***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Background —Bone-marrow mononuclear cell ( BM-MNC ) implantation improves ischemic symptoms in patients with critical limb ischemia ( CLI ) . The purpose of this study was to evaluate long-term clinical outcomes after autologous BM-MNC implantation in patients with CLI . Methods and Results —We assessed long-term clinical outcomes after BM-MNC implantation in 51 patients with CLI , including 25 patients with peripheral arterial disease ( PAD ) and 26 patients with Buerger disease . Forty-six CLI patients who had no BM-MNC implantation served as control subjects . Median follow-up period was 4.8 years . The 4-year amputation-free rates after BM-MNC implantation were 48 % in PAD patients and 95 % in Buerger disease , and they were 0 % in control PAD patients and 6 % in control Buerger disease . The 4-year overall survival rates after BM-MNC implantation  were 76 % in PAD patients and 100 % in Buerger disease , and they were 67 % in control PAD patients and 100 % in control Buerger disease . Multivariable Cox proportional hazards analysis revealed that BM-MNC implantation correlated with prevention of major amputation and that hemodialysis and diabetes mellitus correlated with major amputation . In Buerger disease , ankle brachial pressure index and transcutaneous oxygen pressure were significantly increased after 1 month and remained high during 3-year follow-up . However , in patients with PAD , ankle brachial pressure index and transcutaneous oxygen pressure significantly increased after 1 month and gradually decreased during 3-year follow-up and returned to baseline levels . Conclusions —These findings suggest that BM-MNC implantation is safe and effective in patients with CLI , especially in patients with Buerger disease . Clinical Trial Registration —URL : http://home.hiroshima-u.ac.jp/angio/. Unique identifier : 001769 UNLABELLED The present clinical trial analyzed the safety of gene therapy using plasmidial constructs expressing vascular endothelial and hepatocyte growth factors in patients with critical limb ischemia . The study included 43 patients : 29 in the treatment group and 14 allocated to the placebo group . The primary end points were the rate of major amputations and the clinical safety of the method . Secondary end points were improvement of pain at rest , walking ability and the ankle/brachial pressure index . The overall major amputation rate was 31.04 % in the treatment group and 71.42 % in the placebo group ( p = 0.029 ) . Pain at rest was improved in 65 % of patients in the gene therapy group and in 7 % in the placebo group ( p = 0.0006 ) . There were no significant adverse effects in the treatment group . CONCLUSION Gene therapy with vascular endothelial and hepatocyte growth factors is therapeutically safe and reduces the rate of major amputations and relieves pain at rest in patients with critical limb ischemia OBJECTIVES We have previously reported the results of a dose-finding phase II trial showing that HGF angiogenic gene therapy can increase TcPO2 compared with placebo in patients with critical limb ischemia ( CLI ) . The purpose of this r and omized placebo controlled multi-center trial was to further assess the safety and clinical efficacy of a modified HGF gene delivery technique in patients with CLI and no revascularization options . METHODS Patients with lower extremity ischemic tissue loss ( Rutherford 5 and 6 ) received three sets of eight intramuscular injections every 2 weeks of HGF plasmid under duplex ultrasound guidance . Injection locations were individualized for each patient based on arteriographically defined vascular anatomy . Primary safety end point was incidence of adverse events ( AE ) or serious adverse events ( SAE ) . Clinical end points included change from baseline in toe brachial index ( TBI ) , rest pain assessment by a 10 cm visual analogue scale ( VAS ) as well as wound healing , amputation , and survival at 3 and 6 months . RESULTS R and omization ratio was 3:1 HGF ( n = 21 ) vs placebo ( n = 6 ) . Mean age was 76 ± 2 years , with 56 % male and 59 % diabetic . There was no difference in demographics between groups . There was no difference in AEs or SAEs , which consisted mostly of transient injection site discomfort , worsening of CLI , and intercurrent illnesses . Change in TBI significantly improved from baseline at 6 months in the HGF-treated group compared with placebo ( 0.05 ± 0.05 vs -0.17 ± 0.04 ; P = .047 ) . Change in VAS from baseline at 6 months was also significantly improved in the HGF-treated group compared with placebo ( -1.9 ± 1.3 vs + 0.06 ± 0.2 ; P = .04 ) . Complete ulcer healing at 12 months occurred in 31 % of the HGF group and 0 % of the placebo ( P = .28 ) There was no difference in major amputation of the treated limb ( HGF 29 % vs placebo 33 % ) or mortality at 12 months ( HGF 19 % vs placebo 17 % ) between groups . CONCLUSION HGF gene therapy using a patient vascular anatomy specific delivery technique appears safe , maintained limb perfusion , and decreased rest pain in patients with CLI compared with placebo . A larger study to assess the efficacy of this therapy on more clinical ly relevant end points is warranted Background — The Study to Assess the Safety of Intramuscular Injection of Hepatocyte Growth Factor Plasmid to Improve Limb Perfusion in Patients With Critical Limb Ischemia ( HGF-STAT trial ) determined the effect of hepatocyte growth factor ( HGF ) plasmid on safety and limb tissue perfusion as measured by transcutaneous oxygen tension ( TcPo2 ) in patients with critical limb ischemia ( CLI ) . Methods and Results — R and omized patients with rest pain or ischemic ulcers and TcPo2 < 40 mm Hg and /or toe pressure < 50 mm Hg received placebo or HGF-plasmid intramuscular injection as follows : 0.4 mg at days 0 , 14 , and 28 ( low dose ) ; 4.0 mg at days 0 and 28 ( middle dose ) ; or 4.0 mg at days 0 , 14 , and 28 ( high dose ) . Patients were evaluated for safety , changes in TcPo2 and ankle and toe pressure , amputation , and wound healing .  Ninety-three of 104 treated patients were evaluated for safety ( mean age 70 years , 63 % male , 53 % diabetic , 64 % with tissue loss , mean ankle-brachial index 0.41 , and mean toe pressure 26 mm Hg ) . Adverse events occurred in 86 % of the patients , most of which were related to CLI or comorbid conditions and were not different between groups . TcPo2 ( mean±SE ) increased at 6 months in the high-dose group ( 24.0±4.2 mm Hg , 95 % CI 15.5 to 32.4 mm Hg ) compared with the placebo ( 9.4±4.2 mm Hg , 95 % CI 0.9 to 17.8 ) , low-dose ( 11.1±3.7 mm Hg , CI 3.7 to 18.7 mm Hg ) , and middle-dose ( 7.3±4.8 mm Hg , CI −2.2 to 17.0 mm Hg ) groups ( ANCOVA P=0.0015 ) . There was no difference between groups in secondary end points , including ankle-brachial index , toe-brachial index , pain relief , wound healing , or major amputation . Conclusions — Intramuscular injection of HGF plasmid was safe and well tolerated . Larger studies to determine whether HGF plasmid can improve wound healing and limb salvage in patients with CLI are warranted BACKGROUND Patients with intermittent claudication ( IC ) could benefit from low-cost , effective rehabilitative programs . This retrospective study evaluates compliance , impact on Quality of Life ( QoL ) and cost-effectiveness of a hospital prescribed , at-home performed ( Test-in/Train-out ) rehabilitative program for patients with IC . METHODS AND RESULTS Two-hundred and eighty-nine patients with IC ( 71 ± 10.1 years , M = 210 ) were enrolled for a 2-year period .  Two daily 10-min home walking sessions at maximal asymptomatic speed were prescribed , with serial check-ups at the hospital . Compliance with the program was assessed by assigning a score of 1 ( lowest compliance ) to 4 ( highest compliance ) . The SF-36 question naire and a constant-load treadmill test  were used to evaluate QoL and Initial/Absolute Claudication Distance , respectively . Both direct and indirect costs of the program were considered for cost-effectiveness analysis . Two-hundred and fifty patients ( 70.5 ± 9.2 years , M = 191 ) , at Fontaine 's II-B stage ( 86 % ) , were included in the study . No adverse events were reported . The average compliance score was 3.1 . At discharge , both SF-36 domains and walking performance significantly increased ( P < 0.0001 ) . A total of 1,839 in-hospital check-ups ( 7.36 /patient ) were performed . Direct and indirect costs represented 93 % and 7 % of the total costs , respectively . The average costs of a visit and of a therapy cycle were C68.93 and C507.20 , respectively . The cost to walk an additional meter before stopping was C9.22 . CONCLUSIONS A Test-in/Train-out program provided favourable patient compliance , QoL impact and cost-effectiveness in patients with IC Ixmyelocel-T is a patient-specific , exp and ed , multicellular therapy evaluated in patients with lower extremity critical limb ischemia ( CLI ) with no options for revascularization . This r and omized , double-blind , placebo-controlled , phase 2 trial ( RESTORE-CLI ) compared the efficacy and safety of intramuscular injections of ixmyelocel-T with placebo . Patients received one-time injections over 20 locations in a single leg and were followed for 12 months . Safety assessment s included occurrence of adverse events . Efficacy assessment s included time to first occurrence of treatment failure ( TTF ; major amputation of injected leg ; all-cause mortality ; doubling of total wound surface area from baseline ; de novo gangrene ) and amputation-free survival ( AFS ; major amputation of injected leg ; all-cause mortality ) . A total of 77 patients underwent bone marrow or sham aspiration ; 72 patients received ixmyelocel-T  ( 48 patients ) or placebo  ( 24 patients ) . Adverse event rates were similar . Ixmyelocel-T treatment led to a significantly prolonged TTF ( P = 0.0032 , logrank test ) . AFS had a clinical ly meaningful 32 % reduction in event rate that was not statistically significant ( P = 0.3880 , logrank test ) . Treatment effect in post hoc analyses of patients with baseline wounds was more pronounced ( TTF : P < 0.0001 , AFS : P = 0.0802 , logrank test ) . Ixmyelocel-T treatment was well tolerated and may offer a potential new treatment option BACKGROUND Patients with critical limb ischaemia have a high rate of amputation and mortality . We tested the hypothesis that non-viral 1 fibroblast growth factor ( NV1FGF ) would improve amputation-free survival . METHODS In this phase 3 trial ( EFC6145/TAMARIS ) , 525 patients with critical limb ischaemia unsuitable for revascularisation were enrolled from 171 sites in 30 countries . All had ischaemic ulcer in legs or minor skin gangrene and met haemodynamic criteria ( ankle pressure < 70 mm Hg or a toe pressure < 50 mm Hg , or both , or a transcutaneous oxygen pressure < 30 mm Hg on the treated leg ) . Patients were r and omly assigned to either NV1FGF at 0·2 mg/mL or matching placebo ( visually identical ) in a 1:1 ratio . R and omisation was done with a central interactive voice response system by block size 4 and was stratified by diabetes status and country . Investigators , patients , and study teams were masked to treatment . Patients received eight intramuscular injections of their assigned treatment in the index leg on days 1 , 15 , 29 , and 43 . The primary endpoint was time to major amputation or death at 1 year analysed by intention to treat with a log-rank test using a multivariate Cox proportional hazard model . This trial is registered with Clinical Trials.gov , number NCT00566657 . FINDINGS 259 patients were assigned to  NV1FGF  and 266 to placebo . All 525 patients were analysed . The mean age was 70 years ( range 50 - 92 ) , 365 ( 70 % ) were men , 280 ( 53 % ) had diabetes , and 248 ( 47 % ) had a history of coronary artery disease . The primary endpoint or components of the primary did not differ between treatment groups , with major amputation or 
    Output:
    
None of the nonrevascularization-based treatments were associated with a significant effect on mortality .
Very low- quality evidence , mainly due to imprecision and increased risk of bias , suggests that intermittent pneumatic compression and spinal cord stimulators may reduce the risk of amputations .