The “legacy effect” describes the long-term benefits that may persist for many years after the end of an intervention period, involving different biological processes. The legacy effect in cardiovascular disease (CVD) prevention has been evaluated by a limited number of studies, mostly based on pharmacological interventions, while few manuscripts on dietary interventions have been published. Most of these studies are focused on intensive treatment regimens, whose main goal is to achieve tight control of one or more cardiovascular risk factors. This review aims to summarise the legacy effect-related results obtained in those studies and to determine the existence of this effect in CVD prevention. There is sufficient data to suggest the existence of a legacy effect after intensive intervention on cardiovascular risk factors; however, this effect is not equivalent for all risk factors and could be influenced by patient characteristics, disease duration, and the type of intervention performed. Currently, available evidence suggests that the legacy effect is greater in subjects with moderately-high cardiovascular risk but without CVD, especially in those patients with recent-onset diabetes. However, preventive treatment for CVD should not be discontinued in high-risk subjects, as the level of existing evidence on the legacy effect is low to moderate. Cardiovascular disease (CVD) has emerged as a major cause of morbidity and mortality, accounting for 30% of all deaths worldwide. The intensive management of cardiovascular risk factors is required to reduce its incidence, and some authors suggest that achieving tight control at early stages of the disease, before vascular damage has developed, is a determinant of outcomes .The legacy effect concept refers to long-term sustained benefits after a period of intensive treatment intervention, even after cessation of the intervention . InitialMetabolic memory was first described in 1987 when Engerman et al. observed a higher incidence of diabetic retinopathy among dogs in which good glycaemic control was preceded by a longer period of abnormal glucose levels .However, most studies examining the legacy effect on CVD and its related risk factors for vascular complications are based on pharmacological interventions, with low emphasis on dietary interventions; thus, the long-term effects of strict dietary regimens remains unknown. In this review, we focus on the recent evidence of the legacy effect and metabolic memory in CVD development after intensive pharmacological and non-pharmacological interventions addressing cardiovascular risk factors.The aim of this narrative review was to assess those scientific studies that evaluated the existence of the legacy effect in the prevention of CVD after a nutritional or pharmacologic intervention. We searched for scientific studies published in the last ten years and written in English in PubMed Medline Database by using specific search terms . In addition, recent reviews and meta-analysis about the legacy effect, metabolic memory and its pathophysiological mechanisms were also included. To sensitise the search and select the best articles, we used the aforementioned keywords and applied different Boolean operators. Finally, a total of 64 articles were selected for this review. Most of them were clinical trials in humans, and there was also a small proportion performed in animal models. The differences observed among the outcomes of the trials and their post-trial follow-up studies have been described by using the difference in means, risk ratio (RR), odds ratio (OR) and hazard ratio (HR) measures. The publication, attrition and co-intervention bias, and the baseline characteristics of the patients included in the trials should be taken into consideration for the interpretation of the results.Multiple mechanisms have been described as relevant to the development of the legacy effect. Diabetic models have been used to thoroughly study the concept of metabolic memory. Furthermore, studies performed on hypertension models have shown that similar mechanisms are involved in the maintenance of beneficial post-intervention effects.Chronic hyperglycaemia induces uncoupling of the mitochondrial electron transfer chain in endothelial cells, causing excessive production of superoxide anion and other reactive oxygen species (ROS), thereby increasing cellular oxidative stress and inducing endothelial dysfunction. Moreover, ROS can cross membranes and damage macromolecules , many of which may have longer half-lives, and hence may exert metabolic effects. These oxidative stress markers can persist in endothelial cells despite glucose normalisation after prolonged hyperglycaemia, suggesting a metabolic memory phenomenon  4,5]. F,5. F4,5]Superoxide anion inhibits glyceraldehyde 3-phosphate dehydrogenase (GAPDH) activity, leading to the accumulation of all glycolytic intermediates, which can react non-enzymatically with proteins, lipids, and nucleic acids to form advanced glycation end-products (AGEs). AGEs may accelerate ageing processes, and they cannot be degraded easily by the enzymes involved in normal metabolism. In addition, the most exposed proteins, such as haemoglobin, are also highly glycated . AGEs alEven after glycaemic control has been achieved, AGEs may be used as markers to measure cumulative diabetic exposure, especially in those with vascular complications, whereas intensive treatment is associated with significantly lower AGE levels. These pathways are responsible for metabolic memory and contribute to the development and progression of CVD and diabetic complications. Glycaemic memory can be measured by glycated haemoglobin (HbA1c), although AGEs have also been correlated with retinopathy progression, independent of HbA1c level . Some meChronic hyperglycaemia can induce epigenetic modifications, which could underlie endothelial dysfunction and the development of metabolic memory in diabetic complications. Recent research suggests that DNA methylation and post-translational histone modifications in a hyperglycaemic environment could lead to enhanced expression of proinflammatory genes, such as the increased expression of the key p65 subunit of NF-κB in various target tissues, which persists long after restoration of normoglycemia. Moreover, in cell and animal models exposed to transient-high and subsequent normal glucose levels, an increase in differentially expressed miRNAs has been observed; these may play a role as regulators of endothelial dysfunction in metabolic memory by increasing the constitutive activation of NF-κB pathway. However, the potential reversal of glucotoxicity and lipotoxicity depends on how long the patient has been exposed to this poor metabolic environment ,21.Few studies have assessed the legacy effect after dietary intervention. Most of these have been done in animals. Below, we describe the most relevant findings.One study showed that mice switched from dietary restriction (DR) to ad libitum (AL) intake had significantly better glucose tolerance at 6–10 months compared to the AL group, suggesting that there was positive glycaemic memory in the DR group ,23,24. MThe legacy effect was also confirmed in rats subjected to an HFD, when time-restricted feeding was alternated with AL feeding, with no significant differences in body weight observed between the alternated feeding and the control group (AL feeding only) in a short term-study (12 weeks). However, in the long-term study (25 weeks), when mice were maintained on time-restricted feeding for 13 weeks and then switched to AL feeding for 12 weeks, they showed significantly less body weight gain after returning to an HFD compared to the control group, which were maintained on time-restricted feeding throughout the 25 weeks  . FurtherTo our knowledge, there is limited evidence assessing the existence of a legacy effect in humans after dietary intervention. The effects of caloric restriction (approximately 25% of daily energy intake) or intermittent fasting (up to 18 h/day) in humans have been demonstrated mainly in observational studies, and only one clinical trial, the Comprehensive Assessment of the Long-term Effects of Reducing Energy Intake (CALERIE) study, was performed. Both strategies improve general health indicators and slow or reverse ageing and disease processes, such as obesity, insulin resistance, dyslipidaemia, hypertension and inflammation, although intermittent fasting seems to exert a greater effect. Improvements in health indicators typically begin within the first month, after the start of intermittent fasting, and then dissipate over a period of several weeks after resumption of a normal diet . This efThe Oslo cardiovascular study was a five year randomised intervention conducted in healthy middle-aged men at high risk of coronary heart disease (CHD) assigned to a dietary advice group  compared to a control group. At 40 years of follow-up, a significant reduction (19%) in the risk of death at first myocardial infarction (MI) was detected in the intervention group , 0.51–1.00), with no significant difference in total mortality. The legacy effect was achieved through the dietary intervention (as evidenced by lower cholesterol and serum triglyceride levels and weight reduction) because few men quit smoking; therefore, the effect of this measure was small .In the Look Action for Health in Diabetes (Look-AHEAD) trial, overweight/obese patients with T2DM were randomly assigned to an intensive lifestyle intervention to achieve and maintain a weight loss ≥7%, which included: hypocaloric diet , physical activity and diabetes education, compared to standard care for one year. Patients included in the intensive lifestyle intervention had greater weight reduction with better control of cardiovascular risk factors , and more improvement in fitness levels throughout the four year follow up period compared to the control group .Several clinical trials have assessed legacy effects in different populations of patients with diabetes, the main results of which are listed below. The specific data from each article are shown in The Diabetes Control and Complications Trial (DCCT) was performed in patients with type 1 diabetes mellitus (T1DM), who were randomly assigned to either intensive or standard glycaemic control regimens. After 6.5 years of intervention, the development of severe proliferative or non-proliferative retinopathy , clinical neuropathy , and microalbuminuria  was significantly lower in the intensive treatment group . After tThe United Kingdom Prospective Diabetes Study (UKPDS) recruited patients with newly diagnosed T2DM (six months from diagnosis); after a three-month diet , they were randomised to intensive glucose control with medication  or to conventional dietary treatment, and they were followed-up for ten years. Intensive glucose management was associated with a significant reduction for any diabetes-related endpoint (12%) and for any diabetes-related death (10%) compared to the control group. Most of the risk reduction in the “any diabetes-related aggregate” endpoint was due to a 25% risk reduction in microvascular endpoints. However, there was no significant reduction in macrovascular endpoints between both arms of the study. Moreover, patients in the intensive group had more hypoglycaemic episodes than those in the conventional one . AlthougThe Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial included patients with T2DM with a mean duration of ten years and previous cardiovascular events or multiple cardiovascular risk factors. The patients were assigned to receive intensive or standard therapy  for 3.7 years, with a combination of different hypoglycaemic drugs including insulin . It was The Veterans Affairs Diabetes Trial (VADT) was performed in patients with poorly controlled long-standing T2DM (mean duration of 11.5 years), 40% of whom had already suffered a cardiovascular event. They were randomly assigned to intensive or standard therapy for a median of 5.6 years. Other cardiovascular risk factors were treated uniformly. The intensive glucose-lowering treatment led to a between-group difference of 1.5 percentage points in HbA1c levels (6.9% in the intensive-therapy group vs. 8.4% in the standard-therapy group) during the in-trial period. The only benefit observed was a slower progression of microalbuminuria in the intensive treatment group. However, a significantly lower incidence of CVD  in patients originally assigned to intensive therapy was observed after ten years of follow-up. Nevertheless, over a 15-year follow-up period, the risks of major cardiovascular events , or death from any cause  were not lower in the intensive-therapy group than in the standard therapy group, suggesting a modest and transient long-term cardiovascular benefit of intensive glucose-lowering therapy in patients with more advanced diabetes . In factThe Anglo-Danish-Dutch study of Intensive Treatment in People with Screen-Detected Diabetes in Primary Care (ADDITION) study recruited middle-aged adults with a moderate to high risk of T2DM for diabetes screening, in order to evaluate the risk of CVD and mortality among incident cases of T2DM in a screened group compared to an unscreened population. Participants diagnosed with T2DM were offered intensive multifactorial treatment and compared to those receiving routine care for five years, with a reduction in fatal and nonfatal CVD of 17% shown. After a 10-year follow-up, patients diagnosed after population-based screening had a significant 21% lower risk in all-cause mortality  and a significant 16% lower risk in cardiovascular events , but no significant risk reduction on cardiovascular mortality compared to unscreened patients . MoreoveThe Diabetes and Aging Study was a large observational study of newly diagnosed T2DM patients and followed those with long survival post-diagnosis (≥10 years). The study assessed the impact of HbA1c levels ≥6.5% in the first year after T2DM diagnosis on later CVD risk. The risk of micro- and macrovascular events was higher in those patients with HbA1c levels ≥6.5% compared to those with lower levels, whereas mortality risk was significantly higher in patients with HbA1c levels ≥8%. These results suggest it is necessary to achieve normoglycemia in the first 12 months after T2DM diagnosis to generate a legacy effect  46]..46].Several clinical trials have assessed legacy effects in different populations of hypertensive patients, the main results of which are listed below. The specific data from each article are shown in A separate UKPDS post-trial follow-up study assessed whether risk reductions for micro- and macrovascular complications were achieved and maintained in a subgroup of hypertensive subjects with newly diagnosed T2DM with tight versus less-tight BP control with captopril or atenolol. However, differences in BP between groups (tight vs. less tight) disappeared within two years after trial termination, and most cardiovascular benefits were not sustained during the 10-year post-trial follow-up period. Only a reduced risk for peripheral vascular disease associated with tight BP control was significant . Hence it would be necessary to maintain good BP levels over time to preserve this previous benefit  36,47].,47.36,47The Systolic Hypertension in the Elderly Program (SHEP) trial was performed in elderly patients with isolated systolic hypertension who were randomised to chlortalidone therapy or placebo . Over a mean follow-up of 4.5 years therapy, reduction in fatal or nonfatal stroke , MI , and heart failure  in the chlortalidone group compared to placebo was observed. However, there was no significant risk reduction in all-cause and cardiovascular mortality. After a 22-year follow-up, significant, albeit modest life expectancy gains free from CVD-related deaths were observed in the chlortalidone group, corresponding with approximately one day  gained for each month of treatment.  48]..48].In the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), 32,804 hypertensive patients with at least another cardiovascular risk factor were randomised to receive chlorthalidone, amlodipine, or lisinopril for 4 to 8 years, and thereafter, passive surveillance continued for a total follow-up of 8 to 13 years. During the in-trial period, no statistically significant differences in CHD or nonfatal MI were observed. In the post-trial follow-up, the only significant differences were observed in secondary outcomes, such as heart failure and stroke mortality, which were higher with amlodipine and lisinopril, respectively, compared to chlorthalidone. However, a significant treatment-by-race interaction was detected and, after accounting for multiple comparisons, none of these results were deemed significant  49]..49].The Randomised Olmesartan And Diabetes MicroAlbuminuria Prevention (ROADMAP) trial included patients with T2DM with at least one additional cardiovascular risk factor and normoalbuminuria. They were randomly assigned to olmesartan or placebo for 3.2 years; the main outcome was significantly delayed microalbuminuria onset in the olmesartan group. After a 6.5-year observational follow-up period, researchers concluded that congestive heart failure (CHF) requiring hospitalisation  and diabetic retinopathy  were significantly lower in the former olmesartan group, indicating a legacy effect in these outcomes  50,51].,51.50,51The Second Australian National BP study (ANBP2) observed a lower risk of cardiovascular  and all-cause mortality  in the “treatment-naive” group (participants without BP-lowering medication at study registration) compared to BP-lowering medication or “previous treatment” group  during the in-trial period in an elderly cohort. No differences were found between groups with respect to randomised treatment allocation to either ACEI or diuretic-based regimens; likewise, there were no differences in cardiovascular outcomes or all-cause mortality when the data from the in-trial and ten-year post-trial follow-up were combined  52]..52].The Anglo-Scandinavian Cardiovascular Outcomes Trial (ASCOT) enrolled patients with hypertension and at least three other cardiovascular risk factors. In the BP-lowering arm, patients were randomised to either an amlodipine-based regimen (adding perindopril as required) or an atenolol-based regimen (adding bendroflumethiazide and potassium as required). The in-trial results demonstrated a significant reduction in cardiovascular events, mortality and all-cause mortality in subjects assigned to the amlodipine-based group, but no overall difference in cardiovascular mortality  among treatments. These results could suggest that not all hypotensive drugs are equally effective in preventing CVD, although the resulting BPs are similar. After 16 years of total follow-up (ASCOT Legacy Study), there was no overall difference in all-cause mortality between treatments, although significantly fewer deaths from stroke  occurred in the amlodipine-based treatment group  [53].Finally, a systematic review and meta-analysis of three clinical trials were performed to analyse whether early versus late initiation of antihypertensive treatment was better at reducing cardiovascular morbidity and mortality. The trials involved 4746 mildly hypertensive (systolic BP 140–159 mmHg) middle-aged patients free of CVD at baseline and with low cardiovascular risk. No differences were seen between strategies during the in-trial period (5 years) or during post-trial follow-up (ten years). Therefore, the review showed no clinically adverse legacy effect on mortality or major CVD with delayed pharmacotherapy in middle-aged mildly-hypertensive subjects with low cardiovascular risk .Several clinical trials have assessed the legacy effects in different populations of patients with dyslipidaemia the main results of which are listed below. The specific data from each study are shown in The ALLHAT lipid-lowering trial (LLT) evaluated the impact of large, sustained cholesterol reductions in all-cause mortality in a cohort of hypertensive patients with at least one other cardiovascular risk factor. All-cause mortality did not differ significantly between the pravastatin and usual care treatment groups  at six years of follow-up. Similarly, no significant reductions in CHD events  were observed at the end of the follow-up period  55]..55].The West of Scotland Coronary Prevention Study (WOSCOPS) was a primary prevention trial performed in men (45 to 65 years old) with hypercholesterolemia who were randomised to pravastatin or placebo for five years. The 20-year follow-up study after the initial intervention identified a legacy benefit in the pravastatin group compared to placebo, with a significant reduction in all-cause mortality , attributable mainly to a 21% decrease in cardiovascular death , reduction in hospital admissions for any coronary event (18%), for MI (24%), and for heart failure (35%). The authors suggested that these benefits may be the result of reduced infarct size, prevention and regression of atherosclerotic changes, or pleiotropic effects of statins. On the other hand, there was no difference in non-cardiovascular or cancer death rates between groups  56]. . 56]. The ASCOT lipid-lowering arm (LLA) is a substudy of the ASCOT study previously reported. ASCOT-LLA enrolled ASCOT study participants who had total cholesterol of 6.5 mmol/L or less and no previous lipid-lowering treatment. They were randomised to receive atorvastatin or placebo as primary prevention for CHD; lower nonfatal MI and fatal CHD was demonstrated in the atorvastatin group during the interventional period of the study. The legacy effect was studied for 16 years after initial randomisation and also showed a significant risk reduction in cardiovascular mortality  in those assigned to atorvastatin group. No differences in all-cause mortality or stroke were seen between the atorvastatin and placebo groups during the post-trial study period  52]..52].The ACCORD-Lipid study included a subgroup of ACCORD study participants. Briefly, T2DM patients were randomised to receive simvastatin plus fenofibrate vs. simvastatin plus placebo for five years; no evidence of a beneficial effect of statin-fibrate combined treatment compared to statins alone on cardiovascular outcomes and mortality was found. However, a beneficial reduction in major CHD  was observed in a subgroup of participants with dyslipidaemia. The extended post-trial follow-up study (ACCORDION) showed lower rates of all-cause mortality, cardiovascular mortality, nonfatal MI, CHF and major CHD in the simvastatin-fibrate group in the ten years following randomisation. Moreover, the trial period’s combined statin-fibrate treatment arm conferred a beneficial legacy effect, which was observed in the post-trial follow-up on all-cause mortality . Fibrate therapy, offered as an add-on to statin therapy, may be beneficial for people with diabetes with hypertriglyceridemia and/or reduced HDL-C  57]. . 57]. A recent meta-analysis, including eight placeboes vs. statin randomised clinical trials for primary and secondary cardiovascular prevention, evaluated the legacy effect during a mean post-trial follow-up ranging from 1.6 to 15.1 years. The results mostly showed a significant reduction in cardiovascular and all-cause mortality within the trial period, and less benefit in the post-trial period. The legacy effect was observed in relation to lower all-cause mortality but, appeared to have no effect on CVD mortality. Additionally, in a subgroup analysis, there appeared to be a greater legacy effect when statins were used for primary prevention compared to secondary prevention in CVD and all-cause mortality , suggesting the importance of long-term prevention in these patients .Another meta-analysis carried out by Hirakawa et al. (62) analysed the legacy effect in the post-trial follow up (mean duration six years) after an intervention period with antihypertensive and lipid-lowering treatments. The study demonstrated significant reductions in all-cause and cardiovascular mortality  after discontinuation of antihypertensive and lipid-lowering treatment during the overall follow-up, although this effect was lower than that observed during the in-trial phase. Furthermore, progressive attenuation of post-trial benefits was noted as the length of the post-trial observation increased. However, no clear differences between the effects of BP or lipid-lowering therapies were detected across trials studying different types of therapies or patient populations. These findings indicate that it is important to continue antihypertensive and lipid-lowering treatment in the long-term to provide optimal cardiovascular protection .The Action in Diabetes and Vascular Disease (ADVANCE) trial was performed in 11,140 T2DM patients ≥55 years old, with at least one additional risk factor for CVD. The trial proposed a double strategy to optimise glycaemic control (intensive glucose control or standard control) and BP control (perindopril-indapamide or placebo) for five years. During the intervention phase, there was a reduction in microvascular events (14%), primarily due to reduction in nephropathy incidence in the intensive glucose-control group, as well as a reduction in the relative risk of all-cause mortality (14%) and cardiovascular mortality (18%) in the BP control group. The six-year post-trial follow-up study found a significant reduction in all-cause mortality , and cardiovascular mortality  in those patients originally treated with perindopril-indapamide compared to placebo. Although the confidence limits were wide, the results suggested that one death from any cause would be prevented for every 79 patients assigned to active therapy for five years. On the other hand, there was no evidence that the effects of the treatment could be inferred from initial BP levels or concomitant use of other treatments at baseline. However, intensive glucose control did not provide any long-term benefits during the intervention period nor after post-trial follow-up  60,61,6,661,62.n = 160; mean age 55 years) with microalbuminuria who were randomly assigned to standard treatment or intensified multifactorial intervention during a mean follow-up of 7.8 years. This intervention included simultaneous control of glucose levels, BP, lipid profile, and antiplatelet therapy through pharmacological and non-pharmacological intervention. The latter included dietary advice , light to moderate exercise at least 30 min three to five times a week, and smoking cessation. During the active intervention period, there was risk reduction for nephropathy progression , retinopathy progression , and autonomic neuropathy progression , as well as for cardiovascular complications and all-cause mortality combined  in the intensive treatment group. After a 21-year follow-up from randomisation, a significant reduction in all-cause mortality (45%), cardiovascular mortality (62%), macroalbuminuria (48%), retinopathy progression (33%), and autonomic neuropathy (41%) was demonstrated in the intensive treatment arm, suggesting a legacy effect from intensive multifactorial treatment compared to the standard approach. For patients in the intensive treatment group, death and time to first cardiovascular event was delayed by 7.9 and 8 years, respectively, compared to patients in the standard treatment group , major cardiovascular events  and mortality, as well as analytical parameters. The results obtained have been quite heterogeneous, probably due to differences in the baseline characteristics of the patients included, the type and duration of the interventions, and post-trial follow-up. In general terms, the legacy effect has been observed to be less intense than that achieved in the intervention phase and tends to diminish with longer follow-up. All the data suggest that this effect is greater and longer lasting in patients without known CVD undergoing intensive therapy for recent-onset diabetes, hypertension or dyslipidaemia.A limited number of studies related to the legacy effect after nutritional intervention have been published to date. In studies performed with rats and mice, some authors have demonstrated that after CR  or intermittent fasting, glycaemic control and insulin resistance could improve for several weeks. The evidence in humans is lacking, as health benefits of CR or intermittent fasting have been evaluated mainly in observational studies and a single clinical trial (CALERIE Study). The effect during the intervention period appears to be favourable but disappears shortly after the intervention ends. Therefore, CR or intermittent fasting has not been shown to generate a legacy effect in humans . In addiThe first scientific evidence of the legacy effect in patients with diabetes comes from the DCCT and the UKPDS studies, in which an intensive glycaemic control compared to standard treatment resulted in a significant reduction in cardiovascular mortality, nonfatal MI, stroke and nephropathy. These beneficial effects persisted for more than a decade after the intervention was finished ,37. FurtSeveral clinical trials have analysed the legacy effect after tight BP control with controversial results. On the one hand, the SHEP and the ROADMAP trials showed reductions in cardiovascular mortality, retinopathy and delayed onset of microalbuminuria, whereas the ASCOT study only demonstrated a small reduction in stroke mortality in the amlodipine-treatment group at the end of the entire follow-up ,50,52. ODifferent lipid-lowering trials, including ASCOT, WOSCOPS and ACCORD lipid studies, have also observed a legacy effect, resulting in a reduction in all-cause mortality and CHD mortality for 10–20 years after ending the interventional phase (statin or fibrates treatment), whereas the ALLHAT-LLT study did not provide evidence of a legacy effect after intensive lipid-lowering treatment ,55,56,57Until now, the legacy effect after multifactorial intervention has only been observed in the Steno-2 study, which included pharmacological and non-pharmacological measures. Indeed, lower mortality, CVD incidence and microvascular complications were detected in the intensive treatment arm of the trial compared to the standard treatment group. Surprisingly, the results were obtained in a sample of only 160 patients with intermediate cardiovascular risk but without CVD at baseline. It has been suggested that the positive long-term cardiovascular effects must be the result of a synergistic effect of the multifactorial intervention on cardiovascular risk factors . AlthougThe knowledge of pathophysiological mechanisms underlying the legacy effect adds plausibility to its existence. The best-known mechanisms are those related to the deleterious effects of hyperglycaemia through the development of metabolic memory induced during the first years of diabetes onset, which cannot be reversed with better glycaemic control. Thus, early interventions against hyperglycaemia could reduce ROS production and oxidative stress in the mitochondria of endothelial cells, decrease AGE formation and RAGE expression, and therefore, prevent activation of inflammatory processes and epigenetic changes in the arterial walls in the long term ,17,20,21This review has several strengths and limitations. Firstly, one strength involves the inclusion of well-designed multicentre prospective clinical trials with large participant samples during the interventional phase. Secondly, most trials have a long post-interventional follow-up (6–20 years), which is enough time to detect differences between groups. Likewise, the study of different types of cardiovascular risk factors , as well as variable evolution time and treatment objectives (primary or secondary prevention of CVD) may allow us to identify in which studies the legacy effect may be more or less relevant. However, some limitations should be taken into account. First, loss of patients during post-interventional follow-up can reach 25–30% of subjects included in the trial (attrition bias), therefore data collection during this period may not have been as exhaustive as in the intervention period. The publication of only those trials with positive results (publication bias) and the absence of blindness in several trials (co-intervention bias) should also be considered. Furthermore, the inclusion of post hoc analysis together with the detection of the legacy effect is influenced by different confounding factors , which may lead to a questionable interpretation of the results. Finally, another limitation that must be taken into account is the fact that few non-pharmacological studies  have been carried out. Although dietary recommendations are included in most studies, they are usually quite generic, and it is also difficult to know the degree of adherence to them.In conclusion, there is sufficient data to suggest the existence of a legacy effect after intensive intervention on cardiovascular risk factors in subjects with moderate-high vascular risk. However, this effect is not equivalent for all risk factors and could be influenced by patient characteristics, disease duration and the type of intervention performed. Currently, the available evidence suggests that the legacy effect would be greater in subjects with moderate-high cardiovascular risk but without known CVD, especially in patients with recent-onset diabetes. However, we should not withdraw any treatment to prevent CVD in these individuals as the level of available evidence on the legacy effect is low to moderate. Further investigation should be promoted to determine whether there is a legacy effect associated with nutritional interventions.


Obesity and diabetes are established comorbidities for COVID-19. Adipose tissue demonstrates high expression of ACE2 which SARS- CoV-2 exploits to enter host cells. This makes adipose tissue a reservoir for SARS-CoV-2 viruses and thus increases the integral viral load. Acute viral infection results in ACE2 downregulation. This relative deficiency can lead to disturbances in other systems controlled by ACE2, including the renin-angiotensin system. This will be further increased in the case of pre-conditions with already compromised functioning of these systems, such as in patients with obesity and diabetes. Here, we propose that interactions of virally-induced ACE2 deficiency with obesity and/or diabetes leads to a synergistic further impairment of endothelial and gut barrier function. The appearance of bacteria and/or their products in the lungs of obese and diabetic patients promotes interactions between viral and bacterial pathogens, resulting in a more severe lung injury in COVID-19. Coronavirus disease-2019 (COVID-2019), caused by the highly pathogenic virus SARS-CoV-2, demonstrates very heterogenous clinical severity, ranging from asymptomatic to devastating forms connected with the development of severe acute respiratory syndrome (SARS) accompanied by extensive pulmonary fibrosis (PF). There is rapidly emerging evidence highlighting obesity and type 2 diabetes (T2D) as comorbidities of SARS development in COVID-19 . Clinicahttps://agencia.fapesp.br/adipose-tissue-may-be-a-reservoir-for-sars-cov-2-brazilian-researchers-suggest/33729/). The virus can also profoundly alter the fate of adipocytes in adipose tissue or adipocyte-like cells in the lungs  is compromised and can directly or indirectly be involved in interactions with SARS-CoV-2 at several levels. In the case of direct interactions with the virus, AT, demonstrating higher expression of ACE2  compared to the lungs , can serhe lungs . Additiohe lungs . This meIn the case of indirect interactions, AT can be a source of angiotensin-converting enzyme 2 (ACE2), which is the functional receptor that SARS-CoV/CoV-2 exploits to enter host cells. AT has its own renin-angiotensin system (RAS) that acts in its local microenvironment. Adipocytes express ACE2, and this expression increases during adipogenic differentiation  and is fWhile generally plausible, these mechanisms, however, do not clearly explain the predominant presence of more severe respiratory forms of COVID-19 in patients with obesity and T2D. The main problem is that this phenomenon is not specific for SARS-CoV/CoV2, and obesity was generally associated with a higher risk of severe viral infections . AdiposiObesity and T2D are very prominent, but not the only known comorbidities in COVID-19. Increased risk for severe forms of COVID-19 were also reported in aged individuals and in patients with cardiovascular diseases (CVD)  as well Whereas the appearance of these comorbidities can have distinct causal explanations, it is more straightforward to assume that all of them have some common underlying pathophysiological mechanism. Below, we critically revisit the factors and pathophysiological pathways that connect obesity and diabetes to the relative severity of SARS in COVID-19, and that are at the same time involved in other comorbidities observed in this disease. We also propose a new hypothesis , which, The established comorbidities - obesity and T2D - that are associated with severe outcomes with SARS in COVID-19 appear to contradict the ‘obesity paradox’, a phenomenon epidemiologically well-established for a number of other diseases. Many studies have determined that patients with obesity and T2D have decreased in-hospital mortality rates connected with multiple pulmonary conditions. Survival of patients and the development of severe forms of chronic obstructive pulmonary disease, characterized by poor gas exchange and strong inflammation, demonstrated statistically significant negative correlations with their BMI values . Hospitadb/db mice developed less severe forms of hyperoxia-induced ALI and exhibited better survival rates , which are the major components of the outer membrane of Gram-negative bacteria, to non-diabetic mice promoted acute pulmonary inflammation . In contal rates .On the other hand, mice with high fat diet-induced T2D susceptible to MERS-CoV infection have more severe clinical symptoms and a delayed recovery. These symptoms were primarily connected with a more severe lung pathology . MERS-CoSuch paradoxical reactions of patients with obesity and/or T2D to viral and non-viral pathogens raise the question, which factors can influence the pulmonary severity in COVID-19?One of the most obvious and widely accepted primary factors defining the severity of SARS-CoV/CoV-2 infection is the initial viral load. The initial viral loads in patients with severe forms of COVID-19 are thought to be much higher than in patients demonstrating milder forms of this disease . On the Another factor defining severity of COVID-19 is the integral viral load determined by transfer of SARS-CoV-2 viruses into the host cells. This parameter is connected to expression of ACE2 in the host cells. SARS-CoV-2 binds to ACE2 and induces its endocytosis, leading to internalization of the virus/ACE2 complex and a downregulation of cell surface ACE2. ACE2 has at least three functions: it negatively regulates RAS, facilitates the transport of amino acids through association with amino acid transporters and also serves as a functional receptor for SARS-CoV/CoV-2. This enzyme is widely expressed in different organs and tissues, including lungs and AT . ExpressACE2 gene expression in the lungs  and Ang II receptor blockers (ARBs), both inducing the expression of ACE2, may be beneficial in COVID-19 . In contExposure to ACEi’s or ARB’s induces ACE2 expression, but does not influence its shedding from the cell surface. Such shedding is mainly regulated by Disintegrin and Metalloproteinase Domain 17 (ADAM17), which is a tumor necrosis factor (TNF)-converting enzyme. ADAM17 can however also modulate free ACE2 in circulation  and is aAng II levels in circulation of COVID-19 patients were found to be significantly elevated and linearly associated with viral load and lung injury . DysreguThe suppression of ADAM17 may exert a protective effect on COVID-19 , since AStaphylococcus and Streptococcus bacteria in the lung  and primary human adipocytes in vitro revealed that this pathogen enters adipocytes and survives inside these cells in a non-replicative state, completely protected from anti-mycobacterial drugs (Rickettsia prowazekii (the causative agent of typhus) can infect and replicate in 3T3-L1 cells rendering adipose tissue into a dormant reservoir for this pathogen (Coxiella burnetii (the agent of query fever) is found in AT even four months post-infection, when no bacteria are detectable in other tissues, thus making AT a safe haven and a long-term reservoir, prevailing even after apparent full clinical recovery , resulting in the clearance of LPS through biliary excretion, a smaller part of LPS does not associate with HDL and is responsible for the activation of macrophages and the overproduction of potent inflammatory mediators . Both HDHDL, non-lipoprotein-bounded LPS and SR-BI were found to be associated with plasma membrane invaginations (caveolae) in different cell types . This isSince the pathways involving SR-BI can be exploited both by SARS-CoV2 virus and LPS, this raises the next question concerning the role of interactions between viral and bacterial pathogens in severity of COVID-19.It is already established that microbiota can directly or indirectly impact the outcome of different viral infections . VirusesStrong synergistic effects of combined coronavirus and bacterial infections on the severity of lung injury was demonstrated in the porcine respiratory coronavirus (PRCV) model . PRCV isSimilar results were obtained for the interactions between influenza virus (pH1N1) and LPS in mice: such interactions resulted in a synergistic increase in TNF-α, IL-1β, and IL-6 levels in lung tissue, promoting a hypercytokinemia and a pulmonary pro-inflammatory immune response .LPS induces lung injury through the suppression of ACE2 and the upregulation of Ang II, ACE, and AT1 receptors, thus significantly modulating the whole RAS . There aEnterobacteriaceae spp., which are abundant in the human gut and can release a large amount of endotoxin, were commonly present in the lung tissue ) can improve the adipogenic phenotype in lipofibroblasts thus reducing the trans-differentiation of these cells into myofibroblasts and theoretically preventing the development of pulmonary fibrosis .As we discussed above, several pathophysiological mechanisms may be involved in development of severe forms of COVID-19 . These mWhile all of them can theoretically contribute to the severity of COVID-19, we believe that one of these mechanisms should play the predominant role. Such mechanism must be present not only in obese and diabetic patients, but also in other groups of increased risk in COVID-19, including aged individuals, patients with CVD and some ethnicities. Moreover, taking into account multiple reports underlining the influence of gender and ethnicity on the COVID-19 outcome, this pathway must be also differentially present in males and females as well as in different ethnic groups. Hypothesis concerning the primary relevance of synergistic viral–bacterial interaction in severity of COVID-19 matches all these demands.Indeed, inflammation induced by bacteria and LPS is involved not only in insulin resistance but also in development of vascular abnormalities; hence, it is not surprising that blood-borne microbiota and circulating microbial metabolites were found to be significantly modified not only in diabetes but also in CVD . BacteriOlder patients demonstrate an increased risk for the development of severe forms of COVID-19 . Human gPlasma levels of LPS demonstrate also pronounced ethnic and gender variations. Age-adjusted levels of endotoxin were significantly lower in females than in males and significantly varied in different ethnic groups being the highest in South Asians . This caWhereas clinical arthritis was not revealed as a comorbidity of COVID-19 severity, this question will need additional investigation in the future, especially because some arthritis drugs were applied for treatment of COVID-19. Serum and synovial fluid LPS in osteoarthritis are associated with the presence of activated macrophages in the synovium, indicating that metabolic endotoxemia must be involved in pathogenesis of this disease . MoreoveBlood microbiota were also associated with such cognitive diseases as Alzheimer and Parkinson . LPS as Recently, a study on a mouse model exposed to a refined diet, containing just insoluble but no soluble fibers, demonstrated a significant modification of the gut microbiota independent of the age and gender of the animals . Given tIt is beyond the scope of this article to present an in-depth discussion of possible therapeutic options based on the proposed pathophysiological pathways. Assuming these pathways outlined are pathophysiologically relevant, we can think of three therapeutic options, which may be worthwhile to consider from our perspective. First, it may be of clinical value to apply citrate-based coupled plasma filtration adsorption (CPFA) to reduce the levels of TGF-β as well as of bacteria and bacterial products in circulation to avoid their deposition in the lungs. Second, the use of PPARγ agonists may be highly appropriate in this context, since (a) they can actually be potently anti-inflammatory, (b) can reduce hyperglycemia , (c) can modulate ACE2 expression, (d) reduce LPS levels in circulation, and (e) improve the adipogenic phenotype in lipofibroblasts, thus reducing their trans-differentiation into myofibroblasts. Third, there may be a justification for the development of therapeutic methods that lead to a reduction of hyperoxia in the lung. Hyperoxia can promote trans-differentiation of lipofibroblasts into myofibroblasts as well. Clearly, future endeavors will need to test these proposed therapeutic options and their efficacy.There are several established comorbidities for severe forms of SARS in COVID-19, and obesity and diabetes rank at the very top. Pathophysiological pathways involved in these comorbidities include a series of remarkable synergistic interactions. Adipose tissue demonstrates high expression of ACE2 that SARS-CoV-2 exploits to enter host cells and which makes adipose tissue a prime reservoir for SARS-CoV-2 viruses, thus increasing the integral viral load. Acute viral infection results in ACE2 reduction in different organs and tissues. This deficiency can lead to disturbances in two other systems controlled by ACE2: renin-angiotensin system, where ACE2 has the role of a negative regulator, and transport of amino acids, where ACE2 associates with amino acid transporters, enhancing their function. Such disturbances are further increased in the case of pre-conditions with already compromised function of these systems. This is the case in patients with obesity and diabetes characterized by substantially compromised endothelial function and increased vascular permeability. Whereas such interactions are not specific for SARS-CoV-2 and are observed in other viral infections, COVID-19 exposure is more severe, which is mainly due to the high affinity for ACE2 which is in SARS-CoV-2 at least an order of magnitude higher than for SARS-CoV.We propose that the synergistic interactions of virally-induced ACE2 deficiency with obesity and/or diabetes provide a synergistic impairment of endothelial function and gut barrier function, resulting in the leakage of bacterial pathogens and their products from the gut into circulation. Bacterial DNA and bacterial products can be detected in circulation of obese and T2D individuals, which predisposes patients with these diseases to a system-wide bacterial dissemination. The appearance of bacteria and/or their products in the lungs promotes an additional synergistic interaction between viral and bacterial pathogens - resulting in more severe lung injury in COVID-19 than in the case of a single viral or bacterial infection. This is further supported by the high levels of bacterial products in circulation of patients with severe forms of COVID-19 and the strong modulation of gut microbiota in critically ill COVID-19 patients. Additionally, further experimental support comes from observations demonstrating synergistic viral–bacterial interactions that can lead to the development of a hypercytokinemia (‘cytokine storm’), which is a hallmark of severe COVID-19 cases. The involvement of viral–bacterial interactions can also explain the increased risk of severe COVID-19 in older patients, in patients with cardiovascular diseases, and in some ethnic groups, as previously described in the literature. More comprehensive clinical and experimental research will be needed to further substantiate this interesting pathophysiological mechanism.


This study aims to investigate whether patients undergoing two-stage revision total hip arthroplasty (THA) for prosthetic joint infection (PJI) and one-stage revision THA for aseptic reasons have similar clinical outcomes and patient satisfaction during their post-operative follow-up. We hypothesise that the two-stage revision THA for PJI is associated with poorer outcomes as compared to aseptic revision THA.We reviewed prospectively collected data in our tertiary hospital arthroplasty registry and identified patients who underwent revision THA between 2001 and 2014, with a minimum of two years follow-up. The study group (two-stage revision THA for PJI) consists of 23 patients and the control group (one-stage revision THA for aseptic reasons) consists of 231 patients. Patient demographics, Western Ontario and McMaster Universities Arthritis Index (WOMAC), Oxford Hip Score (OHS), Short Form-36 (SF-36) scores and patient reported satisfaction were evaluated. Student’s t-test was used to compare continuous variables between the two groups. Statistical significance was defined as p <0.05.The pre-operative demographics and clinical scores were relatively similar between the two groups of patients. At two years, patients who underwent revision THA for PJI reported a better WOMAC Pain Score and OHS as compared to aseptic revision THA. A similar proportion of patients were satisfied with their results of surgery in both groups (p=0.093).Although patients who underwent revision THA for PJI had poorer pre-operative functional scores (WOMAC function and SF-36 PF), at two years follow-up, these two groups of patients have comparable post-operative outcomes. Interestingly, patients who had revision THA for PJI reported a better clinical outcome in terms of OHS and WOMAC Pain score as compared to the aseptic group. We conclude that the revision THA for PJI is not inferior to aseptic revision THA in terms of patient satisfaction and clinical outcomes. The long-term outcomes of THA are favourable, with approximately 90% of patients reporting that their expectations have been met by surgery and that they are satisfied with the results of their surgery3. As the number of patients with medically diagnosed arthritis increases, so does the number of primary THA. Similarly, the rates of revision THA have risen4. It has been reported in the literature that approximately 10 to 18% of all THA interventions are revision procedures for aseptic reasons such as aseptic loosening, wear, instability with recurrent dislocations, periprosthetic fractures as well as septic THA revision4.Primary total hip arthroplasty (THA) is a frequently performed orthopaedic surgery that significantly improves a patient’s quality of life and achieves high patient satisfaction rates7. It has been postulated that technical factors, poorer quality of bone and patient-related factors such as older age, more comorbid conditions and poorer pre-operative baseline pain scores are confounding factors for less favourable results for revision THA as compared to primary THA9. Common reasons for revision THA in the United States is aseptic mechanical loosening, instability/dislocation, followed by periprosthetic joint infection (PJI)11. For septic revision THA, a two-stage revision is the most widely accepted and performed intervention, with a high infection eradication rate that exceeds 90% in most studies16. This two-stage procedure involves a first stage procedure of implant replacement with an antibiotic-loaded cement spacer, followed by a second stage procedure of re-implantation with a cemented or uncemented prosthesis.Revision THA as compared to primary THA is associated with significantly higher complications and mortality rates, less improvement in functional outcome and quality of life, as well as lower patient satisfaction16. There have been studies in the literature18 comparing outcome measures between revision total knee arthroplasty for PJI and aseptic reasons. However, there is little literature available that compares patient-reported outcome measures and patient satisfaction between the two-stage revision THA for PJI and the one-stage revision THA for aseptic reasons such as instability and loosening16.Despite the ability to control deep-seated infection in patients with PJI with two-stage revision THA, these patients often report poorer functional outcomes following revision surgery as compared to those who have undergone aseptic revision THAThis study aims to compare the patient-reported outcome measures for patients undergoing revision THA for PJI and aseptic revision THA, in order to evaluate if the two groups of patients have similar clinical outcomes and patient satisfaction in their two years follow-up post-operatively. The hypothesis of this study is that the two-stage revision THA for PJI is associated with poorer outcomes as compared to aseptic revision THA.Centralised institutional review board has approved this study (CIRB: 2016/2422). This is retrospective study of prospectively collected data of a tertiary hospital arthroplasty registry. Seven adult reconstruction trained consultant orthopaedic surgeons within the hospital performed all of the revision THA operations for this study. During the 13 years study period between year 2001 and 2014, we identified patients who underwent revision THA with a minimum of 2 years follow-up. A total of 254 patients were identified for the study. The study group (two-stage revision THA for PJI) consists of 23 patients and the control group (one-stage revision THA for aseptic reasons) consists of 231 patients. Power analysis was performed to ensure that our study sample size is adequate. A total sample size required was 147 with an effect size of 0.3 and achieving a 95% power with an alpha risk of 5%. A larger sample for the aseptic revision THA was chosen to increase the power of the study.The two-staged revision THA for PJI will typically involve explanting the total hip implant with insertion of an articulating antibiotic cement spacer during the Stage 1 procedure. During the Stage 2 procedure, the antibiotic cement spacer will be removed and implantation of total hip implants for both the acetabular and femoral components will be performed.We evaluated patient demographics such as age, gender and body mass index (BMI), Charlson age-comorbidity index from the clinical records as well as database of the arthroplasty registry. Pre-operative baseline scores and postoperative scores were obtained at six-months and two years follow-up. For the PJI group, the pre-operative scores were obtained prior to the first-stage revision THA. Patient-reported outcome measures were assessed using a self-administered patient questionnaire that is given with a validated scoring system: Western Ontario and McMaster Universities Arthritis Index (WOMAC), Oxford Hip Score (OHS) and Short Form-36 (SF-36) Health Survey. The OHS is based on the 12 items on daily activities, and each item is scored from 1 - 5, with 1 representing the best outcome/least symptoms and 5 representing the worst outcome/most symptoms. The WOMAC scoring is based on higher scores indicating that the patient reports less pain, less stiffness and less functional limitations. Post-operatively at six months and two years, we also evaluated patients’ opinions as to whether the surgery met their expectations and whether they were satisfied with the results of their surgery using two questions adopted from the validated North American Spine Society (NASS) Questionnaire, which were (1) “Has the surgery met your expectations so far?” and (2) “How would you rate the overall results of surgery?”. For Question 1, patients had the choice of selecting from the following answers: (1) Yes, totally; (2) Yes, almost totally; (3) Yes, quite a bit; or (4) More or less; (5) No, not quite; (6) No, far from it or (7) No, not at all. For Question 2, patients had the choice of selecting from the following answers: (1) Excellent; (2) Very good; or (3) Good; (4) Fair; (5) Poor or (6) Terrible. Patients were defined as either having had their expectations met by their surgeries (responses to Question 1 = 1-4) or not having had their expectations met by their surgeries (responses to Question 1 = 5-7). Patients were defined as either satisfied (responses to Question 2 = 1-3) or dissatisfied (responses to Question 2 = 4-6). The mean follow-up range is 8.0 ± 3.7 (range 2-16) years for those with PJI two-staged revisions. The mean follow-up range is 6.0 ± 1.6 (range 2-13.2) years for those with aseptic revision THA. The continuous variables of our study were presented as mean ± standard deviation. Comparisons were made by use of unpaired t-test between the aseptic revision THA and revision THA for PJI groups. ANOVA was used to make comparisons between the pre-operative and post-operative follow-up clinical scores at six months and two years among the group. Z-score was used to compare categorical variables between the two groups, such as the gender and proportion of patients satisfied with their results of their surgery.For all analyses, statistical significance was defined as p-value of 0.05 or less. All statistical analysis was performed using SPSS version 23 .The pre-operative demographics of our patients are shown in . Both thThe pre-operative clinical scores for both groups of patients were compared . The preThe six months follow-up scores were compared between both groups of patients . At six The degrees of improvement for both groups of patients were compared at post-operative six months  and two 19. There are several modes of failure for the implanted hip leading to revision THA24. From our study, we report the following causes for revision THA in our patients: 72% were due to wear and aseptic loosening, 13.4% due to instability/dislocation, 2.8% due to component failure. 2.8% due to periprosthetic fracture and 9% due to PJI. From the literature24, early failures are often directly related to surgical technique, such as component malposition, soft tissue laxity leading to instability of the THA implant and operative field inoculation with bacteria causing deep infection and PJI. For late failures, aseptic loosening continues to represent a significantly predominant mode of failure for primary THA, accounting for approximately 52% of revision cases24.THA has been an extremely successful operation for symptomatic relief of end-stage hip arthritis, but a proportion of failures are inevitable29. The use of a spacer will allow a delay of several months between the two stages with a distinct advantage, since the control of deep-seated infection may sometimes require several months of post-operative antibiotic therapy29.The use of a two-stage exchange procedure with antibiotic-loaded cement for chronically infected THA together with the use of adjuvant antibiotic therapy has been successful in eradication of the infection with achievement of satisfactory outcomes29. As compared to aseptic revision THA, septic revision THA requires more costly medical treatment such as the need for long term intravenous antibiotic therapy, which has been reported to be approximately 2 to 2.8 times higher than that for aseptic THA31.Revision THA has its implications of burden of care for the healthcare system. The direct medical costs of revision THA for aseptic loosening was reported to be 4.8 folds higher than that of primary THA29 that have compared revision total knee arthroplasty (TKA) for septic versus aseptic reasons with conflicting results. Meek et al (2004)28 concluded that the two-stage exchange procedure for septic TKA provided comparable patient satisfaction and functional outcome . In a similar study by Patil et al (2010)29, patients who we operated on for septic revision TKA had better outcomes compared to those with aseptic revision TKA, with more improvement in their KSS (p=0.004) and Function Scores (p=0.02). It has been postulated that perhaps it is not that septic revisions are doing better than expected, but that the aseptic revisions may often do worse than it is presently assumed29. On the other hand, there have also been studies18 showing inferior results for septic revision arthroplasty as compared to aseptic revision arthroplasty. However, there is little literature available from prospective comparative studies about how quality of life, patient function and satisfaction rates compare between septic versus aseptic revision THA, which our study aims to contribute to the literature.There are several papers in the literature29. Aseptic revisions are often associated with severe bone defects from osteolysis or from periprosthetic fractures, making the reconstruction technically challenging. Revision surgeries for aseptic failures are also associated with problems of loss of soft tissue integrity resulting from recurrent dislocations or from wear debris meditated inflammatory osteolysis32. However, for revision THA due to PJI, the optimal outcomes are more dependent on the successful eradication of infection. In a two-staged revision THA for PJI, which has high success in bacteria eradication, with no recurrence of deep infection after re-implantation during stage two revision THA and lesser bone defect compared to aseptic revision THA, which could account for the better clinical outcome at two years follow-up.In our study, patients who underwent revision THA for PJI had poorer pre-operative functional scores (WOMAC function and SF-36 PF). However, at two years follow-up, the septic revision THA had “caught up” in their functional scores and both groups of patients had comparable postoperative outcomes. Interestingly, our patients who had revision THA for PJI also reported better clinical outcome in terms of OHS and WOMAC Pain score as compared to the aseptic group at two years follow-up. There was also a greater degree of improvement made for WOMAC , OHS, SF-36  for the patients who underwent revision THA for PJI at two years follow-up as compared to pre-operatively. This finding is similar to that of studies, which have shown that septic revision, arthroplasty provides better outcome than aseptic revision arthroplastyIn terms of patient-reported satisfaction, the patients in our study who underwent revision THA for PJI were equally satisfied compared to the aseptic revision THA patients. The relatively equal rates of patient satisfaction at two years follow-up could be correlated to both patients groups obtaining significant improvement in most aspects of the patient-reported outcome measures with good pain relief and functional outcome. However, a significantly larger proportion of patients did not have their expectations met by surgery in the group of patients who underwent revision THA for PJI as compared to the control group. This could be related to the more extensive, lengthy two-staged surgery required for bacteria eradication prior to re-implantation and also more costly overall medical treatment for two-staged revision THA for PJI. With a longer and more costly treatment for two-staged revision THA for PJI, a larger proportion of patients may not have their expectations met by the surgery, as compared to a one-staged aseptic revision THA. However, the authors acknowledge that the poorer expectation for the PJI group could reflect the weakness of the categorical survey questionnaire, which may not be responsive enough to truly measure the patients’ expectation of their surgery post-operatively for the two groups of non-homogenous patients.33.We report several limitations of our study. This is a retrospective study with a smaller number of patients with septic revision THA as compared to the number of patients with aseptic revision THA. The outcome follow-up period of two years is also relatively short and a more prolonged observation is required to provide information on the long-term outcome in these patients. However, it has been reported that the outcomes of revision THA will plateau at two years follow-up, and our study assumed that these patients with revision THA for aseptic and septic reasons had achieved their maximum clinical improvementWe conclude that revision THA achieved satisfactory functional outcomes and patient-reported satisfaction. In our study, revision THA for PJI achieved a better clinical outcome in terms of OHS and WOMAC Pain score as compared to aseptic revision THA at two years follow-up. There was also a greater degree of improvement made for WOMAC Score (Pain and function), SF-36  for the patients who underwent revision THA for PJI. In terms of patient-reported satisfaction and clinical outcomes, revision THA for PJI is not inferior to that of aseptic revision THA. A good outcome from revision for aseptic failures requires optimal management of bone loss and restoration of soft tissue balance. However, for revision THA in septic failures, the optimal outcomes are more dependent on the successful eradication of infection. We postulate in our study, that the smaller bone defect and no recurrence of deep infection requiring re-revision THA for the PJI patients, could have accounted for the greater degree of improvement and better clinical outcome as compared to aseptic revision THA at two years follow-up.


Objective: The purpose of this study was to elucidate the rapid impact of high-dose intravenous methylprednisolone pulse therapy  on the eventual visual prognosis in patients with serum anti-aquaporin-4 immunoglobulin G (AQP4-IgG)–positive neuromyelitis optica spectrum disorders (NMOSDs) who had an attack of optic neuritis (ON).Methods: Data from 32 consecutive NMOSD patients  with at least one ON attack, involving a total of 36 ON-involved eyes, were evaluated. The following variables at ON onset were evaluated: sex, age at the first ON episode, visual acuity at nadir, visual acuity after 1 year, duration from ON onset to treatment for an acute ON attack, cycles of high-dose intravenous methylprednisolone pulse therapy for the ON attack, and cycles of plasmapheresis for the ON attack. Among the 36 ON-involved eyes, 27 eyes were studied using orbital MRI with a short-T1 inversion recovery sequence and gadolinium-enhanced fat-suppressed T1 imaging before starting treatment in the acute phase.Results: In univariate analyses, a shorter duration from ON onset to the initiation of high-dose intravenous methylprednisolone pulse therapy favorably affected the eventual visual prognosis 1 year later . The lesion length on orbital MRI was also correlated with the eventual visual prognosis . Meanwhile, the days to steroid pulse therapy and lesion length on orbital MRI did not show a significant correlation. These findings suggest that the rapidness of steroid pulse therapy administration affects the eventual visual prognosis independent of the severity of ON. In multivariate analysis, a shorter time from ON onset to the start of acute treatment (p = 0.0004) and a younger age at onset (p = 0.0071) were significantly associated with better visual outcomes.Conclusions: Rapid initiation of high-dose intravenous methylprednisolone pulse therapy is essential to preserve the eventual visual acuity in patients with serum AQP4-IgG-positive NMOSD. Once clinicians suspect acute ON with serum AQP4-IgG, swift administration of steroid pulse therapy before confirming the positivity of serum AQP4-IgG would be beneficial for preserving visual function. Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune-related neurological disorder that primarily causes astrocytic damage throughout the central nervous system and is characterized by the presence of serum anti-aquaporin-4 immunoglobulin G (AQP4-IgG) , 2. PatiCompared with other demyelinating neurological disorders of the central nervous system, such as multiple sclerosis (MS) or anti-myelin oligodendrocyte glycoprotein antibody (MOG-IgG)-associated demyelination, neurological disability resulting from attacks of ON in NMOSD is known to be much more severe , 23, 24.As for the manifestation of ON, patients with MOG-IgG and those with AQP4-IgG often show similar appearance on orbital MRI, often with longitudinally extensive ON lesions and swollen optic nerves in the acute phase , but theA total of 32 consecutive patients with AQP4-IgG-positive NMOSD with at least one ON episode who became legally blind  at nadir in the acute phase were retrospectively studied. All patients were diagnosed and followed at a single university hospital in Japan between 1995 and 2019. Three other NMOSD patients whose VA at nadir was >20/200 were excluded because they had mild visual impairment; their inclusion may have biased the results. Positivity of serum AQP4-IgG and MOG-IgG was examined in all enrolled patients, and brain MRI and contrast-enhanced orbital MRI were performed to make an accurate diagnosis. There were no cases of double-positive AQP4-IgG and MOG-IgG. Only the first ON attack in each eye was evaluated; thus, relapsing ON episodes in each eye were not taken into consideration. Because four patients had ON attacks in both eyes (3 simultaneous and 1 asynchronous), a total of 36 ON-involved eyes in 32 NMOSD patients were evaluated in this study. A flow diagram of the subgroup classification according to the acute therapies is shown in At each occasion of ON attack , the following clinical information was comprehensively collected: sex, age, and medical history , details of the acute treatment for ON, serum AQP4-IgG titer, longitudinal length of ON lesions on orbital MRI before the acute treatments, corrected VA at nadir in the acute phase, corrected VA 1 year later in the chronic phase, the required days from the ON onset to starting the acute treatments with IVMP pulse therapy, and the required days from the ON onset to starting PLEX as an adjunctive therapy.Before starting the treatment, the longitudinal length of the ON lesion on orbital MRI was evaluated in 28 of the 36 ON episodes, which was semi-quantitatively represented by the number of involved segments in the following six areas of the optic nerves: anterior orbital, posterior orbital, canalicular, intracranial, chiasmal, and optic tract . InvolveCorrected VA was initially measured by decimal acuities and later converted to the logarithmic minimum angle of resolution (logMAR) scale because of its statistical usability . The logBefore the initiation of treatment, serum AQP4-IgG titer was evaluated in 27 of the 36 ON episodes with a microscopic live cell–based assay method, using human embryonic kidney 293 (HEK293) cells expressing the human M23-AQP4 protein and Alexa Fluor 488-conjugated secondary antibody  . The titp < 0.10) on the subsequent visual outcomes in the univariate analysis , data from untreated patients were tentatively set to 1,000 for visual convenience after log transformation. Because the correlations were evaluated with a non-parametric statistical method, this tentative numerical conversion did not affect the results of the statistical analyses. After evaluating the correlation between each explanatory variable and the subsequent visual outcomes, multiple regression analysis was performed by employing variables of particular clinical interest and additional variables that had a significant impact  was 44.4 ± 15.8 years. The median  of the serum AQP4-IgG titer was 1:8192 ; median (IQR) number of ON-involved optic nerve segments on orbital MRI was 3 segments (2–4 segments); median (IQR) days from ON onset to IVMP pulse therapy initiation was 9 days (4–33 days); median (IQR) number of cycles of IVMP pulse therapy in the acute phase was 2 cycles (1–2 cycles); and median (IQR) number of cycles of PLEX in the acute phase was 3 times (0–4 times). Six of the 32 patients had a clinical history of accompanying autoimmune-related diseases .Among the 36 ON-involved eyes from 32 patients, 32 ON-involved eyes from 29 patients were treated in the acute phase with high-dose IVMP pulse therapy  for 3 days, followed by low-dose oral prednisolone therapy for relapse prevention, whereas the remaining four ON episodes in three patients were not treated for unknown reasons. A single cycle of IVMP was administered to 11 ON-involved eyes from 10 patients, two cycles of IVMP were administered to six ON-involved eyes from 15 patients, and three cycles of IVMP were administered to five ON-involved eyes from four patients. Of the 32 ON-involved eyes from 29 patients who were treated with IVMP pulse therapy, 21 ON-involved eyes from 19 patients were later treated with adjunctive PLEX 3–6 times to achieve greater recovery in VA, and 1 of them was further treated with IVIg. Intravenous cyclophosphamide was not used in any of the enrolled subjects.p < 0.0001). The days from ON onset to starting IVMP pulse therapy also showed a moderate to strong positive correlation with the visual prognosis . Moreover, the AQP4-IgG titer , repeated cycles of IVMP pulse therapy , days from ON onset to starting PLEX , or cycles of PLEX  showed no significant correlation with the subsequent visual prognosis. The cycles of IVMP pulse therapy , days from ON onset to starting PLEX , or cycles of PLEX  showed no significant correlation with the subsequent visual outcomes even when being calculated within those who received these therapies.Correlation coefficients between the studied candidates of prognostic variables and the subsequent visual prognosis, represented by logMAR VA a year later, are listed in p = 0.0248, test of no correlation).To visually confirm the observed correlation between rapidity of treatment in the acute phase and the subsequent visual prognosis, scatter plots with these two variables are shown in p < 0.10 in the aforementioned univariate regression analyses. Consequently, the time from ON onset to the start of IVMP pulse therapy, cycles of IVMP pulse therapy, cycles of adjunctive PLEX, and age at ON onset were used as explanatory variables. The eventual VA after 1 year was used as the outcome variable. Shorter duration from ON onset to the start of IVMP pulse therapy  and younger age at ON onset  significantly contributed to better visual outcomes, whereas the number of cycles of IVMP  and adjunctive PLEX  did not. On removing the cycles of adjunctive PLEX from the explanatory variables, a shorter duration from ON onset to the start of IVMP pulse therapy  and younger age at ON onset  still significantly contributed to better visual outcomes, but the number of cycles of IVMP  did not.After univariate analyses, multiple regression analysis was additionally performed by employing demographic or therapeutic variables of particular clinical interest and further variables that showed p = 0.32, Mann–Whitney U-test).In addition to these clinical data at ON onset, the prognostic effect of other coexisting autoimmune-related diseases on eventual visual outcomes was also evaluated. The visual prognosis was suggested to be slightly worse in patients with other autoimmune-related diseases, but no statistically significant difference was observed , suggesting that early administration of high-dose IVMP is important to preserve the long-term visual outcomes irrespective of the addition of PLEX as an adjunctive therapy. Meanwhile, the calculated partial correlation coefficient between times of PLEX and visual prognosis was 0.184 (p = 0.29). Based on these results, early IVMP pulse therapy was suggested to be more important than the timing or total times of adjunctive PLEX to preserve the subsequent visual outcomes.Next, to exclude the possibility of confounding effect from PLEX to the prognostic impact of early IVMP pulse therapy, we calculated the partial correlation coefficient by using days from ON onset to start IVMP, times of performed PLEX, and visual outcomes at 1 year. As a result, the partial correlation coefficient between the rapidity of IVMP and visual outcomes was also statistically significant with the value of 0.567  in the acute phase of ON in patients with AQP4-IgG-positive NMOSD significantly improved the subsequent visual outcomes 1 year later. In line with our previous findings, the visual prognosis of ON in those with NMOSD was largely affected by the ON-lesion severity, which was represented by the number of ON-involved segments on orbital MRI in the acute phase . Moreoven = 156): IVMP + oral prednisone group (n = 151) and oral placebo group (n = 150). The result of ONTT was that patients in the IVMP + oral prednisone group showed significantly faster improvement of VA than those in the oral placebo group, but there was no significant difference in the subsequent visual outcomes between the groups both at 6 months and at 1 year. Based on these results, the general opinion among ophthalmologists and neurologists about the effectiveness of IVMP pulse therapy as an acute treatment for ON has long remained controversial. In 2004, a groundbreaking discovery came from a research group of Mayo Clinic that showed the presence of AQP4-IgG in the serum of patients who previously had “atypical” MS that exclusively presented recurrent ON and/or myelitis  was performed , 43. In myelitis –46. Aftemyelitis . Based oBased on the results obtained, we propose a possible therapeutic strategy for patients with undiagnosed ON, as shown in Intravenous administration is usually selected as the route of high-dose steroid  in the acute phase of ON, but oral administration of bioequivalent doses to high-dose IVMP may also be used as an alternative to IVMP . Meanwhip = 0.0348). Thus, apart from the previous article, the present study further reinforced the rationale of swift IVMP pulse therapy in the acute phase of AQP4-ON to preserve long-term visual outcomes. Lastly, this study failed to show the effectiveness of the rapidity and cycles of adjunctive PLEX in preserving long-term visual outcomes, but this does not contradict the effectiveness of PLEX in patients with AQP4-ON. The relatively small number of patients treated with adjunctive PLEX and possible tendency of patients who were refractory to IVMP pulse therapy to be administered adjunctive PLEX may explain why the rapidity and cycles of adjunctive PLEX failed to yield significant results in this study. Overall, a randomized trial is needed to conclude the effectiveness of adjunctive PLEX after IVMP pulse therapy in patients with AQP4-ON.As a limitation of this study, all enrolled patients with NMOSD were Asian. Further clinical studies are needed to determine whether the observed effectiveness of IVMP pulse therapy in the acute phase of AQP4-ON to improve long-term visual outcomes can be generalized to other ethnicities. In addition, because this study was performed in a retrospective manner, a randomized controlled trial with a pure cohort of AQP4-ON is desired in the future to establish high-level evidence of the impact of swiftly initiating IVMP pulse therapy in the acute phase of AQP4-ON. Furthermore, we did not consider visual field impairments in this study. As is well known, AQP4-ON patients often present with sectional visual field impairment, such as bitemporal or altitudinal hemianopia and non-central scotoma , and theIn patients with AQP4-IgG-positive NMOSD, swift administration of high-dose IVMP pulse therapy is recommended to preserve the subsequent long-term visual outcomes, even before obtaining the results of tests for serum AQP4-IgG positivity. Clinicians should consider immediate administration of IVMP pulse therapy in typical ON cases without waiting to confirm AQP4-IgG positivity, especially in female ON cases because of the female predominance in AQP4-ON.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Tohoku University School of Medicine. The patients/participants provided their written informed consent to participate in this study.TA drafted the article and created figures and tables. NH, TTake, and TN measured visual acuity at the nadir and 1 year later. TM, KF, and IN corrected MRI data. KF, MAo, TN, and IN supervised the study process. All authors contributed to the data review, interpretation of results, critical revision of article, and approval of final version of the article.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.


On the top of this, it exhibited a promising in vitro activity against SARS-CoV-2 strains though there are no published studies that substantiate its activity in vivo until the time of this review. There are few phase 3 randomized double-blind placebo controlled trials on the way to investigate the safety and efficacy of remdesivir. Of which, one completed double blind, placebo controlled trial showed that remdesivir showed faster time to clinical improvement in severe COVID-19 patients compared to placebo though not found statistically significant. In addition, two phase 3 randomized open label clinical trials coordinated by Gilead Sciences are being conducted. In addition, WHO Solidarity trial and INSERM DisCoVeRy trials (randomized open labels) were launched recently.The novel coronavirus strain, severe acute respiratory syndrome coronavirus-2, the causative agent of COVID-19 emerged in Wuhan, China, in December 2019 and is skyrocketing throughout the globe and become a global public health emergency. Despite promising preventive measures being taken, there is no vaccine or drug therapy officially approved to prevent or treat the infection. Everybody is waiting the findings of ongoing clinical trials in various chemical and biological products. This review is specifically aimed to summarize the available evidence and ongoing clinical trials of remdesivir as a potential therapeutic option for COVID-19. Remdesivir is an investigational drug having broad spectrum antiviral activity with its target RNA dependent RNA polymerase. It has not yet been officially approved for Ebola and Coronaviruses. Several studies showed that remdesivir had promising  Coronaviruses, belonging to the family Coronaviridae, are positive-sense enveloped RNA viruses that cause infections in humans . The famhttp://www.chictr.org.cn/index.aspx and https://clinicaltrials.gov/ct2/home).As per the World Health Organization (WHO) report, the total number of cases and deaths outside China has overtaken the total number of cases in China . WHO hasAmong the above-mentioned classes of antiviral counterparts, aminoquinolines (chloroquine and its hydroxyl derivative) and protease inhibitors (primarily lopinavir/ritonavir) have taken the largest share of clinical trials since the SARS-CoV-2 outbreak. However, their clinical benefit has become full of controversies according to the various research findings.With regard to the aminoquinolines and their role in COVID-19 therapy, in an open-label non-randomized clinical trial, Gautret et al. reported 100% viral clearance in nasopharyngeal swabs with combination of hydroxychloroquine and azithromycin, 57.1% in hydroxychloroquine group, and 12.5% in standard of care group in cohort of 6 patients after 5 to 6 days follow-up . In addiA randomized, open label clinical trial conducted on protease inhibitors (lopinavir/ritonavir) indicated that treatment with lopinavir/ritonavir did not show statistically significant difference in the time to clinical improvement and mortality censored at day 28 though a secondary outcomes measures were found promising in lopinavir/ritonavir group . This trRemdesivir is one of the frontline medications being used as expanded access and is under extensive clinical investigation. Hereafter, this review aims to address the viral polymerase inhibitor remdesivir as a potential therapeutic option for COVID-19.f][triazin-4-amino] adenine C-nucleoside having broad spectrum antiviral activity (Remdesivir (GS-5734™) is a phosphoramidate prodrug of a Pyrrolo[2,1-activity . It is sactivity . Studiesactivity . Though,activity , Gilead activity .in vitro  administration of remdesivir significantly reduced pulmonary viral load and improved respiratory function and other clinical signs of the disease . LikewisAccording to the paper published at the New England Journal of Medicine on 05 March, 2020, it had been suggested that remdesivir might be a potential therapeutic option for the therapy of COVID-19 patients. In the report, remdisivir intravenous infusion (compassionate use) was started on day 7 in COVID-19 patient. During the treatemnt, no adverse events were observed in association with the IV infusion. The patient's clinical condition improved. The bilateral lower-lobe rales apeared initially were no longer present. His appetite improved, became afebrile and asymptomatic except intermittent dry cough and rhinorrhea . HoweverAs summarized in With the coordination of China-Japan Friendship Hospital, two phase 3 randomized, double blind, placebo controlled clinical trials were intiated in China to evaluate the safety and efficacy of remdesivir paralleled to palcebo therapy.The first phase 3 trial has already involved 308 hospitalized adult patients with mild to moderate cases of COVID-19 . The patWith the coordination of the U.S. National Institute of Allergy and Infectious Diseases (NIAID), Another phase 3 adaptive, randomized, double blind, placebo controlled clinical trial enrolled 394 hospitalized patients with COVID-19 to assess the safety and efficacy of remdesivir. In this trial, patients were randomized to either placebo or 10 days therapy with remdesivir . The primary indicator in this trial is the percentage of patients reporting each severity rating on the 7-point ordinal scale within 15 days  , remdesivir is also provided as expanded access (compassionate use)  through https://clinicaltrials.gov/ct2/show/NCT04315948. The recruiting of participants has not been started but estimated to enroll 3,200 patients in 4 arms in which remdesivir alone is to be provided in usual dosage regimen in one of the interventional arms.On the top of this, WHO has initiated Solidarity trial at global level to evaluate the safety and efficacy of remdesivir in one of the interventional arms . Likewisin vitro, there is no published in vivo study that substantiates the in vitro activities against this global public health threat. A case report and observational studies are not sufficient to generate evidenced-based medicine on the clinical use of remdesivir for this pandemic. A double blind, placebo controlled randomized clinical trial showed that remdesivir did not have statistically significant clinical benefit in reducing the time to clinical improvement in severe COVID-19 patients compared to placebo. Though remdesivir is readily available for compassionate use in many countries, it is imperative to wait the remaining ongoing clinical trials to justify its clinical utility on larger cohort of COVID-19 patients.Despite the promising effects of remdesivir against previous beta-coronaviruses as well as the current novel coronaviruses The author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


More than 1,200 active or recruiting clinical trials for novel coronavirus disease 2019 (COVID-19) treatments and vaccines are registered. Many drugs have shown promise for treatment of COVID-19. Nevertheless, up to date, no drugs have been confirmed as a definitive treatment for COVID-19. Trials such as the SOLIDARITY and RECOVERY are ongoing, and first results were announced in favour of therapy with dexamethasone with a significant trend showing greatest benefit among those patients requiring ventilation. The drawbacks of these trials include exposing the patients to drugs with well-documented systemic adverse effects or unknown complications of novel therapies without proof of clinical benefit. We present here the hypothesis that bronchial artery infusion could be an alternative for systemic drug infusion in COVID-19 trials with superadded benefits of high drug concentration and low systemic adverse effects. The concept of this idea has many uncertainties and no current clinical data to support. Perhaps, the technique should be first applied in animal models to determine its safety and calculate the effective dose of the drugs. Guidelines and reviews of pharmacotherapy for COVID-19 should be implemented for this fiction to come true. COVID-19 is a global pandemic.Many active clinical trials of COVID-19 treatments and vaccines are registered.Bronchial artery infusion (BAI) could be an alternative for systemic drug infusion in COVID-19 trials.The novel coronavirus disease 2019 (COVID-19) is a highly infectious disease caused by a severe acute respiratory syndrome coronavirus (SARS-CoV-2) which started in Wuhan, China, in December 2019. The World Health Organization (WHO) declared COVID-19 a global pandemic on March 11, 2020 [More than 1,200 active or recruiting clinical trials for COVID-19 treatments and vaccines are registered . SeveralOn March 20, 2020, the WHO and partners announced the SOLIDARITY trial . The SOLp < 0.001) [The “Randomized evaluation of COVID-19 therapy” (RECOVERY) trial  is anoth< 0.001) . The drabronchial artery infusion could be an alternative for systemic drug infusion in COVID-19 trials with superadded benefits of high drug concentration and low systemic adverse effects. Studies demonstrated that the bronchial artery is the main feeding artery for lung tumours. Hence, bronchial artery infusion is used as a palliative treatment option for primary and metastatic lung cancers [Based on the first-pass effect of transcatheter therapy, we can hypothesise that  cancers . Additio cancers .However, the situation is different for COVID-19 as the exact pathophysiologic mechanism of ground-glass opacities is still unclear, and the possibility of being fed by bronchial arteries is not proven as in case of lung neoplasms. Furthermore, the blood flow into the lung in cases of pneumonia might be reduced as reported before in experimental animals . The othThe search for successful therapies for COVID-19 infection is a challenging process. To the best of our knowledge, no previous reports or registered trial was proposing the transcatheter drug delivery through the bronchial artery to treat COVID-19. Proposed drugs for transcatheter therapy are drugs evaluated by SOLIDARITY and RECOVERY trials in addition to anticoagulant therapy that were associated with a better outcome.The concept of this idea has many uncertainties and no current clinical data to support. Perhaps, the technique should be first applied in animal models to determine its safety and calculate the effective dose of the drugs. Guidelines and reviews of pharmacotherapy for COVID-19 should be implemented for this fiction to come true.