Mitochondrial dysfunction in human hypertrophic cardiomyopathy is linked to cardiomyocyte architecture disruption and corrected by improving NADH-driven mitochondrial respiration.

AIMS: Genetic hypertrophic cardiomyopathy (HCM) is caused by mutations in sarcomere protein-encoding genes (i.e. genotype-positive HCM). In an increasing number of patients, HCM occurs in the absence of a mutation (i.e. genotype-negative HCM). Mitochondrial dysfunction is thought to be a key driver of pathological remodelling in HCM. Reports of mitochondrial respiratory function and specific disease-modifying treatment options in patients with HCM are scarce. METHODS AND RESULTS: Respirometry was performed on septal myectomy tissue from patients with HCM (n = 59) to evaluate oxidative phosphorylation and fatty acid oxidation. Mitochondrial dysfunction was most notably reflected by impaired NADH-linked respiration. In genotype-negative patients, but not genotype-positive patients, NADH-linked respiration was markedly depressed in patients with an indexed septal thickness ≥10 compared with <10. Mitochondrial dysfunction was not explained by reduced abundance or fragmentation of mitochondria, as evaluated by transmission electron microscopy. Rather, improper organization of mitochondria relative to myofibrils (expressed as a percentage of disorganized mitochondria) was strongly associated with mitochondrial dysfunction. Pre-incubation with the cardiolipin-stabilizing drug elamipretide and raising mitochondrial NAD+ levels both boosted NADH-linked respiration. CONCLUSION: Mitochondrial dysfunction is explained by cardiomyocyte architecture disruption and is linked to septal hypertrophy in genotype-negative HCM. Despite severe myocardial remodelling mitochondria were responsive to treatments aimed at restoring respiratory function, eliciting the mitochondria as a drug target to prevent and ameliorate cardiac disease in HCM. Mitochondria-targeting therapy may particularly benefit genotype-negative patients with HCM, given the tight link between mitochondrial impairment and septal thickening in this subpopulation.

Untargeted Metabolomics Identifies Potential Hypertrophic Cardiomyopathy Biomarkers in Carriers of MYBPC3 Founder Variants.

Hypertrophic cardiomyopathy (HCM) is the most prevalent monogenic heart disease, commonly caused by pathogenic MYBPC3 variants, and a significant cause of sudden cardiac death. Severity is highly variable, with incomplete penetrance among genotype-positive family members. Previous studies demonstrated metabolic changes in HCM. We aimed to identify metabolite profiles associated with disease severity in carriers of MYBPC3 founder variants using direct-infusion high-resolution mass spectrometry in plasma of 30 carriers with a severe phenotype (maximum wall thickness ≥20 mm, septal reduction therapy, congestive heart failure, left ventricular ejection fraction <50%, or malignant ventricular arrhythmia) and 30 age- and sex-matched carriers with no or a mild phenotype. Of the top 25 mass spectrometry peaks selected by sparse partial least squares discriminant analysis, XGBoost gradient boosted trees, and Lasso logistic regression (42 total), 36 associated with severe HCM at a p < 0.05, 20 at p < 0.01, and 3 at p < 0.001. These peaks could be clustered to several metabolic pathways, including acylcarnitine, histidine, lysine, purine and steroid hormone metabolism, and proteolysis. In conclusion, this exploratory case-control study identified metabolites associated with severe phenotypes in MYBPC3 founder variant carriers. Future studies should assess whether these biomarkers contribute to HCM pathogenesis and evaluate their contribution to risk stratification.

Measuring sensory and pain thresholds by Semmes-Weinstein monofilaments in patients with leg ulcers: a pilot study.

OBJECTIVE: Pain is a common and disabling symptom in patients with leg ulcers. Clinical quantification of pain mostly depends on subjective pain reports, which do not reveal underlying mechanisms. The aim of this pilot study is to identify mechanisms underlying the pain in patients with leg ulcers by documenting alterations in pain processing using quantitative sensory testing. METHODS: In nine ulcer patients the mechanical sensory thresholds and the mechanical pain thresholds were determined by Semmes-Weinstein monofilaments (SWM) at three different sites: on the contralateral (unaffected) leg, on the skin of the affected leg 10cm from the ulcer margin, and on the affected leg, close (1-2cm) to the ulcer margin. Besides the mechanical sensory thresholds and mechanical pain thresholds, pain at the site of the ulcer, using an 11-point numeric rating scale (NRS), was documented. RESULTS: Mechanical sensory thresholds were increased in all subjects. Almost half (44%) of patients consistently showed allodynia at the unaffected site. The lowering of mechanical pain thresholds correlated with higher scores on the NRS. CONCLUSION: All patients showed diminished touch and/or protective sensation, which might have contributed to ulcer development via (partial) loss of protective function. The allodynia at the unaffected site suggests the presence of central sensitisation of pain processing.

Penetrance and Prognosis of MYH7 Variant-Associated Cardiomyopathies: Results From a Dutch Multicenter Cohort Study.

BACKGROUND: MYH7 variants cause hypertrophic cardiomyopathy (HCM), noncompaction cardiomyopathy (NCCM), and dilated cardiomyopathy (DCM). Screening of relatives of patients with genetic cardiomyopathy is recommended from 10 to 12 years of age onward, irrespective of the affected gene. OBJECTIVES: This study sought to study the penetrance and prognosis of MYH7 variant-associated cardiomyopathies. METHODS: In this multicenter cohort study, penetrance and major cardiomyopathy-related events (MCEs) were assessed in carriers of (likely) pathogenic MYH7 variants by using Kaplan-Meier curves and log-rank tests. Prognostic factors were evaluated using Cox regression with time-dependent coefficients. RESULTS: In total, 581 subjects (30.1% index patients, 48.4% male, median age 37.0 years [IQR: 19.5-50.2 years]) were included. HCM was diagnosed in 226 subjects, NCCM in 70, and DCM in 55. Early penetrance and MCEs (age <12 years) were common among NCCM-associated variant carriers (21.2% and 12.0%, respectively) and DCM-associated variant carriers (15.3% and 10.0%, respectively), compared with HCM-associated variant carriers (2.9% and 2.1%, respectively). Penetrance was significantly increased in carriers of converter region variants (adjusted HR: 1.87; 95% CI: 1.15-3.04; P = 0.012) and at age ≤1 year in NCCM-associated or DCM-associated variant carriers (adjusted HR: 21.17; 95% CI: 4.81-93.20; P < 0.001) and subjects with a family history of early MCEs (adjusted HR: 2.45; 95% CI: 1.09-5.50; P = 0.030). The risk of MCE was increased in subjects with a family history of early MCEs (adjusted HR: 1.82; 95% CI: 1.15-2.87; P = 0.010) and at age ≤5 years in NCCM-associated or DCM-associated variant carriers (adjusted HR: 38.82; 95% CI: 5.16-291.88; P < 0.001). CONCLUSIONS: MYH7 variants can cause cardiomyopathies and MCEs at a young age. Screening at younger ages may be warranted, particularly in carriers of NCCM- or DCM-associated variants and/or with a family history of MCEs at <12 years.

Integrating Clinical Phenotype With Multiomics Analyses of Human Cardiac Tissue Unveils Divergent Metabolic Remodeling in Genotype-Positive and Genotype-Negative Patients With Hypertrophic Cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is caused by sarcomere gene mutations (genotype-positive HCM) in ≈50% of patients and occurs in the absence of mutations (genotype-negative HCM) in the other half of patients. We explored how alterations in the metabolomic and lipidomic landscape are involved in cardiac remodeling in both patient groups. METHODS: We performed proteomics, metabolomics, and lipidomics on myectomy samples (genotype-positive N=19; genotype-negative N=22; and genotype unknown N=6) from clinically well-phenotyped patients with HCM and on cardiac tissue samples from sex- and age-matched and body mass index-matched nonfailing donors (N=20). These data sets were integrated to comprehensively map changes in lipid-handling and energy metabolism pathways. By linking metabolomic and lipidomic data to variability in clinical data, we explored patient group-specific associations between cardiac and metabolic remodeling. RESULTS: HCM myectomy samples exhibited (1) increased glucose and glycogen metabolism, (2) downregulation of fatty acid oxidation, and (3) reduced ceramide formation and lipid storage. In genotype-negative patients, septal hypertrophy and diastolic dysfunction correlated with lowering of acylcarnitines, redox metabolites, amino acids, pentose phosphate pathway intermediates, purines, and pyrimidines. In contrast, redox metabolites, amino acids, pentose phosphate pathway intermediates, purines, and pyrimidines were positively associated with septal hypertrophy and diastolic impairment in genotype-positive patients. CONCLUSIONS: We provide novel insights into both general and genotype-specific metabolic changes in HCM. Distinct metabolic alterations underlie cardiac disease progression in genotype-negative and genotype-positive patients with HCM.

Crushing lopinavir/ritonavir tablets does not result in lower exposure to lopinavir/ritonavir in adult patients with COVID-19.

OBJECTIVE: Lopinavir/ritonavir (LPV/RTV) exposure is decreased in children after crushing the tablets. Whether exposure is also decreased in adult patients is not known. This study evaluated the exposure of LPV/RTV in adult patients after administration of crushed LPV/RTV tablets. METHODS: Blood samples were drawn from patients with COVID-19 who were receiving crushed LPV/RTV 400/100 mg tablets twice daily. RESULTS: Plasma concentrations for 11 patients with COVID-19 (eight men, mean age 62.6 years) were included. The measured plasma concentrations of LPV were substantially higher than reported for patients with HIV. CONCLUSIONS: There is adequate exposure from crushed LPV/RTV tablets, but because of limited experience, therapeutic drug monitoring is still advised.

Circulating Acylcarnitines Associated with Hypertrophic Cardiomyopathy Severity: an Exploratory Cross-Sectional Study in MYBPC3 Founder Variant Carriers.

Hypertrophic cardiomyopathy (HCM) is a relatively common genetic heart disease characterised by myocardial hypertrophy. HCM can cause outflow tract obstruction, sudden cardiac death and heart failure, but severity is highly variable. In this exploratory cross-sectional study, circulating acylcarnitines were assessed as potential biomarkers in 124 MYBPC3 founder variant carriers (59 with severe HCM, 26 with mild HCM and 39 phenotype-negative [G + P-]). Elastic net logistic regression identified eight acylcarnitines associated with HCM severity. C3, C4, C6-DC, C8:1, C16, C18 and C18:2 were significantly increased in severe HCM compared to G + P-, and C3, C6-DC, C8:1 and C18 in mild HCM compared to G + P-. In multivariable linear regression, C6-DC and C8:1 correlated to log-transformed maximum wall thickness (coefficient 5.01, p = 0.005 and coefficient 0.803, p = 0.007, respectively), and C6-DC to log-transformed ejection fraction (coefficient -2.50, p = 0.004). Acylcarnitines seem promising biomarkers for HCM severity, however prospective studies are required to determine their prognostic value.

Association Between Preventive Dental Care and Healthcare Cost for Enrollees With Diabetes or Coronary Artery Disease: 5-Year Experience.

BACKGROUND: Evidence of preventive dental care impacting healthcare costs among diabetes or coronary artery disease (CAD) patients is sparse. METHODS: This study examined the association between healthcare costs and adherence with preventive dental care protocols among diabetes and CAD patients in a dental plan affiliated with a large commercial health plan in Arkansas. These patients were auto-enrolled in a program with additional benefits at no cost, and support from medical and dental care management teams was evaluated. All-cause cost was defined as the total amount paid by the health plan. RESULTS: Adherence with preventive dental care was associated with significant average yearly cost savings. The ranges of these savings were progressively higher for patients with only diabetes ($515 to $574), only CAD ($548 to $675), and CAD + diabetes ($866 to $1,718). Most of these savings originated in costs associated with inpatient admissions, which were between 25% and 36% for all disease classifications for all years. CONCLUSIONS: Preventive dental care is strongly associated with significant savings for diabetes and CAD patients, and such savings were highest for diabetes + CAD patients, followed by patients with only CAD and only diabetes. PRACTICAL IMPLICATIONS: Health plans should include dental coverage in their benefits package and incentivize adherence with preventive dental care to improve health and lower costs for enrollees with diabetes and CAD.

Blood-based biomarkers for the prediction of hypertrophic cardiomyopathy prognosis: a systematic review and meta-analysis.

AIMS: Hypertrophic cardiomyopathy (HCM) is the most prevalent monogenic heart disease. HCM is an important cause of sudden cardiac death and may also lead to outflow tract obstruction and heart failure. Disease severity is highly variable and risk stratification remains limited. Therefore, we aimed to review current knowledge of prognostic blood-based biomarkers in HCM. METHODS AND RESULTS: A systematic literature search was performed on PubMed, Embase, and the Cochrane library to identify studies assessing plasma or serum biomarkers for outcomes involving malignant ventricular arrhythmia, outflow tract obstruction, and heart failure. Risk of bias was assessed using the QUIPS tool. Meta-analyses were performed using the random effects method. A total of 26 unique cohort studies assessing 42 biomarkers were identified. Overall risk of bias was moderate. Thirty-two biomarkers were significantly associated to an HCM outcome in at least one study (nine biomarkers in at least two studies). In pooled analyses, cardiovascular mortality was predicted by N-terminal prohormone of brain natriuretic peptide (hazard ratio [HR] 5.38 per log[pg/mL], 95% confidence interval [CI] 2.07-14.03, P < 0.001, I2  = 0%) and high-sensitivity C-reactive protein (HR 1.30 per µg/mL, 95% CI 1.00-1.68, P = 0.05, I2  = 78%), all-cause mortality by low-density lipoprotein cholesterol (HR 0.63 per µmol/mL, 95% CI 0.49-0.80, P < 0.001, I2  = 0%), and a combined congestive heart failure, malignant ventricular arrhythmia, and stroke outcome by high-sensitivity cardiac troponin T (pooled HR 4.19 for ≥0.014 ng/mL, 95% CI 2.22-7.88, P < 0.001, I2  = 0%). Quality of evidence was low-moderate. CONCLUSIONS: Several blood-based biomarkers were identified as predictors of HCM outcomes. Additional studies are required to validate their prognostic utility within current risk stratification models.

Automatic Identification of Patients With Unexplained Left Ventricular Hypertrophy in Electronic Health Record Data to Improve Targeted Treatment and Family Screening.

Background: Unexplained Left Ventricular Hypertrophy (ULVH) may be caused by genetic and non-genetic etiologies (e.g., sarcomere variants, cardiac amyloid, or Anderson-Fabry's disease). Identification of ULVH patients allows for early targeted treatment and family screening. Aim: To automatically identify patients with ULVH in electronic health record (EHR) data using two computer methods: text-mining and machine learning (ML). Methods: Adults with echocardiographic measurement of interventricular septum thickness (IVSt) were included. A text-mining algorithm was developed to identify patients with ULVH. An ML algorithm including a variety of clinical, ECG and echocardiographic data was trained and tested in an 80/20% split. Clinical diagnosis of ULVH was considered the gold standard. Misclassifications were reviewed by an experienced cardiologist. Sensitivity, specificity, positive, and negative likelihood ratios (LHR+ and LHR-) of both text-mining and ML were reported. Results: In total, 26,954 subjects (median age 61 years, 55% male) were included. ULVH was diagnosed in 204/26,954 (0.8%) patients, of which 56 had amyloidosis and two Anderson-Fabry Disease. Text-mining flagged 8,192 patients with possible ULVH, of whom 159 were true positives (sensitivity, specificity, LHR+, and LHR- of 0.78, 0.67, 2.36, and 0.33). Machine learning resulted in a sensitivity, specificity, LHR+, and LHR- of 0.32, 0.99, 32, and 0.68, respectively. Pivotal variables included IVSt, systolic blood pressure, and age. Conclusions: Automatic identification of patients with ULVH is possible with both Text-mining and ML. Text-mining may be a comprehensive scaffold but can be less specific than machine learning. Deployment of either method depends on existing infrastructures and clinical applications.

Natural History of MYH7-Related Dilated Cardiomyopathy.

BACKGROUND: Variants in myosin heavy chain 7 (MYH7) are responsible for disease in 1% to 5% of patients with dilated cardiomyopathy (DCM); however, the clinical characteristics and natural history of MYH7-related DCM are poorly described. OBJECTIVES: We sought to determine the phenotype and prognosis of MYH7-related DCM. We also evaluated the influence of variant location on phenotypic expression. METHODS: We studied clinical data from 147 individuals with DCM-causing MYH7 variants (47.6% female; 35.6 ± 19.2 years) recruited from 29 international centers. RESULTS: At initial evaluation, 106 (72.1%) patients had DCM (left ventricular ejection fraction: 34.5% ± 11.7%). Median follow-up was 4.5 years (IQR: 1.7-8.0 years), and 23.7% of carriers who were initially phenotype-negative developed DCM. Phenotypic expression by 40 and 60 years was 46% and 88%, respectively, with 18 patients (16%) first diagnosed at <18 years of age. Thirty-six percent of patients with DCM met imaging criteria for LV noncompaction. During follow-up, 28% showed left ventricular reverse remodeling. Incidence of adverse cardiac events among patients with DCM at 5 years was 11.6%, with 5 (4.6%) deaths caused by end-stage heart failure (ESHF) and 5 patients (4.6%) requiring heart transplantation. The major ventricular arrhythmia rate was low (1.0% and 2.1% at 5 years in patients with DCM and in those with LVEF of ≤35%, respectively). ESHF and major ventricular arrhythmia were significantly lower compared with LMNA-related DCM and similar to DCM caused by TTN truncating variants. CONCLUSIONS: MYH7-related DCM is characterized by early age of onset, high phenotypic expression, low left ventricular reverse remodeling, and frequent progression to ESHF. Heart failure complications predominate over ventricular arrhythmias, which are rare.

Development of a sterile morphine hydrogel for the local treatment of painful skin ulcers.

OBJECTIVES: It is often difficult to relieve the pain from skin ulcers. In several patients, topical morphine, applied as a hydrogel, has been described as useful. There is no such product commercially available. We present a solution for compounding, packaging, sterilisation and chemical stability of a morphine containing hydrogel. METHODS: We developed a morphine containing poloxamer 407 thermoreversible hydrogel with a concentration of 5 mg/g (0.5% w/w) morphine hydrochloride. The hydrogel was packaged into a plastic prefillable syringe system: BD Sterifill SCF. This syringe can be steam sterilised after it has been filled. RESULTS: Sterility tests according to the European Pharmacopoeia showed the product to be sterile directly after production and sterilisation and after 20 months of storage. The stability of the morphine hydrochloride was assessed by monthly analysis of the concentration with a stability indicating HPLC-UV method. Morphine hydrochloride concentrations remained between 90% and 110% of the theoretical concentration for a period of 36 months, when stored at room temperature outside the influence of light. CONCLUSION: With the described formulation, packaging, sterilisation and stability data, together with the previously reported biopharmaceutical dissolution profile, we present a complete solution for a morphine containing poloxamer 407 hydrogel that can be compounded in any pharmacy with a steam or hot water steriliser at their disposal. This might improve the availability of a sterile morphine hydrogel for the treatment of painful skin ulcers.

Distinct Metabolomic Signatures in Preclinical and Obstructive Hypertrophic Cardiomyopathy.

Hypertrophic Cardiomyopathy (HCM) is a common inherited heart disease with poor risk prediction due to incomplete penetrance and a lack of clear genotype-phenotype correlations. Advanced imaging techniques have shown altered myocardial energetics already in preclinical gene variant carriers. To determine whether disturbed myocardial energetics with the potential to serve as biomarkers are also reflected in the serum metabolome, we analyzed the serum metabolome of asymptomatic carriers in comparison to healthy controls and obstructive HCM patients (HOCM). We performed non-quantitative direct-infusion high-resolution mass spectrometry-based untargeted metabolomics on serum from fasted asymptomatic gene variant carriers, symptomatic HOCM patients and healthy controls (n = 31, 14 and 9, respectively). Biomarker panels that discriminated the groups were identified by performing multivariate modeling with gradient-boosting classifiers. For all three group-wise comparisons we identified a panel of 30 serum metabolites that best discriminated the groups. These metabolite panels performed equally well as advanced cardiac imaging modalities in distinguishing the groups. Seven metabolites were found to be predictive in two different comparisons and may play an important role in defining the disease stage. This study reveals unique metabolic signatures in serum of preclinical carriers and HOCM patients that may potentially be used for HCM risk stratification and precision therapeutics.

Mortality Risk Associated With Truncating Founder Mutations in Titin.

Background Truncating titin variants (TTNtv) are the most prevalent genetic cause of dilated cardiomyopathy, found in ≤25% of familial cases. Moreover, TTNtv associated with dilated cardiomyopathy are estimated to be present in 0.5% of the general population. The prognosis of asymptomatic carriers of TTNtv is poorly understood because TTNtv are associated with a highly variable phenotype. We aim to assess the natural history and clinical relevance of TTNtv by analyzing standardized mortality ratios (SMR) in multigenerational pedigrees and in close relatives of present-day patients. Methods Haplotype and genealogical analyses were performed on 3 recurrent TTNtv. Subsequently, the family tree mortality ratio method was used to compare all-cause mortality of subjects at an a priori 50% risk of carrying TTNtv to the general Dutch population. SMRs were stratified for sex, age, and calendar period. Subgroups were compared with Poisson regression. Similarly, SMRs were calculated in parents of 128 present-day dilated cardiomyopathy probands with TTNtv using the reverse parent-offspring method. Results The TTNtv were established as founder mutations and traced to 18th century ancestors. In 20 522 person-years, overall mortality was not significantly increased (SMR, 1.06; 95% CI, 0.95-1.18; P=0.162). However, mortality was significantly increased in subjects living after 1965 (SMR, 1.27; 95% CI, 1.04-1.53; P=0.009) and aged ≥60 years (SMR, 1.17; 95% CI, 1.01-1.35; P=0.02). The reverse parent-offspring analysis showed overall excess mortality (SMR, 1.26; 95% CI, 1.07-1.48; P=0.003), driven by subjects aged ≥60 years. Conclusions The natural history of the analyzed TTNtv shows a relatively mild disease course with significant excess mortality in elderly patients. With increasing life expectancy, TTNtv-associated morbidity and mortality will likely become more prevalent.

No association of Fc gamma RIIa, Fc gamma RIIIa and Fc gamma RIIIb polymorphisms with MS.

Anti-myelin IgGs occur in the cerebrospinal fluid (CSF) and serum of multiple sclerosis (MS) patients, and can induce inflammatory effector functions in leukocytes by crosslinking IgG receptors (FcgammaR). The efficiency of FcgammaR-mediated inflammatory processes is affected by functional polymorphisms of three Fcgamma receptors (FcgammaRIIa, FcgammaRIIIa, FcgammaRIIIb). The relevance of FcgammaR polymorphisms in MS was evaluated by studying the distribution of FcgammaRIIa, FcgammaRIIIa and FcgammaRIIIb genotypes in 432 MS patients and 515 healthy controls. No significant differences were found between MS patients and controls, or between subgroups of patients. We conclude that Fcgamma receptor polymorphisms influence neither susceptibility nor clinical disease course of MS.

Synthesis and Phase Behavior of Poly(N-isopropylacrylamide)-b- Poly(L-Lysine Hydrochloride) and Poly(N-Isopropylacrylamide- co-Acrylamide)-b-Poly(L-Lysine Hydrochloride).

The synthesis of poly(N-isopropylacrylamide)-b-poly(L-lysine) and poly(N- isopropylacrylamide-co-acrylamide)-b-poly(L-lysine) copolymers was accomplished by combining atom transfer radical polymerization (ATRP) and ring opening polymerization (ROP). For this purpose, a di-functional initiator with protected amino group was successfully synthetized. The ATRP of N-isopropylacrylamide yielded narrowly dispersed polymers with consistent high yields (~80%). Lower yields (~50%) were observed when narrowly dispersed random copolymers of N-isopropylacrylamide and acrylamide where synthesized. Amino-terminated poly(N-isopropylacrylamide) and poly(N-isopropylacrylamide- co-acrylamide) were successfully used as macroinitiators for ROP of N6-carbobenzoxy-L- lysine N-carboxyanhydride. The thermal behavior of the homopolymers and copolymers in aqueous solutions was studied by turbidimetry, dynamic light scattering (DLS) and proton nuclear magnetic resonance spectroscopy (¹H-NMR).

Controlled release of morphine from a poloxamer 407 gel.

Treatment of painful ulcers is discouraging. Topical morphine has been described as a useful therapeutic adjunct in some patients. In the development of a new analgesic product, we studied the in vitro release characteristics of a new topical formulation containing 0.5% (w/w) morphine-HCl in a poloxamer 407 (P407) based gel. A diffusion cell was used for measurement of in vitro release characteristics. The donor compartment (DC) and the receptor compartment (RC) were separated by a 5000 Da cellulose acetate membrane. The morphine-HCl release from this developed P407 based gel followed zero-order kinetics with a constant release of 150 µg cm(-2)h(-1). Our results support the use of this P407 gel as a sustained release topical formulation in the pharmacological treatment of painful ulcers. Future research welcomes a formulation with release characteristics leading to less frequent application.

Identification of drug-related problems by a clinical pharmacist in addition to computerized alerts.

BACKGROUND: Both clinical pharmacists and computerized physician order entry systems with clinical decision support (CPOE/CDSS) can reduce drug-related problems (DRPs). However, the contribution of a clinical pharmacist in addition to CPOE/CDSS has not been established in a prospective study. OBJECTIVE: To determine which DRPs can be identified by a clinical pharmacist in a setting with routine use of CPOE/CDSS. SETTING: Two surgical and two neurological wards in St. Elisabeth hospital, a 600-bed teaching hospital in the Netherlands. METHODS: In this observational prospective follow-up study a clinical pharmacist reviewed the pharmacotherapy of patients admitted to surgical and neurological wards to identify DRPs (i.e. medication errors and adverse drug events) and discussed the relevance of identified problems and interventions to resolve these with the responsible physician. Acceptance of the proposed interventions and the presence of alerts in CPOE/CDSS were assessed. Primary outcome was the proportion of DRPs identified by the clinical pharmacist that also triggered a CPOE/CDSS alert. Differences between the DRPs that generated an alert and those that did not were expressed as relative risks or analyzed with Chi square statistics or Mann-Whitney U tests. MAIN OUTCOME MEASURE: The proportion of drug-related problems identified by the clinical pharmacist that also generated an alert in the CPOE/CDSS. RESULTS: During 1206 medication reviews, 442 potential DRPs were identified; 286 (65 %) DRPs were considered relevant and 247 (56 %) of the proposed interventions were accepted. A CPOE/CDSS alert was generated for 35 (8 %) of the DRPs the clinical pharmacist identified. The only difference between problems that triggered an alert and those that did not was the class of the DRP (indication 23 vs. 36 %, effectiveness 23 vs. 13 %, safety 23 vs. 10 % and pharmaceutical care issues 31 vs. 42 %, p = 0.02). CPOE/CDSS triggered 623 additional alerts that were handled during routine pharmacy service. CONCLUSIONS: As most DRPs identified by a clinical pharmacist were not detected in daily clinical practice by CPOE/CDSS, a clinical pharmacist contributes to reducing DRPs. The sensitivity of CPOE/CDSS to detect certain classes of problems should be optimized.

Operative outcome of colon interposition in the treatment of esophageal cancer: a 20-year experience.

BACKGROUND: In patients with esophageal cancer and a history of gastric surgery, colonic interposition is the treatment of choice. Our aim was to review our experience with this technique and to identify possible predictors of the clinical outcome. METHODS: Between 1986 and 2006, 43 patients underwent esophageal reconstruction accomplished by colon interposition in our surgical department. Data from these patients were collected consecutively and reviewed retrospectively. RESULTS: Colon interposition was performed isoperistaltically in 15 patients and was performed in 28 patients anisoperistaltically. In 18 patients, the right colon was used for interposition, whereas in 25 patients, the left colon was used. The mean survival time was 23+/-29 months. Artificial ventilation more than 24h, tumor differentiation grade III, the presence of major complications, and the presence of multivisceral resection had a significant negative influence on the operative outcome of colon interposition for esophageal replacement. CONCLUSION: Colon interposition for esophageal replacement provides a satisfactory operative outcome with high complication rates. Therefore, it should be reserved as a treatment of second choice for cases in which the stomach is not available.