Immunologic risk stratification of pediatric heart transplant patients by combining HLA-EMMA and PIRCHE-II.

Human leukocyte antigen (HLA) molecular mismatch is a powerful biomarker of rejection. Few studies have explored its use in assessing rejection risk in heart transplant recipients. We tested the hypothesis that a combination of HLA Epitope Mismatch Algorithm (HLA-EMMA) and Predicted Indirectly Recognizable HLA Epitopes (PIRCHE-II) algorithms can improve risk stratification of pediatric heart transplant recipients. Class I and II HLA genotyping were performed by next-generation sequencing on 274 recipient/donor pairs enrolled in the Clinical Trials in Organ Transplantation in Children (CTOTC). Using high-resolution genotypes, we performed HLA molecular mismatch analysis with HLA-EMMA and PIRCHE-II, and correlated these findings with clinical outcomes. Patients without pre-formed donor specific antibody (DSA) (n=100) were used for correlations with post-transplant DSA and antibody mediated rejection (ABMR). Risk cut-offs were determined for DSA and ABMR using both algorithms. HLA-EMMA cut-offs alone predict the risk of DSA and ABMR; however, if used in combination with PIRCHE-II, the population could be further stratified into low-, intermediate-, and high-risk groups. The combination of HLA-EMMA and PIRCHE-II enables more granular immunological risk stratification. Intermediate-risk cases, like low-risk cases, are at a lower risk of DSA and ABMR. This new way of risk evaluation may facilitate individualized immunosuppression and surveillance.

From transabdominal to totally extra-peritoneal robotic ventral hernia repair: observations and outcomes.

PURPOSE: While robotic-assisted hernia repair has increased the popularity of minimally invasive hernia surgery, selecting between the types of approaches is a challenge for both experts and novices alike. In this study, we compared a single surgeon's early experience transitioning from transabdominal hernia repair with sublay mesh in either the pre-peritoneal or retrorectus space (TA-SM) and enhanced-view totally extra-peritoneal (eTEP) ventral hernia repair in the peri-operative and long-term post-operative time periods. METHODS: We conducted a retrospective review of 50 eTEP and 108 TA-SM procedures to collect demographics, intraoperative details, and 30-day and 1-year post-operative outcomes. Statistical analysis was performed utilizing Chi-square analysis, Fisher's test, and two sample t-tests with equal variances. RESULTS: There were no significant differences in patient demographics or comorbidities. eTEP patients had larger defects (109.1 cm2 vs. 31.8 cm2, p = 0.043) and mesh used (432.8 cm2 vs. 137.9 cm2, p = 0.001). Operative times were equivalent (158.3 ± 90.6 min eTEP and 155.8 ± 65.2 min TA-SM, p = 0.84), but conversion to alternate procedure type was higher for the transabdominal approach (4% eTEP vs. 22% TA-SM, p < 0.05). Hospital stay was less in the eTEP cohort (1.3 days vs. 2.2 days, p < 0.05). Within 30 days, there were no significant differences in emergency visits or hospital readmissions. There was a greater propensity for eTEP patients to develop seromas (12.0% vs. 1.9%, p < 0.05). At 1 year, there was no statistically significant difference in recurrence rate (4.56% eTEP vs. 12.2% TA-SM, p = 0.28) respective to average time to recurrence (9.17 months eTEP vs. 11.05 months TA-SM). CONCLUSION: The eTEP approach can be adopted safely and efficiently, and may have superior peri-operative outcomes including fewer conversions and reduced hospital stay.

Identification of a promising inhibitor from Illicium verum (star anise) against the main protease of SARS-CoV-2: insights from the computational study.

SARS-CoV-2, the causing agent of coronavirus disease (COVID-19), first broke out in Wuhan and rapidly spread worldwide, resulting in a global health emergency. The lack of specific drugs against the coronavirus has made its spread challenging to control. The main protease (Mpro) is a key enzyme of SARS-CoV-2 used as a key target in drug discovery against the coronavirus. Medicines derived from plant phytoconstituents have been widely exploited to treat various diseases. The present study has evaluated the potential of Illicium verum (star anise) phytoconstituents against Mpro by implementing a computational approach. We performed molecular docking and molecular dynamics simulation study with a set of 60 compounds to identify their potential to inhibit the main protease (Mpro) of SARS-CoV-2. DFT study and post dynamics free energy calculations were also performed to strengthen the findings. The identified four compounds by docking study exhibited the highest potential compared to other selected phytoconstituents. Further, density functional theory (DFT) calculation, molecular dynamics simulation and post dynamics MM-GBSA energy calculation predicted Verimol-G as a potential compound, which formed stable interactions through the catalytic dyad residues. The HOMO orbital energy (-0.250038) from DFT and the post dynamics binding free energy calculation (-73.33 Kcal/mol) correlate, suggesting Verimol-G is the best inhibitor compared to the other phytoconstituents. This compound also complies with the ADME properties of drug likeliness. Thus, based on a computational study, we suggest that Verimol G may be developed as a potential inhibitor against the main protease to combat COVID-19.Communicated by Ramaswamy H. Sarma.

Lactoferrin, a potential iron-chelator as an adjunct treatment for mucormycosis - A comprehensive review.

Mucormycosis is a deadly infection which is caused by fungi of the order Mucorales including species belonging to the genus Rhizopus, Mucor, Mycocladus, Rhizomucor, Cunninghamella, and Apophysomyces. Despite antifungal therapy and surgical procedures, the mortality rate of this disease is about 90-100% which is exceptionally high. The hypersensitivity of patients with raised available serum iron indicates that the Mucorales are able to use host iron as a critical factor of virulence. This is because iron happens to be a crucial element playing its role in the growth of cells and development. In this review, we have described Lactoferrin (Lf) as a potential iron-chelator. Lf is a naturally occurring glycoprotein which is expressed in most of the biological fluids. Moreover, Lf possesses exclusive anti-inflammatory effects along with several anti-fungal effects that could prove to be helpful to the pathological physiology of inexorable mucormycosis cases. This literature summarises the biological insights into the Lf being considered as a potential fungistatic agent and an immune regulator. The review also proposes that unique potential of Lf as an iron-chelator can be exploited as the adjunct treatment for mucormycosis infection.

Comparison of peak wall stress and peak wall rupture index in ruptured and asymptomatic intact abdominal aortic aneurysms.

BACKGROUND: Previous studies have suggested that finite element analysis (FEA) can estimate the rupture risk of an abdominal aortic aneurysm (AAA); however, the value of biomechanical estimates over measurement of AAA diameter alone remains unclear. This study aimed to compare peak wall stress (PWS) and peak wall rupture index (PWRI) in participants with ruptured and asymptomatic intact AAAs. METHODS: The reproducibility of semiautomated methods for estimating aortic PWS and PWRI from CT images was assessed. PWS and PWRI were estimated in people with ruptured AAAs and those with asymptomatic intact AAAs matched by orthogonal diameter on a 1 : 2 basis. Spearman's correlation coefficient was used to assess the association between PWS or PWRI and AAA diameter. Independent associations between PWS or PWRI and AAA rupture were identified by means of logistic regression analyses. RESULTS: Twenty individuals were included in the analysis of reproducibility. The main analysis included 50 patients with an intact AAA and 25 with a ruptured AAA. Median orthogonal diameter was similar in ruptured and intact AAAs (82·3 (i.q.r. 73·5-92·0) versus 81·0 (73·2-92·4) mm respectively; P = 0·906). Median PWS values were 286·8 (220·2-329·6) and 245·8 (215·2-302·3) kPa respectively (P = 0·192). There was no significant difference in PWRI between the two groups (P = 0·982). PWS and PWRI correlated positively with orthogonal diameter (both P < 0·001). Participants with high PWS, but not PWRI, were more likely to have a ruptured AAA after adjusting for potential confounders (odds ratio 5·84, 95 per cent c.i. 1·22 to 27·95; P = 0·027). This association was not maintained in all sensitivity analyses. CONCLUSION: High aortic PWS had an inconsistent association with greater odds of aneurysm rupture in patients with a large AAA.

Robotic ventral hernia repair: a safe and durable approach.

BACKGROUND: Short-term success following robotic-assisted ventral hernia repair (RVHR) is well established; however, data describing outcomes after the first year are limited. In this study, we followed a cohort of patients with an average of 1.8 years of follow-up to demonstrate the durability of this technique and examine risk factors for recurrence. METHODS: A retrospective analysis of RVHR performed by a single surgeon from 2012 to 2016 was done. The technical approach for hernia repair consisted of tension-free primary fascial closure with placement of preperitoneal mesh when possible. The primary end point of hernia recurrence was determined based on physical examination or imaging documented in the medical record. A logistic regression model was used to identify patient risk factors for recurrence. RESULTS: One hundred and eight RVHRs were performed over 4 years. Mean age was 52.72 ± 13.61 years, BMI was 33.07 ± 7.82 kg/m2, and hernia defect size was 70.1 ± 86.3 cm2. In terms of patient characteristics, 17.6% of patients were diabetic, 13.9% were smokers preoperatively, 72.2% were ASA class 3 or higher, and 29.6% had prior VHR. Primary fascial closure was achieved in all RVHRs, with 23.1% requiring component separation. Mesh was used in 97.2% of patients: 79.5% had preperitoneal mesh and 17.6% had intraperitoneal onlay mesh. Ninety-eight percent of patients had long-term follow-up at a mean of 625.6 days. Recurrence rate was 12%, with one recurrence attributed to an inguinal hernia fixed concurrently with a midline defect. There were no statistically significant differences in gender, age, BMI, ASA class, incidence of diabetes, smoking status, or number of previous hernia repairs. Hernia defect size and perioperative complications including SSO, ileus, obstruction, or any other medical complication were not predictive of recurrence. Technical approach did not affect outcomes. CONCLUSION: RVHR is safe and durable with a low recurrence rate at a mean of 21 months postoperatively. Patient characteristics or type of repair were not predictive of recurrence.

Biophysical Characterization of Type III Pantothenate Kinase (PanK) from Acinetobacter baumannii.

BACKGROUND: Type-III Pantothenate kinase from the multi drug resistant bacteria, Acinetobacter baumannii (AbPanK) catalyzes the first step of the essential Coenzyme A biosynthesis pathway. AbPanK is an attractive drug target against the bacteria since it is an essential enzyme and its structure is significantly different from the human PanK. METHODS: AbPanK was cloned, expressed, purified and crystallized. A good quality single crystal was used for X-ray intensity data collection. Dynamic light scattering was done for calculating the hydrodynamic radii and its oligomeric nature in the solution. Binding studies of this protein with its two substrates, Pantothenate and ATP were done using spectrofluorometer. RESULTS: Our results indicated that AbPanK shows a strong affinity with pantothenate with dissociation constant of 1.2 x 10- 8 M and moderate affinity towards ATP of 3.7x 10-3 M. This fact was further substantiated by the calculations of Km of both substrates using kinase assay kit. Dynamic light scattering studies have shown that it exists as homogenous solution with hydrodynamic radii corresponding to the molecular weight of 29.55 kDa. A low-resolution X-ray intensity data set was collected, which shows that AbPank crystallizes in P2 space group with cell dimensions of a= 165 Å, b= 260 Å, and, c= 197 Å and α= 90.0, ß= 113.60, γ= 90.0. DISCUSSION: Recombinant Pantothenate kinase from Acinetobacter baumannii was purified to homogeneity and crystallized. The enzyme exhibits very low sequence identity (28%) to other corresponding enzymes. CONCLUSION: The recombinant enzyme was active and its binding affinities with its substrates pantothenate and ATP have been studied. This information would be very useful while designing the inhibitors of this enzyme in order to fight bacterial infections associated to this pathogen.

Identification of potential drug candidates to combat COVID-19: a structural study using the main protease (mpro) of SARS-CoV-2.

The recent outbreak of the SARS-CoV-2 virus leading to the disease COVID 19 has become a global pandemic that is spreading rapidly and has caused a global health emergency. Hence, there is an urgent need of the hour to discover effective drugs to control the pandemic caused by this virus. Under such conditions, it would be imperative to repurpose already known drugs which could be a quick and effective alternative to discovering new drugs. The main protease (Mpro) of SARS-COV-2 is an attractive drug target because of its essential role in the processing of the majority of the non-structural proteins which are translated from viral RNA. Herein, we report the high-throughput virtual screening and molecular docking studies to search for the best potential inhibitors against Mpro from FDA approved drugs available in the ZINC database as well as the natural compounds from the Specs database. Our studies have identified six potential inhibitors of Mpro enzyme, out of which four are commercially available FDA approved drugs (Cobicistat, Iopromide, Cangrelor, and Fortovase) and two are from Specs database of natural compounds (Hopeaphenol and Cyclosieversiodide-A). While Cobicistat and Fortovase are known as HIV drugs, Iopromide is a contrast agent and Cangrelor is an anti-platelet drug. Furthermore, molecular dynamic (MD) simulations using GROMACS were performed to calculate the stability of the top-ranked compounds in the active site of Mpro. After extensive computational studies, we propose that Cobicistat and Hopeaphenol show potential to be excellent drugs that can form the basis of treating COVID-19 disease.Communicated by Ramaswamy H. Sarma.

Identification of promising drug candidates against NSP16 of SARS-CoV-2 through computational drug repurposing study.

The recent outbreak of the SARS-CoV-2 virus leading to the disease COVID 19, a global pandemic has resulted in an unprecedented loss of life and economy worldwide. Hence, there is an urgent need to discover effective drugs to control this pandemic. NSP16 is a methyltransferase that methylates the ribose 2'-O position of the viral nucleotide. Taking advantage of the recently solved structure of NSP16 with its inhibitor, S-Adenosylmethionine, we have virtually screened FDA approved drugs, drug candidates and natural compounds. The compounds with the best docking scores were subjected to molecular dynamics simulations followed by binding free energy calculations using the MM-PBSA method. The known drugs which were identified as potential inhibitors of NSP16 from SARS-CoV-2 included DB02498, DB03909, DB03186, Galuteolin, ZINC000029416466, ZINC000026985532, and ZINC000085537017. DB02498 (Carba-nicotinamide-adenine-dinucleotide) is an approved drug which has been used since the late 1960s in intravenous form to significantly lessen withdrawal symptoms from a variety of drugs and alcohol addicts and it has the best MM-PBSA binding free energy of-12.83 ± 0.52 kcal/mol. The second best inhibitor, Galuteolin is a natural compound that inhibits tyrosinase enzyme with MM-PBSA binding free energy value of -11.21 ± 0.47 kcal/mol. Detailed ligand and protein interactions were analyzed and common residues across SARS-CoV, SARS-CoV-2, and MERS-CoV were identified. We propose Carba-nicotinamide-adenine-dinucleotide and Galuteolin as the potential inhibitors of NSP16. The results in this study can be used for the treatment of COVID-19 and can also form the basis of rational drug design against NSP16 of SARS-CoV-2.

Studying land use dynamics using decadal satellite images and Dyna-CLUE model in the Mahanadi River basin, India.

Population growth rate indicates the proportional rate of settlement expansion and landscape modification in any river basin. The Mahanadi River basin (MRB), which is a densely populated, cropland and forest-dominated landscape, is selected as a case study area for studying the nature of built-up expansion and the corresponding land cover modifications. Satellite data-derived land use/land cover (LU/LC) maps for the years 1995, 2005, and 2015 were used for identification of landscape changes during the past three decades. One of the major LU/LC changes are observed in terms of increase in the water, which may be attributed to construction of new dams at the cost of the croplands and forest areas. Conversion of forest to cropland and expansion and densification of built-up areas in and around the existing built-up areas are also identified as a major LU/LC change. The geostatistical analysis was performed to identify the relationship between LU/LC classes with drivers, which showed that built-up areas were more in topographically flat terrain with higher soil depth, and expanded more around the existing built-up areas; cropland areas were more at lower elevation and less sloppy terrain, and forest areas were more at higher elevation. The LU/LC scenario of 2025 was projected using a spatially explicit dynamic conversion of land use and its effects (Dyna-CLUE) modeling platform with the LU/LC change trends of past 10 years (2005-2015) and 20 years (1995-2015). The major LU/LC changes observed during 2005-2015 were built-up expansion by 36.53% and deciduous forest and cropland reduction by 0.35% and 0.45%, respectively. Thus, the corresponding predicted change during 2015-2025 estimated built-up expansion by 25.70% and deciduous forest and croplands loss by 0.43% and 0.35%, respectively. On the other hand, during 1995 to 2015, the total built-up expansion and deciduous forest and cropland reduction were observed 50.79%, 0.45%, and 0.73%, respectively. Thus, the predicted changes during 2015-2025 were estimated as 18.48% built-up expansion and 0.22% and 0.21% deciduous forest and cropland loss. However, with the conditions of restricted deforestation and less landscape modification, the LU/LC projections show less built-up area expansion, reducing the cropland, fallow land, plantation, and waste land. The reduced numbers of land cover conversions types during 2005-2015 compared with 1995-2005 indicate more stabilized landscape. The input LU/LC maps and statistical analysis demonstrated the landscape modifications and causes observed in the basin. The model projected LU/LC maps are giving insights to possible changes under multiple pathways, which will help the agriculture, forest, urban, and water resource planners and managers in improved policy-making processes.

Structural and biochemical studies of phosphopantetheine adenylyltransferase from Acinetobacter baumannii with dephospho-coenzyme A and coenzyme A.

Phosphopantetheine adenylyl transferase catalyzes a rate limiting penultimate step of the multistep reaction which produces coenzyme A (CoA) as a final product. CoA is required as an essential cofactor in a number of metabolic reactions. Therefore inhibiting the function of this enzyme will lead to cell death in bacteria. Acinetobacter baumannii is multi drug resistant pathogen and causes infections in immunocompromised patients. AbPPAT has been cloned, expressed, purified and crystallized and structures of two complexes of AbPPAT with dephospho coenzyme A (dPCoA) and coenzyme A (CoA) have been determined. Both dPCoA and CoA molecules are observed in the substrate binding site of AbPPAT. A comparison with the structures of the complexes of PPAT from other species shows that the orientations of dPCoA are identical in all the structures. On the other hand, as observed from the structures of the complexes of CoA with PPAT, the orientations of CoA are found to differ considerably. This shows that the substrates occupy identical positions in the substrate binding sites of enzymes whereas the positions of inhibitors may differ. The binding studies carried out using fluorescence method and surface plasmon resonance techniques showed that binding affinity of CoA towards AbPPAT is nearly three times higher than that of dPCoA.

Lack of an effective drug therapy for abdominal aortic aneurysm.

Abdominal aortic aneurysm (AAA) rupture is a common cause of death in adults. Current AAA treatment is by open surgical or endovascular aneurysm repair. Rodent model and human epidemiology, and genetic and observational studies over the last few decades have highlighted the potential of a number of drug therapies, including medications that lower blood pressure, correct dyslipidaemia, or inhibit thrombosis, inflammation or matrix remodelling, as approaches to managing small AAA. This review summarizes prior AAA pathogenesis data from animal and human studies aimed at identifying targets for the development of drug therapies. The review also systematically assesses past randomized placebo-controlled drug trials in patients with small AAAs. Eleven previously published randomized-controlled clinical trials testing different drug therapies aimed at slowing AAA progression were identified. Five of the trials tested antibiotics and three trials assessed medications that lower blood pressure. Meta-analyses of these trials suggested that neither of these approaches limit AAA growth. Allocation to blood pressure-lowering medication was associated with a small reduction in AAA rupture or repair, compared to placebo (relative risk 0.94, 95% confidence intervals 0.89, 1.00, P = 0.047). Three further trials assessed the effect of a mast cell inhibitor, fibrate or platelet aggregation inhibition and reported no effect on AAA growth or clinical events. Past trials were noted to have a number of design issues, particularly small sample sizes and limited follow-up. Much larger trials are needed to properly test potential therapeutic approaches if a convincingly effective medical therapy for AAA is to be identified.

Inhibition of human 3-hydroxy-3-methylglutaryl CoA reductase by peptides leading to cholesterol homeostasis through SREBP2 pathway in HepG2 cells.

In mammalian cells, human 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), a rate-limiting endoplasmic reticulum (ER) bonded enzyme, plays a central role in the cholesterol homeostasis via the negative feedback mechanism. The present study indicates that the interactions of novel peptides with the catalytic domain of HMGCR, provides an alternative therapeutic candidate for reducing cholesterol. The potential natural origin of HMGCR peptide inhibitors were filtered from the peptide library using the molecular docking, which revealed three strong candidates for inhibition. This information was used for synthesizing peptides, which were evaluated for inhibition against HMGCR. The stronger docking interactions were confirmed by experimental dissociation constant (KD) values of 9.1 × 10-9 M, 1.4 × 10-8 M and 1.2 × 10-8 M for peptides NALEPDNRIESEGG (Pep-1), NALEPDNRIES (Pep-2) and PFVKSEPIPETNNE (Pep-3) respectively. The immunological based interactions show a strong evidence of peptide-HMGCR complexes. The LDL uptake showed enhancements after treatments with peptides in the extracellular environment of HepG2 cells, which was further, corroborated through increase in the immunofluorescence signal of the localized LDL-R protein expression on the cell membrane. The results showed that the mRNA and protein expression of transcription factors were significantly up-regulated showing regulation of cholesterol biosynthesis in peptide treated HepG2 cells. The binding of transcription factors, sterol regulatory element (SRE) and cAMP-response element (CRE) on HMGCR promotor further confirms the cholesterol biosynthesis regulation. All the above results suggested a key role of peptide/s in alleviating cholesterol accumulation in tissue via inhibition of rate-limiting HMGCR enzyme.

Systematic review and meta-analysis of clinical trials examining the effect of hyperbaric oxygen therapy in people with diabetes-related lower limb ulcers.

AIM: To examine the efficacy of hyperbaric oxygen therapy in healing diabetes-related lower limb ulcers through a meta-analysis of randomized clinical trials. METHODS: A literature search was conducted to identify appropriate clinical trials. Inclusion required randomized study design and reporting of the proportion of diabetes-related lower limb ulcers that healed. A meta-analysis was performed to examine the effect of hyperbaric oxygen therapy on ulcer healing. The secondary outcomes were minor and major amputations. RESULTS: Nine randomized trials involving 585 participants were included. People allocated to hyperbaric oxygen therapy were more likely to have complete ulcer healing (relative risk 1.95, 95% CI 1.51-2.52; P<0.001), and less likely to require major (relative risk 0.54, 95% CI 0.36-0.81; P=0.003) or minor (relative risk 0.68, 95% CI 0.48-0.98; P=0.040) amputations than control groups. Sensitivity analyses suggested the findings were dependent on the inclusion of one trial. Adverse events included ear barotrauma and a seizure. Many of the trials were noted to have methodological weaknesses including absence of blinding of outcome assessors, lack of a justifiable sample size calculation and limited follow-up. CONCLUSIONS: This meta-analysis suggests hyperbaric oxygen therapy improves the healing of diabetes-related lower limb ulcers and reduces the requirement for amputation. Confidence in these results is limited by significant design weaknesses of previous trials and inconsistent findings. A more rigorous assessment of the efficacy of hyperbaric the efficacy of hyperbaric oxygen therapy is needed.

Structural and binding studies of phosphopantetheine adenylyl transferase from Acinetobacter baumannii.

Phosphopantetheine adenylyltransferase (PPAT, EC. 2.7.7.3) catalyzes an essential step in the reaction that transfers an adenylyl group from adenosine tri phosphate (ATP) to 4'-phosphopantetheine (pPant) yielding 3'- dephospho-coenzyme A (dPCoA) and pyrophosphate (PP) in the coenzyme A (CoA) biosynthesis pathway. The enzyme PPAT from Acinetobacter baumannii (AbPPAT) was cloned, expressed and purified. The binding studies of AbPPAT were carried out with two compounds, tri­sodium citrate (TSC) and l-ascorbic acid (LAA, vitamin-C) using fluorescence spectroscopic (FS) and surface Plasmon resonance (SPR) methods. Both methods provided similar values of dissociation constants for TSC and LAA which were of the order of 10-8 M and 10-5 M respectively. The computer aided docking studies indicated fewer interactions of LAA with AbPPAT as compared to those of TSC. The freshly purified samples of AbPPAT were crystallized. The crystals of AbPPAT were soaked in the solutions containing TSC and LAA. However, the crystals of the complex of AbPPAT with LAA did not diffract well and hence the structure of the complex of AbPPAT with LAA could not be determined. On the other hand, the crystals of the complex of AbPPAT with TSC diffracted well and the structure was determined at 1.76 Šresolution. It showed that TSC bound to AbPPAT at the ATP binding site and formed several intermolecular contacts including 12 hydrogen bonds. The results of binding studies for both TSC and LAA and the structure of the complex of AbPPAT with TSC clearly indicated a potential role of TSC and LAA as antibacterial agents.

Meta-analysis of clinical trials examining the benefit of structured home exercise in patients with peripheral artery disease.

BACKGROUND: Supervised exercise is recommended for the management of peripheral artery disease (PAD); however, the uptake is limited. Structured home exercise programmes may be more feasible, but their effectiveness is unclear. This systematic review and meta-analysis examined the benefit of structured home exercise programmes for treating PAD in comparison to controls not receiving an exercise programme. METHODS: A literature search was conducted to identify RCTs comparing structured home exercise with controls not receiving an exercise programme among patients with PAD. To be included, studies had to report outcomes from treadmill or corridor walking tests, or objective assessment of physical activity. Inverse variance-weighted meta-analysis was performed to compare changes in maximum walking distance and intermittent claudication onset distance in treadmill tests, walking distance during a 6-min walking test, and physical activity measured using a pedometer or accelerometer. Summarized results are presented in terms of standard deviation differences. RESULTS: Eleven randomized trials involving 807 patients were included. Follow-up ranged from 2 to 24 months; only one trial included follow-up beyond 12 months. Meta-analyses showed that structured home exercise programmes led to significant improvements in maximum walking distance (mean difference (MD) 0·32, 95 per cent c.i. 0·15 to 0·50; P < 0·001), intermittent claudication onset distance (MD 0·45, 0·27 to 0·62; P < 0·001), walking distance in a 6-min walking test (MD 0·28, 0·09 to 0·47; P = 0·004) and physical activity (MD 0·27, 0·11 to 0·43; P = 0·001). CONCLUSION: This meta-analysis suggests that structured home exercise programmes are effective at improving walking performance and physical activity in the short term for patients with PAD.

Systematic Review and Meta-Analysis of the Association Between C-Reactive Protein and Major Cardiovascular Events in Patients with Peripheral Artery Disease.

BACKGROUND: Patients with peripheral artery disease (PAD) are at substantial risk of cardiovascular events. There is interest in using blood markers, such as C-reactive protein (CRP), to monitor prognosis and treatment efficacy in PAD patients. The aim of this meta-analysis was to assess the association between CRP and major cardiovascular events in PAD patients. METHOD: Studies evaluating the association between CRP and major cardiovascular events (myocardial infarction, stroke, cardiac revascularisation and mortality) were identified using MEDLINE and the Cochrane library. Studies that did not include participants with PAD, measure CRP, or follow-up patients for cardiovascular events were excluded. Meta-analyses of published adjusted hazard ratios (HR) were conducted using an inverse variance-weighted random effects model, and heterogeneity was assessed with the I2 index. RESULTS: A total of 16 studies involving 5041 participants met the inclusion criteria for the systematic review. Eight studies were included in the meta-analyses. Summary effect estimates were reported as HR comparing higher and lower quantiles, and HR per unit increase in logeCRP. PAD patients with higher CRP had a significantly greater risk of major cardiovascular events compared with those with lower CRP (HR 2.26, 95% CI 1.65-3.09, p < 0.001). The HR for major cardiovascular events was 1.38 (95% CI 1.16-1.63, p < 0.001) per unit increase in logeCRP. CONCLUSIONS: The present findings suggest that high circulating CRP is predictive of major cardiovascular events in PAD patients.