Observational study of the medical management of patients with peripheral artery disease.

BACKGROUND: Previous research has suggested that patients with peripheral artery disease (PAD) are not offered adequate risk factor modification, despite their high cardiovascular risk. The aim of this study was to assess the cardiovascular profiles of patients with PAD and quantify the survival benefits of target-based risk factor modification. METHODS: The Vascular and Endovascular Research Network (VERN) prospectively collected cardiovascular profiles of patients with PAD from ten UK vascular centres (April to June 2018) to assess practice against UK and European goal-directed best medical therapy guidelines. Risk and benefits of risk factor control were estimated using the SMART-REACH model, a validated cardiovascular prediction tool for patients with PAD. RESULTS: Some 440 patients (mean(s.d.) age 70(11) years, 24·8 per cent women) were included in the study. Mean(s.d.) cholesterol (4·3(1·2) mmol/l) and LDL-cholesterol (2·7(1·1) mmol/l) levels were above recommended targets; 319 patients (72·5 per cent) were hypertensive and 343 (78·0 per cent) were active smokers. Only 11·1 per cent of patients were prescribed high-dose statin therapy and 39·1 per cent an antithrombotic agent. The median calculated risk of a major cardiovascular event over 10 years was 53 (i.q.r. 44-62) per cent. Controlling all modifiable cardiovascular risk factors based on UK and European guidance targets (LDL-cholesterol less than 2 mmol/l, systolic BP under 140 mmHg, smoking cessation, antiplatelet therapy) would lead to an absolute risk reduction of the median 10-year cardiovascular risk by 29 (20-38) per cent with 6·3 (4·0-9·3) cardiovascular disease-free years gained. CONCLUSION: The medical management of patients with PAD in this secondary care cohort was suboptimal. Controlling modifiable risk factors to guideline-based targets would confer significant patient benefit.

Synthesis and summary of patient-reported outcome measures to inform the development of a core outcome set in colorectal cancer surgery.

AIM: Patient-reported outcome (PRO) measures (PROMs) are standard measures in the assessment of colorectal cancer (CRC) treatment, but the range and complexity of available PROMs may be hindering the synthesis of evidence. This systematic review aimed to: (i) summarize PROMs in studies of CRC surgery and (ii) categorize PRO content to inform the future development of an agreed minimum 'core' outcome set to be measured in all trials. METHOD: All PROMs were identified from a systematic review of prospective CRC surgical studies. The type and frequency of PROMs in each study were summarized, and the number of items documented. All items were extracted and independently categorized by content by two researchers into 'health domains', and discrepancies were discussed with a patient and expert. Domain popularity and the distribution of items were summarized. RESULTS: Fifty-eight different PROMs were identified from the 104 included studies. There were 23 generic, four cancer-specific, 11 disease-specific and 16 symptom-specific questionnaires, and three ad hoc measures. The most frequently used PROM was the EORTC QLQ-C30 (50 studies), and most PROMs (n = 40, 69%) were used in only one study. Detailed examination of the 50 available measures identified 917 items, which were categorized into 51 domains. The domains comprising the most items were 'anxiety' (n = 85, 9.2%), 'fatigue' (n = 67, 7.3%) and 'physical function' (n = 63, 6.9%). No domains were included in all PROMs. CONCLUSION: There is major heterogeneity of PRO measurement and a wide variation in content assessed in the PROMs available for CRC. A core outcome set will improve PRO outcome measurement and reporting in CRC trials.

Peripheral arterial disease and revascularization of the diabetic foot.

Diabetes is a complex disease with many serious potential sequelae, including large vessel arterial disease and microvascular dysfunction. Peripheral arterial disease is a common large vessel complication of diabetes, implicated in the development of tissue loss in up to half of patients with diabetic foot ulceration. In addition to peripheral arterial disease, functional changes in the microcirculation also contribute to the development of a diabetic foot ulcer, along with other factors such as infection, oedema and abnormal biomechanical loading. Peripheral arterial disease typically affects the distal vessels, resulting in multi-level occlusions and diffuse disease, which often necessitates challenging distal revascularisation surgery or angioplasty in order to improve blood flow. However, technically successful revascularisation does not always result in wound healing. The confounding effects of microvascular dysfunction must be recognised--treatment of a patient with a diabetic foot ulcer and peripheral arterial disease should address this complex interplay of pathophysiological changes. In the case of non-revascularisable peripheral arterial disease or poor response to conventional treatment, alternative approaches such as cell-based treatment, hyperbaric oxygen therapy and the use of vasodilators may appear attractive, however more robust evidence is required to justify these novel approaches.

Management of peripheral arterial disease and the diabetic foot.

The management of peripheral arterial disease (PAD) in patients with diabetic foot ulceration (DFU) is complex and there is a lack of robust evidence to guide definitive treatment strategies. Due to the distinct differences in etiology, disease distribution and treatment outcomes patients with diabetes, PAD and foot ulceration should be considered separately from those without diabetes. There is no randomized trial data to compare angioplasty and surgical bypass for revascularization in patients with DFU and PAD and the decision of whether, and how, to revascularize should be taken by experienced surgeons, in a multidisciplinary setting. Revascularization is only part of a treatment regimen which includes aggressive management of infection, neuropathy, foot deformity and cardiovascular risk. The burden and challenge of DFU in the context of PAD is continuing to increase and new research studies should be targeted specifically towards this ever-expanding group of patients.

A systematic review of outcome reporting in colorectal cancer surgery.

AIM: Evaluation of surgery for colorectal cancer (CRC) is necessary to inform clinical decision-making and healthcare policy. The standards of outcome reporting after CRC surgery have not previously been considered. METHOD: Systematic literature searches identified randomized and nonrandomized prospective studies reporting clinical outcomes of CRC surgery. Outcomes were listed verbatim, categorized into broad groups (outcome domains) and examined for a definition (an appropriate textual explanation or a supporting citation). Outcome reporting was considered inconsistent if results of the outcome specified in the methods were not reported. Outcome reporting was compared between randomized and nonrandomized studies. RESULTS: Of 5644 abstracts, 194 articles (34 randomized and 160 nonrandomized studies) were included reporting 766 different clinical outcomes, categorized into seven domains. A mean of 14 ± 8 individual outcomes were reported per study. 'Anastomotic leak', 'overall survival' and 'wound infection' were the three most frequently reported outcomes in 72, 60 and 44 (37.1%, 30.9% and 22.7%) studies, respectively, and no single outcome was reported in every publication. Outcome definitions were significantly more often provided in randomized studies than in nonrandomized studies (19.0% vs 14.9%, P = 0.015). One-hundred and twenty-seven (65.5%) papers reported results of all outcomes specified in the methods (randomized studies, n = 21, 61.5%; nonrandomized studies, n = 106, 66.2%; P = 0.617). CONCLUSION: Outcome reporting in CRC surgery lacks consistency and method. Improved standards of outcome measurement are recommended to permit data synthesis and transparent cross-study comparisons.

The safety profile of anti-tumour necrosis factor therapy in inflammatory bowel disease in clinical practice: analysis of 620 patient-years follow-up.

BACKGROUND: Anti-TNF agents are now widely used in Crohn's disease (CD), and in ulcerative colitis (UC). AIM: To review the safety profile of anti-TNF agents in all patients treated with infliximab in Edinburgh from 1999 to 2007. METHODS: Complete data were available on 202/207 patients comprising 157 CD, 42 UC and three coeliac disease. Median follow-up was 2.4 years (1.0-4.9) with a total of 620 patient-years follow-up. About 19.1% of CD patients were subsequently treated with adalimumab. RESULTS: Seven deaths (3.3%) occurred in follow-up; only one death was <1 year post-infliximab (at day 72, from lung cancer). A total of six malignancies (three haematological, three bronchogenic) and six cases of suspected demyelination (three with confirmed neurological disease) were reported. In the 90 days following infliximab, 95 adverse events (36 serious) occurred in 58/202 (28.7%) patients. In all, 42/202 (20.8%) had an infectious event (22 serious) and 27/202 (13.4%) of patients had an infusion reaction: 19 acute (four serious) and eight delayed (three serious). CONCLUSIONS: Serious infections, malignancies and neurological disease complicate anti-TNF use in clinical practice. Although evidence for causality is unclear, potential mechanisms and predisposing factors need to be explored. In individual patients, the risk/benefit analysis needs to be carefully assessed and discussed prior to commencement of therapy.

Blunt splenic trauma.

The treatment of blunt splenic injury has evolved over time from splenectomy in all patients to nonoperative management in stable patients with operation reserved for failures of NOM. While rates of OPSI remain low in trauma patients, splenic salvage in stable patients should be attempted. However, clinical evidence of ongoing blood loss or instability should be addressed with prompt splenectomy. Careful patient selection is of paramount importance in nonoperative management of blunt splenic injury.

Hematopoietic failure after hemorrhagic shock is mediated partially through mesenteric lymph.

OBJECTIVE: To determine whether hemorrhagic shock-induced bone marrow failure is mediated by the gut through the production of toxic mesenteric lymph and whether shock-induced bone marrow failure could be prevented by division of the mesenteric lymphatics. DESIGN: Prospective, controlled study. SETTING: University surgical research laboratory. SUBJECTS: Male Sprague-Dawley rats. INTERVENTIONS: Rats were divided into five groups: unmanipulated controls (n = 12), hemorrhagic shock with laparotomy (n = 8), hemorrhagic shock with mesenteric lymph duct ligation (n = 10), sham shock with laparotomy (n = 6), and sham shock with mesenteric lymph duct ligation (n = 7). At either 3 or 6 hrs after resuscitation, bone marrow was obtained for determination of early (cobblestone forming cells) and late (granulocyte-macrophage colony forming unit and erythroid burst forming unit) hematopoietic progenitor cell growth. Parallel cultures were plated with plasma (1% and 2% v/v) from all groups to determine the effect of lymphatic ligation on hematopoiesis. MEASUREMENTS AND MAIN RESULTS: Bone marrow cellularity, cobblestone forming cells, granulocyte-macrophage colony forming unit, and erythroid burst forming unit growth in rats subjected to hemorrhagic with lymph duct ligation were similar to those observed in sham-treated animals and significantly greater than in rats subjected to shock and laparotomy without lymphatic duct ligation. Plasma from rats subjected to shock without lymph ligation was inhibitory to hematopoietic progenitor cell growth. In contrast, this shock-induced inhibition was not observed with plasma obtained from shocked rats that underwent mesenteric lymph ligation. CONCLUSIONS: Hemorrhagic shock suppresses bone marrow hematopoiesis as measured by a decrease in early and late progenitor cell growth. This suppression appears mediated through mesenteric lymph as the effect is abrogated by mesenteric lymph duct ligation. These data clearly demonstrate a link between the gut and bone marrow failure after hemorrhagic shock

Injury-enhanced calcium mobilization in circulating rat neutrophils models human PMN responses.

G-protein coupled (GPC) chemoattractants are important neutrophil (PMN) activators in human shock and sepsis, acting in part by increasing cytosolic calcium ([Ca2+]i). Rats are widely used as laboratory models of shock and sepsis, but reports of [Ca2+]i flux in circulating rat PMN are rare. Moreover, the [Ca2+]i values reported often differ markedly from human systems. We developed study methods where basal [Ca2+]i values in circulating rat PMN were comparable to human PMN, but rat PMN still mobilized calcium poorly after stimulation. Trauma (laparotomy) did not change rat PMN basal [Ca2+]i, but induced brisk [Ca2+]i responses to chemokine and lipid mediators that approximated human PMN responses. This was associated with marked loading of microsomal calcium stores. Formyl peptides still mobilized calcium less well in rat than human PMN. Normal rat PMN appear to circulate in a less mature or primed form than human PMN. A very limited injury rapidly converts rat PMN to a more activated phenotype. PMN thus activated act quite similar to human PMN in terms of GPC receptor-mediated calcium mobilization. Trauma enhances rat PMN responses to GPC agonists at least in part by loading cell calcium stores.

Assessment of potential groundwater contamination sources in a wellhead protection area.

Determining the human health dangers from potential contamination sources, within a wellhead protection area (WHPA), requires that a risk analysis be undertaken. In this study, a desktop geographic information system and spreadsheet software are used to implement an EPA risk screening methodology for WHPAs called 'Managing Ground Water Contamination Sources in Wellhead Protection Areas--A Priority Setting Approach'. The methodology was applied to a WHPA in Gaston County, North Carolina. Results indicate that the risk of well contamination from an interstate highway and gas station with old steel underground storage tanks were comparatively high. Medium risks included a thoroughfare and highway, while low risks were assigned to machine shops, a body shop, septic systems and a gas station with new underground storage tanks and secondary containment. A sensitivity analyses of the Priority Setting Approach indicated that risk scores were extremely sensitive to hydrogeologic variables such as hydraulic conductivity. It is recommended that risk assessors utilize a range of hydrogeologic parameters to assess overall risk from each potential contamination source.

The immunomodulatory effects of damage control abdominal packing on local and systemic neutrophil activity.

BACKGROUND: Damage control laparotomy (DCL) with abdominal packing has become commonplace after major trauma, but the immune consequences of DCL are unknown. METHODS: We collected 37 fluid samples from laparotomy pads (LPF) removed from 28 patients 1 hour to 7 days after DCL. Samples from eight patients who underwent serial packing were assayed for their mediator content and effects on neutrophil (PMN) function. Respiratory burst (RB) to N-formyl-methionyl-leucyl-phenylalanine and phorbol myristate acetate (PMA), as well as PMN calcium ([Ca2+]i) mobilization by GRO-alpha and platelet-activating factor were studied using dihydrorhodamine and fura-2-acetoxymethyl ester fluorescence. Brief exposure to 20% LPF (LPF20) modeled LPF acting on peritoneal PMNs and 2% LPF (LPF2) modeled the systemic effects on PMNs. Endotoxin (ETX), GRO-alpha, and leukotriene B4 were assayed by enzyme-linked immunosorbent assay. Data analysis was by analysis of variance with Dunn's comparisons or the Mann-Whitney test when indicated. RESULTS: LPF increased N-formyl- methionyl-leucyl-phenylalanine-induced RB from 0.4 +/- 0.1 x 103 counts per second (control) to 0.7 +/- 0.1 (LPF2) to 1.3 +/- 0.3 (LPF20) (p < 0.05), with LPF2 increasingly active at later times after injury. PMA-elicited RB was primed only by LPF2 from < 24 hours. Both LPF2 and LPF20 markedly suppressed GRO-alpha [Ca2+]i flux. Suppression by LPF2 was maximal at < 24 hours, abating after 48 hours. Suppression of GRO-alpha response was dose dependent: 150 +/- 8 nmol/L in control PMNs, 97 +/- 19 after LPF2, and 59 +/- 4 after LPF20 (all p < 0.05). [Ca2+]i flux after 1 nmol/L platelet-activating factor was only suppressed (from 181 +/- 14 nmol/L to 149 +/- 15 nmol/L, p < 0.05) by LPF20. LPF contained ETX, GRO-alpha, and leukotriene B4 at 10- to 20-fold plasma concentration in trauma patients. CONCLUSION: DCL results in peritoneal ETX and mediator accumulation even when cultures are sterile. LPF exposure primes PMN RB elicited by nonreceptor- (PMA) or receptor-coupled agonists that resist receptor desensitization. Conversely, LPF suppresses PMN responses to agonists that undergo receptor desensitization at high mediator concentrations. PMN dysfunction in such circumstances probably reflects a concomitant priming of some cell functions (e.g., RB) and desensitization of other (receptor-dependent) functions after an exposure to concentrated mediators. Peritoneal mediator production after DCL may be ETX driven, and may contribute to systemic inflammatory response syndrome. DCL trades early hemostasis for later inflammation. This should be considered in planning management strategies.

Intestinal perforation secondary to Salmonella typhi: case report and review of the literature.

The case of a young woman presenting with fever, abdominal distention, and diarrhea is presented. While hospitalized, she developed peritonitis, and a laparotomy was performed emergently. Intraoperative and pathologic examinations are highly suggestive of Salmonella typhi as an etiology for her symptoms and eventual perforation. Salmonella enteritis can be a difficult diagnosis to make, but in most cases it is a self-limited disease process. In a minority of cases, multidrug antibiotic therapy may be required secondary to an increasing prevalence of resistant strains. Patients who perforate require prompt operation to limit morbidity and mortality. Outcome is significantly improved in those patients by directed resection of the affected segment of bowel and by aggressive perioperative care.

Estimation of equilibrium constants using automated group contribution methods.

MOTIVATION: Group contribution methods are frequently used for estimating physical properties of compounds from their molecular structures. An algorithm for estimating Gibbs energies of formation through group contribution methods has been automated in an object-oriented framework. The algorithm decomposes compound structures according to a basis set of groups. It permits the use of wildcards and is able to distinguish between ring groups and chain groups that use similar search structures. Past methods relied on manual decomposition of compounds into constituent groups. RESULTS: The software is written in Common LISP and requires < 2 min to estimate Gibbs energies of formation for a database of 780 species of varying size and complexity. The software allows rapid expansion to incorporate different basis sets and to estimate a variety of other physical properties.

Model reduction in the computational modeling of reaction systems.

The underlying assumption for most lumping techniques is that the reduced models must be valid for the entire composition space. This is a harsh requirement that often limits the models that are generated. The scheme that is presented here uses the inherent structure of reaction systems to divide the composition space into regions. Within each region, the order-of-magnitude relationships that exist between terms in the rate equations are used to systematically reduce the order and coupling of the model. The full system is then described through piecewise combination of these simpler, region-specific models. Although these reduced models are based on assumptions that make them invalid globally, they are accurate within the regions for which they have been crafted.

Food safety: a global perspective.

The health of the population of the U.S. is affected by many factors, not the least of which is its food supply. A major source of high quality animal protein comes from poultry, eggs, and meat. The major effect of personal habits and the environment, diet, tobacco, alcohol, are considered, along with the microbiological effect on foodborne illness and health. The inspection system for meat and poultry is reviewed, in light of the publication of significant revisions being instituted at this time. The role of research, regulatory reform, and political science is considered as supportive of food service and consumer education. Education of food service workers, institutional employees, and consumers is a responsibility that the land grant universities should take very seriously. Networking with associations like the National Restaurant Association and its regional affiliates will be invaluable in improving the health of the people of the U.S.

Risk: reality versus perception.

Public perception of food safety and the risks involved with eating are of major concern. Even good science does little to reduce these perceptions of risk. The public does not understand dose response and looks at risk from a different point of view than scientists. Surveys of consumer attitudes do not always accurately reflect what actions consumers prefer.