Efficient rate-power allocation for OFDM in a realistic fading environment

The implementation of practical adaptive resource allocation scheme remains a key criterion to be satisfied for realising spectrally efficient multitone wireless communications. The ever-increasing demand for spectrally efficient broadband wireless transmission technologies has spurred intensive research leading towards the implementation of adaptive OFDM and adaptive MIMO systems. Efforts in this direction have been frustrated however by the lack of a clear and accurate description of the fading behaviour typically encountered in the broadband wireless transmission environment. This has been partially been overcome by the use of mathematical modelling which captures certain large-scale characteristics of the channel and facilitates theoretical research. The “average” channel parameters gleaned from these processes is typically then used to inform the design and configuration of wireless networking equipment after the broad application of generous safety margins. The resulting solu�tion is therefore quite robust to certain transient channel quality degradation yet the generous safety tolerances render it unable to exploit other transient transmission quality improvements We seek to overcome the problems associated with this ap�proach by applying a theoretically sound novel adaptive resource allocation framework to actual broadband wireless channel development data. The allocation framework is derived from the optimal OFDM allocation scheme for a known channel [1]: the channel development data is obtained from actual measurement of a broadband wireless mobile environment [2]. Prediction tech�niques are employed to overcome the time lag between channel assessment and symbol transmission. We present the details of the predictive resource allocation scheme used and include a broad characterisation of the transmission environment in terms of the time-varying fading processes observed. We provide some results of the application of this scheme as typical performance levels that may be achieved in an actual transmission environment

Time to footpad swelling.

<p>Post infection time to foot pad swelling in mice treated with either rifampin (RIF) or rifapentine (RPT) containing regimens for one week, two weeks, three weeks or four weeks. Untreated controls are shown in black squares, streptomycin (STR) + rifampin (RIF) for 5 days a week (5/7) in blue circles, STR+RIF for 7 days a week (7/7) in green triangles and STR+ rifapentine (RPT) (5/7) is in red asterisk.</p

Scheme of the study.

<p>The number in parenthesis indicates the number of mice kept for footpad swelling.</p><p>D-25 is the day after infection while D0 is the time of start of treatment.</p><p>Drugs and their doses were, STR = streptomycin, 150 mg/kg; RIF = rifampin, 10 mg/kg; RPT = rifapentine, 10 mg/kg.</p><p>Treatment was either 5 days a week (5/7) or 7 days a week (7/7).</p

Decrease in log₁₀ CFU counts in footpads.

<p>Decrease in the log₁₀ CFU counts in the footpads of mice treated with, streptomycin+ rifampin for 5 days a week (STR+RIF 5/7), STR+RIF for 7 days a week (STR+RIF 7/7) and STR+ rifapentine (RPT) (STR+RPT 5/7) compared to untreated controls. The day after infection counts are shown at −25 (Mice were infected at D-26) and treatment was started after 25 days (D0).</p

Efficacy of Rifampin Plus Clofazimine in a Murine Model of <i>Mycobacterium ulcerans</i> Disease

<div><p>Treatment of Buruli ulcer, or <i>Mycobacterium ulcerans</i> disease, has shifted from surgical excision and skin grafting to antibiotic therapy usually with 8 weeks of daily rifampin (RIF) and streptomycin (STR). Although the results have been highly favorable, administration of STR requires intramuscular injection and carries the risk of side effects, such as hearing loss. Therefore, an all-oral, potentially less toxic, treatment regimen has been sought and encouraged by the World Health Organization. A combination of RIF plus clarithromycin (CLR) has been successful in patients first administered RIF+STR for 2 or 4 weeks. Based on evidence of efficacy of clofazimine (CFZ) in humans and mice with tuberculosis, we hypothesized that the combination of RIF+CFZ would be effective against <i>M</i>. <i>ulcerans</i> in the mouse footpad model of <i>M</i>. <i>ulcerans</i> disease because CFZ has similar MIC against <i>M</i>. <i>tuberculosis</i> and <i>M</i>. <i>ulcerans</i>. For comparison, mice were also treated with the gold standard of RIF+STR, the proposed RIF+CLR alternative regimen, or CFZ alone. Treatment was initiated after development of footpad swelling, when the bacterial burden was 4.64±0.14log₁₀ CFU. At week 2 of treatment, the CFU counts had increased in untreated mice, remained essentially unchanged in mice treated with CFZ alone, decreased modestly with either RIF+CLR or RIF+CFZ, and decreased substantially with RIF+STR. At week 4, on the basis of footpad CFU counts, the combination regimens were ranked as follows: RIF+STR>RIF+CLR>RIF+CFZ. At weeks 6 and 8, none of the mice treated with these regimens had detectable CFU. Footpad swelling declined comparably with all of the combination regimens, as did the levels of detectable mycolactone A/B. In mice treated for only 6 weeks and followed up for 24 weeks, there were no relapses in RIF+STR treated mice, one (5%) relapse in RIF+CFZ-treated mice, but >50% in RIF+CLR treated mice. On the basis of these results, RIF+CFZ has potential as a continuation phase regimen for treatment of <i>M</i>. <i>ulcerans</i> disease.</p></div

Response to antibiotic treatment in footpads of mice infected with <i>M</i>. <i>ulcerans</i>.

<p><b>(A) Footpad swelling</b>. After infection of both hind footpads, treatment began when swelling approached grade 2 at week 7. Swelling continued to increase for the next two weeks in untreated control mice (black squares) and in mice treated with clofazimine (CFZ) alone, but was arrested in mice treated with either rifampin and streptomycin (RIF+STR, green circles), rifampin and clarithromycin (RIF+CLR, blue triangles) or rifampin and CFZ (RIF+CFZ, solid red circles) and then declined at a comparable rate to a grade of less than 1 over the 8-week treatment period. <b>(B). Mycolactone A/B concentrations</b>. At day 0, there was 10 ng mycolactone A/B per footpad detected. Mycolactone concentrations continued to increase for the next two weeks in untreated control mice (black squares), reaching 20 ng. Mycolactone production was arrested in mice treated with either RIF+STR (green circles), RIF+CLR (blue triangles), RIF+CFZ (solid red circles), or CFZ alone (orange X) and became undetectable after 6 weeks of RIF+STR or RIF+CFZ. The decline was slower in RIF+CLR mice. <b>(C) <i>M</i>. <i>ulcerans</i> CFU</b>. At day 0, there were 4.64±0.14 <i>M</i>. <i>ulcerans</i> CFU detected in the footpads. CFU numbers increased in untreated controls to 5.37±0.07 by day 10. The CFU levels remained essentially unchanged in mice receiving CFZ alone (4.72±0.59) while in the combination regimens, there was a consistent decline and all mice were culture negative by week 6.</p

Relapse after treatment completion.

<p>Mice were monitored weekly for renewed swelling of infected footpads after treatment completion. In four mice, lesions instead appeared at ectopic sites (A) Mouse treated with RIF+CLR for 6 weeks began to show inflammation at the base of the right ear ~14–15 weeks after treatment cessation and was sacrificed at week 21. (B) AFB staining of lesion in right ear shows abundant bacilli as did growth of bacilli in culture at 32°C. (C) Mouse treated with RIF+CLR for 8 weeks showed essentially no sign of relapse and no cultivable bacilli in footpads but had a severe lesion at the base of the tail 31 weeks after treatment completion with abundant AFB and cultivable bacilli.</p

Clofazimine accumulation in tissues of <i>M</i>. <i>ulcerans</i> infected mice.

<p>(A) Untreated control mouse, showing normal skin (i.e. ears, tail, footpads) coloration. (B) Mouse treated with CFZ, 11 days after treatment initiation; note yellow-orange tinge to ears, dark red footpads and tail. CFZ-related discoloration was no longer apparent 3 weeks after the cessation of treatment. (C) CFZ concentrations detected by mass spectrometric analysis in CFZ mice (orange X) and untreated control mice (black square) at day 11 and RIF+CFZ mice (solid red circles) and RIF+STR mice (green circles) at weeks 2, 4, 6, and 8 of treatment. Dotted line, lower limit of detection.</p

Original experimental scheme to compare activities of RIF+STR, RIF+ CLR, RIF+CFZ and CFZ alone in <i>M</i>. <i>ulcerans</i>-infected footpads of BALB/c mice.

<p>Due to animal welfare reasons, mice were sacrificed early as explained in text.</p><p>D, day; w, week; CFU, colony forming units; RIF, rifampin, 10mg/kg; STR, streptomycin, 150mg/kg; CLR, clarithromycin 100mg/kg; CFZ, clofazimine 25mg/kg; CLR and CFZ are given one hour after RIF to prevent adverse pharmacokinetic interactions [<a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0003823#pntd.0003823.ref030" target="_blank">30</a>].</p><p>Original experimental scheme to compare activities of RIF+STR, RIF+ CLR, RIF+CFZ and CFZ alone in <i>M</i>. <i>ulcerans</i>-infected footpads of BALB/c mice.</p

Time to footpad swelling after completion of antibiotic treatment.

<p>Time to footpad swelling (or ectopic lesions) in mice treated with either RIF+STR (green circles), RIF+CLR (blue triangles), or RIF+CFZ (red circles) regimens for six weeks (A) or eight (B) weeks after the development of swollen foot pads. Footpads had little or no swelling at treatment completion (see <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0003823#pntd.0003823.g001" target="_blank">Fig 1A</a>).</p