Concomitant oral potassium chloride and anticholinergic therapy is associated with upper gastrointestinal bleeding: A cohort study.

AIM: To determine whether oral potassium chloride (KCI) therapy with concomitant anticholinergic exposure among hospitalized patients is associated with an excess risk for upper gastrointestinal bleeding (UGIB). METHODS: A retrospective controlled study among hospitalized patients between January 2007 and April 2019 who were treated with oral KCI. Patients were divided into two groups: with or without concomitant exposure to agents with anticholinergic activity. Outcome was defined as any UGIB. RESULTS: The final sample included 13 728 subjects who received oral KCI treatment, of them 3542 (25.8%) had at least one documented overlap with an anticholinergic agent. Mean age was 67.6 (±17.2) and 6893 (50.2%) were females. Median KCI dose was 2.4 g (interquartile range [IQR] 1.2-5.4, n = 9416) with the majority (90.4%) being treated with the wax-matrix form (Slow-K). Twenty-six (0.2%) patients experienced an UGIB event. Univariate analysis demonstrated a significantly higher rate of UGIB among patients concomitantly treated with oral KCI and anticholinergics (0.3%) compared to those without anticholinergic exposure (0.1%, P = 0.018), with median 7 days (IQR 3-16.8) from first KCI dose to bleeding event. Multivariate analysis demonstrated that concomitant anticholinergic exposure (Odds Ratio 2.48, 95% Confidence Interval 1.11-6.51, P = 0.022) and anticoagulation treatment among patients with hemato-oncologic disease (OR 6.61, 95% CI 1.96-22.25, P = 0.002) were significantly associated with UGIB. CONCLUSION: Hospitalized patients treated concomitantly with oral KCI and anticholinergic agents have significantly increased risk for UGIB.

Clinically significant incidental QTc prolongation is subject to within-individual variability.

BACKGROUND: Prolonged QTc interval observed in daily practice is often deemed to be drug induced and might result in drug discontinuation, with possible therapeutic consequences. However, whether clinically significant prolonged QTc may be due to within-individual variability occurs has yet to be described. METHODS: A retrospective cohort study documenting within-individual QTc variability in subjects attending annual routine medical evaluation. At each visit, QT interval was measured and corrected for heart rate using Bazett and three other commonly used formulae. Outcome measures were rates of ΔQTc ≥60 msec, absolute QTc ≥500 msec and QTc ≥25% from baseline. RESULTS: A total of 188 subjects [54 (29%)] females were recruited. Mean age at first ECG was 54 ± 12.8 years with mean time interval of 12.2 ± 1.1 months between measurements. Mean Bazett QTc was higher compared to the other 3 formulae: 412 ± 20 vs. 400 ± 16 msec. Using Bazett formula, 18/188 (9.6%) and 5/188 (2.7%) subjects showed at least one measurement with ΔQTc ≥60 msec and QTc ≥500 msec, respectively. Of the former, 5/18 (27.8%) showed QTc ≥25% prolongation. In multivariate analysis, QTc ≥500 msec was significantly associated with number of measurements (HR: 5.01, 95%CI: 1.21-20.78, p = .026) with no effect of other known confounders. Lower rates were demonstrated with the other three formulae. CONCLUSION: In clinical practice, significant prolonged QTc may be attributed to within-individual variability, particularly when adjusting the QT interval with Bazett correction. This should be taken into consideration when decisions on changing current drug regimens are to be made.

Implementation of a clinical decision support system for computerized drug prescription entries in a large tertiary care hospital.

BACKGROUND: Prescription errors are common in hospitalized patients and result in significant morbidity, mortality and costs. Electronic prescriptions with computerized physician order entry systems (CPOE) and integrated computerized decision support systems (CDSS providing online alerts) reduce prescription errors by approximately 50%. However, the introduction of CDSS is often met by opposition due to the flood of alerts, and most prescribers eventually ignore even crucial alerts ("alert fatigue"). OBJECTIVES: To describe the implementation and customization of a commercial CDSS (SafeRx) for electronic prescribing in Internal Medicine departments at a tertiary care center, with the purpose of improving comprehensibility and substantially reducing the number of alerts to minimize alert fatigue. METHODS: A multidisciplinary expert committee was authorized by the hospital administration to customize the CDSS according to the needs of six internal medicine departments at Sheba Medical Center. We assessed volume of prescriptions and alert types during the period February-August 2012 using the statistical functions provided by the CDSS. RESULTS: A mean of 339 +/- 13 patients per month per department received 11.2 +/- 0.5 prescriptions per patient, 30.1% of which triggered one or more CDSS alerts, most commonly drug-drug interactions (43.2%) and dosing alerts (38.3%). The review committee silenced or modified 3981 alerts, enhancing comprehensibility, and providing dosing instructions adjusted to the patient's renal function and recommendations for follow-up. CONCLUSIONS: The large volume of drug prescriptions in internal medicine departments is associated with a significant rate of potential prescription errors. To ensure its effectiveness and minimize alert fatigue, continuous customization of the CDSS to the specific needs of particular departments is required.

"Body packers" in Israel: a case series.

BACKGROUND: "Body packers" swallow multiple packets filled with illicit drugs, mainly cocaine, in order to smuggle them across international borders. In recent years, an increasing number of body packers have been hospitalized after their detention by the police upon arrival in Israel. OBJECTIVES: To characterize the clinical features and outcomes of body packers hospitalized at the Sheba Medical Center. METHODS: We conducted a retrospective case series of body packers hospitalized between January 2010 and October 2012 in our medical center. Electronic medical records and imaging files were reviewed to extract clinical, laboratory and radiological data as well as details on medical treatments. RESULTS: We identified 23 body packers (mean age 38 +/- 10 years), 20 of whom smuggled cocaine from South America. The number of packets transported ranged from 1 to 242 (median 42) and duration of hospitalization from 1 to 14 days (median 2). Two subjects required surgical intervention. All others were treated conservatively by polyethylene glycol-electrolyte lavage solution, laxatives, or watchful waiting. Ten patients underwent a urinary screen for illicit drugs, 7 of whom tested positive for cocaine and 2 for cannabinoids. Abdominal X-rays were performed in all patients at admission, and 14 had follow-up imaging, including abdominal CT scans without contrast media in 8. CONCLUSIONS: The main treatment goals for body packers are the rapid excretion of drug packets and early detection of complications, i.e., drug intoxication and bowel obstruction. We suggest the use of a structured treatment approach for the in-hospital management of body packers.

Muscle pain and serum creatine kinase are not associated with low serum 25(OH) vitamin D levels in patients receiving statins.

OBJECTIVE: Vitamin D deficiency has been associated in some studies with nonspecific musculoskeletal pain and, more specifically, with statin-induced myalgia, which was ameliorated by high-dose vitamin D supplements. Our objective was to explore the association between vitamin D status and statin-induced myalgia and elevation of serum creatine kinase (CK). DESIGN: Retrospective cohort study, based on the electronic database of a health maintenance organization. PATIENTS: Six thousand eight hundred and eight patients (71·5% women) to whom statins were dispensed during 2008 and who had ≥1 CK and 25-hydroxy vitamin D (25OHD) levels measured during statin exposure. Of these, 376 patients (5·5%) had switched from a first-line statin to atorvastatin because of muscle pain (n = 220) or other reasons (n = 156). Measurements; In the entire cohort, we compared serum CK levels among serum 25OHD quartiles. In addition, we compared CK and 25OHD levels among patients with myalgia, other switchers and nonswitchers. RESULTS: The median 25OHD level in the entire cohort was 21·8 ng/ml [interquartile range (IQR), 16·3-27·4]. CK levels were marginally lower in patients in the lowest 25OHD quartile [median CK (IQR) in 25OHD quartiles 1-4, 87 (61-130), 90 (65-131), 91 (65-132) and 91 (67-131) IU/ml, respectively; P = 0·007]. 25OHD levels in statin switchers were similar to those in nonswitchers; moreover, there were no differences in 25OHD among switchers with muscle pain and other switchers. CONCLUSION: Our findings do not support an association between low 25OHD levels and statin-induced myalgia or CK elevation.

Effects of imatinib on glycemic and lipid profiles: a retrospective cohort study.

Despite a favorable effect of imatinib on glucose metabolism in animal models, human reports are inconsistent. We retrospectively studied the long-term effect of imatinib on fasting plasma glucose (FPG), glycated hemoglobin (HbA1C), LDL-cholesterol (LDL), and triglycerides (TGs) in a large HMO cohort of patients initiating therapy. In patients with diabetes (n = 118), significant reductions in HbA1c (0.53%, IQR 0.09, 1.19; p < .001) and FPG (10.2 mg/dL, IQR -3.5, 32.2; p < .001), independent of demographics and of glucose-lowering drugs utilization, were observed during the first year of imatinib treatment. Significant reductions in LDL (17.8 mg/dL, IQR -1.3, 34.0; p < .001) and TG (25.0 mg/dL, IQR -2.3, 58.3; p < .001), also independent of demographics and of statin utilization, were evident in the entire cohort (n = 611) during the first imatinib year. All reductions persisted during the second treatment year. To conclude, imatinib is associated with durable metabolic benefits, which may guide TKI choice in patients with cardiovascular co-morbidities.

Linearity and stability of intravenous busulfan pharmacokinetics and the role of glutathione in busulfan elimination.

High-dose busulfan (Bu) is frequently used in preparative myeloablative conditioning (MAC) regimens for patients undergoing hematopoietic stem cell transplantation (HSCT). MAC and reduced-intensity conditioning (RIC) protocols for i.v. Bu infusion have been developed to achieve reliable systemic exposure while minimizing toxicity and treatment failure (relapse). The objectives of the present study were to (1) compare the pharmacokinetics (PK) of i.v. Bu in different dosing protocols, (2) compare intrasubject variability of Bu PK over repeated administrations; (3) examine the effect of concomitant administration of fludarabine on Bu PK, and (4) examine the effect of plasma concentrations of glutathione (GSH), the cosubstrate in Bu metabolism, on Bu clearance. We studied Bu PK twice in each of 46 HSCT patients (after the first and then after the middle dose of the treatment cycle) receiving one of 4 dosing protocols, 2 MAC (cumulative dose, 12.8 mg/kg) and 2 RIC (cumulative dose, 6.4 mg/kg), with daily doses administered either as an individual infusion (3.2 mg/kg) or as 4 infusions of 0.8 mg/kg each. Blood samples were obtained for 6-24 hours after dosing for measurement of Bu plasma concentrations. PK parameters were estimated using compartmental analyses. In a subgroup of patients (n = 14), GSH blood concentrations were determined before Bu administration. Dose- and weight-corrected Bu PK parameters (clearance, 0.173 ± 0.051 L/hour · kg; volume of distribution, 0.71 ± 0.17 L/kg; half-life time, 3.0 ± 0.7 hours) did not differ among treatment protocols (all P >.14) and remained stable between the first and mid-cycle doses. Fludarabine did not affect Bu PK. Blood GSH concentrations before Bu dosing were positively correlated with Bu clearance (adjusted R(2) = 0.45; P = .009). Our data indicate that Bu PK parameters are linear, stable, and predictable in different i.v. protocols and are unaffected by coadministration of fludarabine. Differences in whole blood GSH might contribute to variability in Bu clearance.

Warfarin and vitamin K intake in the era of pharmacogenetics.

The considerable variability in the warfarin dose-response relationship between individuals, is explained mainly by genetic variation in its major metabolic (CYP2C9) and target (VKORC1) enzymes. Despite the predominance of pharmacogenetics, environmental factors also affect the pharmacokinetics and pharmacodynamics of warfarin, and are often overlooked. Among these factors, dietary and supplemental vitamin K consumption is a controllable contributor to within-, and between-patient variability of warfarin sensitivity. In this commentary we review the current role of vitamin K in warfarin anticoagulation therapy, with emphasis on the following: 1 The effect of dietary and supplemental vitamin K on warfarin anticoagulation, beyond the impact of genetic variability in CYP2C9 and VKORC1. We deal separately with the effects of vitamin K on warfarin dose requirements during the induction of therapy, as opposed to its effect on stability of anticoagulation control during maintenance therapy. 2 The role of vitamin K supplementation in warfarin treated patients with vitamin K deficiency as well as in patients with unstable warfarin anticoagulation, and 3 The role of therapeutic vitamin K in cases of warfarin over-anticoagulation.

Uninterrupted direct oral anticoagulant treatment during acute illness: Impact on clinical outcomes.

BACKGROUND: Uninterrupted drug therapy during acute illness is often associated with pharmacokinetic and pharmacodynamic variations. Among warfarin treated patients, these changes are reflected in the INR. However, in the case of direct oral anticoagulants (DOACs), given that routine laboratory monitoring is not recommended, these changes may result in unforeseen thromboembolic or bleeding events. OBJECTIVES: To determine the rate of thromboembolic (TEE) and bleeding events associated with uninterrupted DOAC compared to warfarin treatment during acute illness. METHODS: A retrospective cohort study of patients treated with DOACs or warfarin, both at steady state, who were hospitalized for acute illness. Primary outcome was any TEE or major bleeding requiring re-hospitalization within one month from discharge. Secondary outcome was a composite of major bleeding and clinically relevant non-major bleeding (CRNMB) events. RESULTS: A total of 410 patients continued oral anticoagulant treatment during their hospitalization, of whom 191 (46.6%) were on DOACs and 219 (53.4%) on warfarin, with a total of 18 (4.4%) events. Rates of TEE and major bleeding events did not differ between DOACs and warfarin treated patients (0.9% vs. 0.5% and 0.5% vs. 1%, respectively). Similarly, rate of secondary outcome was comparable between DOACs (4.7%) and warfarin (2.7%, p = 0.29). Sub-analyses demonstrated significantly higher rates among rivaroxaban (10.4%) treated patients compared to warfarin (p = 0.03). CONCLUSION: Uninterrupted treatment with DOACs during acute illness is not associated with increased risk for re-hospitalizations due to bleeding or thromboembolic events compared to warfarin. Our results suggest a higher bleeding rate among rivaroxaban treated patients at high bleeding risk.

Hepatitis C, B, and human immunodeficiency virus infections in illicit drug users in Israel: prevalence and risk factors.

BACKGROUND: Infections with blood-borne viruses are a major health problem among illicit drug users. There is little information about infection rates and risk factors for hepatitis virus B, C or the human immunodeficiency virus in drug users in Israel. OBJECTIVES: To determine the prevalence of HCV, HBV and HIV infections in a large cohort of drug users in Israel; to compare rates of HCV, HBV and HIV between injecting versus non-injecting drug users and between different countries of origin; and to identify risk factors for HCV among illicit drug users. METHODS: We conducted a cross-sectional study using an interviewer-administered questionnaire and serological screening for HCV, HBV and HIV in 1443 consecutive drug users diagnosed at the Israeli National Center for Diagnosis of Drug Addicts between January 2003 and December 2005. RESULTS: Fourteen (0.9%), 51 (3.5%) and 515 (35.7%) subjects tested positive for HIV, HBV and HCV, respectively. All three infections (HIV, HBV and HCV) were significantly more common among injecting drug users and immigrants from the former Soviet Union and other East European countries compared to native Israelis. Multivariate analysis showed that HCV infection was associated with age (> 40 years) (OR=2.06, 95% CI 1.40-3.03), immigration from East European countries and the former Soviet Union (OR=4.54, 95% CI 3.28-6.28), and injecting drug use (OR=16.44, 95% CI 10.79-25.05). CONCLUSIONS: HIV, HBV and HCV prevalence among drug users in Israel is significantly lower than in North America and West Europe. Risk factors for HCV infection in this population include injecting drug use, older age, and immigration from the former Soviet Union.

Effects of exercise training on quadriceps muscle gene expression in chronic obstructive pulmonary disease.

Exercise capacity and training response are limited in chronic obstructive pulmonary disease (COPD), but the extent to which this is related to altered skeletal muscle function is not fully understood. To test the hypothesis that muscle gene expression is altered in COPD, we performed needle biopsies from the vastus lateralis of six COPD patients and five sedentary age-matched healthy men, before and after 3 mo of exercise training. RNA was hybridized to Affymetrix U133A Genechip arrays. In addition, peak O(2) uptake and other functional parameters (e.g., 6-min walk) were measured before and after training. The 6-min walk test increased significantly following training in both groups (53.6 +/- 18.6 m in controls, P = 0.045; 37.1 +/- 6.7 m in COPD, P = 0.002), but peak O(2) uptake increased only in controls (19.4 +/- 4.5%, P = 0.011). Training significantly altered muscle gene expression in both groups, but the number of affected genes was lower in the COPD patients (231) compared with controls (573). Genes related to energy pathways had higher expression in trained controls. In contrast, oxidative stress, ubiquitin proteasome, and COX gene pathways had higher expression in trained COPD patients, and some genes (e.g., COX11, COX15, and MAPK-9) were upregulated by training only in COPD patients. We conclude that both COPD and control subjects demonstrated functional responses to training but with somewhat different patterns in muscle gene expression. The pathways that are uniquely induced by exercise in COPD (e.g., ubiquitin proteasome and COX) might indicate a greater degree of tissue stress (perhaps by altered O(2) and CO(2) dynamics) than in controls.

Brand versus generic alendronate: gastrointestinal effects measured by resource utilization.

BACKGROUND: Adverse reactions related to the upper gastrointestinal tract (UGIT) that are associated with generic alendronate formulations may differ from those associated with the brand drug. OBJECTIVE: To test the hypothesis that adverse UGIT effects of alendronate formulations may differ between generic and brand products. METHODS: We conducted a database health resource utilization analysis of UGIT outcomes in patients who started treatment with generic or brand alendronate formulations during 2001-2005. We included 6962 patients who were treated continuously for 3 months with 1 of 4 alendronate formulations: brand 10 mg/day (Merck, Sharpe & Dohme, n = 1418), generic A 10 mg/day (Teva, Israel, n = 650), generic B 10 mg/day (Unipharm, Israel, n = 628), and brand 70 mg/wk (n = 4266). In these patients, who had neither filled a prescription for alendronate nor had any gastrointestinal problems in the year preceding the study, we compared incidence rates of new use of gastric medications (H2-blockers, proton-pump inhibitors, or antacids), gastroenterology visits, endoscopies, and hospital admissions. RESULTS: Incident rate ratios (IRR) for treatment discontinuation were higher with both daily generic products (IRR 1.3; 95% CI 1.04 to 1.63). Adherence (medication possession ratio [MPR] >80%) was better with brand 10 mg/day (IRR 1.19; 95% CI 1.11 to 1.27). All comparisons were adjusted for use of concurrent corticosteroids, nonsteroidal antiinflammatory drugs, and potassium supplements. Hospitalization rates (2.7-3.2%) were similar in all groups. New use of gastric medications (3.4-4.9%) was lower with brand 10 mg/day (IRR 0.71; 95% CI 0.53 to 0.95). Rates of UGIT endoscopy (n = 49) in patients receiving 10 mg were 0.6% (brand), 1.1% (generic A), and 1.6% (generic B), with generic B higher (IRR 2.88; 95% CI 1.14 to 7.29) in the entire cohort, but not among new users (n = 273) of gastric drugs (IRR 2.46; 95% CI 0.55 to 11.05). Endoscopic findings were normal in 22 patients, hiatal hernia with no mucosal lesion was present in 10 patients, and there was mild-to-moderate esophagitis or gastritis in 17 patients; there were no significant differences among the formulations. CONCLUSIONS: We found insufficient evidence to indicate major differences in UGIT adverse effects related to use of daily generic, as compared with brand, alendronates.

[Description of a diabetes disease register extracted from a central database].

OBJECTIVES: To describe the development of inclusion criteria for identifying diabetic patients using administrative, laboratory and pharmacy data on a large central electronic database. DESIGN: A descriptive study in which entry criteria were developed, validated then changed in an iterative fashion and revalidated. The final register was compared with a traditionally built diabetes register. RESULTS: The four criterion chosen were: 1) HbAlc> or = 7.25%; 2) Glucose> or = 200mg/dl (for individuals who are included in the register on this criterion alone, supporting data for the diagnosis of diabetes is required at six months. If none are found, the patient is deleted from the register); 3) Purchase of diabetic medication twice in the last two months; 4) A diagnosis of diabetes (ICD9 code) in the chart and HbA1c6.5% or Glucose > 125mg/dl. CONCLUSION: Adoption of criteria for identification of diabetic patients using data sets on central computers can provide the registers necessary for diabetes care.

Prescriber response to computerized drug alerts for electronic prescriptions among hospitalized patients.

BACKGROUND: Clinical decision support systems (CDSS) reduce prescription errors, but their effectiveness is reduced by high alert rates, "alert fatigue", and indiscriminate rejection. OBJECTIVES: To compare acceptance rates of alerts generated by the SafeRx® prescription CDSS among different alert types and departments in a tertiary care hospital, identify factors associated with alert acceptance, and determine whether alert overrides were justified. METHODS: In a retrospective study, we compared acceptance rates of all prescription alerts generated in 2013 in 18 departments of Israel's largest tertiary care center. In a prospective study in 2 internal medicine departments, we collected data on factors potentially associated with alert override, and an expert panel evaluated the justification for each overridden alert. We used multivariate analyses to examine the association between patient and physician-related factors and alert acceptance. RESULTS: In the retrospective study, of 390,841 prescriptions, 37.1% triggered at least one alert, 5.3% of which were accepted. Acceptance rates ranged from 7.9% for excessive dose alerts to 4.0% for duplicate drug and major drug-drug interactions alerts (p<0.001). In the prospective study, common reasons for alert overriding included "irrelevance to the specific condition" and "medication previously tolerated by the patient". Weekend shifts (incident rate ratio [IRR]=1.50 [95% CI, 1.01-2.22]) and a specific department (IRR=1.87 [1.23-2.87]) were associated with higher alert acceptance, while night shift (IRR=0.47 [0.26-0.85]) was associated with alert override. Most alert overrides (88.6%) were judged justified. CONCLUSIONS: The vast majority of SafeRx® alerts are overridden, and overriding is justified in most cases. Minimizing the number of alerts is essential to reduce the likelihood of developing "alert fatigue". Our findings may inform a rational, department-specific approach for alert silencing.

Combined genetic profiles of components and regulators of the vitamin K-dependent gamma-carboxylation system affect individual sensitivity to warfarin.

We examined the influence of combined genotypes on interindividual variability in warfarin dose-response. In 100 anticoagulated patients we quantified the effects of polymorphisms in: CYP2C9, VKORC1, calumenin (CALU), gamma-glutamyl carboxylase (GGCX) and microsomal epoxide hydrolase (EPHX1) on warfarin dose requirements. The G(1542)C VKORC1 polymorphism was associated with decreased warfarin doses in the hetero- and homozygous mutant patients (21% and 50% lower, respectively; p < 0.0001). Warfarin daily dose was predominantly determined by VKORC1 and CYP2C9 genotypes (partial r(2) = 0.21; 0.20, respectively). Together with age and body weight, these two genotypes explained 63% of the dose variance. A single patient, homozygous for G(11)A CALU mutant allele, required an exceptionally high warfarin dose (20 mg/day) and the prevalence of heterozygous (11)A allele carriers in the upper 10(th) dose percentile was significantly higher (0.27 vs. 0.18, p < 0.02). Combined genotype analysis revealed that CYP2C9 andVKORC1 wild type and CALU mutant patients required the highest warfarin doses (7.8 +/- 1.5mg/day; n = 9) as compared to the CYP2C9 and VKORC1 mutant and CALU wild type genotypes (2.8 +/- 0.3 mg/day; n = 18; p < 0.01). The odds ratio for doses <3mg/day was 5.9 (1.9-18.4) for this genotype. Compound genetic profiles comprising VKORC1, CALU and CYP2C9 improve categorization of individual warfarin dose requirements in more than 25% of patients at steady-state anticoagulation.

The implementation of managed care for diabetes using medical informatics in a large Preferred Provider Organization.

BACKGROUND: It has been demonstrated by meta analysis that if a regular review of patients is guaranteed, the standard of primary care can be as good or better than hospital outpatient care, however, empirical data suggests that compliance with diabetes clinical practice recommendations is inadequate in primary care. This study describes the reorganization of diabetes care using disease management principles in a Preferred Provider Organization (PPO) operating on a country-wide basis in which each diabetes clinic became responsible for the overall care of all patients with diabetes. METHODS: This descriptive pre and post change study was undertaken in a large public-funded PPO insuring over one and half million individuals. The study was possible due the use of a centralized electronic disease registry which enabled the collection of all patient data. Several markers, such as HbA1C and LDC-cholesterol levels, were used to assess the quality of care for the diabetic patients. RESULTS: Mean HbA1C results of the cohort showed a continuous reduction from 8.1% (S.D. = 1.55) in 1999 to 7.68% (S.D. = 1.47) in 2002 and to 7.79 (S.D. = 1.54) in 2004. Improved results were also recorded for LDL-C 126.37 (S.D. = 35.16) in 1999 to 114.74 (S.D. = 34.49) in 2002, and to 113.39 (S.D. = 33.8) in 2004. The number of diabetic patients seen by the diabetologist increased by 62% over this period, despite an increase in diabetologist work hours of only 23%. CONCLUSION: The reorganization of health delivery for diabetic patients within a country-wide PPO, based on the principles of disease management and supported by medical informatics improves quality of care.

[Generic drug substitution].

The rapidly rising health care expenditures, attributed mainly to the high cost of prescription drugs, have led governments around the world to look to generics as a means of containing costs in the pharmaceutical market. Generic drugs provide a less expensive alternative to brand name drugs due to the elimination of the need to perform lengthy and costly clinical trials, as required for innovative drugs. Essentially, generic substitution of drugs may be performed only after showing unequivocally that the generic formulation is identical in its active ingredients, strength, and route of administration as its innovative counterpart, and that they are bioequivalent to each other. Although the two are in essence the same, generic substitution is occasionally a controversial matter.

Database evaluation of the association between serum magnesium levels and the risk of atrial fibrillation in the community.

BACKGROUND: In population studies, mild hypomagnesemia, determined by a single measurement, was associated with incident atrial fibrillation, over ~20 years of follow-up. We sought to determine whether mild (≤ 1.7 mg/dL) and moderate (≤ 1.5mg/dL) hypomagnesemia are temporally associated with increased incidence of atrial fibrillation (AF) in the community. METHODS: Health Maintenance Organization (HMO) database cohort study including beneficiaries with ≥ 1 serum magnesium measurement between 2004 and 2013. The follow-up period was defined from the first magnesium measurement to first listing in an AF registry (for cases) and December 2013 or date of death or loss to follow-up (for controls). We analyzed the association between serum magnesium quintiles, as well as the above clinically relevant hypomagnesemia thresholds, and incident AF using Cox proportional hazard regression analysis, adjusting for confounders. The association between serum magnesium and AF occurring within 3 months was also examined. RESULTS: Among 162,162 subjects, 2228 (1.4%) developed AF over a median follow-up of 25.3 months. Compared to the middle quintile the lowest magnesium quintile (≤ 1.9 mg/dL) had a significantly higher risk of AF (HR, 1.21; 95% CI: 1.07-1.37). Increased AF risk was also associated with mild (HR, 1.44; 95% CI: 1.20-1.73) and moderate hypomagnesemia (HR, 1.57; 95% CI: 1.14-2.15). No association was found when limiting the follow-up period to 3 months. CONCLUSIONS: In our study, hypomagnesemia was associated with incident AF over prolonged but not short-term follow-up periods, suggesting that this association may not be causal.