Human CD19-Targeted Mouse T Cells Induce B Cell Aplasia and Toxicity in Human CD19 Transgenic Mice.

The clinical success of chimeric antigen receptor (CAR) T cell therapy for CD19+ B cell malignancies can be limited by acute toxicities and immunoglobulin replacement needs due to B cell aplasia from persistent CAR T cells. Life-threatening complications include cytokine release syndrome and neurologic adverse events, the exact etiologies of which are unclear. To elucidate the underlying toxicity mechanisms and test potentially safer CAR T cells, we developed a mouse model in which human CD19 (hCD19)-specific mouse CAR T cells were adoptively transferred into mice whose normal B cells express a hCD19 transgene at hemizygous levels. Compared to homozygous hCD19 transgenic mice that have ∼75% fewer circulating B cells, hemizygous mice had hCD19 frequencies and antigen density more closely simulating human B cells. Hemizygous mice given a lethal dose of hCD19 transgene-expressing lymphoma cells and treated with CAR T cells had undetectable tumor levels. Recipients experienced B cell aplasia and antigen- and dose-dependent acute toxicities mirroring patient complications. Interleukin-6 (IL-6), interferon γ (IFN-γ), and inflammatory pathway transcripts were enriched in affected tissues. As in patients, antibody-mediated neutralization of IL-6 (and IFN-γ) blunted toxicity. Apparent behavioral abnormalities associated with decreased microglial cells point to CAR-T-cell-induced neurotoxicity. This model will prove useful in testing strategies designed to improve hCD19-specific CAR T cell safety.

Combination Therapy Use and Associated Events in Clinical Practice Following Dissemination of Trial Findings: A De-Implementation Study Using Interrupted Time Series Analysis.

PURPOSE: It takes 17 years, on average, for trial results to be implemented into practice. Using data from the Department of Veterans Affairs (VA), this study assessed the potential impact on clinical practice of the dissemination of findings from a randomized, controlled trial reporting harm with the use of combination therapy. Communication between research and VA Pharmacy Benefits Management Services (PBM)  provided the impetus for communication from the PBM about the findings of the trial in accordance with policy. METHODS: In this de-implementation study, interrupted time series analysis was used for assessing prescribing patterns and adverse clinical events before and after the dissemination of the trial findings. The de-implementation strategy was multicomponent and multilevel. Strategies were aligned with categories outlined in the Expert Recommendations for Implementing Change: train and educate stakeholders, use evaluative and iterative strategies, develop stakeholder inter-relationships, change infrastructure, provide interactive assistance, and engage consumers. VA patients with type 2 diabetes mellitus, chronic kidney disease stages 1 to 3, and a moderate or severe albuminuria who received care between July 2008 and November 2017 were included. Patients were subgrouped according to treatment with an angiotensin-converting enzyme inhibitor + angiotensin receptor blocker. The primary end point was the prevalence of combination therapy use. Secondary end points were the incidences of acute kidney injury and hyperkalemia. FINDINGS: This study followed 712,245 patients, 9297 of whom used combination therapy. Data were available from 428,535 and 283,710 patients pre- and post-intervention, respectively; among these, 8324 and 973 patients used combination therapy, the median ages were 66 and 68 years, and 96.92% and 98.82% were men. One month following communication from the PBM, the reductions in combination therapy users, acute kidney injury events, and hyperkalemia were 331.94 (95% CI, 500.27-163.32), 36.58% (95% CI, 31.90%-41.95%), and 25.49% (95% CI, 14.17%-36.07%) per 100,000 patients per month, respectively (all, P < 0.001), whereas before the communication, these changes were +14.84 (95% CI, 10.27-19.42), -3.46% (95% CI, 3.18-3.74), and -3.27% (95% CI, 2.66%-3.87%) (all, P < 0.001). IMPLICATIONS: The apparent speed and impact of the implementation of changes resulting from the dissemination of trial findings into VA clinical practice are encouraging. The speed of implementation was much faster than average for health care providers in the United States. Established communications between research and clinical practice, as well as established policy and communications between PBM and clinical practice, may be a model for other health care organizations.

Medication adherence assessment in a clinical trial with centralized follow-up and direct-to-patient drug shipments.

BACKGROUND: Assessment of adherence to study medications is a common challenge in clinical research. Counting unused study medication is the predominant method by which adherence is assessed in outpatient clinical trials but it has limitations that include questionable validity and burdens on research personnel. PURPOSE: To compare capsule counts, patient questionnaire responses, and plasma drug levels as methods of determining adherence in a clinical trial that had 2056 participants and used centralized drug distribution and patient follow-up. METHODS: Capsule counts from study medication bottles returned by participants and responses to questions regarding adherence during quarterly telephone interviews were averaged and compared. Both measures were compared to plasma drug levels obtained at the 3-month study visit of patients in the treatment group. Counts and questionnaire responses were converted to adherence rates (doses taken divided by days elapsed) and were categorized by stringent (≥85.7%) and liberal (≥71.4%) definitions. We calculated the prevalence-adjusted bias-adjusted kappa to assess agreement between the two measures. RESULTS: Using a pre-paid mailer, participants returned 76.0% of study medication bottles to the central pharmacy. Both capsule counts and questionnaire responses were available for 65.8% of participants and were used to assess adherence. Capsule counts identified more patients who were under-adherent (18.8% by the stringent definition and 7.5% by the liberal definition) than self-reports did (10.4% by the stringent definition and 2.1% by the liberal definition). The prevalence-adjusted bias-adjusted kappa was 0.58 (stringent) and 0.83 (liberal), indicating fair and very good agreement, respectively. Both measures were also in agreement with plasma drug levels determined at the 3-month visit (capsule counts: p = 0.005 for the stringent and p = 0.003 for the liberal definition; questionnaire: p = 0.002 for both adherence definitions). LIMITATIONS: Inconsistent bottle returns and incomplete notations of medication start and stop dates resulted in missing data but exploratory missing data analyses showed no reason to believe that the missing data resulted in systematic bias. CONCLUSIONS: Depending upon the definition of adherence, there was fair to very good agreement between questionnaire results and capsule counts among returned study bottles, confirmed by plasma drug levels. We conclude that a self-report of medication adherence is potentially comparable to capsule counts as a method of assessing adherence in a clinical trial, if a relatively low adherence threshold is acceptable, but adherence should be confirmed by other measures if a high adherence threshold is required.

Health-related quality of life changes associated with buprenorphine treatment for opioid dependence.

BACKGROUND: Few studies have described improvement in health-related quality of life (HRQOL) associated with opioid dependence treatment with buprenorphine (ODT-B). OBJECTIVE: To evaluate HRQOL changes in domain scores, physical and mental component summaries, and health utilities (HUs) associated with ODT-B using the Short Form 36 (SF-36). METHODS: We assessed HRQOL changes in a substudy of a pharmacokinetic study that compared buprenorphine oral tablet and liquid dosage formulations over 16 weeks. Individuals, aged 18-65 years, were screened for opioid dependence. They were excluded if they would not agree to birth control or had a serious medical condition. Subjects received psychosocial counseling and weekly group therapy. The SF-36 was administered upon enrollment and at 4-week intervals. We used the SF-6D to estimate HUs. We performed intention to treat (ITT) analyses based on the last observation available for each subject. Paired t tests of each domain and HU, limited to remaining patients at each 4-week interval, were also conducted. RESULTS: Of 96 subjects enrolled, cumulative dropouts over time resulted in 80, 69, 59, and 44 subjects remaining at 4, 8, 12, and 16 weeks. There were no significant differences in opioid-positive urines, dropout rates, or dosage changes between formulations. In the ITT analyses, HRQOL improvements over time were bodily pain (62.1 vs. 69.1, P = 0.017), vitality (49.8 vs. 56.5, P = 0.001), mental health (59.9 vs. 66.0, P = 0.001), social function (66.4 vs. 74.7, P = 0.001), role emotional (59.4 vs. 71.9, P = 0.003), role physical (60.9 vs. 70.6, P = 0.005), and mental component summary (41.9 vs. 45.4, P<0.001). HU scores also improved (0.674 vs. 0.715, P = 0.001). Results from paired t tests, with only concurrently enrolled patients, showed similar improvements from baseline to 4, 8, 12, or 16 weeks. CONCLUSION: Buprenorphine, accompanied with psychosocial counseling, was associated with improved HRQOL and HUs.

Plasmodium falciparum: the potential of the cancer chemotherapeutic agent cisplatin and its analogues as anti-malarials.

The anti-malarial activity of the cancer chemotherapeutic agent cisplatin and cisplatin analogues was determined in Plasmodium falciparum. The cisplatin analogues included DNA-targeted acridine-tethered platinum compounds, carboplatin and transplatin. A [(3)H]-hypoxanthine incorporation assay was utilised to determine the IC(50) of cisplatin and related analogues. The DNA-targeted Pt compounds and cisplatin were shown to have IC(50) values that were less than 1 µM in P. falciparum, with the acridine-tethered compounds having the greatest cytotoxicity. Carboplatin and transplatin had IC(50) values of 12 and 16 µM, respectively. The outcome for transplatin was particularly interesting since it is not cytotoxic in mammalian cells. These results were discussed with respect to the potential use of cisplatin and cisplatin analogues as anti-malarial agents.

Chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) or acetaminophen and relationship with mortality among United States Veterans after testing positive for COVID-19.

Non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen are among the most-frequently used medications. Although these medications have different mechanisms of action, they have similar indications and treatment duration has been positively correlated with cardiovascular risk although the degree of risk varies by medication. Our objective was to study treatment effects of chronic use of individual NSAID medications and acetaminophen on all-cause mortality among patients who tested positive for COVID-19 while accounting for adherence. We used the VA national datasets in this retrospective cohort study to differentiate between sporadic and chronic medication use: sporadic users filled an NSAID within the last year, but not recently or regularly. Using established and possible risk factors for severe COVID-19, we used propensity scores analysis to adjust for differences in baseline characteristics between treatment groups. Then, we used multivariate logistic regression incorporating inverse propensity score weighting to assess mortality. The cohort consisted of 28,856 patients. Chronic use of aspirin, ibuprofen, naproxen, meloxicam, celecoxib, diclofenac or acetaminophen was not associated with significant differences in mortality at 30 days (OR = 0.98, 95% CI: 0.95-1.00; OR = 0.99, 95% CI: 0.98-1.00; OR = 1.00, 95% CI: 0.98-1.01; OR = 0.99, 95% CI: 0.98-1.00; OR = 1.00, 95% CI: 0.98-1.01; OR = 0.99, 95% CI: 0.97-1.01; and OR = 1.00, 95% CI: 0.99-1.02, respectively) nor at 60 days (OR = 0.97, 95% CI: 0.95-1.00; OR = 1.00, 95% CI: 0.99-1.01; OR = 0.99, 95% CI: 0.98-1.01; OR = 0.99, 95% CI: 0.97-1.00; OR = 0.99, 95% CI: 0.97-1.01; OR = 0.99, 95% CI: 0.97-1.01; and OR = 1.01, 95% CI: 0.99-1.02, respectively). Although the study design cannot determine causality, the study should assure patients as it finds no association between mortality and chronic use of these medications compared with sporadic NSAID use among those infected with COVID-19.

A novel method for handling pre-existing conditions in multivariate prediction model development for COVID-19 death in the Department of Veterans Affairs.

Many mathematical models have been proposed to predict death following the Coronavirus Disease 2019 (COVID-19); all started with comorbidity subsets for this still-little understood disease. Thus, we derived a novel predicted probability of death model (PDeathDx) upon all diagnostic codes documented in the Department of Veterans Affairs. We present the conceptual underpinnings and analytic approach in estimating the independent contribution of pre-existing conditions. This is the largest study to-date following patients with COVID-19 to predict mortality. Cases were identified with at least one positive nucleic acid amplification test. Starting in 1997, we use diagnoses from the first time a patient sought care until 14 days before a positive nucleic acid amplification test. We demonstrate the clear advantage of using an unrestricted set of pre-existing conditions to model COVID-19 mortality, as models using conventional comorbidity indices often assign little weight or usually do not include some of the highest risk conditions; the same is true of conditions associated with COVID-19 severity. Our findings suggest that it is risky to pick comorbidities for analysis without a systematic review of all those experienced by the cohort. Unlike conventional approaches, our comprehensive methodology provides the flexibility that has been advocated for comorbidity indices since 1993; such an approach can be readily adapted for other diseases and outcomes. With our comorbidity risk adjustment approach outperforming conventional indices for predicting COVID-19 mortality, it shows promise for predicting outcomes for other conditions of interest.

Weight-Based Compared With Fixed-Dose Enoxaparin Prophylaxis After Cesarean Delivery: A Randomized Controlled Trial.

OBJECTIVE: To evaluate fixed compared with weight-based enoxaparin dosing to achieve prophylactic anti-Xa levels after cesarean delivery. METHODS: Individuals meeting institutional criteria for enoxaparin thromboprophylaxis after cesarean delivery were randomly allocated to fixed (40 mg daily for body mass index [BMI, calculated as weight in kilograms divided by height in meters squared] lower than 40; 40 mg every 12 hours for BMI 40 or higher) or weight-based (0.5 mg/kg every 12 hours) enoxaparin dosing. Enoxaparin was initiated during inpatient hospitalization and continued at discharge for 14 days. Those with contraindication to anticoagulation, plan for therapeutic anticoagulation, or known renal impairment were excluded. The trial was unmasked. The primary outcome was prophylactic (0.2-0.6 international units/mL) peak anti-Xa level 4-6 hours after at least the third enoxaparin dose (at steady state). Secondary outcomes included subprophylactic and supraprophylactic peaks, outpatient peak, and venous thromboembolism (VTE) and wound complications in the first 6 weeks postpartum. Sample size of 121 per group was planned. At interim analysis with 50% enrollment, the trial was stopped early for efficacy. Primary analyses followed intention-to-treat principle with worst-case imputation for missing outcomes. Secondary analyses were complete case. RESULTS: From June 2020 to November 2021, 74 individuals were randomized to weight-based enoxaparin and 72 to fixed-dose enoxaparin. Those who received weight-based dosing were more likely to achieve prophylactic anti-Xa levels than those who received fixed dosing in primary analysis (49/74 [66%] vs 32/72 [44%], relative risk [RR] 1.49, 95% CI 1.10-2.02) and secondary analysis (49/60 [82%] vs 32/57 [56%], RR 1.45, 95% CI 1.12-1.88). Subprophylactic levels occurred more frequently with fixed dosing; supraprophylactic levels did not differ significantly by dosing. At the outpatient postoperative visit, 52% of participants (15/29) with weight-based dosing compared with 15% (5/33) with fixed dosing achieved prophylactic peak anti-Xa level (RR 3.41, 95% CI 1.42-8.24). There were no VTEs in either group. Wound complications occurred in five individuals (7%) with weight-based enoxaparin dosing compared with one individual (1%) with fixed enoxaparin dosing (RR 4.86, 95% 0.58-40.63). CONCLUSION: Weight-based dosing was more effective than fixed enoxaparin dosing in achieving prophylactic peak anti-Xa levels after cesarean delivery. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT04305756.

Effect of vaccination on the case fatality rate for COVID-19 infections 2020-2021: multivariate modelling of data from the US Department of Veterans Affairs.

OBJECTIVES: To evaluate the benefits of vaccination on the case fatality rate (CFR) for COVID-19 infections. DESIGN, SETTING AND PARTICIPANTS: The US Department of Veterans Affairs has 130 medical centres. We created multivariate models from these data-339 772 patients with COVID-19-as of 30 September 2021. OUTCOME MEASURES: The primary outcome for all models was death within 60 days of the diagnosis. Logistic regression was used to derive adjusted ORs for vaccination and infection with Delta versus earlier variants. Models were adjusted for confounding factors, including demographics, comorbidity indices and novel parameters representing prior diagnoses, vital signs/baseline laboratory tests and outpatient treatments. Patients with a Delta infection were divided into eight cohorts based on the time from vaccination to diagnosis. A common model was used to estimate the odds of death associated with vaccination for each cohort relative to that of unvaccinated patients. RESULTS: 9.1% of subjects were vaccinated. 21.5% had the Delta variant. 18 120 patients (5.33%) died within 60 days of their diagnoses. The adjusted OR for a Delta infection was 1.87±0.05, which corresponds to a relative risk (RR) of 1.78. The overall adjusted OR for prior vaccination was 0.280±0.011 corresponding to an RR of 0.291. Raw CFR rose steadily after 10-14 weeks. The OR for vaccination remained stable for 10-34 weeks. CONCLUSIONS: Our CFR model controls for the severity of confounding factors and priority of vaccination, rather than solely using the presence of comorbidities. Our results confirm that Delta was more lethal than earlier variants and that vaccination is an effective means of preventing death. After adjusting for major selection biases, we found no evidence that the benefits of vaccination on CFR declined over 34 weeks. We suggest that this model can be used to evaluate vaccines designed for emerging variants.

Plasmodium falciparum: DNA sequence specificity of cisplatin and cisplatin analogues.

In this paper, we provided evidence that cisplatin is able to form adducts with cellular DNA in Plasmodium falciparum. The DNA sequence specificity of cisplatin adduct formation was determined in trophozoite-enriched P. falciparum cells and this paper represents the first occasion that the sequence specificity of cisplatin DNA damage has been observed in malaria cells. Utilising a sub-telomeric, 692 bp repeat sequence in the P. falciparum genome, we were able to investigate the DNA adducts formed by cisplatin and five analogues. A run of eight consecutive guanines was the most prominent site of DNA damage in the malarial cells. This study suggests that the mechanism of P. falciparum cell death caused by cisplatin involves damage to DNA and hence inhibition of DNA replication and cell division.

Development and validation of prediction rules to target care intensification in veteran patients with diabetes.

BACKGROUND: Diabetes affects 30.3 million people in the USA. Among these people, a major risk factor for microvascular complications is having a glycated haemoglobin (HbA1c) value of ≥75 mmol/mol; therefore, it would be helpful to identify patients who will obtain future HbA1c values of <75 mmol/mol. OBJECTIVES: To develop and validate two prediction rules among patients with diabetes having a baseline HbA1c value of ≥75 mmol/mol: (1) HbA1c measurement ever <75 mmol/mol and (2) final HbA1c measurement of <75 mmol/mol. METHODS: Retrospective cohort study using a registry extracting data from the Department of Veterans Affairs's (VA's) electronic health records system. Baseline was 1 Jul 2013-30 June 2014; patients were followed up until 31 July 2016. RESULTS: Our population consisted of 145 659 patients. Across models, predictors were age, sex, minority status, baseline HbA1c value, time, HbA1c≥75 mmol/mol, receiving insulin treatment and consecutive number of HbA1c values of 75 mmol/mol. The overall likelihood of a patient ever having an HbA1c<75 mmol/mol was 73.65%; with the rule, predicted probabilities were 38.94%, 50.75% and 78.88%. The overall likelihood of patients having a final HbA1c measurement of <75 mmol/mol was 55.35%; the rule provided predicted probabilities of 29.93%, 50.17% and 68.58%. CONCLUSIONS: Within each rule, there were similar observed and predicted tertile probabilities; maintaining HbA1c values of <75 mmol/mol resulted in probability shifts in the majority of patients. We recommend psychosocial screening for 15% of patients for whom there is less than one-third chance of maintaining HbA1c<75 mmol/mol. We plan to conduct additional research to see whether this approach helps.

Pharmacoeconomic analysis of angiotensin-converting enzyme inhibitors in type 2 diabetes: a Markov model.

BACKGROUND: Prevention of cardiovascular disease (CVD) events by initiating an angiotensin-converting enzyme (ACE) inhibitor on diagnosis of type 2 diabetes may increase survival and decrease costs. OBJECTIVE: To determine the incremental cost-effectiveness ratios of ACE inhibitor initiation in normoalbuminuric, microalbuminuric, and macroalbuminuric patients with newly diagnosed type 2 diabetes. METHODS: A cohort of patients with newly diagnosed type 2 diabetes was followed for 8 years in a Markov model. Clinical outcomes included CVD events, dialysis, all-cause mortality, and the composite endpoints of the 3 events. Probabilities and costs were obtained from the literature. One-way and two-way sensitivity analyses were conducted to test the robustness of the model. RESULTS: Implementation of ACE inhibitor therapy on diagnosis of type 2 diabetes in normoalbuminuric and microalbuminuric patients is a dominant strategy (ie, more effective and less costly) across all outcomes. In macroalbuminuric patients, an additional $4.10 and $4.58 saves one life and avoids one composite endpoint, respectively; however, in these patients, not giving an ACE inhibitor is dominant for prevention of CVD events and dialysis. This is due to a 28.62% higher mortality rate in patients not receiving an ACE inhibitor. Thus, analysis of the composite endpoint shows that not giving an ACE inhibitor does not remain dominant. A limitation of our study is the inability to determine causality. CONCLUSIONS: If every newly diagnosed patient with type 2 diabetes in the US was prescribed an ACE inhibitor, our model shows that 68,314 CVD events would be averted, 46,410 lives would be saved, and 48 people would be prevented from needing dialysis over 8 years. These findings suggest that ACE inhibitors prevent numerous events in patients with type 2 diabetes who are normoalbuminuric at diagnosis, in addition to those already identified as being at risk for CVD events.

A comparison of veteran and nonveteran motivations and reasons for participating in clinical trials.

OBJECTIVE: Knowledge of distinct motivations and reasons toward or against future trial participation is invaluable to any organization conducting trial research. Study delays often occur due to lack of recruitment. This study's primary objective was to compare veteran and nonveteran motivations and reasons. METHODS: People in two outpatient waiting rooms were approached. The questionnaire assessed motivation toward trial involvement through use of five-point Likert-type scales and hypothetical trial scenarios; it also analyzed reasons for participation through subject ranking of reasons. RESULTS: Veterans were more likely to participate in a trial in which all participants received the active treatment (p = 0.025). Veterans had different reasons for participation than nonveterans. Specifically, veterans felt altruism and "paying back" people who treated them were more important (p = 0.024 and p = 0.003) while financial compensation for volunteering was less important (p < 0.001). CONCLUSIONS: Knowledge of the varying reasons for participation could potentially aid recruitment efforts.

GI risk factors and use of GI protective agents among patients receiving nonsteroidal antiinflammatory drugs.

BACKGROUND: Patient characteristics increase the risk of gastrointestinal (GI) complications associated with nonsteroidal antiinflammatory drugs (NSAIDs). Patients at risk may not be prescribed protective therapies that might mitigate their risk of NSAID-associated GI complications. OBJECTIVE: To assess GI risk among Veterans Affairs (VA) patients on NSAID therapy, determine whether therapy conformed to VA guidelines for lessening the risk of GI complications, and identify patient risk factors associated with conformance. METHODS: Using databases from 3 VA medical centers, we retrospectively identified patients receiving NSAIDs and obtained data regarding age, history of GI bleed over 8 years, GI adverse effects associated with NSAIDs, diagnoses, and medication history over one year. We inferred health status from age-adjusted Charlson comorbidity index values. Each patient's risk of developing GI complications over one year was calculated using these data. Among patients at significant or substantial risk, we assessed conformance to VA guidelines. We used logistic regression to identify risk factors associated with conformance and determine adjusted ORs (AORs) with 95% CIs for each risk factor. RESULTS: There were 19 122 patients receiving NSAIDs. Of 4589 patients at significant risk and 1246 at substantial risk, 1161 (25.3%) and 356 (28.6%), respectively, were prescribed guideline-conformant therapy. Risk factors associated with conformance (p < or = 0.001) among patients at significant risk were rheumatoid arthritis (AOR 1.34; 95% CI 1.13 to 1.58) and GI adverse effects (AOR 1.53; 95% CI 1.42 to 1.64). For substantial risk patients, risk factors associated with conformance (p < or = 0.031) were rheumatoid arthritis (AOR 1.65; 95% CI 1.37 to 1.98), concomitant corticosteroids (AOR 1.21; 95% CI 1.02 to 1.43), GI hospitalization (AOR 2.01; 95% CI 1.57 to 2.59), and GI adverse effects (AOR 1.79; 95% CI 1.47 to 2.18). CONCLUSIONS: Many patients at risk for GI adverse events do not receive guideline-conformant therapy. Educational interventions to improve conformance could focus on specific risk factors for GI complications.

A contest to create media messages aimed at recruiting adolescents for stop smoking programs.

This project engaged adolescents in a contest to create advertising messages aimed at recruiting teens for stop smoking programs. Middle school students were invited to design a media message for television, radio, Web, or print (newspaper or billboard). Of 4,289 students in eight middle schools of Rochester, Minn., 265 (6.2%) developed 172 stop smoking messages. The quality of their work confirmed that teens can design media messages to encourage their smoking adolescent peers to enroll in a program to stop smoking.

Angiotensin-converting enzyme inhibitors versus angiotensin receptor blockers for end-stage renal disease/mortality in type 2 diabetes.

AIMS: To compare angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) for end-stage renal disease (ESRD) development and all-cause mortality in veterans with macroalbuminuria and with newly documented type 2 diabetes. METHODS: A retrospective cohort study utilizing data from the national Department of Veterans Affairs (VA) databases. The study followed 5166 subjects without a history of use of ACEIs or ARBs. To control for differences in baseline characteristics between groups, comparisons of subjects ACEIs and ARBs were made by incorporating propensity scores analysis into multivariate logistic regression. This resulted in adjusted odds ratios and 95% confidence intervals for ESRD development and all-cause mortality. RESULTS: The sample was followed up to five years with a mean follow-up of three years. Subjects taking ACEIs has lower odds of ESRD development (OR, 0.33 [95% CI, 0.13-0.82]) and all-cause mortality (OR, 0.10 [95% CI, 0.04-0.21]) than ARBs. CONCLUSIONS: This study shows that ACEIs are associated with lower ESRD development and all-cause mortality than ARBs. This may have implications for guidelines which currently suggest that these two therapeutic classes provide similar benefits in people with newly diagnosed type 2 diabetes and macroalbuminuria.

Relationship between diet, exercise habits, and health status among patients with diabetes.

BACKGROUND: The American Diabetes Association recommends that people with diabetes should engage in physical activity and healthy eating. Similarly, diets rich in fruits or vegetables (5-13 servings) have been found to lower the risk of stroke, cardiovascular conditions, cancer, and diabetes. OBJECTIVES: To examine the associations between eating fruits and vegetables and exercising on physical/mental health among diabetes patients. A secondary objective was to describe the relationship between socioeconomic status and physical/mental health. Finally, we used the Health Belief Model (HBM) to help providers understand how they can work best with their patients to implement healthy lifestyle. METHODS: The 2005 Centers for Disease Control's Behavioral Risk Factor Surveillance System was used to determine the relationship between eating fruits/vegetables and exercise on physical and mental health. The sample was restricted to individuals who self-reported being diagnosed with diabetes (N=33,320) in 2005. Eating fruits and vegetables was categorized by the number of fruit and vegetable servings consumed daily (0, 1-2, 3-4, and ≥5). Poisson regression was used to assess these associations. RESULTS: Only 26% of individuals ate 5 or more servings of fruits and vegetables, whereas only 33% met exercise recommendations. Individuals who ate 5 or more servings of fruits and vegetables reported better mental health but poor physical health. Compared with meeting exercise recommendations, no exercise was associated with more days of poor physical/mental health. CONCLUSIONS: Reinforcement of daily exercise is helpful to patients with diabetes (PWDS); meeting exercise recommendations was associated with better outcomes of physical and mental health. Pharmacists and other public health providers should focus on interventions that incorporate the promotion of healthy lifestyles. The HBM can be used to improve health behavior among PWDS. Pharmacists are in a unique position to advocate change with consistent access to care.

Sudden sensorineural hearing loss associated with vardenafil.

The phosphodiesterase type 5 (PDE-5) inhibitors-sildenafil, vardenafil, and tadalafil-are used primarily in erectile dysfunction, but sildenafil is also indicated for pulmonary hypertension. Common adverse effects of vardenafil include headache, flushing, nasal congestion, dyspepsia, and nausea. Recently, PDE-5 inhibitors have been associated with adverse vision effects, and emerging evidence now indicates that they may also be responsible for hearing changes and hearing loss. We describe a patient who developed unilateral sudden sensorineural hearing loss possibly related to the use of vardenafil for erectile dysfunction. To our knowledge, only one other case of hearing loss related to this drug class has been published. Our patient was a 57-year-old man who came to the emergency department with right-sided mild-to-moderate hearing loss in the 500-3000-Hz range, confirmed by audiogram, that occurred after ingestion of vardenafil. The patient was hospitalized 2 days later for administration of intravenous dexamethasone, followed by oral prednisone. He reported that his hearing had improved on the fourth hospital day and was discharged 3 days later, continuing to taper the prednisone on an outpatient basis. A repeat audiogram after 10 days of corticosteroid therapy confirmed that his hearing in the 500-3000-Hz range was within normal limits. Use of the Naranjo adverse drug reaction probability scale indicated a possible (score of 3) adverse reaction of sudden sensorineural hearing loss associated with vardenafil consumption. We also performed an analysis of hearing loss cases related to PDE-5 inhibitors in the United States Food and Drug Administration's Adverse Event Reporting System database to compare the characteristics of our patient with those of other reported adverse event cases. Based on the temporal relation of the sudden sensorineural hearing loss to this patient's drug consumption, we propose that the vardenafil is a likely cause of the hearing loss. This case provides further evidence that PDE-5 inhibitor consumption should be considered as a possible cause in patients presenting with sudden sensorineural hearing loss.