20/20 in the left eye. She received 3 days of IV corticosteroids followed by oral prednisone treatment for her first episode in September 2014, and 1,250 mg of prednisone for 3 days followed by a tapered dose for the 2015 and 2016 relapses. After treatment, her corrected VA was 20/30-2 in the right eye and 20/20-2 in the left eye, with right RAPD. The brain and spine MRI examinations were unremarkable. Her CSF examination was negative for OCB with a normal IgG index. After treatment, her EDSS score improved from 4.0 to 2.0 with no further disease activity and normal brain MRI findings until 2018, despite no DMT upon patient preference.A 58-year-old female patient presented in February 2018 with ataxic gait along with bladder and bowel urgency and incontinence. She was initially evaluated by a urologist and received an undetermined diagnosis. Her neurological assessment revealed severe gait and truncal ataxia, and an EDSS score of 3.5. Her brain MRI indicated two foci of increased T2 signal in the subcortical area, and these lesions were non-specific. No lesions were identified in the spinal cord. Her CSF examination was negative for OCB, and she had a normal IgG index. She did not receive any first-line therapy and was maintained on azathioprine with disease stability but a subtle increase in the size of the T2 lesions. The EDSS score at the final follow-up in March 2019 had worsened from 3.5 to 2.0.A 69-year-old female patient who experienced two separate relapses of optic neuritis, one in each eye, with partial spontaneous recovery, re-presented in January 2018 with right arm weakness. She received 1,250 mg of prednisone for 3 days, but her right arm strength did not return to baseline. Her EDSS score was 2.5 according to visual and pyramidal findings. Her brain MRI was compatible with the DIS criteria. No cord lesions were identified . Her CSFA 34-year-old female patient presented in July 2018 with sensory symptoms, bladder frequency and urgency, along with L'hermitte phenomena. Her EDSS score was 2.5 according to the bladder symptoms and pyramidal findings. Her brain MRI was normal, but longitudinal extension was identified from T2 to T11. Her CSF examination was negative for OCB and she had a normal IgG index and slight increase in CSF proteins. The patient recovered with no treatment within 4 weeks, and her EDSS score improved to 1.0. Repeat MRI revealed subtle lesions at T2 in the spinal cord.A 35-year-old female patient presented with left-sided paresthesia and weakness, without bowel or bladder symptoms, that gradually progressed over the course of 2 weeks. There was no history of visual symptoms, nausea, vomiting, hiccups, or change in appetite. Her initial EDSS score was 3.5 according to the severe pyramidal and moderate sensory findings. Her spine MRI revealed an extensive lesion from the dorsal medulla to C6. On the axial T2 view, there was prominent gray matter involvement forming an H sign . Her braCurrently, there are no published diagnostic criteria for MOG-IgG-related disease. However, there are some recommendations based on expert consensus regarding appropriate testing for MOG antibody as well as some preliminary diagnostic criteria . Optic nIn an immune-mediated optic neuritis analysis , MOG-IgGArea postrema syndrome/lesions have been identified as disease-defining symptoms for AQP4-positive NMOSD , 14; howMOG-IgG-related disease more frequently presents with a relapsing course, although monophasic cases have been described. A monophasic course may be attributed to age and a short follow-up duration in previous studies. In a large cohort of 197 cases reported by Cobo-Calvo et al. , the cumNo patient has been reported to test positive for MOG-Ab and NMO-Ab simultaneously , 17. AllMisdiagnosis of MOG-IgG-related disease as MS can be common. Among 16 MOG-IgG-related disease patients , 6  followed by brainstem 29%) and cerebellar lesions (13%). Orbital MRI findings include unilateral or bilateral optic nerve lesions, which can be longitudinal and involve the optic chiasma. Contrast enhancement is a commonly reported feature in the optic nerve, reported in 80–100% of the cases, in association with optic nerve swelling and perineural enhancement –23. The % and cerAlthough it may be difficult to distinguish MOG-Ab positive cases from NMO seropositive cases radiologically, it has been proposed that MOG-Ab positive cases can be distinguished radiologically from MS, with high sensitivity and specificity . LesionsThe optimal treatment for MOG-IgG-related disease remains controversial. Due to the lack of randomized clinical trials and rarity of the disease, the choice of immunosuppressive therapy depends on the clinical experience of the treating physician. The treatment typically follows the same approach as that for NMOSD. Azathioprine, mycophenolate, rituximab, and a longer corticosteroid taper (6 months) are all possible treatment options , 21.In our case series, the patients did not receive prolonged steroid tapers. Long-term treatment was a shared patient decision; most were started on steroid sparing agents such azathioprine and mycophenolic acid, although two patients preferred not to be on any treatment.Traditionally, it was thought that MOG-Ab-positive cases carry a benign course and good prognosis. With the expanding clinical phenotype and accumulating experience, we have learned that disability can occur, and a relapsing course is not uncommon. Patients can have severe disability at presentation, but recovery from the acute relapse may be better than that of NMO seropositive cases. Further, significant residual disability does occur , 28. To Our case series provides practical and clinical indications of MOG-Ab-positive cases, which expand our knowledge of this disease. However, there are potential limitations regarding possible false-positive serology results in those with atypical presentation. The short-term follow-up of some cases and variable treatment modalities could be another limitation in this cases series.Our study demonstrates that MOG-Ab-positive cases can have a variable clinical presentation and overlap with seropositive NMO or MS cases. Relapsing courses were more frequent in our case series, and persisting disability was also observed. Distinction of this disease from others such as MS based on clinical and radiological features can be challenging. Anti-MOG testing in all patients with suggestive demyelinating events is recommended, although the possibility of false-positive tests should not be ignored. Randomized controlled trials are needed to determine the optimal treatment option and duration.The datasets generated for this study are available on request to the corresponding author.Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


This study was designed to describe demographic and clinical characteristics of patients diagnosed with advanced or metastatic soft tissue sarcoma (STS) and to examine treatment and healthcare resource utilization patterns of this patient population in a United States (US) community-based oncology practice setting over time.T test for continuous variables and chi-squared test for categorical variables. Data were available for analysis through 31 August 2018.A retrospective observational study was conducted within the US Oncology Network (USON). Patients were eligible if they were diagnosed with advanced or metastatic STS and were treated at a USON site between 01 July 2015 and 31 August 2018. Demographic, clinical, and treatment characteristics were described for the overall study population. Comparisons between patients by time period (prior to and after October 2016) were evaluated using the N = 376) were similar between patients who initiated treatment before and after October 2016 . Forty-three unique regimens were observed in the first-line setting, with the predominant regimen (gemcitabine + docetaxel) received by 33.2% (n = 125) patients. Prior to October 2016, 45.4% of patients received first-line gemcitabine + docetaxel, while 29.0% received this regimen after October 2016.Demographic and clinical characteristics of the eligible study cohort (While demographic and clinical characteristics were similar, treatment patterns changed in 2016. Future research should evaluate the impact of changing drug approvals and clinical trial results on future treatment patterns. In the United States (US), soft tissue sarcoma (STS) is considered a relatively rare cancer, accounting for fewer than 1% of all malignancies . Fewer tFor patients with advanced, unresectable or metastatic non-GIST STS, systemic chemotherapy, particularly containing anthracyclines, has been the standard of care for several decades , 5, 8. TThe National Comprehensive Cancer Network (NCCN) guidelines 4.2019) recommend over 20 different regimens for the treatment of STS with nonspecific histologies [9 recommeA high degree of treatment heterogeneity has been observed in the previous observational research of patients diagnosed with STS in the US. Based on a medical record review of 99 patients with metastatic or relapsed STS treated in a tertiary academic cancer care center between 2001 and 2011, most patients received anthracycline- or gemcitabine-based regimens, but there was not a predominant treatment in any line of therapy . SimilarOlaratumab is a monoclonal antibody that selectively binds platelet-derived growth factor receptor alpha and blocks ligand binding . On 19 OP = 0.04). As such, in January 2019, the company announced that the phase III trial did not confirm the clinical benefit of olaratumab in combination with doxorubicin as compared with doxorubicin alone, and it was subsequently withdrawn from the market.The clinical benefit of olaratumab and doxorubicin, however, was not confirmed in the subsequent phase III ANNOUCE trial . In thisThis study was designed to describe current clinical and demographic characteristics, treatment patterns, and healthcare resource utilization (HCRU) among patients diagnosed with advanced or metastatic STS in a US community-based network of oncology practices. These factors were compared among the cohorts treated prior to and following the October 2016 FDA-accelerated approval of olaratumab.A retrospective observational cohort study was conducted of adult patients newly diagnosed with advanced or metastatic STS within the US Oncology Network (USON). The USON is a network of more than 450 community-based oncology clinics across the US . More thBoth structured and unstructured variables from the USON's electronic health record (EHR) and targeted chart review were used to build the study database. The EHR of the USON, iKnowMed (iKM), captures outpatient practice encounter histories for patients under community-based care, including but not limited to: patient demographics such as age and gender; clinical information such as disease diagnosis, diagnosis stages, performance status information, and laboratory testing results; and treatment information, such as line of therapy and treatment administrations within the USON. The claims and remittance database of the USON was used to assess HCRU of services provided within the USON.A targeted chart review was performed to capture information on key variables that were anticipated to be poorly documented in the structured EHR fields. This included capture of some data only available in unstructured fields, including information on hospitalizations and emergency department (ED) visits that occurred during the study observation period, as well as histological subtypes and tumor location. Chart review was accomplished by use of a secure, web-based electronic case report form and conducted by trained oncology professionals. These chart reviewers captured information as it was explicitly documented in the medical record; central pathology review was not undertaken to verify what physicians recorded in the patient record. The chart review was conducted for a subset of eligible patients who initiated first-line treatment between 01 July 2015 and 31 August 2017.Eligible patients were at least 18 years of age with a documented diagnosis of STS and who initiated first-line treatment between 01 July 2015 and 31 August 2018. Additionally, patients were required to have at least two follow-up visits within the USON after first-line treatment initiation at clinics that had fully implemented the EHR system, iKM. Patients enrolled in clinical trials or who were diagnosed with another primary cancer were excluded from the analysis. Additional exclusion criteria included the following: diagnosis of Ewing's sarcoma, osteosarcoma or Kaposi's sarcoma, and receipt of treatments suggestive of clinical trial participation or nonsarcoma diagnosis .Patients were followed from initiation of first-line treatment until the end of the study period (31 August 2018) or last USON visit date. All study variables and outcomes were assessed regardless of maximum follow-up using data available until the end of the study period. Baseline variables were assessed for the 60-day period prior to and up to 30 days after first-line treatment initiation. Patients were categorized in the pre-October 2016 cohort if they initiated first-line treatment between 01 July 2015 and 18 October 2016, and in the post-October 2016 cohort if they initiated treatment between 19 October 2016 and 31 August 2018. If a patient was included in the pre-October 2016 cohort but advanced to second-line treatment after 19 October 2016, they remained classified in the pre-October 2016 cohort.Descriptive statistics were used to examine demographic, clinical, and treatment characteristics for patients in the first- and second-line settings. Categorical variables  were reported as frequencies and percentages. Continuous variables such as age were reported as mean, standard deviation, median, and range. In the case of missing observations, the number and percentage of missing values were reported. Programmatic logic was applied to categorize therapy sequences across lines of therapy based on start and stop dates, as well as the predefined line of therapy indicator in iKM.F test, T test, or Kruskal–Wallis test  were used for continuous variables. An alpha level of less than 0.05 was the primary criterion for statistical significance in this study. Results were compared between the pre- and post-October 2016 cohorts.Chi-squared or Fisher's exact test was used to assess differences between categories of variables when at least 5 patients were represented in each group. In total, 376 patients met eligibility criteria and were included in the analysis; 211 of these patients were selected for chart review, while the remaining 165 patients contributed to structured data only. Among the overall study population, 97 patients initiated first-line treatment in the pre-October 2016 period and 279 in the post-October 2016 period . Patients who initiated first-line treatment during the pre-October 2016 period had a median duration of follow-up of 12.5 months  compared with a median duration of 5.6 months  among patients who initiated first-line treatment during the post-October 2016 period.Baseline demographic and clinical characteristics of patients who initiated first-line treatment and those who received second-line treatment are presented in n = 87), followed by undifferentiated pleomorphic sarcoma (n = 36), liposarcoma (n = 16), and angiosarcoma (n = 11), with the remaining each having 10 or fewer patients. Forty-seven patients had lower limb tumors, 45 uterine tumors, 20 retroperitoneal tumors, and 16 upper limb tumors, with 10 or fewer patients having tumors in each of the other documented locations.Tumor histology and location were not documented in structured fields of the EHR and, as such, were only captured for patients selected for chart review . Among tAmong the 196 patients who received second-line treatment, at initiation of first-line treatment the median age was 60 years , with 45.9% male and 73.5% Caucasian . ApproxiP < 0.0001). A higher proportion of the patients in the pre-October 2016 cohort had documented bone, lymph node, and lung metastases than in the post-October 2016 cohort . In the second-line setting, a higher proportion of the patients in the pre-October 2016 cohort had lung metastases (P=0.0183); no other significant differences were observed between the groups.Overall, demographic and clinical characteristics were similar between patients in the pre- and post-October 2016 cohorts . Evidencn = 125, 33.2%), followed by olaratumab + doxorubicin , gemcitabine , doxorubicin + ifosfamide , and doxorubicin monotherapy (n = 24. 6.4%), with each of the remaining first-line regimens received by fewer than 5% of the study population. Fifty patients (13.3%) received a first-line regimen classified into an “other” category because it was received by fewer than 5 patients total .n = 44) of patients received first-line gemcitabine + docetaxel, 13.4% (n = 13) doxorubicin, and 7.2% (n = 7) liposomal doxorubicin (n = 81) received gemcitabine + docetaxel, 22.9% (n = 64) olaratumumab + doxorubicin, and 7.9% (n = 22) gemcitabine.During the pre-October 2016 period, 45.4% (orubicin . Among tn = 5) patients in the pre-October 2016 cohort and 5.0% (n = 14) in the post-October 2016 cohort).In total, 180 patients (47.9%) did not receive second-line treatment and 291 (77.4%) did not receive third-line treatment during the study period within the USON . IncludiDuring the post-October 2016 period, 111 patients in the study dataset received olaratumab either alone or in combination with other agents in the first- through third-line treatment settings. A small proportion of patients (6.5%) who initiated first-line treatment in the pre-October 2016 period proceeded to receive second-line olaratumab + doxorubicin during the post-October 2016 period .Among patients who initiated first-line treatment in the post-October 2016 period, 22.9% and 15.1% received olaratumab + doxorubicin in the first- and second-line setting, respectively . The proP < 0.01 for all).Among the 211 patients who underwent a chart review, hospitalizations were documented for 116 (55.0%), ED visits for 83 (39.3%) and surgeries for 42 19.9%; . In bothP < 0.0001 for both first- and second-line). Across the entire study cohort, 3.5% had a record of dexrazoxane use.Patients in the pre-October 2016 cohort had similar utilization of outpatient visits and laboratory procedures compared with those in the post-October 2016 cohort . The useThe results of this study provide insight into the patient characteristics and treatment patterns of patients diagnosed with advanced or metastatic STS receiving care in a US community-based practice setting before and shortly after the time of the accelerated approval of olaratumab on 19 October 2016. At initiation of first-line treatment, the baseline characteristics of the study population were similar to those observed in other real-world studies , 11, 16.As observed in previously published observational studies of patients with advanced or metastatic STS, a high degree of treatment heterogeneity was observed across lines of therapy in this study , 17, 18.During the approximate 2-year period following the accelerated approval of olaratumab, 111 patients (29.5%) received olaratumab in the first-, second- or third-line settings. Among patients who initiated first-line treatment during the pre-October 2016 period, 45% received first-line gemcitabine + docetaxel. During the post-October 2016 period, first-line use of gemcitabine + docetaxel was 29% and 23% received olaratumab + doxorubicin. These findings suggest that olaratumab was being utilized in community-based practice settings for the care of patients with advanced or metastatic STS. Given the limited follow-up period subsequent to olaratumab approval, the data were not mature enough to support survival analyses. Sufficient data were not available to examine the shift in treatment patterns following the results of the phase III study.The GeDDiS trial was published during the observation period of this study and may have influenced the lower use of first-line gemcitabine + docetaxel in the post-October 2016 period . In the Approximately 50% of patients did not receive second-line treatment in the USON database; however, this could in part be due to limited follow-up on the study population. The analyses did not account for patients who had recently discontinued first-line therapy, were still receiving first-line therapy at the end of the database, or who sought additional treatment outside of the USON. With similar limitations, approximately 60% of those treated in the second-line setting did not receive third-line therapy in the database.P < 0.01 for all), which could be due to approximately 7 months of additional follow-up among patients who initiated treatment during the pre-October 2016 period (median 12.5 vs. 5.6 months of follow-up).Compared with patients who initiated first-line treatment prior to the October 2016 approval of olaratumab, those who initiated treatment in the post-October 2016 period had fewer observed hospitalizations, ED visits, and surgeries documented in the EHR (Data for this study were sourced from the USON's EHR database, which contains information documented during the course of routine patient care and was not collected for research purposes. Consequently, data entry errors and incomplete records could neither be verified nor corrected. Certain variables of interest were inconsistently documented. To enhance the study dataset, a chart review was performed to capture information that was not well-represented in the structured fields of the EHR, including histology and tumor location, for a subset of the study population. Likewise, information for services performed outside of the USON, such as hospitalizations and ED visits, was restricted to records and progress notes and could only be captured for patients undergoing chart review. By sourcing data solely from USON that utilized the full EHR capacities of iKM, the generalizability of this study may also be limited, and the cohort cannot be generalized to the overall US population.This real-world retrospective study of patients with advanced or metastatic STS treated in a large community-based oncology network provides data regarding patient characteristics and treatment patterns outside of a clinical trial setting. The demographic and clinical data observed were consistent with those of the previous studies. The treatment pattern data suggest a dynamic treatment landscape that changed following the accelerated approval of olaratumab. Despite the increased utilization of olaratumab plus doxorubicin during the study period, considerable heterogeneity in treatment regimens was observed across the lines of therapy, suggesting the need for more evidence-based decision support to facilitate the care of the patient with STS.


IntroductionSeveral comorbid conditions have been identified as risk factors in patients with coronavirus disease 2019 (COVID-19). However, there is a dearth of data describing the impact of COVID-19 infection in patients with end-stage renal disease on hemodialysis (ESRD-HD).Methods2).This retrospective case series analyzed 362 adult patients consecutively hospitalized with confirmed COVID-19 illness between March 12, 2020, and May 13, 2020, at a teaching hospital in the New York City metropolitan area. The primary outcome was severe pneumonia as defined by the World Health Organization. Secondary outcomes were the (1) the Combined Outcome of Acute respiratory distress syndrome or in-hospital Death (COAD), and (2) need for high levels of oxygen supplementation , p=.02] and COAD , when compared to patients without ESRD. In contrast, higher odds for severe pneumonia, COAD and HiO2 were seen with advancing age. African Americans were over-represented in the hospitalized patient cohort, when compared to their representation in the community (35% vs 18%). Hispanics had higher odds for severe illness and HiO2 when compared to Caucasians.Patients with ESRD-HD had lower odds for poor outcomes including severe pneumonia , HiOConclusionsPatients with ESRD-HD had a milder course of illness with a lower likelihood of severe pneumonia and a lesser need for aggressive oxygen supplementation when compared to patients not on chronic dialysis. The lower odds of severe illness in ESRD-HD patients might have a pathophysiologic basis and need to be further explored. At the time of writing, 25 million cases of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) have been described worldwide, resulting in 850,000 deaths [It is crucial to identify the demographic and comorbid factors that impact illness severity among hospitalized COVID-19 patients. Several comorbid conditions, such as hypertension, diabetes, chronic obstructive pulmonary disease and atherosclerotic cardiovascular diseases, have been identified as risk factors in patients with COVID-19 ,3. HowevBeing on the frontlines at one of the earliest epicenters in the United States, we observed that patients with ESRD-HD were having a milder course of illness compared to patients not on HD. Here, we present data analyzing the impact of patient characteristics on illness severity among hospitalized COVID-19 patients, while specifically investigating the effect of ESRD-HD on outcomes. Data sourceThis retrospective observational study includes patients consecutively hospitalized with confirmed COVID-19 illness between March 10, 2020, and May 13, 2020, at a 242-bed teaching community hospital in the NYC metropolitan region. Cases were confirmed through positive results for SARS-CoV-2 virus by reverse-transcriptase polymerase-chain-reaction testing of the nasopharyngeal swab specimen. Data was manually abstracted from electronic health records by the authors, and included demographics, comorbid conditions and clinical data . Three authors  independently reviewed the data for accuracy.Hospital course was followed up until June 15, 2020. Details on the criteria for hospitalization are provided in the supplementary material in the Appendix. Of the 377 patients admitted during the study period, those who were transferred to another facility for tertiary level care (n=5), those who left against medical advice (n=2) and those who were still receiving care at our hospital (n=8) were excluded from the analysis. After said exclusions, final analysis included 362 patients.Definition of patient characteristics2 was used to identify obesity. Race/ethnicity was classified into one of the four categories: Caucasian, African American, Hispanic ethnicity regardless of race, and others.Comorbidities derived from the patients or nursing home transfer forms were abstracted from physician documentation on the electronic health records. Patients were classified into three categories based on the presence or absence of kidney disease: (i) no chronic kidney disease, (ii) presence of chronic kidney disease and (iii) presence of ESRD-HD. Outcomes were analyzed in patients with chronic kidney disease versus those without kidney disease and patients with ESRD-HD versus those without kidney disease. Cardiac disease was defined as chronic heart conditions including previous myocardial infarction, cardiac arrhythmias, congestive heart failure, presence of pacemaker or defibrillator device and previous coronary artery bypass grafting or percutaneous coronary intervention. Body mass index >=30 kg/m2).Severe disease was defined as clinical pneumonia with a respiratory rate >30 breaths/minute or oxygen saturation <90% on room air, per the WHO guidelines . Acute rOutcome measures and statistical analysis2), and (2) Combined Outcome of a diagnosis of ARDS or in-hospital Death (COAD).The study was done according to the STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) guidelines for observational studies . We compLogistic regression analysis by univariate and age-adjusted models was performed for patient characteristics. Subsequently, to determine independent association between these characteristics and outcomes, multivariable logistic regression models were used to estimate odds ratios (ORs) adjusted for clinical covariates. Multivariable analysis was performed using the least absolute shrinkage and selection operator (Lasso) inference, a standard model building approach . Lasso iEthicsThe study was approved by the departmental research review committee with a waiver of informed consent due to its retrospective design .Among the 362 patients, 55.3% were men, 35.4% were African American and 232 (63%) had severe disease; the median age was 71 years (59-82)  and Middle East respiratory syndrome (2012), in addition to virus-induced cytopathic effects, an excessive and dysregulated host immune response played a crucial role in the pathology and mortality ,16. ThisESRD-HD is simultaneously associated with immune activation leading to systemic inflammation and immune deficiency . The actAn immune-deficient state was indeed demonstrated by Ma et al. in their study . A signiThus, on one hand, ESRD-HD patients were at a higher risk due to the decreased ability for an effective anti-viral response from an immunodeficient state, and on the other hand, they benefited from a lower propensity for inflammatory tissue damage secondary to a dampened cytokine release and a lower likelihood of cytokine storm. Our observation of the lower likelihood of severe disease and lesser requirement for oxygen supplementation suggests that the balance between the benefit from anti-viral immune response and harm from associated inflammatory damage is tilted favorably for individuals with ESRD on HD.This raises another question, as to why do ESRD-HD patients, who chronically demonstrate an inflammatory state -22, had Another mechanism for better outcomes in chronic-dialysis patients could be related to the renin-angiotensin system (RAS). It has been suggested that excessive activation of the RAS might contribute to the progression of COVID-19-related lung injury . ChronicThe previously described phenomenon of “reverse epidemiology”, the finding that conventional cardiovascular risk factors such as obesity, hypertension, and dyslipidemia are not associated with increased mortality in the hemodialysis population, also points to the fact that ESRD-HD patients are a distinct subgroup and do not respond to risks and insults the same way as general population ,30. FromStrengths and limitationsLimitations include a patient cohort that comprised only hospitalized patients, from a single hospital and included older individuals, and thus, the findings might not be generally applicable. We did not review the effect of medications targeting the RAS (acetyl cholinesterase inhibitors and angiotensin receptor blockers) on illness severity. Strengths of the study include the accuracy of data that was manually extracted from patient charts, a relatively large cohort and using a standardized model building technique (Lasso) for multivariable analysis.Patients with ESRD-HD had a milder course of illness with lower likelihood of development of severe pneumonia and lower need for aggressive oxygen supplementation when compared to patients not on chronic dialysis. Our observations suggest that the balance between the benefit from an anti-viral immune response and harm from associated inflammatory damage is tilted favorably for individuals with ESRD-HD. The lower odds of severe illness in ESRD-HD patients might have a pathophysiologic basis and need to be further explored. Additionally, age had the greatest impact on illness severity, oxygen requirement and mortality in patients hospitalized with COVID-19. African Americans were over-represented among the hospitalized COVID-19 patients compared to the community, and Hispanics had a more severe illness course compared to Caucasians.


Objective: To describe the ischemic stroke subtypes related to coronavirus disease 2019 (COVID-19) in a cohort of New York City hospitals and explore their etiopathogenesis.Background: Most neurological manifestations are non-focal, but few have reported the characteristics of ischemic strokes or investigated its pathophysiology.Methods: Data were collected prospectively April 1-April 15, 2020 from two centers in New York City to review possible ischemic stroke types seen in COVID-19-positive patients. Patient presentation, demographics, related vascular risk factors, associated laboratory markers, as well as imaging and outcomes were collected.Results: The age of patients ranged between 27 and 82 years. Approximately 81% of patients had known vascular risk factors, the commonest being hypertension (75%) followed by diabetes (50%) coronary disease or atrial fibrillation. Eight patients presented with large vessel occlusion (LVO) with median age 55 years (27-82) and all were male. Eight patients presented with non-LVO syndromes, with median age 65.5 years (59–82) and most were female (62.5%). Both groups were 50% African Americans and 37.5% South Asian. Both groups had similar D-dimer levels although other acute phase reactants/disease severity markers  were higher in the LVO group. The LVO group also had a significantly higher mortality compared to the non-LVO group. The most common etiology was cryptogenic (6 patients) followed by small vessel occlusion (3 patients) and undetermined-unclassified (3 patients). For the remaining 4 patients, 2 were identified as cardioembolic and 2 with large artery atherosclerosis.Conclusion: COVID-19-related ischemic events can present as small vessel occlusions, branch emboli or large vessel occlusions. The most common etiology is cryptogenic. Patients with LVO syndromes tend to be younger, male and may have elevated acute inflammatory markers. The novel Coronavirus outbreak came to the fore in December 2019 . MultiplIn the last 3 months, multiple case reports have highlighted the extra-pulmonary complications of the disease –12. A prMost neurological complications have focused on non-focal presentations like headaches, encephalopathy and skeletal muscle injury , 15. WhiThe objective of this study was to study the characteristics of ischemic strokes in COVID-19 patients in two NYC hospital systems serving some of the most affected zip codes of Brooklyn and Queens . These cInstitutional Review Board approval as well as waiver for informed consent for the study was obtained independently from the IRBs at Brookdale Hospital University Medical Center and Jamaica Medical Center, respectively. A retrospective analysis of prospectively-maintained stroke databases was performed.The period between April 1st through 15th was chosen for analysis due to universal implementation of SARS-CoV-2 screening policy for every admitted patient and peak admission rate and census for COVID-19 at these centers. Furthermore, 75% of all COVID-19 related neurovascular events for the period of March-May happened in this short 15-day window. This sample, thus, approximated with the full spectrum of disease manifestation and variability in these centers. This was also the most comprehensive and complete data we were able to collect at the time of writing this paper. All consecutive patients with ischemic stroke were chosen and results from both NYC hospitals were pooled for this analysis.Only patients who tested positive for SARS-CoV-2 were included for this study. We excluded any cases that were thought to be COVID-19 positive based only on clinical or radiological suspicion. Tests which were administered at these organizations to confirm SARS-CoV-2 infections included: Cobas SARS-CoV-2 real time RT-PCR , Xpert® Xpress SARS-CoV-2  and Abbott Real-time SARS-CoV-2 PCR assay .Acute onset of a focal neurological deficit was used as a clinical identification criterion for a neurovascular event. All patients underwent parenchymal imaging with non-contrast computed tomography (NCCT) and/or magnetic resonance imaging (MRI) of the brain to confirm evidence of an acute stroke. Vascular imaging with CT angiography (CTA) or MR angiography (MRA) was performed whenever feasible to define different types of vascular lesions. Using the aforementioned clinical definition, we identified 23 patients who sustained acute neurovascular events. We first excluded non-ischemic neurovascular events based on the initial NCCT imaging. This excluded 4 patients, two with subarachnoid hemorrhage and two with intracerebral hemorrhage, one of which was associated with venous thrombosis. Thus, there were 19 primary ischemic events detected. Based on further imaging with MRI and/or follow -up NCCT we excluded three more patients who were deemed to have transient ischemic attacks (TIA). In the period from April 1st−15th, 3,488 patients tested positive and a total of 207 patients were admitted with stroke or TIA. Of these, 27 (13.0%) were COVID positive. This yielded 16 patients eligible for final analysis comprising a pooled analysis of nine patients from Jamaica Hospital Medical Center and seven from Brookdale Hospital Medical Center.We recorded ASPECTS (Alberta Stroke Program Early CT Score) for all patients with anterior circulation LVOs in our stroke database. Our institutional protocol is to perform mechanical thrombectomy only on patients with ASPECTS of 6 or greater. This is done in order to avoid malignant hyper-perfusion injury or for reasons of futility. However, all patients were included in the LVO category irrespective of therapy offered. Follow-up parenchymal imaging with NCCT or MRI was typically performed 2–5 days after initial presentation to define the full extent of infarcted tissue.For the purpose of etiological classification, we utilized the SSS-TOAST classification system in order to best capture the cryptogenic etiology as well as approximate causative etiology for therapeutic reasons . Lesion Demographics including age, sex, race were collected. Past medical history, especially pertaining to vascular risk factors like diabetes, hypertension, smoking, stroke or chronic kidney disease (CKD) was also collected. COVID-19-related variables that were collected were as follows: type of symptoms, timeline from first symptoms to ischemic event, antibiotic/antiviral treatment protocol and extra-pulmonary and extra-neurological diseases. Stroke-related variables included time of onset (or last known well) and presentation time to a healthcare facility, acute parenchymal (CT or MRI) and vascular imaging (CTA or MRA), acute treatment (tPA and/or endovascular thrombectomy), pre- or post- stroke prophylaxis (anticoagulation vs. antiplatelet therapy) as well as post-stroke follow up imaging with MRI or CT. Relevant laboratory information was collected and included stroke work-up related data like routine blood counts, basic metabolic panel, coagulation profile (PT/PTT/INR), hemoglobin A1c (HbA1c), LDL, triglycerides and troponin values as well as COVID-related laboratory markers such as neutrophil-lymphocyte ratio, D-dimer, c-reactive protein (CRP), procalcitonin, ferritin, and lactate dehydrogenase. Non-neurological imaging information included chest x-ray findings, transthoracic echocardiography and deep venous thrombosis ultrasonography when available.p < 0.05 was considered significant.Univariable analysis of all 16 patients was performed using descriptive statistics. This included mean, standard deviation (SD), median and interquartile range (IQR) for variables with continuous distribution. Percentages were calculated for dichotomous or categorical variables. Following this, the groups were divided into LVO and non-LVO patients. Univariable analysis of intra-group variables were reported using descriptive statistics. Finally, a bivariable analysis to evaluate inter-group differences between LVO and non-LVO groups was performed. We used the Mann Whitney U-Test for continuous variables due to non-parametric distribution of both groups. Analysis was performed using the “SciPy” data science library in Python (version 3.7) and two-sided During the month of March, testing kits were limited, and universal testing had not been implemented. Also, many patients who had a terminal event within 24 h of arrival were not tested. Therefore, while 16 COVID-positive strokes were identified, the true incidence of stroke in this population remains unknown.The age of patients ranged between 27 and 82 years. There was an overall male preponderance 68.8% Racial distribution in descending order was as follows: African American (50%), South Asian (37.5%) and one each of Hispanic (6.3%) and Caucasian (6.3%). Approximately 81% of the patients had known vascular risk factors, the most common being hypertension (75%) followed by diabetes (50%). The majority (62.5%) of diabetics were in poor long-term control. The most common prodromal symptoms were fever and cough. Median time from first COVID symptom onset to stroke was 4 days (IQR: 7 days). The majority of our patients (75%) presented to the emergency room (ER) from the community. Four patients were admitted with respiratory symptoms and developed stroke during the hospital course. Only two patients (12.5%) presented within the window to receive intravenous thrombolytic therapy. Median time from last known well to symptom recognition was 9 h and 45 min. Median time from symptom recognition to seeking neurological care was 2 h and 16 min. Nearly a third of the patients (31%) were put on anticoagulation therapy for COVID. However, only one of them (6.3%) was on anticoagulation prophylactically secondary to elevated D-dimer levels. This patient developed a stroke in spite of full dose anticoagulation. Common laboratory derangements in our series included: elevated neutrophil-lymphocyte ratio , elevated D-dimer , increased CRP  and high ferritin values . Involvement in other systems besides the lungs and brain was seen in 60%. Death during hospitalization occurred in 37.5%. A third of those deaths could be attributed to respiratory disease from COVID-19. No deep venous thrombosis or pulmonary embolism was detected in our series.The patients with large vessel occlusion (LVO) had a median age of 55 years old  and all were male. Vascular risk factors were present in 75% of patients, the commonest being hypertension (62.5%) and diabetes (50%) albeit with no know coronary or cerebrovascular disease. The median NIHSS for this group was 22 (IQR: 5). Only one patient was aware of being COVID-positive prior to arrival to the hospital. Three patients were admitted for pulmonary worsening and developed strokes while they were inpatients. All of them were in isolation contributing to delays in recognition of stroke. All others presented to the ER as a stroke and were found to be COVID-positive during work up of their stroke. Six patients had an echocardiogram and one (12.5%) was found to have a low ejection fraction. Three patients (37.5%) were put on anticoagulation for poststroke prophylaxis based on D-dimer levels. Another three patients were on antiplatelet agents including both patients with large artery atherosclerosis who were on dual therapy with aspirin and clopidogrel. Mortality was seen in 62.5% cases and correlated with severity of neurovascular morbidity. The mean mRS and standard deviation at discharge for this group was 5 and 1.4, respectively, while the median mRS and IQR at discharge was 6 and 2.25, respectively .Only two patients were able to undergo mechanical thrombectomy. One of these patients (Patient #5) both received IV tPA and underwent mechanical thrombectomy. The details of the case are discussed in Eight patients presented with non-LVO syndromes. The median age was 65.5  and most of the patients were female (62.5%). Median NIHSS was 9.5 (IQR: 5.75). All had multiple vascular risk factors except one albeit with no known coronary disease or atrial fibrillation. This latter patient (Patient #8) was however morbidly obese. Only one patient (12.5%) presented early enough for IV thrombolysis. Based on parenchymal and vascular imaging, four patients were classified as small vessel disease, two with large artery atherosclerosis and two were classified as cardioembolic or cryptogenic. The latter were treated with anticoagulation while the others were treated with antiplatelet therapy. Only one patient had an EF < 30% but the presentation as well as imaging was most consistent with small vessel occlusion. The median mRS at discharge was 3.5 (IQR: 1.25) .Patient #10 was the youngest patient in this second group. This patient had no known vascular risk factors except for morbid obesity. Reason for admission was pulmonary worsening and was being treated with ceftriaxone, azithromycin and remdesivir. This was the only case started preemptively on anticoagulation with low molecular weight heparin (LMWH) based on D-Dimer elevation, with agent being enoxaparin in all cases. Due to respiratory distress, the patient has to be intubated and 27 h post-intubation developed a seizure. This prompted further imaging with MRI which revealed multiple small embolic infarcts in all three main territories with normal-appearing vasculature on MRA. This was the only inpatient stroke in this group as well as its only mortality. The latter was secondary to septic shock.When comparing both groups, we found that both had similar racial makeup with 50% African American and 37.5% South Asian. The LVO group identified their stroke symptoms earlier and sought emergency medical care earlier than their non-LVO counterparts. Only one patient in each group presented early enough to receive thrombolysis. More patients in the LVO group were started on anticoagulation. Both groups had similar D-dimers although other acute phase reactants/disease severity markers  were higher in the LVO group. Counterintuitively, the neutrophil-lymphocyte ratio (NLR) was higher in the non-LVO group. Both groups also had similar levels of pre-admission diabetic control (HbA1c) as well as median number of vascular risk factors per patient. The results of analysis between both groups are summarized in On further interrogation with bivariate analysis, we found both groups were significantly different in terms of age, gender and severity of presentation. Patients with LVO were younger, belonged to the male gender and had a higher NIHSS at presentation. The LVO group also had a significantly higher mortality. While most of the laboratory markers were not significantly different, ferritin value was significantly higher in the LVO group as compared to the non-LVO group. There was insufficient power with this sample size for determination beyond the aforementioned variables. These results are summarized in We used the SSS-TOAST criteria to define the etiologies of stroke encountered. We used parenchymal, vascular as well as cardiac monitoring and imaging to arrive at these diagnoses. The most common etiology was undetermined-cryptogenic (6 patients) followed by small vessel occlusion (3 patients) and undetermined-unclassified category (3 patients). For the remaining 4 patients, two were identified as cardioembolic and two as large artery atherosclerosis.The undetermined-unclassified category included three patients. One patient (Patient #14) had infarcts in two separate vascular territories, both consistent with small-vessel occlusion as well as a putative cardioembolic source. Another patient (Patient #8) was brought in symptoms of right sided weakness with unknown time of onset and he was last known normal about 9 h ago. His symptoms were recognized in the morning, but he was brought in 3 h later to the Emergency Department of the receiving hospital. On arrival, his imaging revealed no evidence of intracranial occlusion but a partial occlusion of the left cervical ICA secondary to a mural thrombus. Three hours later while the patient was admitted to the ICU, he deteriorated secondary to his respiratory status and required intubation. We proceeded to perform an emergent MRI, post intubation, that revealed the mural thrombosis had deteriorated into complete ICA-MCA occlusion and complete infarction of the left anterior hemisphere. The third patient to be categorized as such had multi-territorial infarction in spite of anticoagulation, pre-stroke elevation of inflammatory and coagulation pathway markers as well as evidence of septic shock.In nearly half  of our cases, no echocardiogram was available making it difficult to objectively exclude cardioembolic etiology. In three of these cases we used parenchymal distribution to determine etiology . Two were defined as large artery atherosclerosis based on vascular findings while one was cardioembolic due to presence of bilateral anterior circulation LVOs. Two were assigned to the undetermined-unclassified category based on reasons mentioned above (Patients #8 and #14).COVID-19 patients may have an asymptomatic, moderate or a severe course of illness . The sevSeveral case reports have also suggested the possibility of a hypercoagulable condition caused by SARS-CoV-2 , 25, 26.Most neurological manifestations of COVID-19 have been non-focal presentations such as headaches, encephalopathy, long tract cortical signs or seizures , 15, 16.Recently data from several institutions in the US have been published on COVID-strokes , 31, 32.In our series, we differentiated our population into LVO and non-LVO groups. This was done as the former is historically known to have a higher NIHSS and worse outcome neurologically when not treated . Our youNearly 70% of our patients had pre-existing conditions, similar to other studies , 20, 32.In terms of etiological distributions, we encountered the gamut of small vessel occlusions, cardiogenic emboli, large artery atherosclerosis as well as stroke of undetermined etiology. The most common were the cryptogenic category (6 patients) followed by small vessel occlusions and unclassified-undetermined etiologic category (3 patients). Our results were thus similar to Yaghi et al. with undetermined being the most common etiology in our analysis (50%) of which cryptogenic predominated . HoweverOur study has several limitations. This is an inherently small analysis of neurovascular cases presenting to two hospitals. As the number of cases in our hospitals often overwhelmed the capacity for testing or intensive care during the initial surge, many were not tested. Thus, we cannot determine the true incidence rate of neurovascular events in COVID patients. Due to the stress on the resources created by COVID-19 some of the patients did not receive advanced imaging such as MRI to confirm whether unknown infarcts may have occurred. Additionally, many cases had other risk factors and the embolic events may have been related to the underlying risk factor rather than the viral infection, or simply exacerbated by it. Finally, the type of strokes caused by the disease fit into several etiologic pathways rendering it difficult to delineate an appropriate treatment or prevention strategy.Stroke in the setting of COVID-19 has an unusual presentation including atypical demographics and delayed time windows. COVID-19 related ischemic events can present as small vessel occlusions, multi-territorial embolic infarcts or large vessel occlusions. The most common etiology is cryptogenic followed by undetermined secondary to multiple mechanisms. Ischemic stroke can be a presenting symptom of COVID-19 and may not always be associated with severe disease markers including in the young, minorities and frontline workers.All datasets presented in this study are included in the article/Study regarding human participants were reviewed and approved by the IRB committees at Brookdale Hospital University Medical Center & Jamaica Medical Center, respectively. Written informed consent from the patients/next of kin was not required to participate in this study in accordance with the national legislation and the institutional requirements.AT was responsible for concept, data collection, review as well as writing the manuscript. AD and KA were responsible for concept, review as well as editing the final manuscript. SK, KH, MS, AL, TN, TZ, and DK were responsible for clinical care and review of the manuscript. JFr and SY were responsible for clinical care, editing, restructuring, and review of the manuscript. DT-P, JL, and JFa were responsible for the cases and review of the manuscript. VV, SA, and AK were responsible for data collection and review of the manuscript. KB was responsible for data collection, review as well as writing the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


MMb were safely collected via a NIRS-assisted treadmill test as area-under-curve for the spectra of oxygenated (-oxy), deoxygenated (-deoxy), differential (-diff) and total (-tot) hemoglobin traces. MMb, ankle–brachial index (ABI), pain-free (PFWD) and 6-min (6MWD) walking distances were assessed at baseline and after four months. MMb were correlated at baseline with ABI (MMb-oxy r = 0.46) and 6MWD (MMb-tot r = 0.51). After treatments, MMb-oxy showed an expected increase, which was more relevant for Rev group than the Ex (56% vs. 20%), with trends towards normalization for the other MMb. These changes were significantly correlated with variations in ABI  and 6MWD . The MMb-diff in Rev group and MMb-deoxy in Ex group at baseline predicted clinical outcomes being correlated with PFWD improvements after 4-month . A noninvasive NIRS-based test, feasible in a clinical setting, identified muscle metabolism biomarkers in PAD. The novel MMb were associated with validated outcome measures, selectively modified after different interventions and able to predict long-term functional improvements after surgery or exercise training.We assessed whether muscle metabolism biomarkers (MMb) identified by near-infrared spectroscopy (NIRS) are valid for determining adaptations following revascularization or exercise training in peripheral artery disease (PAD). Eighteen patients (males  Peripheral artery disease (PAD) affects millions of people worldwide, particularly elderly individuals ,2. In a Hemodynamic severity and functional capacity are generally assessed in clinical practice by the ankle–brachial index (ABI) and treadmill or ground walking tests, which estimate patients’ peripheral blood supply and walking capability, respectively ,5. TheseHowever, these methods, which are progressively more attractive, are limited in their potential routine use by the frequent need to administer radioactive or contrast products , by the Moreover, in addition to perfusion, other peripheral factors  contribute to muscle metabolism by improving or affecting oxygen utilization with a direct impact on functional outcomes ,14.Considering all these aspects, support in the study of peripheral adaptations is offered by the use of near-infrared spectroscopy (NIRS). This technique noninvasively explores tissue microvascular hemodynamics, monitoring the local balance between oxygen delivery and consumption ,17,18,19Since NIRS represent a useful technique for both dynamic and bedside measurements ,19, seveAfter validating the quantification of muscle perfusion changes by a NIRS-assisted treadmill test , we usedThe present study represents a secondary analysis of a pilot randomized trial in PAD patients with intermittent claudication , includiTo assess the metabolic muscle adaptations induced by different interventions in PAD, we studied a group of patients randomized in a previous single-center clinical pilot trial  that toon = 18; males n = 13; 69 ± 7 years) were identified from a cohort of consecutive new patients with PAD and intermittent claudication. The inclusion criteria were as follows: males and females aged 60–80; Rutherford category 2 or 3; initial claudication distance <100 m; one or more arterial stenoses at aorto–iliac or femur–popliteal district with >50% reduction in diameter requiring revascularization. The exclusion criteria were as follows: abdominal aortic aneurysm; clinical conditions limiting treadmill testing; incapacitating cardiac disease or any other condition contraindicating revascularization procedures; anemia and hemoglobinopathies; and other disorders masking or confounding vascular symptoms  [Eligible participants (ication) .Patients were randomized with a 2:1 ratio to receive structured home-based exercise training (Ex) or peripheral revascularization (Rev).The noninvasive intervention was based on the structured home-based walking test in–train out program prescribed at the hospital and performed at home ,32. The Revascularization procedures were performed at the Department of Vascular Surgery. For each patient, the option that was most likely to yield the best hemodynamic improvement  was selected by the surgeon. After the intervention, the patients received standardized recommendations to be physically active at home according to the guidelines and they underwent a clinical and instrumental evaluation.Outcome measures were assessed at baseline (T0) and 4 months (T4) from the day of the intervention or the beginning of the Ex program. We collected baseline demographic data. All of the measurements were taken in the afternoon between 13:30 and 16:30 in a temperature-controlled environment and separated by 10-min intervals. The same expert outcome assessor, not blinded to the treatments, performed all the measurement sessions.The ankle–brachial index was measured according to published standards . The legThe 6-min walking test was performed to determine patients’ pain-free walking distance (PFWD) and 6-min walking distance (6MWD) . PatientAn incremental treadmill test ,35 suppoA continuous wave NIRS system , consisting of two channels using intensity-modulated light at 1 Hz frequency and 3 wavelengths  corresponding to high absorption of oxyhemoglobin (oxy) and deoxyhemoglobin (deoxy), was employed. Near-infrared light propagating through biologic tissue is partly absorbed or scattered by the tissues and partly recollected by the detector; therefore, the intensity of the recollected light provides information about oxy- and deoxyhemoglobin concentrations. From these changes, additional parameters were calculated as the sum of oxy- and deoxy- or total hemoglobin (tot) and the difference between oxy- and deoxy- or differential hemoglobin (diff). After taking skinfold measurements, NIRS optodes with an interoptode distance of 3.5 cm, allowing light penetration of approximately 20 mm, were placed on the medial side of the calf (gastrocnemius muscles) and secured with tape.Patients were asked to perform a treadmill test ,35 basedAt the end of the testing session, semiquantitative data collected by the NIRS instrument were analyzed using the software Oxysoft 2.0.47 . The traces obtained are shown in To quantify the variations, after assigning the first value (beginning of the test) of each hemoglobin trace test to be 0, the area under the curve (AUC) for each variable was calculated by summing all the single values obtained until the end of the test. The parameters considered were the AUC of oxy-, deoxy-, diff- and tot–hemoglobin that were calculated for the more diseased limb of each patient, as determined by the lower ABI value or the worst duplex ultrasound examination record in case of incompressible vessels. For this study, the AUCs were considered muscle metabolism biomarkers (MMb) for each of the four hemoglobin traces: MMb-oxy, MMb-deoxy, MMb-diff and MMb-tot.At T4, when the treadmill test were longer with respect to baseline, the AUC calculation was stopped at the exact second when the test at T0 ended to ensure the same length for each hemoglobin trace.The data distribution was verified by the Shapiro–Wilk test. Continuous variables are expressed as the mean ± standard deviation or median (interquartile range), and categorical variables are expressed as numbers and percentages.t-tests, Mann–Whitney tests or chi-squared tests, as appropriate. Differences between groups were assessed by Mann–Whitney test or unpaired Student’s t-tests, as appropriate. Within-group variations were verified by paired-sample t-tests or Wilcoxon tests.The characteristics of the study groups were compared using unpaired Student’s p value ≤ 0.05 was considered statistically significant. Data were analyzed using MedCalc Statistical Software version 19.1.5 . Correlations between study variables were assessed by means of Spearman’s rho. A http://dx.doi.org/10.17632/r3sxt3m8xj.1.Data availability: Research data are available at: Of the 27 patients enrolled in the study, 18 participants completed the scheduled interventions and the 4-month testing session. Twelve patients belonged to the Ex group and six to the Rev group. A flow diagram of the participants is reported elsewhere . The twoAll patients randomized to the Ex group completed the rehabilitation treatment without any adverse events. As reported in the logbooks, patients completed 218 ± 49 exercise sessions, for a total of approximately 34 h of walking exercise over 4 months. Patients in the Rev group underwent revascularization procedures (2 endovascular (angioplasty), 2 surgical (bypass in autologous vein), 2 hybrid (thromboendarterectomy plus angioplasty)) without adverse outcomes. No changes in therapy were reported, except for the dual antiplatelet therapy prescribed. At T4, they verbally reported being active after the interventions, referring to having performed a bout of at least 20 min of exercise at a self-selected speed for a median of 2 days per week.r = 0.23 p = 0.40 for PFWD and r = 0.41 p = 0.13 for 6MWD).Baseline data are reported in After the interventions, the ABI significantly increased in both groups, with a significantly between-group difference in favor of the Rev group. Similarly, the PFWD and 6MWD increased in both groups, with a significant difference between groups in favor of the Rev group for the 6MWD only. The data are summarized in The skin folds for the calf were less than 10 mm for all participants, allowing for reliable measurement of the region by the NIRS system. All patients completed the testing sessions without local or general adverse effects during the NIRS measurements.The NIRS parameters exhibited variations after both interventions. In the Rev group, the MMb represented by the AUC of the hemoglobin traces collected with the NIRS system showed a trend towards normalization .A marked reduction in MMb-oxy (56%) and changes in the other AUCs of 12%, 31% and 7% for MMb-diff, MMb-deoxy and MMb-tot, respectively, were observed, even in the absence of statistically significant variations .A similar trend towards normalization was observed in the Ex group for all four biomarkers without significant variations. The changes observed were 20%, 19% 10% and 2% for MMb-oxy, MMb-diff, MMb-deoxy and MMb-tot, respectively .Despite no significant between-group differences, different magnitudes of changes were observed for MMb. In particular, a 3-fold variation was observed for MMb-oxy in the Rev group compared to the Ex group; conversely, a two-fold variation in MMb-deoxy was observed in the Ex group vs. the Rev group.r = 0.46; p = 0.071) and ABI, MMb-oxy and PFWD  and MMb-tot and 6MWD .At baseline, in the whole population, a correlation between NIRS biomarkers and validated outcome measures was observed, particularly between MMb-oxy .Specifically, variations in MMb-oxy and MMb-diff were significantly correlated with changes in ABI. Moreover, variations in MMb-deoxy and MMb-tot were directly correlated with improvements in 6MWD , but notr = 0.78; p = 0.065) variations in the Rev group and with MMb-tot  variations in the Ex group.When analyzing the response to different interventions, despite the reduced sample size, the changes in ABI were correlated with MMb-diff . A moderate statistically insignificant correlation was noted for MMb-oxy   a.r = −0.57, p = 0.05; and r = −0.53, p = 0.07, respectively)  b.Conversely, no significant correlations were observed between traditional outcome measures  at baseline and variations in PFWD and 6MWD after the interventions in the whole population or in either groups.This study identified novel muscle metabolism biomarkers that allowed to quantify and compare peripheral muscle adaptations occurring in active patients with PAD four months after a revascularization intervention or the start of a home-based pain-free walking program. The NIRS biomarkers correlated with validated parameters and predicted the recovery of mobility following two interventions in a group of patients.A testing method that was previously described  has beenHowever, a previous study based on the same NIRS-assisted test as that employed in the present study distinguished between local exercise-induced adaptations occurring in two groups of PAD patients and in healthy subjects . The stuIn the present study, the MMb showed improved dynamic oxygenation at the gastrocnemius following both the invasive and noninvasive interventions, as evidenced by a reduction in the values of MMb-oxy in both groups after four months. In particular, an expected higher oxygen supply in the Rev group than in the Ex group was observed, as witnessed by the oxygenation area, which improved 2-fold (56% compared to 20%) without statistical significance due to the small sample size and the large standard deviations determined.Interestingly, the variations in MMb-oxy were congruent and highly correlated with the variations in ABI observed in the more impaired limb in the whole population and separately in the two groups despite the small sample size.These variations in ABI and muscle perfusion, as expected, were largely superior in the Rev group, being obtained with different revascularization procedures and in some cases related to multiple districts.However, an increase in ABI was also present and measurable in the Ex group, with an average variation of approximately 15%. The ABI increase, not reported after supervised exercise programs , but preIn addition, in the Ex group, the NIRS technique also showed better aerobic efficiency in terms of oxygen utilization, with a larger improvement in the median differential hemoglobin area than the Rev group . Adaptations in mitochondrial function accounting for the functional improvements observed were recently reported following an exercise training assisted by NIRS at moderate deoxygenation . InteresA further interesting observation is represented by the fact that MMb expressed selective adaptations in response to different interventions. Moreover, their changes were also correlated with walking ability at baseline, unlike the ABI. As a further point of interest, the changes in NIRS markers were supported in their validity by their correlation with the ABI and performance variations.In this respect, a further intriguing aspect is represented by the predictive ability of the NIRS values determined at baseline for the measured individual functional recovery. In the Rev group, only the NIRS biomarkers, not the ABI and functional baseline values, were correlated with the changes in walking performance, especially the PFWD at four months, suggesting the possibility to estimate performance changes after revascularization and therefore define the benefit–cost ratio for patients.The study has several limitations. The main weakness is the sample size and the different sample size in each group, derived from randomization. In addition, the limitations related to the NIRS technique must be considered. We analyzed only a localized region of a particular muscle, but oxygen saturation may vary within and between specific muscles . In geneFrom a practical point of view, a non-invasive NIRS-assisted test allowed to measure and compare at the same time both muscle oxygen availability and utilization following different interventions. In addition, the test may estimate the medium-term benefits on mobility before revascularization, thus enabling the vascular surgeon and the patient with claudication to evaluate the risk-benefit ratio.The study confirms that the NIRS-based assessment of perfusion at the calf muscle following interventions may provide additional information than that obtained by the ABI and walking parameters. An incremental test assisted with the NIRS technique, performed in a rehabilitative setting quickly and safely produced different biomarkers. These MMb showed a selective response to each intervention, with variations that were congruent and associated with validated hemodynamic and functional parameters. In addition, only these novel biomarkers showed a correlation with functional outcomes four months after surgery and exercise training. The present novel results need to be confirmed in a larger study.