Whereas these guidelines have addressed five key areas in the care of DFUs, they do not cover all the aspects of this complex condition. Going forward as future evidence accumulates, we plan to update our recommendations accordingly.

Background Critical limb ischemia (CLI) portends a risk of major amputation of 25-35% within 1 year of diagnosis. Pre-clinical studies provide evidence that intramuscular injection of autologous CD34+ cells improve limb perfusion and reduce amputation risk. In this randomized, double-blind, placebo-controlled pilot study, we evaluated the safety and efficacy of intramuscular injections of autologous CD34+ cells in subjects with moderate or high-risk CLI who were poor or non-candidates for surgical or percutaneous revascularization (ACT34-CLI). Methods and Results Twenty-eight CLI subjects were randomized and treated: 7 to 1×105 (low-dose) and 9 to 1×106 (high-dose) autologous CD34+ cells/kg; 12 to placebo (control). Intramuscular injections were distributed into 8 sites within the ischemic lower extremity. At 6 months post-injection 67% of control subjects experienced a major or minor amputation versus 43% of low-dose and 22% of high-dose cell-treated subjects (P=0.137). This trend continued at 12 months with 75% of control subjects experiencing any amputation versus 43% of low-dose and 22% of high-dose cell-treated subjects (P=0.058). Amputation incidence was lower in the combined cell-treated groups compared with control group (6 months: P=0.125; 12 months: P=0.054), with the low-dose and high-dose groups individually showing trends towards improved amputation free survival at 6 and 12 months. No adverse safety signal was associated with cell administration. Conclusions This study provides evidence that intramuscular administration of autologous CD34+ cells was safe in this patient population. Favorable trends toward reduced amputation rates in cell-treated versus control subjects were observed. These findings warrant further exploration in later phase clinical trials.

Background Studies suggest that vitamin D deficiency is a risk factor for cardiovascular disease and diabetes. Vitamin D deficiency is prevalent in HIV patients but the effect of vitamin D supplementation on cardiovascular risk in this population is unknown. Methods We conducted a randomized, double-blind, placebo-controlled trial among 45 HIV-infected adults in Cleveland (OH, USA) on stable antiretroviral therapy with durable virological suppression and a baseline serum 25-hydroxyvitamin D level of ≤20 ng/ml. Participants were randomized 2:1 to vitamin D3 4,000 IU daily or placebo for 12 weeks. The primary outcome was a change in flow-mediated brachial artery dilation (FMD). Results Baseline demographics were similar except for age (vitamin D versus placebo, mean ±SD 47 ±8 versus 40 ±10 years; P=0.009). Both groups had reduced FMD at baseline (median values 2.9% [IQR 1.6–4.8] for vitamin D versus 2.5% [IQR 1.7–6.4] for placebo; P=0.819). Despite an increase in the concentration of serum 25-hydroxyvitamin D from baseline to 12 weeks (5.0 ng/ml [IQR −0.9–7.4] versus −1.9 ng/ml [IQR −4.0–0.1] for vitamin D versus placebo, respectively; P=0.003), there was no difference in FMD change (0.55% [IQR −1.05–2.13] versus 0.29% [IQR −1.61–1.77]; P=0.748). Vitamin D supplementation was associated with a decrease in total and non-high-density lipoprotein cholesterol, and an increase in indices of insulin resistance. Conclusions Among HIV-infected individuals with vitamin D deficiency, supplementation with 4,000 IU vitamin D3 daily for 12 weeks modestly improved vitamin D status and cholesterol but worsened insulin resistance without change in endothelial function. The mechanisms of resistance to standard doses of vitamin D and the complex role of vitamin D in glucose metabolism in this population require further investigation.