Systematic review and narrative synthesis of surveillance practices after endovascular intervention for lower limb peripheral arterial disease.

OBJECTIVE: The optimal timing and modality of surveillance after endovascular intervention for peripheral arterial disease is controversial, and no randomized trial to assess the value of peripheral endovascular intervention has ever been performed. The aim of this systematic review was to examine the practice of surveillance after peripheral endovascular intervention in randomized trials. METHODS: We used the Medline, Embase, Cochrane Library, and WHO trial registry databases in this systematic review of the literature to capture surveillance strategies used in randomized trials comparing endovascular interventions. Surveillance protocols were assessed for completeness, modalities used, duration, and intensity. RESULTS: Ninety-six different surveillance protocols were reported in 103 trials comparing endovascular interventions. Protocol specification was incomplete in 32% of trials. The majority of trials used multiple surveillance modalities (mean of 3.46 modalities), most commonly clinical examination (96%), ankle-brachial index (80%), duplex ultrasound examination (75%), and digital subtraction angiography (51%). Trials involving infrapopliteal lesions used more angiographic surveillance than trials with femoropopliteal lesions (P = .006). The median number of surveillance visits in the first 12 months after intervention was three and the mean surveillance duration was 21 months. Trials treating infrapopliteal vessels had a higher surveillance intensity compared with those treating femoropopliteal lesions in the first 12 months after endovascular intervention (mean 5 vs 3 surveillance visits; P = .017). Trials with drug-eluting devices had longer surveillance duration compared with those without (mean 26 vs 19 months; P = .020). CONCLUSIONS: There is a high level of variation in the modality, duration, and intensity of surveillance protocols used in randomized trials comparing different types of peripheral endovascular arterial intervention. Further research is required to determine the value and impact of postprocedural surveillance on patient outcomes.

Prevalence of BRAFV600 in glioma and use of BRAF Inhibitors in patients with BRAFV600 mutation-positive glioma: systematic review.

BACKGROUND: Detailed prevalence estimates of BRAFV600 mutations and BRAF inhibitor (BRAFi) treatment responses in V600-mutant glioma will inform trial development. METHODS: Our systematic review analyzed overall prevalence of BRAFV600 mutations in glioma and BRAFi treatment response. RESULTS: Based on 13 682 patients in 182 publications, the prevalence of BRAFV600 in epithelioid glioblastoma (eGBM) was 69% [95% CI: 45-89%]; pleomorphic xanthoastrocytoma (PXA): 56% [48-64%] anaplastic pleomorphic xanthoastrocytoma (aPXA): 38% [23-54%], ganglioglioma (GG): 40% [33-46%], and anaplastic ganglioglioma (aGG): 46% [18-76%]. Prevalence in astroblastoma was 24% [8-43%], desmoplastic infantile astrocytoma (DIA): 16% [0-57%], subependymal giant cell astrocytoma (SEGA): 8% [0-37%], dysembryoplastic neuroepithelial tumor (DNET): 3% [0-11%], diffuse astrocytoma (DA): 3% [0-9%], and pilocytic astrocytoma (PA): 3% [2-5%]. We reviewed 394 V600-mutant gliomas treated with BRAFi from 130 publications. One hundred and twenty-nine pediatric low-grade gliomas showed 4 (3.1%) complete response (CR); 53 (41.1%) partial response (PR); 64 (49.6%) stable disease (SD) and 8 (6.2%) progressive disease (PD). 25 pediatric high-grade gliomas showed CR; PR; SD; PD in 4 (16.0%); 10 (40.0%), 4 (16.0%); and 7 (28.0%) respectively. Thirty-nine adult low-grade gliomas showed CR; PR; SD; PD of 4 (10.3%); 17 (43.6%); 16 (41.0%) and 2 (5.1%) respectively. Ninety-seven adult high-grade gliomas showed CR; PR; SD; PD of 6 (6.2%); 31 (32.0%); 27 (27.8%); and 33 (34.0%) respectively. CONCLUSIONS: BRAFV600 prevalence is highest in eGBM, PXA, aPXA, GG, aGG, and lower in astroblastoma, DIA, SEGA, DNET, DA, and PA. Our data provide the rationale for adjuvant clinical trials of BRAFi in V600-mutant glioma.

MGMT promoter methylation testing to predict overall survival in people with glioblastoma treated with temozolomide: a comprehensive meta-analysis based on a Cochrane Systematic Review.

BACKGROUND: The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) causes resistance of tumor cells to alkylating agents. It is a predictive biomarker in high-grade gliomas treated with temozolomide, however, there is no consensus on which test method, methylation sites, and cutoff values to use. METHODS: We performed a Cochrane Review to examine studies using different techniques to measure MGMT and predict survival in glioblastoma patients treated with temozolomide. Eligible longitudinal studies included (i) adults with glioblastoma treated with temozolomide with or without radiotherapy, or surgery; (ii) where MGMT status was determined in tumor tissue, and assessed by 1 or more technique; and (iii) where overall survival was an outcome parameter, with sufficient information to estimate hazard ratios (HRs). Two or more methods were compared in 32 independent cohorts with 3474 patients. RESULTS: Methylation-specific PCR (MSP) and pyrosequencing (PSQ) techniques were more prognostic than immunohistochemistry for MGMT protein, and PSQ is a slightly better predictor than MSP. CONCLUSIONS: We cannot draw strong conclusions about use of frozen tissue vs formalin-fixed paraffin-embedded in MSP and PSQ. Also, our meta-analysis does not provide strong evidence about the best CpG sites or threshold. MSP has been studied mainly for CpG sites 76-80 and 84-87 and PSQ at CpG sites ranging from 72 to 95. A cutoff threshold of 9% for CpG sites 74-78 performed better than higher thresholds of 28% or 29% in 2 of the 3 good-quality studies. About 190 studies were identified presenting HRs from survival analysis in patients in which MGMT methylation was measured by 1 technique only.

Prognostic value of test(s) for O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation for predicting overall survival in people with glioblastoma treated with temozolomide.

BACKGROUND: Glioblastoma is an aggressive form of brain cancer. Approximately five in 100 people with glioblastoma survive for five years past diagnosis. Glioblastomas that have a particular modification to their DNA (called methylation) in a particular region (the O6-methylguanine-DNA methyltransferase (MGMT) promoter) respond better to treatment with chemotherapy using a drug called temozolomide. OBJECTIVES: To determine which method for assessing MGMT methylation status best predicts overall survival in people diagnosed with glioblastoma who are treated with temozolomide. SEARCH METHODS: We searched MEDLINE, Embase, BIOSIS, Web of Science Conference Proceedings Citation Index to December 2018, and examined reference lists. For economic evaluation studies, we additionally searched NHS Economic Evaluation Database (EED) up to December 2014. SELECTION CRITERIA: Eligible studies were longitudinal (cohort) studies of adults with diagnosed glioblastoma treated with temozolomide with/without radiotherapy/surgery. Studies had to have related MGMT status in tumour tissue (assessed by one or more method) with overall survival and presented results as hazard ratios or with sufficient information (e.g. Kaplan-Meier curves) for us to estimate hazard ratios. We focused mainly on studies comparing two or more methods, and listed brief details of articles that examined a single method of measuring MGMT promoter methylation. We also sought economic evaluations conducted alongside trials, modelling studies and cost analysis. DATA COLLECTION AND ANALYSIS: Two review authors independently undertook all steps of the identification and data extraction process for multiple-method studies. We assessed risk of bias and applicability using our own modified and extended version of the QUality In Prognosis Studies (QUIPS) tool. We compared different techniques, exact promoter regions (5'-cytosine-phosphate-guanine-3' (CpG) sites) and thresholds for interpretation within studies by examining hazard ratios. We performed meta-analyses for comparisons of the three most commonly examined methods (immunohistochemistry (IHC), methylation-specific polymerase chain reaction (MSP) and pyrosequencing (PSQ)), with ratios of hazard ratios (RHR), using an imputed value of the correlation between results based on the same individuals. MAIN RESULTS: We included 32 independent cohorts involving 3474 people that compared two or more methods. We found evidence that MSP (CpG sites 76 to 80 and 84 to 87) is more prognostic than IHC for MGMT protein at varying thresholds (RHR 1.31, 95% confidence interval (CI) 1.01 to 1.71). We also found evidence that PSQ is more prognostic than IHC for MGMT protein at various thresholds (RHR 1.36, 95% CI 1.01 to 1.84). The data suggest that PSQ (mainly at CpG sites 74 to 78, using various thresholds) is slightly more prognostic than MSP at sites 76 to 80 and 84 to 87 (RHR 1.14, 95% CI 0.87 to 1.48). Many variants of PSQ have been compared, although we did not see any strong and consistent messages from the results. Targeting multiple CpG sites is likely to be more prognostic than targeting just one. In addition, we identified and summarised 190 articles describing a single method for measuring MGMT promoter methylation status. AUTHORS' CONCLUSIONS: PSQ and MSP appear more prognostic for overall survival than IHC. Strong evidence is not available to draw conclusions with confidence about the best CpG sites or thresholds for quantitative methods. MSP has been studied mainly for CpG sites 76 to 80 and 84 to 87 and PSQ at CpG sites ranging from 72 to 95. A threshold of 9% for CpG sites 74 to 78 performed better than higher thresholds of 28% or 29% in two of three good-quality studies making such comparisons.

Antiplatelet and Anticoagulant Use in Randomised Trials of Patients Undergoing Endovascular Intervention for Peripheral Arterial Disease: Systematic Review and Narrative Synthesis.

OBJECTIVE: Randomised trials of new devices for peripheral arterial endovascular intervention are published regularly. The evidence for which antiplatelet and/or anticoagulant (antithrombotic) therapy to use after an intervention is lacking. The aim of this systematic review was to examine the antithrombotic regimens in randomised trials for peripheral arterial endovascular intervention to understand choices made and trends with time or type of device. METHODS: Data sources were the Medline, Embase, and Cochrane Library databases. Randomised trials including participants with peripheral arterial disease undergoing any endovascular arterial intervention were included. Trial methods were assessed to determine whether an antithrombotic protocol had been specified, its completeness, and the agent(s) prescribed. Antithrombotic therapy protocols were classed as peri-procedural (preceding and during intervention), immediate post-procedural (up to 30 days following intervention), and maintenance post-procedural (therapy continuing beyond 30 days). RESULTS: Ninety-four trials were included in narrative synthesis. Study quality was low. None of the trials justified their antithrombotic therapy protocol. Only 29% of trials had complete peri-procedural antithrombotic protocols, and 34% had complete post-procedural protocols. In total, 64 different peri-procedural protocols, and 51 separate post-procedural protocols were specified. Antiplatelet monotherapy and unfractionated heparin were the most common regimen choices in the peri-procedural setting, and dual antiplatelet therapy (55%) was most commonly utilised post procedure. Over time there has been an increasing tendency to use dual therapy (p < .001). This corresponds with the introduction of newer technologies and trials focussed on below knee intervention. CONCLUSION: Randomised trials comparing different types of peripheral endovascular arterial intervention have a high level of heterogeneity in their antithrombotic regimens. Antiplatelet therapy needs to be standardised in trials comparing endovascular technologies to reduce potential confounding. To do this, an independent randomised trial specifically examining antiplatelet therapy following peripheral arterial endovascular intervention is needed.

Intravenous iron delivers a sustained (8-week) lowering of pulmonary artery pressure during exercise in healthy older humans.

In older individuals, pulmonary artery pressure rises markedly during exercise, probably due in part to increased pulmonary vascular resistance and in part to an increase in left-heart filling pressure. Older individuals also show more marked pulmonary vascular response to hypoxia at rest. Treatment with intravenous iron reduces the rise in pulmonary artery pressure observed during hypoxia. Here, we test the hypothesis that intravenous iron administration may also attenuate the rise in pulmonary artery pressure with exercise in older individuals. In a randomized double-blind placebo-controlled physiology study in 32 healthy participants aged 50-80 years, we explored the hypothesis that iron administration would deliver a fall in systolic pulmonary artery pressure (SPAP) during moderate cycling exercise (20 min duration; increase in heart rate of 30 min-1 ) and a change in maximal cycling exercise capacity ( V˙O2max ). Participants were studied before, and at 3 h to 8 weeks after, infusion. SPAP was measured using Doppler echocardiography. Iron administration resulted in marked changes in indices of iron homeostasis over 8 weeks, but no significant change in hemoglobin concentration or inflammatory markers. Resting SPAP was also unchanged, but SPAP during exercise was lower by ~3 mmHg in those receiving iron (P < 0.0001). This effect persisted for 8 weeks. Although V˙O2max remained unaffected in the iron-replete healthy participants studied here, this study demonstrates for the first time the ability of intravenous iron supplementation to reduce systolic pulmonary artery pressure during exercise.

Effects of modest iron loading on iron indices in healthy individuals.

Intravenous iron administration is typically indicated in individuals who have iron deficiency refractory to oral iron. However, in certain chronic disease states such as heart failure, it may be beneficial to administer intravenous iron to individuals who are not strictly iron deficient. The purpose of this study was to define a dose-response relationship between clinical indices of iron status and modest loading with intravenous iron in healthy, iron-replete participants. This was a double-blind, controlled study involving 18 male participants. Participants were block-randomized 2:1 to the iron and saline (control) groups. Participants in the iron group received 3.75 mg/kg body wt up to a maximum of 250 mg of intravenous iron, once a month for 6 mo, provided that their ferritin remained measured <300 µg/l within the week before a dose was due and their transferrin saturation remained <45%. Otherwise they received a saline infusion, as did the control participants. Iron indices were measured monthly during the study. The pulmonary vascular response to sustained hypoxia and total hemoglobin mass were measured before, at 3 mo (hemoglobin mass only), and at 6 mo as variables that may be affected by iron loading. Serum ferritin was robustly elevated by intravenous iron by 0.21 µg·l-1·mg-1 of iron delivered (95% confidence interval: 0.15-0.26 µg·l-1·mg-1), but the effects on all other iron indices did not reach statistical significance. The pulmonary vascular response to sustained hypoxia was significantly suppressed by iron loading at 6 mo, but the hemoglobin mass was unaffected. We conclude that the robust effect on ferritin provides a quantitative measure for the degree of iron loading in iron-replete individuals.NEW & NOTEWORTHY There has been an increasing interest in administering intravenous iron to patients to alter their iron status. Here, we explore various indices of iron loading and show that in healthy volunteers serum ferritin provides a robust indicator of the amount of iron loaded, with a value of 21 µg/l increase in ferritin per 100 mg of iron loaded.

Intraoperative interventions for preventing surgical site infection: an overview of Cochrane Reviews.

BACKGROUND: Surgical site infection (SSI) rates vary from 1% to 5% in the month following surgery. Due to the large number of surgical procedures conducted annually, the costs of these SSIs can be considerable in financial and social terms. Many interventions are used with the aim of reducing the risk of SSI in people undergoing surgery. These interventions can be broadly delivered at three stages: preoperatively, intraoperatively and postoperatively. The intraoperative interventions are largely focused on decontamination of skin using soap and antiseptics; the use of barriers to prevent movement of micro-organisms into incisions; and optimising the patient's own bodily functions to promote best recovery. Both decontamination and barrier methods can be aimed at people undergoing surgery and operating staff. Other interventions focused on SSI prevention may be aimed at the surgical environment and include methods of theatre cleansing and approaches to managing theatre traffic. OBJECTIVES: To present an overview of Cochrane Reviews of the effectiveness and safety of interventions, delivered during the intraoperative period, aimed at preventing SSIs in all populations undergoing surgery in an operating theatre. METHODS: Published Cochrane systematic reviews reporting the effectiveness of interventions delivered during the intraoperative period in terms of SSI prevention were eligible for inclusion in this overview. We also identified Cochrane protocols and title registrations for future inclusion into the overview. We searched the Cochrane Library on 01 July 2017. Two review authors independently screened search results and undertook data extraction and 'Risk of bias' and certainty assessment. We used the ROBIS (risk of bias in systematic reviews) tool to assess the quality of included reviews, and we used GRADE methods to assess the certainty of the evidence for each outcome. We summarised the characteristics of included reviews in the text and in additional tables. MAIN RESULTS: We included 32 Cochrane Reviews in this overview: we judged 30 reviews as being at low risk of bias and two at unclear risk of bias. Thirteen reviews had not been updated in the past three years. Two reviews had no relevant data to extract. We extracted data from 30 reviews with 349 included trials, totaling 73,053 participants. Interventions assessed included gloving, use of disposable face masks, patient oxygenation protocols, use of skin antiseptics for hand washing and patient skin preparation, vaginal preparation, microbial sealants, methods of surgical incision, antibiotic prophylaxis and methods of skin closure. Overall, the GRADE certainty of evidence for outcomes was low or very low. Of the 77 comparisons providing evidence for the outcome of SSI, seven provided high- or moderate-certainty evidence, 39 provided low-certainty evidence and 31 very low-certainty evidence. Of the nine comparisons that provided evidence for the outcome of mortality, five provided low-certainty evidence and four very low-certainty evidence.There is high- or moderate-certainty evidence for the following outcomes for these intraoperative interventions. (1) Prophylactic intravenous antibiotics administered before caesarean incision reduce SSI risk compared with administration after cord clamping (10 trials, 5041 participants; risk ratio (RR) 0.59, 95% confidence interval (CI) 0.44 to 0.81; high-certainty evidence - assessed by review authors). (2) Preoperative antibiotics reduce SSI risk compared with placebo after breast cancer surgery (6 trials, 1708 participants; RR 0.74, 95% CI 0.56 to 0.98; high-certainty evidence - assessed by overview authors). (3) Antibiotic prophylaxis probably reduce SSI risk in caesarean sections compared with no antibiotics (82 relevant trials, 14,407 participants; RR 0.40, 95% CI 0.35 to 0.46; moderate-certainty evidence; downgraded once for risk of bias - assessed by review authors). (4) Antibiotic prophylaxis probably reduces SSI risk for hernia repair compared with placebo or no treatment (17 trials, 7843 participants; RR 0.67, 95% CI 0.54 to 0.84; moderate-certainty evidence; downgraded once for risk of bias - assessed by overview authors); (5) There is currently no clear difference in the risk of SSI between iodine-impregnated adhesive drapes compared with no adhesive drapes (2 trials, 1113 participants; RR 1.03, 95% CI 0.66 to 1.60; moderate-certainty evidence; downgraded once for imprecision - assessed by review authors); (6) There is currently no clear difference in SSI risk between short-term compared with long-term duration antibiotics in colorectal surgery (7 trials; 1484 participants; RR 1.05 95% CI 0.78 to 1.40; moderate-certainty evidence; downgraded once for imprecision - assessed by overview authors). There was only one comparison showing negative effects associated with the intervention: adhesive drapes increase the risk of SSI compared with no drapes (5 trials; 3082 participants; RR 1.23, 95% CI 1.02 to 1.48; high-certainty evidence - rated by review authors). AUTHORS' CONCLUSIONS: This overview provides the most up-to-date evidence on use of intraoperative treatments for the prevention of SSIs from all currently published Cochrane Reviews. There is evidence that some interventions are useful in reducing SSI risk for people undergoing surgery, such as antibiotic prophylaxis for caesarean section and hernia repair, and also the timing of prophylactic intravenous antibiotics administered before caesarean incision. Also, there is evidence that adhesive drapes increase SSI risk. Evidence for the many other treatment choices is largely of low or very low certainty and no quality-of-life or cost-effectiveness data were reported. Future trials should elucidate the relative effects of some treatments. These studies should focus on increasing participant numbers, using robust methodology and being of sufficient duration to adequately assess SSI. Assessment of other outcomes such as mortality might also be investigated as part of non-experimental prospective follow-up of people with SSI of different severity, so the risk of death for different subgroups can be better understood.

Human hypoxic pulmonary vasoconstriction is unaltered by 8 h of preceding isocapnic hyperoxia.

Exposure to sustained hypoxia of 8 h duration increases the sensitivity of the pulmonary vasculature to acute hypoxia, but it is not known whether exposure to sustained hyperoxia affects human pulmonary vascular control. We hypothesized that exposure to 8 h of hyperoxia would diminish the hypoxic pulmonary vasoconstriction (HPV) that occurs in response to a brief exposure to hypoxia. Eleven healthy volunteers were studied in a crossover protocol with randomization of order. Each volunteer was exposed to acute isocapnic hypoxia (end-tidal PO2 = 50 mmHg for 10 min) before and after 8 h of hyperoxia (end-tidal PO2 = 420 mmHg) or euoxia (end-tidal PO2 = 100 mmHg). After at least 3 days, each volunteer returned and was exposed to the other condition. Systolic pulmonary artery pressure (an index of HPV) and cardiac output were measured, using Doppler echocardiography. Eight hours of hyperoxia had no effect on HPV or the response of cardiac output to acute hypoxia.

Elevation of iron storage in humans attenuates the pulmonary vascular response to hypoxia.

Sustained hypoxia over several hours induces a progressive rise in pulmonary artery systolic pressure (PASP). Administration of intravenous iron immediately prior to the hypoxia exposure abrogates this effect, suggesting that manipulation of iron stores may modify hypoxia-induced pulmonary hypertension. Iron (ferric carboxymaltose) administered intravenously has a plasma half-life of 7-12 h. Thus any therapeutic use of intravenous iron would require its effect on PASP to persist long after the iron-sugar complex has been cleared from the blood. To examine this, we studied PASP during sustained (6 h) hypoxia on 4 separate days (days 0, 1, 8, and 43) in 22 participants. On day 0, the rise in PASP with hypoxia was well matched between the iron and saline groups. On day 1, each participant received either 1 g of ferric carboxymaltose or saline in a double-blind manner. After administration of intravenous iron, the rise in PASP with hypoxia was attenuated by ∼50%, and this response remained suppressed on both days 8 and 43 (P < 0.001). Following administration of intravenous iron, values for ferritin concentration, transferrin saturation, and hepcidin concentration rose significantly (P < 0.001, P < 0.005, and P < 0.001, respectively), and values for transferrin concentration fell significantly (P < 0.001). These changes remained significant at day 43 We conclude that the attenuation of the pulmonary vascular response to hypoxia by elevation of iron stores persists long after the artificial iron-sugar complex has been eliminated from the blood. The persistence of this effect suggests that intravenous iron may be of benefit in some forms of pulmonary hypertension.

Clinical iron deficiency disturbs normal human responses to hypoxia.

BACKGROUND: Iron bioavailability has been identified as a factor that influences cellular hypoxia sensing, putatively via an action on the hypoxia-inducible factor (HIF) pathway. We therefore hypothesized that clinical iron deficiency would disturb integrated human responses to hypoxia. METHODS: We performed a prospective, controlled, observational study of the effects of iron status on hypoxic pulmonary hypertension. Individuals with absolute iron deficiency (ID) and an iron-replete (IR) control group were exposed to two 6-hour periods of isocapnic hypoxia. The second hypoxic exposure was preceded by i.v. infusion of iron. Pulmonary artery systolic pressure (PASP) was serially assessed with Doppler echocardiography. RESULTS: Thirteen ID individuals completed the study and were age- and sex-matched with controls. PASP did not differ by group or study day before each hypoxic exposure. During the first 6-hour hypoxic exposure, the rise in PASP was 6.2 mmHg greater in the ID group (absolute rises 16.1 and 10.7 mmHg, respectively; 95% CI for difference, 2.7-9.7 mmHg, P = 0.001). Intravenous iron attenuated the PASP rise in both groups; however, the effect was greater in ID participants than in controls (absolute reductions 11.1 and 6.8 mmHg, respectively; 95% CI for difference in change, -8.3 to -0.3 mmHg, P = 0.035). Serum erythropoietin responses to hypoxia also differed between groups. CONCLUSION: Clinical iron deficiency disturbs normal responses to hypoxia, as evidenced by exaggerated hypoxic pulmonary hypertension that is reversed by subsequent iron administration. Disturbed hypoxia sensing and signaling provides a mechanism through which iron deficiency may be detrimental to human health. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01847352). FUNDING: M.C. Frise is the recipient of a British Heart Foundation Clinical Research Training Fellowship (FS/14/48/30828). K.L. Dorrington is supported by the Dunhill Medical Trust (R178/1110). D.J. Roberts was supported by R&D funding from National Health Service (NHS) Blood and Transplant and a National Institute for Health Research (NIHR) Programme grant (RP-PG-0310-1004). This research was funded by the NIHR Oxford Biomedical Research Centre Programme.

A cross-sectional study of the prevalence and associations of iron deficiency in a cohort of patients with chronic obstructive pulmonary disease.

OBJECTIVES: Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality. Iron deficiency, with or without anaemia, is associated with other chronic conditions, such as congestive heart failure, where it predicts a worse outcome. However, the prevalence of iron deficiency in COPD is unknown. This observational study aimed to determine the prevalence of iron deficiency in COPD and associations with differences in clinical phenotype. SETTING: University hospital outpatient clinic. PARTICIPANTS: 113 adult patients (65% male) with COPD diagnosed according to GOLD criteria (forced expiratory volume in 1 s (FEV1): forced vital capacity (FVC) ratio <0·70 and FEV1 <80% predicted); with age-matched and sex-matched control group consisting of 57 healthy individuals. MAIN OUTCOME MEASURES: Prevalence of iron deficiency, defined as: any one or more of (1) soluble transferrin receptor >28.1 nmol/L; (2) transferrin saturation <16% and (3) ferritin <12 µg/L. Severity of hypoxaemia, including resting peripheral arterial oxygen saturation (SpO2) and nocturnal oximetry; C reactive protein (CRP); FEV1; self-reported exacerbation rate and Shuttle Walk Test performance. RESULTS: Iron deficiency was more common in patients with COPD (18%) compared with controls (5%). In the COPD cohort, CRP was higher in patients with iron deficiency (median 10.5 vs 4.0 mg/L, p<0.001), who were also more hypoxaemic than their iron-replete counterparts (median resting SpO2 92% vs 95%, p<0.001), but haemoglobin concentration did not differ. Patients with iron deficiency had more self-reported exacerbations and a trend towards worse exercise tolerance. CONCLUSIONS: Non-anaemic iron deficiency is common in COPD and appears to be driven by inflammation. Iron deficiency associates with hypoxaemia, an excess of exacerbations and, possibly, worse exercise tolerance, all markers of poor prognosis. Given that it has been shown to be beneficial in other chronic diseases, intravenous iron therapy should be explored as a novel therapeutic option in COPD.

Mechanism-based inhibition of HsaD: a C-C bond hydrolase essential for survival of Mycobacterium tuberculosis in macrophage.

Mycobacterium tuberculosis remains the leading cause of death by a bacterial pathogen worldwide. Increasing prevalence of multidrug-resistant organisms means prioritizing identification of targets for antituberculars. 2-hydroxy-6-oxo-6-phenylhexa-2,4-dienoate hydrolase (HsaD), part of the cholesterol metabolism operon, is vital for survival within macrophage. The C-C bond hydrolase, HsaD, has a serine protease-like catalytic triad. We tested a range of serine protease and esterase inhibitors for their effects on HsaD activity. As well as providing a potential starting point for drug development, the data provides evidence for the mechanism of C-C bond hydrolysis. This screen also provides a route to initiate development of fragment-based inhibitors.