Prioritizing Research Informing Antibiotic Prophylaxis Guidelines for Knee Arthroplasty Patients.

INTRODUCTION: Guidelines for routine antibiotic prophylaxis (AP) before dental procedures to prevent periprosthetic joint infection (PJI) have been hampered by the lack of prospective clinical trials. OBJECTIVES: To apply value-of-information (VOI) analysis to quantify the value of conducting further clinical research to reduce decision uncertainty regarding the cost-effectiveness of AP strategies for dental patients undergoing total knee arthroplasty (TKA). METHODS: An updated decision model and probabilistic sensitivity analysis (PSA) evaluated the cost-effectiveness of AP and decision uncertainty for 3 AP strategies: no AP, 2-y AP, and lifetime AP. VOI analyses estimated the value and cost of conducting a randomized controlled trial (RCT) or observational study. We used a linear regression meta-modeling approach to calculate the population expected value of partial perfect information and a Gaussian approximation to calculate population expected value of sample information, and we subtracted the cost for research to obtain the expected net benefit of sampling (ENBS). We determined the optimal trial sample sizes that maximized ENBS. RESULTS: Using a willingness-to-pay threshold of $100,000 per quality-adjusted life-year, the PSA found that a no-AP strategy had the highest expected net benefit, with a 60% probability of being cost-effective, and 2-y AP had a 37% probability. The optimal sample size for an RCT to determine AP efficacy and dental-related PJI risk would require approximately 421 patients per arm with an estimated cost of $14.7 million. The optimal sample size for an observational study to inform quality-of-life parameters would require 2,211 patients with an estimated cost of $1.2 million. The 2 trial designs had an ENBS of approximately $25 to $26 million. CONCLUSION: Given the uncertainties associated with AP guidelines for dental patients after TKA, we conclude there is value in conducting further research to inform the risk of PJI, effectiveness of AP, and quality-of-life values. KNOWLEDGE TRANSFER STATEMENT: The results of this value-of-information analysis demonstrate that there is substantial uncertainty around clinical, health status, and economic parameters that may influence the antibiotic prophylaxis guidance for dental patients with total knee arthroplasty. The analysis supports the contention that conducting additional clinical research to reduce decision uncertainty is worth pursuing and will inform the antibiotic prophylaxis debate for clinicians and dental patients with prosthetic joints.

Is Antibiotic Prophylaxis Cost-effective for Dental Patients Following Total Knee Arthroplasty?

INTRODUCTION: Routine antibiotic prophylaxis (AP) to prevent prosthetic joint infection remains controversial. The lack of prophylaxis guideline consensus from the American Academy of Orthopaedic Surgeons (AAOS) and the American Dental Association (ADA) contributes to clinician confusion. OBJECTIVES: This cost-effectiveness decision model informs the AP debate and guideline development by comparing the benefits, harms, and costs of alternative prophylaxis strategies. METHODS: A Markov state-transition model was developed comparing lifetime health outcomes and costs of alternative AP strategies for dental patients aged 65 y with a history of total knee arthroplasty (TKA). Based on our interpretation of AP recommendations from the AAOS and ADA, incremental cost-effectiveness ratios were calculated to compare the following strategies: no AP, AP for the first 2 y after a TKA, and lifetime AP. RESULTS: The no-AP strategy had the lowest average lifetime costs ($17,119) and quality-adjusted life years (11.2151). Compared with a no-prophylaxis strategy, the 2-y AP strategy had incremental costs of $56 and 0.0006 QALYs gained and was cost-effective (incremental cost-effectiveness ratio = $95,100) when a willingness-to-pay threshold of $100,000 per quality-adjusted life year was used. Based on the results of 1-way sensitivity analysis, the no-AP strategy was cost-effective when we modestly increased base case amoxicillin adverse event estimates that were substantially lower than estimates reported in previous models. When plausible combinations of important model parameters were varied, model results suggested that there may be clinical scenarios when AP may be appropriate for some medically at-risk patient populations. CONCLUSION: The results of cost-effectiveness decision modeling generally support questioning routine AP for dental patients with TKA. Sensitivity analyses suggest that prophylaxis may be cost-effective for patient populations with a higher medical risk of infection. This finding is consistent with the recommendations of the 2015 ADA practice guideline and the appropriate use criteria jointly developed by the AAOS and the ADA. KNOWLEDGE TRANSFER STATEMENT: The results of this decision modeling research support the contention that routine AP before invasive dental procedures to prevent prosthetic joint infection may not be cost-effective for patients without medical conditions, potentially conferring a higher infection risk. Model sensitivity analyses suggest that there may be clinical situations when medically at-risk patients benefit from AP.

Analysis of the RELN gene as a genetic risk factor for autism.

Several genome-wide screens have indicated the presence of an autism susceptibility locus within the distal long arm of chromosome 7 (7q). Mapping at 7q22 within this region is the candidate gene reelin (RELN). RELN encodes a signaling protein that plays a pivotal role in the migration of several neuronal cell types and in the development of neural connections. Given these neurodevelopmental functions, recent reports that RELN influences genetic risk for autism are of significant interest. The total data set consists of 218 Caucasian families collected by our group, 85 Caucasian families collected by AGRE, and 68 Caucasian families collected at Tufts University were tested for genetic association of RELN variants to autism. Markers included five single-nucleotide polymorphisms (SNPs) and a repeat in the 5'-untranslated region (5'-UTR). Tests for association in Duke and AGRE families were also performed on four additional SNPs in the genes PSMC2 and ORC5L, which flank RELN. Family-based association analyses (PDT, Geno-PDT, and FBAT) were used to test for association of single-locus markers and multilocus haplotypes with autism. The most significant association identified from this combined data set was for the 5'-UTR repeat (PDT P-value=0.002). These analyses show the potential of RELN as an important contributor to genetic risk in autism.

Potential risk factors associated with thrombocytopenia in a surgical intensive care unit.

We conducted a retrospective chart review of 193 patients admitted during a 3-month period to determine the frequency of and potential risk factors associated with thrombocytopenia, and the association of acquired thrombocytopenia with length of stay in a surgical-trauma intensive care unit (SICU) and mortality. All records were reviewed beginning 24 hours after admission. Patients were followed for the duration of SICU stay or until death. Data collected and analyzed as potential risk factors for thrombocytopenia were age, gender, admitting diagnosis, classification (trauma, surgical, medical), APACHE II score, medical history, all scheduled drugs with start and stop dates, select laboratory values, arterial or central line placement, and complications. Thrombocytopenia occurred in 25 (13%) patients. These patients were more likely (p<0.05) than those without thrombocytopenia to have the following potential risk factors: presence of a central or arterial line (76% vs 46%, p<0.025), nonsurgical diagnosis (60% vs 37%, p<0.05), diagnosis of sepsis (p<0.001), and administration of phenytoin (p<0.01), piperacillin (p<0.005), imipenem-cilastatin (p<0.001), and vancomycin (p<0.005). A longer SICU stay (mean 21 vs 4.5 days, p<0.05) and increased mortality (16% vs 4%, p<0.05) were significantly associated with thrombocytopenia. Cefazolin administration was significantly associated with nonthrombocytopenia (p<0.05). Factors not associated with thrombocytopenia were age, gender, and administration of histamine2-receptor antagonists, heparin, enoxaparin, penicillins, ceftazidime, ceftriaxone, chloramphenicol, and amphotericin B. A central or arterial line was the only factor associated with the development of thrombocytopenia in a multiple linear regression analysis (p=0.0003, multiple r=0.2580). Thrombocytopenia is not a common occurrence in the SICU, but is associated with a longer SICU stay and increased mortality.

Treatment of refractory status epilepticus with propofol: clinical and pharmacokinetic findings.

PURPOSE: We compared propofol with high-dose barbiturates in the treatment of refractory status epilepticus (RSE) and propose a protocol for the administration of propofol in RSE in adults, correlating propofol's effect with plasma levels. METHODS: Sixteen patients with RSE were included; 8 were treated primarily with high-dose barbiturates and 8 were treated primarily with propofol. RESULTS: Both groups of patients had multiple medical problems and a subsequent high mortality. A smaller but not statistically significant fraction of patients had their seizures controlled with propofol (63%) than with high-dose barbiturate therapy (82%). The time from initiation of high-dose barbiturate therapy to attainment of control of RSE was longer (123 min) than the time to attainment of seizure control in the group receiving propofol (2.6 min, p = 0.002). Plasma concentrations of propofol associated with control of SE were 14 microM +/- 4 (2.5 microg/ml). Recurrent seizures were common when propofol infusions were suddenly discontinued but not when the infusions were gradually tapered. CONCLUSIONS: If used appropriately, propofol infusions can effectively and quickly terminate many but not all episodes of RSE. Propofol is a promising agent for use in treating RSE, but more studies are required to determine its true value in comparison with other agents.

Mechanical ventilation and pharmacologic strategies for acute respiratory distress syndrome.

Acute or adult respiratory distress syndrome (ARDS) contributes to mortality and morbidity in the intensive care environment. Appropriate application of microprocessor-controlled mechanical ventilatory support, pathophysiology of the disease, and new pharmacologic modalities are currently being investigated. Mechanical ventilation is usually begun when respiratory failure is caused by alveolar hypoventilation or hypoxia. Primary choices for this therapy are control-mode ventilation, assist-control ventilation, pressure-control ventilation, intermittent mandatory ventilation, and synchronized intermittent mandatory ventilation with the addition of positive end-expiratory pressure. Patients who deteriorate despite these interventions may require alternative modes of ventilation. Pharmacologic agents in ARDS is important due to the multifactorial pathophysiologic and pharmacodynamic processes that are part of the disease. Clinical studies will continue to determine advantageous agents. Unfortunately, no convincing data exist that any pharmacologic or nonpharmacologic strategy is superior for the support of these patients or results in a better outcome than others.

The fluconazole era: management of hematogenously disseminated candidiasis in the nonneutropenic patient.

Hematogenously disseminated candidiasis arising from nosocomial fungal infection is a life-threatening complication in critically ill, nonneutropenic patients. The overall nosocomial fungal infection rate in United States hospitals doubled from 1980-1990. Until recently, amphotericin B was the only agent available for the treatment of life-threatening candidal infections, but its use is plagued by toxicities including nephrotoxicity and infusion-related reactions such as rigors and hypotension. The availability of fluconazole, which is regarded as much less toxic than amphotericin B, prompted a surge in research to determine if it is as efficacious in the management of candidemia and hematogenously disseminated candidiasis. Complicating the interpretation of studies is the broad range of infection severity, from candidemia that may be transient and self-limiting to life-threatening hematogenously disseminated candidiasis. Clinical trials comparing fluconazole and amphotericin B demonstrate the efficacy of fluconazole for catheter-associated candidemia in critically ill patients when the likely pathogen is Candida albicans. Amphotericin B should remain the first-line agent for the management of candidemia and hematogenously disseminated candidiasis in all other patients.

Metformin, a promising oral antihyperglycemic for the treatment of noninsulin-dependent diabetes mellitus.

Noninsulin-dependent diabetes mellitus has historically been treated with diet therapy alone or the addition of an oral hypoglycemic agent such as a sulfonylurea, or the two in combination with insulin. Although these medical interventions lower blood glucose concentrations, they may also potentiate hyperinsulinism through increased serum insulin concentrations. Insulin resistance and hyperinsulinism are associated with cardiovascular risk factors such as hypertriglyceridemia, decreased high-density lipoprotein cholesterol levels, hypertension, and hyperglycemia, among others. Therefore, a desirable therapeutic alternative would lower blood glucose, not result in hyperinsulinism, and have beneficial effects on lipid profiles. Metformin is a biguanide antihyperglycemic agent that provides these effects. When administered to carefully selected patients and monitored appropriately metformin may prove to be valuable in the treatment of diabetes mellitus and in altering its cardiovascular sequelae.

Phenytoin protein binding and dosage requirements during acute and convalescent phases following brain injury.

OBJECTIVE: To longitudinally evaluate unbound and total serum phenytoin concentrations during intravenous phenytoin maintenance dosage and to determine the relationship among phenytoin protein binding, serum albumin, and unbound fatty acid concentrations in patients with head injuries during intensive care unit (ICU) and convalescent care. DESIGN: Serum albumin and phenytoin unbound fraction were determined twice weekly during ICU and convalescent care in 10 patients receiving phenytoin following acute brain injury. Phenytoin protein binding was also determined in 10 healthy control subjects. MAIN OUTCOME MEASURES: Longitudinal serum phenytoin concentrations associated with dosage adjustments targeted to achieve unbound phenytoin serum concentrations between 1.0 and 2.0 mg/L were documented during ICU and convalescent care. Longitudinal phenytoin binding was correlated with serum albumin and unbound fatty acid concentrations in neurotrauma patients. RESULTS: ICU patients received intravenous therapy for a mean of 15.0 days. The mean +/- SD initial phenytoin intravenous dosage regimen of 6.0 +/- 0.7 mg/kg/d resulted in mean +/- SD total and unbound phenytoin concentrations of 3.2 +/- 2.3 and 0.3 +/- 0.2 mg/L. Two patients had seizures associated with low phenytoin concentrations. Four patients continued to receive oral phenytoin therapy during convalescent care; phenytoin dosage requirements decreased over time in these patients. During acute and convalescent care, the phenytoin unbound fraction ranged from 6.0% to 18.3% and correlated with albumin (r2 = 0.61, p < 0.0001) but did not correlate with unbound fatty acid concentrations. The mean phenytoin unbound fraction was 10.1% and 8.9% for the ICU and convalescent patients with brain injuries, respectively, and was 7.0% for the healthy volunteers. CONCLUSIONS: Phenytoin protein binding was significantly correlated with albumin and was more variable in ICU and convalescent patients with brain injuries than in healthy volunteers. The high dosage requirements and subtherapeutic unbound phenytoin concentrations observed during acute care are best explained by increased metabolism. Phenytoin dosage requirements decreased during convalescence.

A follow-up case report of Actinobacillus actinomycetemcomitans in human periodontal disease.

The purpose of this investigation was to compare clinical and microbial parameters in a follow-up case report of adult subjects harboring Actinobacillus actinomycetemcomitans (Aa) with clinically matched subjects who did not have detectable Aa. 16 subjects with Aa and 16 subjects without Aa at the baseline examination were re-examined at an average of 46 months following collection of baseline data. Clinical measurements were recorded and subgingival plaque sampled and evaluated for microbial flora from each maxillary first molar. In 16 subjects with Aa at baseline, 4 sites in 3 subjects had detectable actinobacilli at the follow-up appointment. 26 sites in 13 individuals with Aa at baseline had a significantly increased gingival index at the follow-up visit (p less than or equal to 0.05), but there was no significant increase in probing depth or attachment loss. 32 sites in the 16 subjects without Aa at baseline still did not have detectable levels of this microorganism at the follow-up examination nor was there any significant difference between baseline and the follow-up appointment for the gingival index, probing depth and attachment level measurements. In subjects with Aa at baseline, 1 of 12 teeth without Aa and 5 of 20 teeth with Aa had been extracted prior to the follow-up visit. In this population group, having sites where Aa was detected, 6 of 9 teeth which had a probing depth greater than or equal to 5 mm were lost before the follow-up data collection appointment. In the control group, which did not have detectable Aa at baseline, 9 teeth with probing depths greater than or equal to 5 mm were not lost. These observations, although not proving, suggest in this population group, that deeper probing depths taken together with the presence of Aa may have placed an individual at greater risk of tooth loss.

Masked tonal hearing thresholds in the beluga whale.

Masked tonal thresholds were measured for a beluga whale at one noise level and 32 frequencies between 40 Hz and 115 kHz. Critical ratios were estimated and compared with those previously measured for the bottlenose dolphin. Beluga whale critical ratios were found to be about 3 dB lower than those of the bottlenose dolphin. Absolute tonal thresholds were extended below previous measurements to 40 Hz.

Interindividual and intraindividual variability in labetalol pharmacokinetics.

The between-subject and within-subject variability in the pharmacokinetics of labetalol at steady state were determined. Sixteen nonobese normal volunteers (mean age, 27 years) received five different formulations of labetalol orally on five different occasions every 12 hours for five doses. A 7-day washout separated each administration phase. Plasma concentration-time data for labetalol were obtained over the 24-hour period after the fifth dose in each phase. Labetalol concentrations in plasma were measured using high-performance liquid chromatography (HPLC). Pharmacokinetic parameters for each subject after each study phase were estimated. The mean V beta/F, Vdss/F, TBC/F, t1/2 beta, and AUC tau 0 for each subject ranged between 18.1 and 161.9 L/kg, 7.1 and 53.9 L/kg, 1.3 and 5.72 L/hr/kg, 6.9 and 11.0 hours, and 154 and 520 micrograms.hr/L, respectively, indicating large interindividual variability. Considerable intraindividual variability in each of the pharmacokinetic parameters was also observed. These data indicate that a larger number of subjects will be required to detect "significant" differences in the disposition of labetalol.

Biological effects of kepone and mirex in freshwater invertebrates.

Acute and chronic toxicity studies of Kepone (chlordecone) and mirex were conducted with daphnids (Daphnia magna), amphipods (Gammarus pseudolimnaeus), and larvae of a midge (Chironomus plumosus). Acute toxicities of Kepone ranged from a 48-hr EC50 of 350 microgram/L for midges to a 96-hr LC50 of 180 microgram/L for amphipods, whereas the acute toxicities of mirex to all three taxa exceeded 1000 microgram/L. Maximum acceptable toxicant concentrations (MATC's) for Kepone and mirex were estimated by measuring reproduction of daphnids, growth of amphipods, emergence of midges, and survival of all organisms. MATC for Kepone was estimated to be between 9 and 18 microgram/L for daphnids, between 1 and 2 microgram/L for amphipods, and between 8.4 and 18 microgram/L for midges; MATC for mirex exceeded 34 microgram/L for daphnids and midges, but less than 2.4 microgram/L for amphipods. The concentration of Kepone and mirex accumulated by daphnids was 760 and 8025 times, respectively, the concentration in water. Estimated times for elimination of 50% of the residues by daphnids were 141 hr for Kepone and 12 hr for mirex.