A Non-catalytic Function of SETD1A Regulates Cyclin K and the DNA Damage Response.

MLL/SET methyltransferases catalyze methylation of histone 3 lysine 4 and play critical roles in development and cancer. We assessed MLL/SET proteins and found that SETD1A is required for survival of acute myeloid leukemia (AML) cells. Mutagenesis studies and CRISPR-Cas9 domain screening show the enzymatic SET domain is not necessary for AML cell survival but that a newly identified region termed the "FLOS" (functional location on SETD1A) domain is indispensable. FLOS disruption suppresses DNA damage response genes and induces p53-dependent apoptosis. The FLOS domain acts as a cyclin-K-binding site that is required for chromosomal recruitment of cyclin K and for DNA-repair-associated gene expression in S phase. These data identify a connection between the chromatin regulator SETD1A and the DNA damage response that is independent of histone methylation and suggests that targeting SETD1A and cyclin K complexes may represent a therapeutic opportunity for AML and, potentially, for other cancers.

Early Outcomes of Interwoven Nitinol Wire Stent Placement versus Endarterectomy for the Treatment of Atherosclerotic Disease of the Common Femoral Artery.

PURPOSE: To compare the clinical outcomes of common femoral artery (CFA) atherosclerotic disease treated with either surgical endarterectomy or an interwoven nitinol wire stent system. MATERIALS AND METHODS: A retrospective review was conducted of all patients with chronic, de novo atherosclerotic CFA disease treated with surgical endarterectomy (CFAE) or stent placement between July 2019 and March 2022. Outcome measures assessed up to 12 months after procedure included clinical improvement, primary restenosis, target vessel revascularization (TVR), major adverse limb events (MALEs), and all-cause mortality. RESULTS: Thirty-nine stents were deployed in 33 patients, and 56 CFAEs were performed in 55 patients. No differences were noted in the rate of primary patency (95.5% vs 94.4%, P = .618), TVR (2.9% vs 1.8%, P = .777), MALE (5.1% vs 5.4%, P = .949), and all-cause mortality (14.1% vs 3.6%, P = .076) between the stent and CFAE groups up to 12 months after procedure. There was greater improvement in median clinical severity in the stent group than in the CFAE group (Rutherford score change of 3.0 vs 1.5, P = .013). The median length of stay was less for the stent group (3 vs 7 days, P = .002), and there was a lower likelihood of severe or disabling adverse events in the stent group (0 vs 9 cases, P = .010). CONCLUSIONS: Patients treated with an interwoven nitinol wire stent had patency rates comparable to those treated with CFAE while having a lower incidence of severe adverse events and a shorter length of hospital stay than those who underwent CFAE.

Role of noninvasive ocular imaging as a biomarker in peripheral artery disease (PAD): A systematic review.

This study aimed to review the current literature exploring the utility of noninvasive ocular imaging for the diagnosis of peripheral artery disease (PAD). Our search was conducted in early April 2022 and included the databases Medline, Scopus, Embase, Cochrane, and others. Five articles were included in the final review. Of the five studies that used ocular imaging in PAD, two studies used retinal color fundus photography, one used optical coherence tomography (OCT), and two used optical coherence tomography angiography (OCTA) to assess the ocular changes in PAD. PAD was associated with both structural and functional changes in the retina. Structural alterations around the optic disc and temporal retinal vascular arcades were seen in color fundus photography of patients with PAD compared to healthy individuals. The presence of retinal hemorrhages, exudates, and microaneurysms in color fundus photography was associated with an increased future risk of PAD, especially the severe form of the disease. The retinal nerve fiber layer (RNFL) was significantly thinner in the nasal quadrant in patients with PAD compared to age-matched healthy individuals in OCT. Similarly, the choroidal thickness in the subfoveal region was significantly thinner in patients with PAD compared to controls. Patients with PAD also had a significant reduction in the retinal and choroidal circulation in OCTA compared to healthy controls. As PAD causes thinning and ischemic changes in retinal vessels, examination of the retinal vessels using retinal imaging techniques can provide useful information about early microvascular damage in PAD. Ocular imaging could potentially serve as a biomarker for PAD. PROSPERO ID: CRD42022310637.

The ability of the Global Leadership Initiative on Malnutrition (GLIM) to diagnose protein-energy malnutrition in patients requiring vascular surgery: a validation study.

Identifying nutritional deficits and implementing appropriate interventions in patients requiring vascular surgery is challenging due to the paucity of appropriate screening and assessment tools in this group. This retrospective study aimed to determine the validity of the Global Leadership Initiative on Malnutrition (GLIM) in identifying protein-energy malnutrition (PEM) in inpatients admitted to a vascular surgery unit, using the PG-SGA as the comparator. Diagnostic accuracy and consistency were determined between the GLIM and the Patient-Generated Subjective Global Assessment (PG-SGA) global rating. The GLIM determination was made retrospectively using the relevant parameters collected at baseline in the original study. Two hundred and twenty-four (70·1 % male) participants were included. The prevalence of PEM was 28·6 % on GLIM and 17 % via the PG-SGA. Compared with the PG-SGA, the GLIM achieved sensitivity of 73·7 % and specificity of 80·6 %; however positive predictive value was 43·7 % indicating that the GLIM over-diagnosed malnutrition compared with the PG-SGA. Kappa reached 0·427 indicating moderate diagnostic consistency. Due to the absence of an ideal instrument and the complexity of malnutrition often seen in this group which extends beyond PEM to significant micronutrient deficiencies, further work is required to determine the most appropriate instrument in this patient group, and how micronutrient status can also be included in the overall assessment given the critical role of micronutrients in this group.

Accuracy and Reliability of Peripheral Artery Calcium Scoring Systems Using an Intravascular Ultrasound Reference Standard.

BACKGROUND: Peripheral artery calcium scoring systems are commonly used in clinical trials to categorize calcium severity but there are little data on their accuracy and reliability. The purpose of this study was to investigate the accuracy and reliability of these systems. METHODS: Angiographic, computed tomography angiography, and intravascular ultrasound (IVUS) imaging were obtained from 47 consecutive cases sourced from a prospectively collected database of patients undergoing femoropopliteal artery endovascular intervention. Two independent blinded readers graded calcium severity using the Peripheral Arterial Calcium Scoring System, Peripheral Academic Research Consortium, and Fanelli calcium scoring systems. IVUS maximum arc of calcium and calcium length were compared between severity grades for each scoring system. The diagnostic accuracy of each scoring system for identifying severe calcium was calculated using the reference standard of an IVUS maximum calcium arc ≥ 180°. Agreement testing was performed between scoring systems and between and within observers for each system. RESULTS: IVUS identified calcium in 85% (42/47) of cases, compared to 68% (32/47) of cases with angiography. There were no differences in IVUS calcium parameters between grades of calcium for any of the scoring systems. Severe calcium was detected by IVUS in 30 cases, in 23 cases by Peripheral Arterial Calcium Scoring System (sensitivity: 73%, specificity: 33%, positive predictive value [PPV]: 83%, negative predictive value [NPV]: 22%), in 12 cases by Peripheral Academic Research Consortium (sensitivity: 42%, specificity: 83%, PPV: 92%, NPV: 25%), and in 10 cases by Fanelli (sensitivity: 39%, specificity: 100%, PPV: 100%, NPV: 27%). Agreement between scoring systems was weak to moderate (range: k = 0.55-0.74). Interobserver agreement was weak (k = 0.41-0.54) and intraobserver agreement was highly variable ranging from k = 0.41 to k = 0.92. CONCLUSIONS: The poor diagnostic accuracy and weak-to-moderate reliability of calcium scoring systems raise doubts about the use of current calcium scoring systems for use in clinical trials.

Comparison of Angiographic Dissection Classification Systems in the Femoropopliteal Arteries Using IVUS Validation and Reliability Testing.

PURPOSE: Objective assessment of dissection severity is difficult. Recognition of this has led to the creation of classification systems. This study investigated the performance of the National Heart Lung and Blood Institute (NHLBI) and Kobayashi systems at differentiating severity of femoropopliteal dissection using intravascular ultrasound (IVUS) as the reference standard. Comparison between the 2 systems and the inter- and intra-observer reliability were also investigated. MATERIALS AND METHODS: Angiographic and IVUS imaging was assessed in 51 cases sourced from a RCT investigating the use of IVUS in femoropopliteal disease. A total of 2 readers independently scored the angiography images according to NHLBI and Kobayashi dissection classification systems and a consensus score was obtained for each system in each case. The NHLBI classification was condensed into 3 grades of dissection to allow comparison between systems. Dissection length, dissection arc, minimum lumen area, and lumen area stenosis were obtained from the IVUS imaging. IVUS parameters were compared between grades of severity for both systems. Agreement in grading between the systems was assessed and IVUS parameters for each level of dissection severity were compared between systems. Inter and intra-observer agreement tested for each system. RESULTS: Dissection was present on IVUS in 92.2% (47/51) of cases and angiography identified 78.7% (37/47) of these. No difference was present in any IVUS parameters between mild and severe dissections with either classification system. No difference in IVUS findings was present for the same grades of dissection between systems. The 2 systems agreed on severity grade in 47 of 51 cases. The inter-observer agreement was for NHLBI was k=0.549 and k=0.627 for Kobayashi. Intra-observer agreement for NHLBI was k=0.633 and k=0.633 and for Kobayashi was k=0.657 and k=0.297. CONCLUSION: The lack of difference in IVUS parameters between mild and severe dissection for the NHLBI and Kobayashi systems raises doubts about their ability to effectively differentiate dissection severity. Weak to moderate reliability suggests that variability in interpreting dissection may be higher than acceptable. IVUS imaging is more sensitive for detecting dissection than angiography and research is required to establish the value of adding IVUS to dissection classification systems.

The Impact of Degenerative Connective Tissue Disorders on Outcomes Following Endovascular Aortic Intervention in the Global Registry for Endovascular Aortic Treatment.

OBJECTIVE: Endovascular therapy for the management of aortic pathology in patients with degenerative connective tissue disorder (DCTD) is controversial. Current guidelines are based on a paucity of literature and registry data are lacking. This study reports on medium term outcomes of patients with diagnosed DCTD compared to those without DCTD who were included in the W.L. Gore Global Registry for Endovascular Aortic Treatment (GREAT). METHODS: Patients included in the GREAT registry who underwent treatment for any thoracic or abdominal aortic pathology were included and grouped according to the presence or absence of a DCTD. Baseline demographic and procedural data were collected as well as data relating to key outcomes within 5 years follow-up, including all-cause mortality, aortic-related mortality, reinterventions and serious adverse events (SAE). Multivariable Cox proportional hazards models were built to determine if any association existed between the presence of DCTD and any key outcomes. RESULTS: The analysis included 92 (1.9%) with DCTD and 4741 (98.1%) without DCTD. Patients with DCTD were more likely to be female (34.8% vs. 18.5%, P < .0001) and younger (66.8 [15.1] vs. 71.7 [10.3] years, P = .013) than those without DCTD. They were also more likely to have had prior aortic intervention (22.8% vs. 13.9%, P = .015) and an associated branch vessel procedure with the index operation (30.3% vs. 18.6%, P = .005). The majority of reinterventions in both groups occurred within the first 2 years and multivariable models demonstrated that the presence of DCTD was not predictive of all-cause mortality, aortic-related mortality, reinterventions or SAE within 5 years. CONCLUSIONS: Within the limitations of registry data, this work demonstrates the medium term safety and durability of endovascular stent-grafts across a spectrum of aortic pathology in some patients with DCTD. More work is required to determine the applicability of these findings to specific sub-types of DCTD and aortic pathology.

Identification of micro-channels within chronic total occlusions using contrast-enhanced ultrasound.

BACKGROUND: Vascular micro-channels within chronic total occlusions (CTO) have been identified in histopathology and animal studies. They have been proposed as a potential path for achieving endovascular crossing via the lumen. There are currently no noninvasive means of imaging these structures. The aim of this study was to investigate whether contrast-enhanced ultrasound (CEUS) examination can identify micro-channels within CTO in humans. METHODS: CTO within the femoropopliteal arteries were imaged with CEUS examination in 38 patients. Segments containing micro-channels were identified and their length measured. The proportion of occlusion length containing micro-channels was assessed for each case. Micro-channel appearances including linear or tortuous configuration, crossing of occlusion caps, and connections to vasa vasorum were recorded. RESULTS: The median CTO length was 17.0 cm (interquartile range [IQR], 6.9-27.9 cm) and median age of CTO was 12 months (IQR, 6-16 months). Micro-channels were identified in 92.1% of cases (35/38). The median length within a lesion containing micro-channels was 6.4 cm (IQR, 2.4-14.3 cm) and median proportion of CTO containing micro-channels was 47.9% (IQR, 1.7%-28.5%). A linear micro-channel configuration was seen in 84.2% of cases and a tortuous configuration was seen in 57.9% of cases. Micro-channel connections through the cap were seen in 50% (19/38 cases) and connections to the vasa vasorum in 71.1% (27/38 cases). No association was found between the proportion of each lesion containing micro-channels and CTO age, lesion length or calcification severity. There were no adverse effects related to contrast use. CONCLUSIONS: CEUS can be used to detect micro-channels in CTO in human femoropopliteal arteries. This imaging technique is safe and minimally invasive and may represent a practical method for selection of occlusion crossing method. Further work is required to determine whether identification of micro-channels can be used to improve treatment decision-making and provide a better understanding of the natural history of femoropopliteal CTO.

Self-Assembled Nickel-4 Supramolecular Squares and Assays for HER Electrocatalysts Derived Therefrom.

Solid-state structures find a self-assembled tetrameric nickel cage with carboxylate linkages, [Ni(N2S'O)I(CH3CN)]4 ([Ni-I]40), resulting from sulfur acetylation by sodium iodoacetate of an [NiN2S]22+ dimer in acetonitrile. Various synthetic routes to the tetramer, best described from XRD as a molecular square, were discovered to generate the hexacoordinate nickel units ligated by N2Sthioether, iodide, and two carboxylate oxygens, one of which is the bridge from the adjacent nickel unit in [Ni-I]40. Removal of the four iodides by silver ion precipitation yields an analogous species but with an additional vacant coordination site, [Ni-Solv]+, a cation but with coordinated solvent molecules. This also recrystallizes as the tetramer [Ni-Solv]44+. In solution, dissociation into the (presumed) monomer occurs, with coordinating solvents occupying the vacant site [Ni(N2S'O)I(solv)]0, ([Ni-I]0). Hydrodynamic radii determined from 1H DOSY NMR data suggest that monomeric units are present as well in CD2Cl2. Evans method magnetism values are consistent with triplet spin states in polar solvents; however, in CD2Cl2 solutions no paramagnetism is evident. The abilities of [Ni-I]40 and [Ni-Solv]44+ to serve as sources of electrocatalysts, or precatalysts, for the hydrogen evolution reaction (HER) were explored. Cyclic voltammetry responses and bulk coulometry with gas chromatographic analysis demonstrated that a stronger acid, trifluoroacetic acid, as a proton source resulted in H2 production from both electroprecatalysts; however, electrocatalysis developed primarily from uncharacterized deposits on the electrode. With acetic acid as a proton source, the major contribution to the HER is from homogeneous electrocatalysis. Overpotentials of 490 mV were obtained for both the solution-phase [Ni-I]0 and [Ni-Solv]+. While the electrocatalyst derived from [Ni-Solv]+ has a substantially higher TOF (102 s-1) than [Ni-I]0 (19 s-1), it has a shorter catalytically active lifespan (4 h) in comparison to [Ni-I]0 (>18 h).

Multi-omics tools for studying microbial biofilms: current perspectives and future directions.

The advent of omics technologies has greatly improved our understanding of microbial biology, particularly in the last two decades. The field of microbial biofilms is, however, relatively new, consolidated in the 1980s. The morphogenic switching by microbes from planktonic to biofilm phenotype confers numerous survival advantages such as resistance to desiccation, antibiotics, biocides, ultraviolet radiation, and host immune responses, thereby complicating treatment strategies for pathogenic microorganisms. Hence, understanding the mechanisms governing the biofilm phenotype can result in efficient treatment strategies directed specifically against molecular markers mediating this process. The application of omics technologies for studying microbial biofilms is relatively less explored and holds great promise in furthering our understanding of biofilm biology. In this review, we provide an overview of the application of omics tools such as transcriptomics, proteomics, and metabolomics as well as multi-omics approaches for studying microbial biofilms in the current literature. We also highlight how the use of omics tools directed at various stages of the biological information flow, from genes to metabolites, can be integrated via multi-omics platforms to provide a holistic view of biofilm biology. Following this, we propose a future artificial intelligence-based multi-omics platform that can predict the pathways associated with different biofilm phenotypes.

Effect of student-led health interventions on patient outcomes for those with cardiovascular disease or cardiovascular disease risk factors: a systematic review.

BACKGROUND: As the need for health care services rise, alternative service delivery models such as student-led health interventions become attractive alternatives to alleviate the burden on healthcare. Predominantly, student-led health interventions were free clinics servicing socially disadvantaged communities in the USA. A 2015 systematic review identified that students value these student-run clinics and reported skill and knowledge attainment from participating. Previous research has reported on patient satisfaction outcomes, but less frequently about the clinical outcomes patients accrue from these student-delivered services. As cardiovascular disease is the leading cause of death worldwide, this review aimed to explore the effectiveness of student-led health interventions through examining their impact on objective clinical outcomes, using the case of patients at risk of, or with, cardiovascular disease. METHODS: A systematic literature search was conducted in eight electronic databases to identify student-led health interventions conducted on adults with a cardiovascular disease risk factor or established cardiovascular disease, and a clinical outcome of interest. Through double-blinded screening and data extraction, sixteen studies were identified for synthesis. RESULTS: The majority of student-led health interventions for patients at risk of cardiovascular disease demonstrated a positive impact on patient health. Statistically significant changes amongst patients at risk of cardiovascular disease appeared to be associated with student-led individualised intervention or group-based interventions amongst patients with diabetes or those who are overweight or obese. The evidence was of moderate quality, as included studies lacked a control group for comparison and detail to enable the intervention to be replicated. CONCLUSIONS: Future research applying a student-led health intervention through a randomised control trial, with rigorous reporting of both student and patient interventions and outcomes, are required to further understand the effectiveness of this alternative service delivery model.

Outcomes of Sub-threshold Abdominal Aortic Aneurysms Undergoing Surveillance in Patients Aged 85 Years or Over.

OBJECTIVE: Despite an increasing elderly population there is limited evidence regarding the surveillance and management of small abdominal aortic aneurysms (AAAs) in octogenarians. This study investigated outcomes of patients aged ≥85 years undergoing AAA surveillance to identify whether discontinuation of surveillance might be safe. METHODS: This was a retrospective cohort study of all patients aged 85 years undergoing surveillance with a small (30-54 mm) AAA between January 2007 and November 2017. Patients were stratified depending on aneurysm diameter at index (<40 mm, 40-50 mm, > 50 mm). A threshold of 55 mm was used to decide intervention in all patients. Subsequent management of threshold aneurysms, aneurysm related and all cause mortality were also collected. RESULTS: One hundred and one patients were included (88 male, mean diameter at index 45 mm, median follow up 56.0 months). The majority of patients (72.3%) undergoing surveillance had not reached threshold at the end of follow up. Only one patient in the <40 mm group developed a threshold aneurysm, compared with five (11.6%) and 22 (75.9%) in the 40-50 mm and >50 mm groups, respectively (p < .0001). Of the 28 patients reaching threshold, eight (28.6%) underwent surgical repair (5 standard endovascular, one complex endovascular, and two open). Twenty-six (25.7%) patients died during follow up, with cardiorespiratory pathologies being the leading cause of death. Only three aneurysm related deaths were observed, including two fatal ruptures and one death following repair from an infected stent graft (all in the >50 mm index group). CONCLUSION: The present data suggests that discontinuation of aneurysm surveillance in patients aged 85 years with aneurysms < 40 mm might be safe. In patients with a larger aneurysm or those approaching threshold, early assessment of fitness for surgery may prevent unnecessary surveillance. The decision to treat aneurysms reaching threshold is complex but is appropriate in selected patients.

An evaluation of the validity of nutrition screening and assessment tools in patients admitted to a vascular surgery unit.

Vascular surgery patients are nutritionally vulnerable. Various malnutrition screening and assessment tools are available; however, none has been developed or validated in vascular patients. The present study aimed to: (1) investigate the validity of four commonly administered malnutrition screening tools (Malnutrition Screening Tool (MST), Malnutrition Universal Screening Tool (MUST), Nutrition Risk Screen-2002 (NRS-2002) and the Mini-Nutritional Assessment - Short Form (MNA-SF) and an assessment tool (the Patient-Generated Subjective Global Assessment (PG-SGA)) compared against a comprehensive dietitian's assessment and (2) evaluate the ability of the instruments to predict outcomes. Vascular inpatients were screened using the four malnutrition screening tools and assessed using the PG-SGA. Each was assessed by a dietitian incorporating nutritional biochemistry, anthropometry and changes in dietary intake. Diagnostic accuracy, consistency and predictive ability were determined. A total of 322 (69·3 % male) patients participated, with 75 % having at least one parameter indicating nutritional deficits. No instrument achieved the a priori levels for sensitivity (14·9-52·5 %). Neither tool predicted EuroQoL 5-dimension 5-level score. All tools except the MNA-SF were associated with length of stay (LOS); however, the direction varied with increased risk of malnutrition on the MUST and NRS-2002 being associated with shorter LOS (P=0·029 and 0·045) and the reverse with the MST and PG-SGA (P=0·005 and <0·001). The NRS-2002 was associated with increased risk of complications (P=0·039). The MST, NRS-2002 and PG-SGA were predictive of discharge to an institution (P=0·004, 0·005 and 0·003). The tools studied were unable to identify the high prevalence of undernutrition; hence, vascular disease-specific screening and/or assessment tools are warranted.

Nutritional status of patients admitted to a metropolitan tertiary care vascular surgery unit.

BACKGROUND AND OBJECTIVES: Undernutrition in vascular surgery patients has a significant impact on clinical outcomes. This observational study aimed to investigate the nutritional status of a heterogeneous sample of vascular surgery inpatients and to determine the prevalence of nutritional risk, malnutrition (including nutrient deficiencies) and sarcopenia. METHODS AND STUDY DESIGN: All participants were screened for risk of malnutrition using the Malnutrition Universal Screening Tool (MUST) and assessed using the Patient-Generated Subjective Global Assessment (PG-SGA). Micronutrient status was examined via plasma/serum samples. The presence of sarcopenia was explored using an accepted algorithm incorporating gait speed, muscle mass (DEXA) and grip strength. RESULTS: 322 participants (69% male, mean age 67.6±14.1y) consented to the study. 12.5% were identified as at risk of malnutrition by the MUST while 15.8% were deemed malnourished by the PG-SGA. Only 5% were diagnosed as sarcopenic. Prevalence of malnutrition was much higher when micronutrients were examined with 79% showing low vitamin C, 56% low vitamin D and over 40% having low zinc, vitamin B-12 and folate. A smaller proportion were also low in selenium (19%). CONCLUSIONS: Patients with vascular disease are a nutritionally vulnerable group. The MUST and PG-SGA did not identify the full extent of nutritional deficiencies. Further investigation is warranted to assess tool validity in this group. A number of micronutrients are crucial in these patients and hence a more comprehensive assessment that encompasses a wider range of parameters, including micronutrient status appears warranted.

The effect of supervised exercise therapy for intermittent claudication on lower limb lean mass.

OBJECTIVE: Supervised exercise is currently recommended for the first-line treatment of intermittent claudication based on improvement in walking capacity. However, the promotion of skeletal muscle atrophy by repetitive ischemia-reperfusion caused by treadmill-based programs remains a concern. Because preservation of skeletal muscle mass (SMM) and lean mass (LM) is integral to functional capacity and longevity, this study measured the effect of standard treadmill-based supervised exercise on SMM and regional lower limb LM in patients with intermittent claudication. METHODS: Patients with calf claudication caused by infrainguinal peripheral artery disease underwent whole-body dual-energy X-ray absorptiometry scanning before and after completion of a 12-week supervised treadmill exercise program. Total body SMM and lower limb LM were measured according to anatomical regions of the lower limb (thigh vs calf) and side of symptoms. Walking performance was assessed using pain-free walking distance and 6-minute walking distance tests. RESULTS: Thirty-six patients with calf claudication completed exercise training and dual-energy X-ray absorptiometry scanning, allowing analysis of 55 symptomatic and 17 asymptomatic lower limbs. No difference in total body SMM (P = .41) or LM of symptomatic (P = .53) or asymptomatic calves (P = .59) was detected after the program. In contrast, a significant decrease in LM was observed in symptomatic (P = .04) and asymptomatic thighs (P = .005). Pain-free walking distance (P = .001) and the 6-minute walking distance both improved significantly (P = .004) but were not associated with changes in LM. CONCLUSIONS: Twelve weeks of standard treadmill-training for intermittent calf claudication did not result in loss of calf LM; however, a significant decrease in bilateral thigh LM was observed, even in patients with unilateral symptoms. Further research on optimum exercise modalities and end points are required to determine the pathophysiology and effects of these changes on function and survival.

Do Medications Commonly Prescribed to Patients with Peripheral Arterial Disease Have an Effect on Nutritional Status? A Review of the Literature.

BACKGROUND: Polypharmacy is common among patients with peripheral arterial disease (PAD) with a combination of medications used for risk-factor modification and medical management of the disease itself. Interaction between commonly prescribed medications and nutritional status has not previously been well described. This review aims to critically appraise evidence exploring associations between medications commonly prescribed to patients with PAD and nutritional status and provide recommendations for practice. METHODS: A comprehensive literature search was conducted to locate studies relating to nutrient interactions among lipid-lowering, antihypertensive, antiplatelet, and oral hypoglycemic drug classes. Quality of the evidence was rated on the basis of recommendations by the National Health and Medical Research Council. RESULTS: A total of 25 articles were identified as suitable and included in the review. No studies were specific to patients with PAD, and hence findings highlighting risk of ubiquinone (coenzyme Q10 [CoQ10]) depletion with lipid-lowering medications, zinc depletion with antihypertensive medications, and vitamin B12 depletion with oral hypoglycemic medications are extrapolated from heterogeneous groups of patients and healthy adults. The body of evidence ranged in quality from satisfactory to poor. CONCLUSIONS: High-quality research is required to confirm the interactions suggested by the included studies in patients with PAD specifically. It is, however, recommended that patients with PAD that are long-term consumers of the selected medications are monitored for CoQ10, zinc, and vitamin B12 to facilitate early identification of deficiencies and initiation of treatment. Treatment may involve dietary intervention and/or supplementation.

Validation of a Brief Dietary Assessment Tool for Estimating Dietary EPA and DHA Intake in Australian Adults at Risk of Cardiovascular Disease.

BACKGROUND: Short food frequency questionnaires (FFQs) are powerful screening instruments for estimating nutrient intakes and play an important role in risk stratification in vulnerable populations. Omega-3 fatty acids are of increasing importance in the prevention of chronic and degenerative disease, especially in older adults who are at higher risk of these chronic conditions. A short FFQ exists to rapidly assess omega-3 intake from marine sources, however it has not previously been validated for agreement with total omega-3 intake and ability to identify suboptimal omega-3 intakes in older adults or for use in Australia. OBJECTIVE: The aim of the study was to validate a 9-item marine omega-3 FFQ (MFQ) for assessment of omega-3 intake against a validated 74-item semiquantitative FFQ. METHODS: One hundred and eight participants (mean age 67 ± 10 years, 47% male) completed the MFQ designed to estimate omega-3 intake from marine sources and the 74-item FFQ designed to estimate usual omega-3 and total energy intake in addition to other nutrients. To test agreement between the two questionnaires for estimating total omega-3 intake, mean bias and 95% limits of agreement (LOA) were calculated. Sensitivity and specificity were assessed using 2 × 2 contingency tables based on whether participants did or did not meet National Heart Foundation (NHF) recommendations for omega-3 intake per day. RESULTS: Mean intake of omega-3 estimated from the MFQ was 210 ± 235 mg/day compared with 295 ± 260 mg/day as estimated by the FFQ. Mean bias (95% LOA) for omega-3 assessed by the two questionnaires was 89 mg/day (-475 mg to 653 mg). The MFQ achieved 98% sensitivity and 31% specificity for the omega-3 cut-off of 500 mg/day. When nutrient composition of the marine products were replaced with Australian data, mean intake of omega-3 was 230 ± 253 mg and the mean bias improved to 64 mg (-681 mg to 553 mg) and achieved 93% sensitivity and 40% specificity. CONCLUSIONS: The MFQ shows promise as a rapid screening tool for identifying older adults with intakes of omega-3 fatty acids likely to be below recommendations for chronic and degenerative disease risk reduction. Given the clinically meaningful mean bias and wide LOA, it cannot be recommended as an appropriate tool for the purpose of reporting average intake of individuals. Use of Australian nutrient data improved the mean bias of the tool in estimating total omega-3 intake. The values should be replaced and the MFQ could then be a useful tool for research purposes at the population level.

The impact of different supervised exercise regimens on endothelial function in patients with intermittent claudication.

BACKGROUND AND OBJECTIVES: The impact of supervised exercise training on endothelial function in patients with intermittent claudication is unclear. This study assesses the impact of treadmill-based supervised exercise training alone or in combination with resistance training on pain free walking distance, flow-mediated dilatation, reactive hyperaemia index, nitric oxide and asymmetric dimethylarginine. METHODS: Thirty-five patients with intermittent claudication were randomised to 12 weeks of treadmill-only supervised exercise training (Group 1) or a combination of treadmill and lower-limb resistance supervised exercise training (Group 2). Pain free walking distance was assessed by six-minute walk test. Endothelial function was assessed by brachial artery flow-mediated dilatation, reactive hyperaemia index and serum analysis of asymmetric dimethylarginine and nitric oxide. RESULTS: Pain free walking distance improved within Group 1 (160 m to 204 m, p = 0.03) but not Group 2 (181 m to 188 m, p = 0.82), no between group difference. No significant change in flow-mediated dilatation or reactive hyperaemia index in either group. Nitric oxide decreased in Group 1 (15.0 µmol/L to 8.3 µmol/L, p = 0.003) but not Group 2 (11.2 µmol/L to 9.1 µmol/L, p = 0.14), p = 0.07 between groups. Asymmetric dimethylarginine decreased in Group 2 (0.61 µmol/L to 0.56 µmol/L, p = 0.03) but not Group 1 (0.58 µmol/l to 0.58 µmol/L, p = 0.776), no between group difference. CONCLUSION: Supervised exercise training does not improve endothelial function as measured by flow-mediated dilatation, reactive hyperaemia index and nitric oxide bioavailability.

Pharmacogenomics of EGFR-targeted therapies in non-small cell lung cancer: EGFR and beyond.

Commonly observed aberrations in epidermal growth factor receptor (EGFR) signaling have led to the development of EGFR-targeted therapies for various cancers, including non-small cell lung cancer (NSCLC). EGFR mutations and overexpression have further been shown to modulate sensitivity to these EGFR-targeted therapies in NSCLC and several other types of cancers. However, it is clear that mutations and/or genetic variations in EGFR alone cannot explain all of the variability in the responses of patients with NSCLC to EGFR-targeted therapies. For instance, in addition to EGFR genotype, genetic variations in other members of the signaling pathway downstream of EGFR or variations in parallel receptor tyrosine kinase (RTK) pathways are now recognized to have a significant impact on the efficacy of certain EGFR-targeted therapies. In this review, we highlight the mutations and genetic variations in such genes downstream of EGFR and in parallel RTK pathways. Specifically, the directional effects of these pharmacogenetic factors are discussed with a focus on two commonly prescribed EGFR inhibitors: cetuximab and erlotinib. The results of this comprehensive review can be used to optimize the treatment of NSCLC with EGFR inhibitors. Furthermore, they may provide the rationale for the design of subsequent combination therapies that involve the inhibition of EGFR.

Pharmacist influence on prescribing in peripheral arterial disease (PIPER).

The objective of this study was to determine the association between a specialist clinical pharmacist working in collaboration with medical staff and prescribing in peripheral arterial disease (PAD). A retrospective cohort study was conducted comparing the influence of a dedicated clinical pharmacist on two samples of patients admitted to a single vascular surgery unit in either 2007 (control group) prior to implementation of a comprehensive clinical pharmacy service or 2009 (comparison group) post implementation. Data were obtained via review of medical records and electronic reports. A total of 685 patients were identified, resulting in 964 admissions. The patient to pharmacist ratio decreased from 62 to 33 patients per day in 2009. More patients were initiated on an antiplatelet (OR 4.6, 95% CI 2.26 to 9.53, p<0.001) and statin (OR 3.4, 95% CI 1.97 to 6, p<0.001) in 2009 compared to 2007. Risk factor modification increased in 2009, resulting in action being taken more often for HbA1c>7% (OR 3.45, 95% CI 1.64 to 7.27, p=0.001), total cholesterol >4 mmol/L in females (OR 14.5, 95% CI 2.67 to 78.6, p=0.002) and blood pressure above target (OR 1.9, 95% CI 1.01 to 3.73, p=0.05) when a comprehensive clinical pharmacist service was available. There was a non-significant reduction in mortality (18.7% (65) to 14.2% (46), p=0.13) and cardiovascular outcomes (5.5% (19) to 4.3% (14), p=0.44) within 12 months of discharge. In conclusion, prescribing of evidence-based medication for PAD and risk factor modification increased with a comprehensive clinical pharmacist service. This study provides important insight into optimising treatment in this patient group and how a pharmacist can be a helpful addition to the multidisciplinary team.