Supportive Clinical Data Research Articles

Anti-TNF-α therapies in chronic obstructive pulmonary diseases

Background: Chronic obstructive pulmonary disease (COPD) and asthma are chronic diseases in which inflammation of the airways leads to progressive transient airway obstruction and TNF-α plays an important pro-inflammatory role. Objective: To assess the plausibility of anti-TNF-α therapies playing an anti-inflammatory role in asthma and COPD. Methods: Scientific rationale of TNF-α targeting in asthma and COPD was assessed individually and the available data on the use of anti-TNF-α in each disease were reviewed. Results and conclusion: Anti-TNF-α therapies demonstrate different efficacies in asthma and COPD and further supportive preclinical and clinical data are needed, especially about subsets of certain diseases which could benefit the most from these therapies.

The Burden of Hepatitis C Virus Infection Is Growing: A Canadian Population-Based Study of Hospitalizations from 1994 to 2004

Nearly 1% of Canadians are infected with the hepatitis C virus (HCV). Simulation analyses have suggested that HCV will place an increasing burden on the health care system as the infected population ages, but supportive clinical data are limited. To study temporal trends in HCV-related hospitalizations and predictors of increased health care utilization from a Canadian population-based perspective. An administrative hospitalization database from the Calgary Health Region was used to identify patients who were admitted for HCV between 1994 and 2004. The primary outcomes were liver-related HCV hospitalizations, length of stay, hospital costs and in-hospital mortality. Average annual growth rates in outcomes were calculated and subgroup analyses were conducted according to age, sex and HIV/HCV coinfection status. Between 1994 and 2004, there were 4002 HCV-related hospitalizations; 22% were liver-related. Liver-related hospitalizations, lengths of stay and in-hospital mortality increased approximately fourfold or an average of 15% to 18% annually (P<0.0005). Patients aged 40 to 59 years and HIV/HCV coinfected patients experienced the largest average annual growth rates (19% to 27% and 30% to 40%, respectively; P<0.0005), reflecting the accelerated natural history of HCV in these subgroups. Hospital costs for liver-related HCV hospitalizations increased by an average of 41% annually (P=0.001) between 2000 and 2004. The average annual increase in liver-related hospitalizations remained significant in a sensitivity analysis, even when 75% of HCV cases were under-reported in 1994. The present studies' findings confirm the growing burden of HCV on the Canadian health care system. Strategies to prevent HCV infection and maximize the dissemination and most effective use of potentially curative antiviral therapies are necessary to reduce these trends.

Intensity-Modulated Radiation Therapy: Supportive Data for Prostate Cancer

Since its introduction into clinical use in the mid-1990s, intensity-modulated radiation therapy (IMRT) has emerged as the most effective and widely used form of external-beam radiotherapy for localized prostate cancer. Multiple studies have confirmed the importance of delivering sufficiently high doses to the prostate to achieve cure. The dosimetric superiority of IMRT over conventional techniques to produce conformal dose distributions that allow for organ sparing has been shown. A growing number of reports have confirmed that IMRT is the safest way to deliver high doses of external-beam irradiation to the prostate and the regional lymph nodes. Advances in imaging and onboard verification systems continue to advance the capabilities of IMRT and have potential implications with regards to further dose escalation and hypofractionated regimens. The clinical data in support of IMRT and the associated technical aspects of IMRT treatment planning and implementation are highlighted in this review.

Safety and efficacy of insulin detemir in clinical practice: 14-week follow-up data from type 1 and type 2 diabetes patients in the PREDICTIVETM European cohort

PREDICTIVE (Predictable Results and Experience in Diabetes through Intensification and Control to Target: An International Variability Evaluation) is a large, multi-national, open-label, prospective, observational study assessing the safety and efficacy of insulin detemir in clinical practice. A total of 20,531 patients with type 1 or 2 diabetes from 11 countries were prescribed insulin detemir and followed up after a mean of 14.4 weeks. The primary endpoint was incidence of serious adverse drug reactions (SADRs), including major hypoglycaemia. Secondary endpoints were: haemoglobin A(1c) (HbA(1c)), mean self-monitored fasting glucose, within-patient fasting glucose variability and body weight change. Two hundred and fourteen patients (1%) reported SADRs, including major hypoglycaemia. The incidence of major hypoglycaemic episodes was reduced from 3.0/patient-year at baseline to 0.7/patient-year at follow-up in type 1 patients (p < 0.0001), and from 0.8 to 0.1/patient-year in type 2 patients (p < 0.0001). Insulin detemir improved glycaemic control in type 1 and type 2 patients, with reductions in mean HbA(1c) (0.5% and 0.9%, respectively, p < 0.0001 for both), fasting glucose (1.7 and 2.6 mmol/l, p < 0.0001 for both) and within-patient fasting glucose variability (0.7 and 0.5 mmol/l, p < 0.0001 for both). There was a small decrease in mean body weight in both type 1 and 2 patients (-0.1 kg, p < 0.01 and -0.4 kg, p < 0.0001 respectively). Insulin detemir was used once- or twice-daily in 49% and 50% of type 1 patients, and 77% and 23% of type 2 diabetes patients, respectively. The 14-week observations from PREDICTIVE support clinical trial data showing that insulin detemir improves glycaemic control, with a lowered risk of hypoglycaemia and no weight gain.

Comparison of Interleukin-6 and C-Reactive Protein for the Risk of Developing Hypertension in Women

Although markers of systemic inflammation may have a role in the development of hypertension, supportive clinical data remain limited. We, therefore, examined interleukin (IL)-6 and C-reactive protein (CRP) in a nested case-control study of 400 women developing hypertension and an equal number of age-matched normotensive control subjects during 10 years of follow-up as part of the Women's Health Study. All of the women initially had nonhypertensive blood pressure values and no history of diagnosis or treatment. Subjects provided self-reported risk factors, and IL-6 and CRP were measured from baseline bloods. Case subjects reported elevated systolic (>or=140 mm Hg) or diastolic (>or=90 mm Hg) blood pressure, newly diagnosed hypertension, or initiating antihypertensive treatment during follow-up. In crude-matched models, IL-6 and CRP quartiles were each strongly associated with hypertension risk (both Ps for trend <0.0001). In multivariate models, the linear trends became nonsignificant, and the relative risks (95% CIs) of hypertension for IL-6 reduced to 1.00 (ref), 1.29 (0.76 to 2.19), 2.14 (1.23 to 3.73), and 1.70 (0.92 to 3.13) and for CRP were 1.00 (ref), 2.09 (1.16 to 3.76), 2.51 (1.42 to 4.44), and 2.44 (1.29 to 4.64), primarily because of confounding by body mass index. Simultaneous adjustment for IL-6 and CRP modestly attenuated both sets of relative risks, although more for IL-6. Finally, there was no effect modification by baseline blood pressure or other risk factors (all Ps for interaction >0.05). Therefore, after multivariate adjustment and strong confounding by body mass index, IL-6 was weakly associated and CRP strongly associated with hypertension risk. In models simultaneously examining IL-6 and CRP, only CRP remained strongly associated with an increased risk of hypertension.

Clinical Validation of a Physiologically-Based Computer Model of Human Granulopoiesis and Its Use for Improving Cancer Therapy by Doxorubicin and Granulocyte Colony-Stimulating Factor (GCSF).

Neutropenia is a dose-limiting toxicity in dose-intensified chemotherapy regimens. Yet to be determined are the lower limit of inter-dosing interval of chemotherapy and the optimal schedules of GCSF support. In the absence of better tools, the most promising schedules to be tested in clinical trials are selected by trial and error. In order to provide a scientific tool for treatment selection, a physiologically-based, computer-implemented, mathematical model of human granulopoiesis was recently developed (Vainstein et al, J Theor Biol, 2005). The aim of the current study is to validate the model clinically and to use it for suggesting an improved doxorubicin monotherapy schedule, with GCSF support. First, the model was validated by showing its accurate predictions of neutropenia dynamics in patients treated by doxorubicin 75mg/m2 q14d, with GCSF support (clinical data from Bronchud et al, Br J Cancer, 1989). To validate the model ability to predict treatment outcomes for individual patients, it was simulated in conjunction with base-line blood counts and treatment schedules of ten breast cancer patients, who received different doxorubicin monotherapy protocols (20–30mg/m2 q7d, 60–75mg/m2 q21d). Model predictions for each patient were then compared with the patient's neutrophil profile. Results showed that the model accurately predicted doxorubicin-induced neutropenia course in all patients examined (see example in Figure 1). To identify a new intensified regimen, which minimizes myelotoxicity, simulations were performed of different doxorubicin+GCSF treatment schedules. Results suggest that 4 days is the optimal gap before starting GCSF support, following administration of doxorubicin 75mg/m2 q14d. No grade 3/4 neutropenia is expected under such a regimen, as compared to 3–4 days neutropenia when the gap before starting GCSF support was 1 day (Bronchud et al, 1989). It is further predicted that under the suggested schedule of GCSF support, doxorubicin monotherapy can be intensified, either to120mg/m2 q14d, by dose-escalation alone, or to 90mg/m2 q10d, by combining dose-escalation and increased dose-density. Such intensification is expected to result in 1–2 days of grade 3/4 neutropenia, as compared to 3–4 days long neutropenia in the doxorubicin schedule used by Bronchud et al., which has only 62% of the proposed doxorubicin dose intensity. Further research is warranted for clinically validating the superiority of the suggested treatment schedules. These results suggest that if the involved cellular dynamics are precisely calculated, doxorubicin schedule can be further intensified, accompanied by GCSF support, with no significant increase in myelotoxicity. Showing precision in predicting individual patient's counts, the computer model of human granulopoiesis can be used for treatment personalization. [Display omitted]

Haemodynamic effects of adrenaline (epinephrine) depend on chest compression quality during cardiopulmonary resuscitation in pigs

Adrenaline (epinephrine) is used during cardiopulmonary resuscitation (CPR) based on animal experiments without supportive clinical data. Clinically CPR was reported recently to have much poorer quality than expected from international guidelines and what is generally done in laboratory experiments. We have studied the haemodynamic effects of adrenaline during CPR with good laboratory quality and with quality simulating clinical findings and the feasibility of monitoring these effects through VF waveform analysis. After 4 min of cardiac arrest, followed by 4 min of basic life support, 14 pigs were randomised to ClinicalCPR (intermittent manual chest compressions, compression-to-ventilation ratio 15:2, compression depth 30-38 mm) or LabCPR (continuous mechanical chest compressions, 12 ventilations/min, compression depth 45 mm). Adrenaline 0.02 mg/kg was administered 30 s thereafter. Plasma adrenaline concentration peaked earlier with LabCPR than with ClinicalCPR, median (range), 90 (30, 150) versus 150 (90, 270) s (p = 0.007), respectively. Coronary perfusion pressure (CPP) and cortical cerebral blood flow (CCBF) increased and femoral blood flow (FBF) decreased after adrenaline during LabCPR (mean differences (95% CI) CPP 17 (6, 29) mmHg (p = 0.01), FBF -5.0 (-8.8, -1.2) ml min(-1) (p = 0.02) and median difference CCBF 12% of baseline (p = 0.04)). There were no significant effects during ClinicalCPR (mean differences (95% CI) CPP 4.7 (-3.2, 13) mmHg (p = 0.2), FBF -0.2 (-4.6, 4.2) ml min(-1)(p = 0.9) and CCBF 3.6 (-1.8, 9.0)% of baseline (p = 0.15)). Slope VF waveform analysis reflected changes in CPP. Adrenaline improved haemodynamics during laboratory quality CPR in pigs, but not with quality simulating clinically reported CPR performance.

Severe respiratory failure: Advanced treatment options

Severe respiratory failure (including acute lung injury and acute respiratory distress syndrome) continues to be associated with significant mortality and morbidity in patients of all ages. To review the laboratory and clinical data in support of and future directions for the advanced treatment of severe respiratory failure. MEDLINE/PubMed search of all relevant primary and review articles. Our understanding of lung pathophysiology and the role of ventilator-induced lung injury through basic science investigation has led to advances in lung protective strategies for the mechanical ventilation support of patients with severe respiratory failure. Specific modalities reviewed include low-tidal volume ventilation, permissive hypercapnia, the open lung approach, recruitment maneuvers, airway pressure release ventilation, high-frequency oscillatory ventilation, prone positioning, and extracorporeal life support. The pharmacologic strategies (including corticosteroids, surfactant, and nitric oxide) investigated for the treatment of severe respiratory failure are also reviewed. In patients with severe respiratory failure, an incremental approach to the management of severe hypoxemia requires implementation of the strategies reviewed, with knowledge of the evidence base to support these strategies.

Farnesyltransferase Inhibitors Reverse Taxane Resistance

The combination of farnesyltransferase inhibitors (FTIs) and taxanes has been shown to result in potent antiproliferative and antimitotic synergy. Recent phase I and II clinical trials have shown that this combination shows clinical activity in taxane-refractory or taxane-resistant cancer patients. To understand the mechanism behind these clinical observations, we used a cancer cell model of paclitaxel resistance and showed that the FTI/taxane combination retains potent antiproliferative, antimitotic, and proapoptotic activity against the paclitaxel-resistant cells, at doses where each drug alone has little or no activity. To probe the mechanistic basis of these observations, paclitaxel activity was monitored in living cells using the fluorescently conjugated paclitaxel, Flutax-2. We observed that all FTIs tested increase the amount of microtubule-bound Flutax-2 and the number of microtubules labeled with Flutax-2 in both paclitaxel-resistant and paclitaxel-sensitive cells. Importantly, we observed a consequential increase in microtubule stability and tubulin acetylation with the combination of the two drugs, even in paclitaxel-resistant cells, confirming that the enhanced taxane binding in the presence of FTI affects microtubule function. Furthermore, this mechanism is dependent on the function of the tubulin deacetylase, HDAC6, because in cells overexpressing a catalytically inactive HDAC6, FTIs are incapable of enhancing Flutax-2-microtubule binding. Similar results were obtained by using an FTI devoid of farnesyltransferase inhibitory activity, indicating that functional inhibition of farnesyltransferase is also required. Overall, these studies provide a new insight into the functional relationship between HDAC6, farnesyltransferase, and microtubules, and support clinical data showing that the FTI/taxane combination is effective in taxane-refractory patients.

Urine Steroid Hormone Profile Analysis in Cytochrome P450 Oxidoreductase Deficiency: Implication for the Backdoor Pathway to Dihydrotestosterone

Although the "backdoor" pathway to dihydrotestosterone has been postulated in the fetal-to-early-infantile period of patients with cytochrome P450 oxidoreductase deficiency (PORD), clinical data in support of this pathway remain limited. The objective of this study was to obtain clinical evidence for the presence of the backdoor pathway in PORD. This was a collaboration study between laboratories and hospitals. Twenty-two Japanese patients with molecularly confirmed PORD and 1763 control subjects participated in this study. Urine steroid profile analysis was performed by gas chromatography/mass spectrometry. In five patients and 776 control subjects, urine samples were obtained before 12 months of age. The main outcome measure was identification of a urine steroid(s) indicating the backdoor pathway. In the PORD patients, pregnanediol, pregnanetriolone, and pregnanetriol were obviously elevated, and the urine steroid ratios reflecting CYP17A1 and CYP21A2 activities were decreased throughout the examined ages. Furthermore, etiocholanolone and 11-hydroxyandrosterone, which should originate almost exclusively from androstenedione in the conventional "frontdoor" pathway, were grossly normal or somewhat decreased since early infancy, whereas androsterone, which can be derived not only from androstenedione and dihydrotestosterone in the conventional frontdoor pathway but also from 5alpha-pregnane-3alpha,17alpha-diol-20-one in the backdoor pathway, was increased during early infancy and remained grossly normal thereafter. Thus, the androsterone to etiocholanolone ratio was increased during early infancy and remained grossly normal thereafter. 5alpha-Pregnane-3alpha,17alpha-diol-20-one was elevated throughout the examined ages. The increased androsterone excretion during early infancy, as compared with the etiocholanolone and 11-hydroxyandrosterone excretions in the same period, suggests the presence of the backdoor pathway in PORD.

Antimicrobial stewardship

Antimicrobial stewardship is a key component of a multifaceted approach to preventing emergence of antimicrobial resistance. Good antimicrobial stewardship involves selecting an appropriate drug and optimizing its dose and duration to cure an infection while minimizing toxicity and conditions for selection of resistant bacterial strains. Studies conducted over the years indicate that antibiotic use is unnecessary or inappropriate in as many as 50% of cases in the United States, and this creates unnecessary pressure for the selection of resistant species. Because the pharmaceutical industry pipeline for new antibiotics has been curtailed in recent years, and it may be > or = 10 years before important new antibiotics to treat certain resistant bacteria find their way to market, a premium has been set on maintaining the effectiveness of currently available agents. Several strategies, including prescriber education, formulary restriction, prior approval, streamlining, antibiotic cycling, and computer-assisted programs have been proposed to improve antibiotic use. Although rigorous clinical data in support of these strategies are lacking, the most effective means of improving antimicrobial stewardship will most likely involve a comprehensive program that incorporates multiple strategies and collaboration among various specialties within a given healthcare institution. Computer-assisted software programs may be especially useful in implementing these comprehensive programs. The antimicrobial stewardship program at the Hospital of the University of Pennsylvania, which has been shown to improve appropriateness of antibiotic use and cure rates, decrease failure rates, and reduce healthcare-related costs, is used as an example in support of this multifaceted, multidisciplinary approach. At this time, data from well-controlled studies examining the effect of antibacterial stewardship on emergence of resistance are limited, but available data suggest that good antibiotic stewardship reduces rates of Clostridium difficile-associated diarrhea, resistant gram-negative bacilli, and vancomycin-resistant enterococci.

Antimicrobial Stewardship

Antimicrobial stewardship is a key component of a multifaceted approach to preventing emergence of antimicrobial resistance. Good antimicrobial stewardship involves selecting an appropriate drug and optimizing its dose and duration to cure an infection while minimizing toxicity and conditions for selection of resistant bacterial strains. Studies conducted over the years indicate that antibiotic use is unnecessary or inappropriate in as many as 50% of cases in the United States, and this creates unnecessary pressure for the selection of resistant species. Because the pharmaceutical industry pipeline for new antibiotics has been curtailed in recent years, and it may be ≥10 years before important new antibiotics to treat certain resistant bacteria find their way to market, a premium has been set on maintaining the effectiveness of currently available agents. Several strategies, including prescriber education, formulary restriction, prior approval, streamlining, antibiotic cycling, and computer-assisted programs have been proposed to improve antibiotic use. Although rigorous clinical data in support of these strategies are lacking, the most effective means of improving antimicrobial stewardship will most likely involve a comprehensive program that incorporates multiple strategies and collaboration among various specialties within a given healthcare institution. Computer-assisted software programs may be especially useful in implementing these comprehensive programs. The antimicrobial stewardship program at the Hospital of the University of Pennsylvania, which has been shown to improve appropriateness of antibiotic use and cure rates, decrease failure rates, and reduce healthcare-related costs, is used as an example in support of this multifaceted, multidisciplinary approach. At this time, data from well-controlled studies examining the effect of antibacterial stewardship on emergence of resistance are limited, but available data suggest that good antibiotic stewardship reduces rates of Clostridium difficile–associated diarrhea, resistant gram-negative bacilli, and vancomycin-resistant enterococci.

Human histology and persistence of various injectable filler substances for soft tissue augmentation.

An increasing number of soft tissue filler substances have been introduced to the beauty market outside the U.S. which lack experimental and clinical data in support of their claim. Ten commercially available filler substances were examined for biocompatibility and durability: 0.1 cc of each substance was injected deep intradermally into the volar forearm of one of the authors and observed for clinical reaction and permanence. At 1, 3, 6, and 9 months the test sites were excised, histologically examined, and graded according to foreign body reactions classification. Collagen (Zyplast) was phagocytosed at 6 months and hyaluronic acid (Restylane) at 9 months. PMMA microspheres (Artecoll) had encapsulated with connective tissue, macrophages, and sporadic giant cells. Silicone oil (PMS 350) was clinically inconspicuous but dissipated into the tissue, causing a chronic foreign body reaction. Polylactic acid microspheres (New-Fill) induced a mild inflammatory response and had disappeared clinically at 4 months. Dextran microspheres (Reviderm intra) induced a pronounced foreign body reaction and had disappeared at 6 months. Polymethylacrylate particles (Dermalive) induced the lowest cellular reaction but had disappeared clinically at 6 months. Polyacrylamide (Aquamid) was well tolerated and remained palpable to a lessening degree over the entire testing period. Histologically, it dissipated more slowly and was kept in place through fine fibrous capsules. Polyvinylhydroxide microspheres suspended in acrylamide (Evolution) were well tolerated, slowly diminishing over 9 months. Calcium hydroxylapatite microspheres (Radiance FN) induced almost no foreign body reaction but were absorbed by the skin at 12 months. Host defense mechanisms react differently to the various filler materials, but all substances-resorbable or nonresorbable-appeared to be clinically and histologically safe, although all exhibit undesirable side effects. Since the mechanism of late inflammation or granuloma formation is still unknown, early histological findings are not useful in predicting possible late reactions to filler substances.

A reality check for molecular diagnostics in clinical practice.

Molecular diagnostics, while still evolving, has had a major impact on the practice of laboratory medicine. Overall, the technologies that define molecular pathology as a discipline are universally applied to support clinicians in their healthcare delivery. The molecular pathology laboratory began with the transition of a few molecular biology research tools into the clinical laboratory to the more recent development of new technologies and instrumentation solely for clinical laboratory practice. Concomitantly, the demands for expanded applications to address diagnostic/prognostic, risk assessment, predisposition, and therapeutic testing have far outnumbered the capacity of laboratory delivery systems. As this discipline continues to mature, we must be willing to address issues pertaining to clinical utility, financial responsibility, advanced technologies, training and education. In light of the successes of the Human Genome Project and other genome projects, the number of potential nucleic acid targets for molecular diagnostics continues to increase. Given the current technologies, it is possible for a laboratory to develop ‘in-house’ or ‘laboratory developed’ assays on a routine basis for the purpose of diagnostic testing. In addition, industry is rapidly providing reagents under the analyte specific reagent (ASR) rule of the US Food & Drug Administration (FDA). The critical question is which of these nucleic acid targets will be most useful in patient care? In order for this discipline to move forward, we must better understand the clinical utility of tests offered in the laboratory. For example, most infectious diseases have been characterized by the fulfillment of Koch’s postulates which have most often associated a specific organism with a pathologic process. Therefore, identifying this organism in a patient specimen should indicate the presence of disease. However, molecular diagnostic testing has an unprecedented level of sensitivity and specificity. Latent or dormant infections, the presence of normal flora, and co-infections are all issues related to the clinical utility of a molecular microbiologic test. As another example, through genetic testing or genotyping, we are able to identify a gene target in a patient specimen. This qualitative type of data may not be sufficient without supportive clinical outcomes data. We must better understand mutation spectra, the penetrance of a specific mutation, the role of polymorphisms in normal and disease processes, as well as the association of haplotypes with disease processes. A laboratory test is only as meaningful as its interpretation. In this growing arena of molecular diagnostic tests, the paradigm has shifted from that of a technologic/scientific concern to one of a financial concern. Clearly, molecular diagnostic testing has proven itself. Yet, the addition of highly complex testing in conjunction with lack of replacement of traditional testing is viewed as an increase in laboratory costs. Keep in mind that under certain circumstances, an increase in laboratory cost may in fact result in decreased overall institutional healthcare costs. Reimbursement for molecular diagnostic testing varies considerably from state to state and is dependent upon payor mix and capitation rates.

Meeting summary.

Meeting summary.

Low-level inotropic stimulation with type III phosphodiesterase inhibitors in patients with advanced symptomatic chronic heart failure receiving beta-blocking agents.

beta-blocking agents are now well established as a cornerstone therapy in mild to moderate heart failure. Patients with more advanced heart failure depend on adrenergic activation to maintain adequate myocardial function. This leads to significant difficulties in using beta-blockers in advanced or severe heart failure. In addition, recent data indicate that adrenergic withdrawal might be detrimental in some of these patients. In higher doses, positive inotropic agents have been shown to increase mortality when used alone in subsets with advanced heart failure. Preliminary data suggest that the combination of low-dose phosphodiesterase inhibitors and a beta-blocker may be better tolerated and does not appear to be associated with the adverse effects of either therapy used alone. We discuss the theoretic underpinning of this approach and the supportive clinical data.

Aibumin dialysis as a new tool for extracoporeal liver support-clinical data from 19 centers reporting 103 patients and two prospective randomised controlled trials

Aibumin dialysis as a new tool for extracoporeal liver support-clinical data from 19 centers reporting 103 patients and two prospective randomised controlled trials

Aibumin dialysis as a new tool for extracoporeal liver support-clinical data from 19 centers reporting 103 patients and two prospective randomised controlled trials

Aibumin dialysis as a new tool for extracoporeal liver support-clinical data from 19 centers reporting 103 patients and two prospective randomised controlled trials

Application of topographical methods to clinical esophageal manometry

OBJECTIVE: Topographical manometric methods have improved the understanding of esophageal peristalsis in research applications but require a large number of recording sensors. Commonly used methods limited to four sensors were compared to topographical methods to determine whether the latter also had significant clinical utility. METHODS: Two hundred twelve patients referred for esophageal manometry were studied with a data acquisition system having 21 intraluminal recording sites, and the findings were analyzed independently using both limited (pull-through plus four recording sites) and topographical approaches (all sites). Discrepant results were clarified using supportive clinical data. RESULTS: The two methods were in diagnostic agreement in 187 cases (88.2%). Topographical methods correctly identified all 26 patients with achalasia within the group with aperistalsis (n = 36). The limited methods could not confidently identify six achalasia patients and were significantly less effective in segregating aperistaltic disorders ( p < 0.05 across methods). Topographical methods alone detected evidence of incomplete lower esophageal sphincter relaxation in 12 additional patients, eight of whom had clinical data supporting the findings. Topographical methods identified the upper margin of the lower sphincter in all but three subjects (1.4%); limited methods could not identify this location in these and five additional subjects (3.8%) and differed from the topographical measurement by ≥2 cm in 11.9% of cases. CONCLUSIONS: Topographical methods are more accurate than commonly used methods in diagnosing the type of severe motor dysfunction and provide additional information important in the clinical practice of esophageal manometry.

Programs promoting timely sequential antimicrobial therapy: an American perspective

Interventional programs promoting the timely conversion of intravenous to oral antimicrobial therapy have been reported from several hospitals in the U.S.A. and elsewhere. Factors influencing the initiation and conduct of these programs include technological advances, changes in health care delivery or reimbursement, publication of supportive clinical data and growth of clinical pharmacy services. Successful programs employ comprehensive, multidisciplinary strategies to contain antimicrobial-related expenditures using interventions based on structured criteria. Future emphasis on cost-effective drug therapy, advances in computer-based information technology and development of care maps can have favourable influences on the growth of these programs in the U.S.A.