Utility of Serial Microbial Cell-free DNA Sequencing for Inpatient and Outpatient Pathogen Surveillance Among Allogeneic Hematopoietic Stem Cell Transplant Recipients.

Background: This study characterizes the clinical utility and validity of the Karius test (KT), a plasma microbial cell-free DNA sequencing platform, as an infection surveillance tool among hematopoietic stem cell transplant (HCT) recipients, including monitoring for cytomegalovirus (CMV) and detecting infections relative to standard microbiologic testing (SMT). Methods: A prospective, observational cohort study was performed among adult HCT recipients as inpatients and outpatients. Serial KTs were performed starting with 1 sample within 14 days before HCT, then weekly from 7-63 days posttransplant then monthly from 3-12 months post-HCT. Diagnostic performance of KT versus CMV polymerase chain reaction was evaluated with positive percent agreement and negative percent agreement. Infectious events (<12 months post-HCT) were extracted from medical records. For infectious events without positive SMT, 2 clinicians adjudicated KT results to determine if any detections were a probable cause. Difference in time from KT pathogen detection and infection onset was calculated. Results: Of the 70 participants, mean age was 49.9 years. For CMV surveillance, positive percent agreement was 100% and negative percent agreement was 90%. There was strong correlation between CMV DNA and KT molecules per microliter (r 2: 0.84, P < .001). Of the 32 SMT+/KT+ infectious events, KT identified 26 earlier than SMT (median: -12 days) and an additional 5 diagnostically difficult pathogens identified by KT but not SMT. Conclusions: KT detected CMV with high accuracy and correlation with quantitative polymerase chain reaction. Among infectious events, KT demonstrated additive clinical utility by detecting pathogens earlier than SMT and those not detected by SMT.

Vaccine response after pneumococcal vaccination in allogeneic hematopoietic stem cell transplant recipients.

Current guidelines for vaccination in allogeneic hematopoietic stem cell transplant (HCT) recipients recommend initiation of pneumococcal vaccination series three to six months post-HCT, with most data supporting initiation at six months due to a more robust immune response. This single-center, retrospective, observational chart review aimed to evaluate the impact of initiating the pneumococcal vaccine series at three months post-HCT compared to six months post-HCT. The primary endpoints were defined as a percentage of patients with a serologic response of >1 and >1.3 µg/mL for over 50% of the defined serotypes. Outcomes showed no difference in immunologic response between the two groups.

Evaluation of direct oral anticoagulants versus low molecular weight heparins for venous thromboembolism treatment in patients with gastrointestinal malignancies.

BACKGROUND: Direct oral anticoagulant (DOAC) use in cancer-associated venous thromboembolism (CA-VTE) has increased due to updates in recent guidelines and literature. However, select guidelines caution against DOAC use in patients with gastrointestinal (GI) malignancies due to reported increased bleeding events. The objective of this study was to compare the safety and effectiveness of DOACs versus low-molecular-weight heparins (LMWHs) for CA-VTE treatment in patients with GI malignancies. PATIENTS AND METHODS: This multicenter, retrospective cohort study included patients with primary GI malignancies who received therapeutic anticoagulation with a DOAC or LMWH for CA-VTE between January 1, 2018, and December 31, 2019. The primary outcome was the incidence rate of bleeding events (major, clinically relevant non-major, or minor bleeding events) within a 12-month period following the initiation of therapeutic anticoagulation. The secondary endpoint was the incidence rate of recurrent VTE events within a 12-month period following the start of therapeutic anticoagulation. RESULTS: After screening, 141 patients met inclusion criteria. The incidence rate of all bleeding events significantly differed between DOAC (4.98 events/100 person-months) and LWMH (10.2 events/100 person-months) recipients. The corresponding incidence rate ratio (IRR) with the DOAC group serving as the reference was 2.05 (p = 0.01), with the majority of bleeds in both groups presenting as minor bleeds. No difference was found between the incidence rate of recurrent VTE within a 12-month period of starting therapeutic anticoagulation between groups (IRR 3.08, p = 0.06). CONCLUSION: Our results suggest that DOACs do not pose an additional bleeding risk compared to LMWH in patients with certain GI malignancies. Careful selection of DOAC therapy with respect to bleeding risk is still warranted.

Predictors of lenalidomide maintenance duration after autologous stem cell transplant in patients with multiple myeloma.

BACKGROUND: For patients with multiple myeloma (MM) who have undergone autologous stem cell transplant (auto-SCT), the immunomodulatory agent lenalidomide is a first-line option for maintenance therapy. Because longer durations of lenalidomide maintenance are associated with improved survival, identifying strategies to avoid premature cessation of maintenance is an important priority in the post-transplant setting. OBJECTIVES: The primary objective of this analysis was to identify specific clinical predictors of lenalidomide treatment duration that could guide optimal medication management. Key secondary objectives included predictors of intolerable toxicity, rationale for lenalidomide dose reduction/discontinuation, and characterization of dose adjustments. STUDY DESIGN: This retrospective, multi-center cohort study included adults with MM who underwent auto-SCT and initiated maintenance lenalidomide between 01/01/2012 and 02/28/2021. Variables assessed as potential predictors of maintenance duration or intolerable toxicity included age, body mass index (BMI), Eastern Cooperative Oncology Group (ECOG) performance status at time of auto-SCT, renal function, initial lenalidomide dose, use of combination maintenance therapy, and cytogenetic risk category. RESULTS: Among 299 patients included, the median age at time of auto-SCT was 62 years (range 30-77). The majority of patients had standard-risk cytogenetics (64%) and an ECOG performance status of 0 or 1 (72%). In the overall population, the median duration of maintenance was 1.3 years (range 0.3-8.6 years). The median initial dose of lenalidomide was 10 mg daily (range 2.5-25 mg). During the study period, 35% of patients had a dose reduction due to toxicity, 21% stopped lenalidomide due to disease progression, and 19% stopped due to toxicity. Multivariate linear regression analyses did not identify any significant predictors of lenalidomide duration or discontinuation due to intolerable toxicity. The most frequently reported toxicities leading to discontinuation were cytopenias, rash, and fatigue. CONCLUSION: This analysis did not identify any significant risk factors to predict the duration of lenalidomide maintenance or discontinuation for toxicity following auto-SCT in patients with MM. While limited by the retrospective design and relatively small sample size, our findings suggest that a priori lenalidomide dose reductions based on patient co-morbidities or performance status may not substantially affect the duration of lenalidomide maintenance.

Prevalence and Predictors of Pseudomonas aeruginosa Among Hospitalized Patients With Diabetic Foot Infections.

Background: Diabetic foot infections (DFIs) are commonly associated with antibiotic overuse. Empiric DFI treatment often includes coverage for Pseudomonas aeruginosa (PsA), but the frequency of PsA DFIs is poorly understood. The study objectives were to quantify the prevalence of and determine predictors for PsA DFIs. Methods: This multicenter, retrospective cohort included hospitalized patients with DFI from 2013 through 2020 who were age ≥18 years; diabetes mellitus diagnosis; and DFI based on International Classification of Diseases, Tenth Revision coding, antibiotic treatment, and DFI culture with organism growth. Osteomyelitis was excluded. Patient characteristics were described and compared; the primary outcome was presence of PsA on DFI culture. Predictors of PsA DFI were identified using multivariable logistic regression. Results: Two hundred ninety-two patients were included. The median age was 61 (interquartile range [IQR], 53-69) years; the majority were men (201 [69%]) and White (163 [56%]). The most commonly isolated organisms were methicillin-susceptible Staphylococcus aureus (35%) and streptococci (32%); 147 (54%) cultures were polymicrobial. Two hundred fifty-seven (88%) patients received empiric antibiotics active against PsA, but only 27 (9%) patients had PsA DFI. Immunocompromised status (adjusted odds ratio [aOR], 4.6 [95% confidence interval {CI}, 1.3-16.7]) and previous outpatient DFI antibiotic treatment failure (aOR, 4.8 [95% CI, 1.9-11.9]) were associated with PsA DFI. Conclusions: PsA DFI is uncommon, but most patients receive empiric antipseudomonal antibiotics. Empiric broad-spectrum antibiotics are warranted given the frequency of mixed infections, but patient-specific risk factors should be considered before adding antipseudomonal coverage.

Characterisation of infections in patients with acute myeloid leukaemia receiving venetoclax and a hypomethylating agent.

We investigated the incidence of invasive fungal infections (IFIs) and other infectious complications in patients receiving venetoclax and hypomethylating agent therapy for acute myeloid leukaemia (AML). This retrospective, multicentre cohort study included adult patients with AML who received at least one cycle of venetoclax and either azacitidine or decitabine between January 2016 and August 2020. The primary outcome was the incidence of probable or confirmed IFI. Secondary outcomes included antifungal prophylaxis prescribing patterns, incidence of bacterial infections, and incidence of neutropenic fever hospital admissions. Among 235 patients, the incidence of probable or confirmed IFI was 5.1%. IFI incidence did not differ significantly according to age, antifungal prophylaxis use, or disease status. In the subgroup of patients with probable or confirmed IFIs, six (50%) were receiving antifungal prophylaxis at the time of infection. The overall incidence of developing at least one bacterial infection was 33.6% and 127 (54%) patients had at least one hospital admission for febrile neutropenia. This study demonstrated an overall low risk of developing probable or confirmed IFI as well as a notable percentage of documented bacterial infections and hospital admissions due to neutropenic fever.

Comparing drug interaction frequencies of various hepatitis C treatment regimens among monoinfected patients.

INTRODUCTION AND OBJECTIVES: Four regimens are recommended for treating hepatitis C (HCV) genotype 1 infection. Study aims were to (1) compare frequencies of contraindicated drug interactions (XDDIs) when each HCV regimen is added to medication profiles of HCV-monoinfected patients, (2) quantify the proportion of patients with XDDIs to all four regimens and (3) determine covariates independently associated with having a XDDI to all four regimens. MATERIALS AND METHODS: A cross-sectional study was performed within Upstate New York Veterans Healthcare Administration. INCLUSION CRITERIA: (1) age ≥18 years, (2) HCV monoinfection and (3) available medication list. Data extracted were: demographics, comorbidities, and medication list. Primary outcome was XDDIs involving patient's home medications and each HCV regimen. University of Liverpool drug interaction website was used to define XDDIs. Two-way comparisons of regimens were performed using McNemar's test where p<0.0083 was considered statistically significant. Multivariate regression analyses were performed to determine predictors. RESULTS: Of the 4047 subjects, mean±standard deviation age was 59.8±7.6. Median (interquartile range) number of medications used was 7 [4-11]. Frequencies of XDDIs after the addition of each regimen ranged from 2.8% to 17.8% and were mostly statistically different from one another. There were 95 (2.3%) patients with XDDIs to all four regimens. Predictors of having XDDIs to all four regimens were ≥6 medications and HCV infection ≥10 years. CONCLUSION: The frequencies of XDDIs varied between HCV regimens. Number of medications and duration of HCV infection were predictors of having XDDIs to all four regimens.

Short Communication: Relationship Between Contraindicated Drug-Drug Interactions and Subsequent Hospitalizations Among Patients Living with HIV Initiating Combination Antiretroviral Therapy.

Persons living with HIV (PLWH) are at an increased risk of contraindicated drug-drug interactions (XDDIs), which may result in deleterious outcomes. Study objectives were to (1) compare the frequency of hospitalizations between patients with and without XDDIs and (2) determine if XDDIs are independently associated with hospitalizations in PLWH. A retrospective cohort study was performed among PLWH receiving care at the Upstate New York Veterans' Healthcare Administration or University of New Mexico Truman Health Services from 2000 to 2013. Hospitalization was defined as an admission to an inpatient hospital facility for ≥24 h. Of the 1329 patients evaluated, 149 (11.2%) patients were hospitalized within 1 year of antiretroviral therapy initiation. A significantly higher proportion of patients with XDDIs were hospitalized compared with those who did not have XDDIs (20.3% vs. 10.2%, risk ratio: 1.98, 95% confidence interval [CI]: 1.35-2.91, p = .001). In the multivariate Cox proportional hazards regression analyses, XDDIs were independently associated with hospitalizations (hazard ratio [HR]: 1.58; 95% CI: 1.00-2.48; p = .05), after adjustment for CD4 < 242 cells/mm3 (HR: 2.38; 95% CI: 1.72-3.33; p < .001), protease inhibitor (PI)-based regimen (HR: 1.35; 95% CI: 0.97-1.89; p = .08), recreational drug use (HR: 2.58, 95% CI: 1.85-3.58, p < .001), and non-HIV medications ≥10 (HR: 1.62; 95% CI: 0.97-2.69; p = .07). In this study an increased risk of hospitalization was observed among PLWH with XDDIs compared with those without XDDIs. This relationship persisted after adjustment for CD4 count, use of a PI-based regimen, recreational drug use, and number of non-HIV medications.

Relationship between vitamin D and human immunodeficiency virus (HIV) viral load among HIV-infected patients in Kazakhstan.

INTRODUCTION: Human immunodeficiency virus (HIV) is associated with inflammation. An association between vitamin D deficiency and inflammation also exists. Our study attempts to examine whether there may be a relationship between vitamin D and HIV viral load (HIV RNA) by: 1) characterizing the distribution of 25-hydroxyvitamin D (25-OHD), and 2) determining if 25-OHD is independently associated with HIV RNA. METHODOLOGY: A cross-sectional study among HIV-infected adults was conducted. Demographics, clinical / social / HIV characteristics and data on antiretroviral therapy were collected by questionnaire, medical records and laboratory testing. All patients provided blood samples. Bivariate and multivariate analyses were conducted to quantify the relationship between vitamin D and HIV RNA. RESULTS: Among the 564 patients, the median (interquartile range, IQR) 25-OHD value was 24.42 (16.22 - 34.10) ng/mL. The mean (standard deviation, SD) log-HIV RNA was 3.51 (1.11) copies/mL. There were 304 patients (53.9%) with an undetectable HIV RNA (< 500 copies/mL). In the bivariate analyses, no differences were observed between patients with and without an undetectable HIV RNA in mean (SD) 25-OHD, 25-OHD insufficiency (< 30 ng/mL), or 25-OHD deciles. In the log-binomial regression analyses, there was no association between 25-OHD and an undetectable HIV RNA (prevalence ratio: 1.00, 95% confidence interval: 0.99 - 1.01, p = 0.67). CONCLUSIONS: No relationship was observed between 25-OHD and HIV RNA among HIV-infected patients in Kazakhstan.

A Cross-Sectional Study Comparing the Frequency of Drug Interactions After Adding Simeprevir- or Sofosbuvir-Containing Therapy to Medication Profiles of Hepatitis C Monoinfected Patients.

INTRODUCTION: This study compares the expected occurrence of contraindicated drug-drug interactions (XDDIs) when simeprevir (SIM)- or sofosbuvir (SOF)-containing therapy is added to medication profiles of patients with hepatitis C (HCV) monoinfection to quantify, in relative terms, the population-based risk of XDDIs. Second, this study identified the predictors of XDDIs when HCV therapies are added to medication profiles. METHODS: A cross-sectional study was performed among Veterans' Affairs patients. Inclusion criteria were: (1) age ≥18 years, (2) HCV infection, and (3) availability of a medication list. Patients with human immunodeficiency virus were excluded. Demographics, comorbidities, year of HCV diagnosis, and most recent medication list were collected from medical records. The primary outcome was the presence of XDDIs involving HCV therapy and the medications in the patient's home medication list after the addition of either SIM- or SOF-containing regimens. To define XDDIs, Lexi-Interact drug interaction software was used. RESULTS: 4,251 patients were included. The prevalence of XDDIs involving SIM- or SOF-containing therapy were 12.6% and 4.7% (p < 0.001), respectively. In multivariable analyses examining the predictors of XDDIs involving SIM-containing therapy, the only medication-related predictor was use of ≥6 home medications (odds ratio OR 4.58, 95% confidence interval CI 3.54-5.20, p < 0.001). Similarly, use of ≥6 home medications was also the only variable associated with an increased probability of XDDI involving SOF-containing therapy (OR 3.83, 95% CI 2.57-5.70, p < 0.001). CONCLUSIONS: Sofosbuvir-containing therapy had a lower frequency of XDDIs than SIM-containing therapy. Polypharmacy with various classes of home medications predicted XDDIs involving SIM- or SOF-containing therapy.

Retrospective comparison of outcomes, diagnostic value, and complications of percutaneous prolonged drainage versus surgical pericardiotomy of pericardial effusion associated with malignancy.

Surgical pericardiotomy is often preferred as a primary option in patients with malignant pericardial effusions. Recent series have revealed that prolonged drainage substantially reduces pericardial effusion recurrence rates, even in the setting of malignancy. The aim of the study was to directly compare the efficacy of pericardiocentesis with prolonged drainage with the primary surgical pericardiotomy in patients with symptomatic pericardial effusion associated with a malignancy. We retrospectively evaluated 88 patients who presented with pericardial tamponade associated with a malignancy. Pericardiocentesis with extended drainage was performed in 43 patients and surgical pericardiotomy in 45 patients. The recurrence rate was not significantly different in patients with prolonged catheter drainage versus surgical pericardiotomy (12% vs 13%, respectively, p = 0.78). In addition, there was no significant difference in diagnostic yield between percutaneous drainage and surgical window (44% vs 53%, respectively, p = 0.39). The overall rate of complications was significantly lower in the prolonged drainage group (2% vs 20%, p = 0.007). Moreover, there were no serious complications in the prolonged drainage group versus 9% in the surgical pericardiotomy group. In conclusion, (1) surgical pericardiotomy with pericardial biopsy does not add significant diagnostic value beyond the cytologic assessment available with pericardiocentesis, (2) surgical pericardiotomy does not improve clinical outcomes over pericardiocentesis, and (3) surgical pericardiotomy is associated with a higher rate of complications.

Bilateral sinonasal polyposis in a patient with unilateral choanal atresia.

Sinonasal polyposis is a disorder of hyperplastic mucosal inflammation that subsequently leads to the development of smooth, pale, non-neoplastic masses. The theories on its pathogenesis are diverse and remain debated within the medical community. A distinct, widely accepted, and unifying theory is absent, and probably unrealistic given the varying possible causes. The case reported here, which demonstrates nasal polyp formation within an atretic nasal cavity, suggests that nasal airflow or aerodynamics may have little to no effect on its etiology. It also seems to provide evidence that at least in some individuals nasal polyps appear to be due to an inflammatory disorder independent of inhalant allergen challenge.

Effect of tympanostomy tube surface on occlusion.

OBJECTIVE: Premature tympanostomy tube (TT) occlusion frequently leads to TT replacement surgery. TT surface preparations have been suggested as a means of reducing TT occlusion. The purpose of this study is to determine if commercial TT compositions or surface preparations impact the rate of TT occlusion using an in vitro model. METHODS: Commercial TTs composed of titanium, fluoroplastic, and silicone, as well as human serum albumin coated titanium, phosphorylcholine coated fluoroplastic, and polyvinylpyrrolidone coated silicone TTs, were tested for occlusion development in a previously validated in vitro model that simulates middle ear air and mucus flow. RESULTS: Time to occlusion was longer with all coated TTs relative to all uncoated TTs (p=0.038). Polyvinylpyrrolidone coated silicone TTs had the lowest rate of occlusion and improvement relative to silicone (36% vs. 70%). Time to occlusion was longer in all coated TTs, but individually, none reached statistical significance. CONCLUSION: TT composition and surface preparations do not dramatically impact the development of TT occlusion. All tested surface coatings seem to delay TT occlusion in this in vitro model. In vivo testing will be necessary to validate these findings.

Odontogenic sinusitis: an ancient but under-appreciated cause of maxillary sinusitis.

PURPOSE OF REVIEW: For well over 100 years, it has been appreciated that maxillary dental infections can cause sinusitis. This insight has been largely overlooked with the advent of functional endoscopic sinus surgery (ESS) and its emphasis on the osteomeatal complex. We review several recent case series and reviews of odontogenic sinusitis that characterize and discuss emerging diagnostic modalities in odontogenic sinusitis. RECENT FINDINGS: In recent publications on odontogenic sinusitis, up to 40% of chronic bacterial maxillary sinus infections are attributed to a dental source, which is far higher than the previously reported incidence of 10%. Plain dental films and dental evaluations frequently fail to detect maxillary dental infection that can be causing odontogenic sinusitis. However, sinus computed tomography (CT) or Cone Beam Volumetric CT (CBVCT) are far more successful in identifying dental disease causing sinusitis. The microbial pathogens of odontogenic sinusitis remain unchanged from earlier reviews; however, the clinical findings in odontogenic sinusitis are better described in recent reviews. Successful treatment of odontogenic sinusitis requires management of the odontogenic source and may require concomitant or subsequent sinus surgery. SUMMARY: Odontogenic sinusitis is frequently recalcitrant to medical therapy and usually requires treatment of the dental disease. Sometimes dental treatment alone is adequate to resolve the odontogenic sinusitis and sometimes concomitant or subsequent ESS is required. Evaluation of all patients with persistent chronic rhinosinusitis (CRS) should include inspection of the maxillary teeth on CT scan for evidence of periapical lucencies. Unilateral recalcitrant disease associated with foul smelling drainage is especially characteristic of odontogenic sinusitis. High-resolution CT scans and CBVCT can assist in identifying dental disease.

Frequency of recurrence of pericardial tamponade in patients with extended versus nonextended pericardial catheter drainage.

Recurrence of pericardial tamponade is relatively common after pericardiocentesis. We evaluated the clinical and procedural predictors of recurrent pericardial tamponade after pericardiocentesis. We included 157 consecutive patients with pericardial tamponade (age 62 ± 18 years, 54% men) who had undergone pericardiocentesis from 2000 to 2007. An intrapericardial catheter was used for prolonged drainage of the pericardial effusion (78% of cases) at the discretion of the operator. The overall recurrence rate 11.8 ± 0.6 months after pericardiocentesis was 20% and the mean interval to recurrence was 1.2 ± 2.1 months. However, patients with extended catheter drainage had a reduced recurrence rate of 12% compared to 52% in patients without extended drainage (p <0.001). In the Cox regression modeling, absence of extended drainage (hazard ratio [HR] 4.1, 95% confidence interval [CI] 1.7 to 10, p = 0.002), incomplete drainage of pericardial effusion (HR 9.7, 95% CI 3.6 to 22.7, p <0.001), loculated effusion (HR 11.1, 95% CI 2.9 to 43, p = 0.001), and malignancy (HR 3.3, 95% CI 1.8 to 10.3, p = 0.037) independently correlated with recurrence at 1 year. In conclusion, extended pericardial drainage after catheter placement is associated with a reduced recurrence of pericardial tamponade after pericardiocentesis.

DNA replication licensing factors and aneuploidy are linked to tumor cell cycle state and clinical outcome in penile carcinoma.

PURPOSE: The DNA replication licensing machinery is integral to the control of proliferation, differentiation, and maintenance of genomic stability in human cells. We have analyzed replication licensing factors (RLF), together with DNA ploidy status, to investigate their role in progression of penile squamous cell carcinoma and to assess their utility as novel prognostic tools. EXPERIMENTAL DESIGN: In a cohort of 141 patients, we linked protein expression profiles of the standard proliferation marker Ki67 and the RLFs Mcm2 and geminin to clinicopathologic variables, ploidy status, and clinical outcome. RESULTS: Increased Ki67, Mcm2, and geminin levels were each significantly associated with arrested tumor differentiation (P < 0.0001) and aneuploidy (P < or = 0.01). Accelerated cell cycle progression was linked to increasing tumor size, stage, and depth of invasion. Aneuploid tumors significantly correlated with tumor grade (P < 0.0001). Biomarker expression and DNA ploidy status were significant predictors of locoregional disease progression [Mcm2 (P = 0.02), geminin (P = 0.02), Ki67 (P = 0.03), and aneuploidy (P = 0.03)] in univariate analysis. Importantly, aneuploidy was a strong independent prognosticator for overall survival (hazard ratio, 4.19; 95% confidence interval, 1.17-14.95; P = 0.03). Used in conjunction with conventional pathologic information, multiparameter analysis of these variables can stratify patients into low- or high-risk groups for disease progression (Harrell's c-index = 0.88). CONCLUSIONS: Our findings suggest that RLFs and tumor aneuploidy may be used as an adjunct to conventional prognostic indicators, identifying men at high risk of disease progression. Our results also identify the DNA replication initiation pathway as a potentially attractive therapeutic target in penile squamous cell carcinoma.

Relationship between initial vancomycin concentration-time profile and nephrotoxicity among hospitalized patients.

BACKGROUND: Data suggest that higher doses of vancomycin can increase the risk of nephrotoxicity. No study has been undertaken to determine the pharmacodynamic index (ie, the area under the curve [AUC] or the trough value) that best describes the relationship between vancomycin exposure and onset of nephrotoxicity. METHODS: A retrospective study was conducted among patients who received vancomycin for a suspected or proven gram-positive infection during the period from 1 January 2005 through 31 December 2006 at Albany Medical Center Hospital. Patients were included in our study if they (1) were > or =18 years old, (2) had an absolute neutrophil count of > or =1000 cells/mm(3), (3) received vancomycin for >48 h, (4) had 1 vancomycin trough level collected within 96 h of vancomycin therapy, and (5) had a baseline serum creatinine level of <2.0 mg/dL. Patients were excluded if they (1) had a diagnosis of cystic fibrosis, (2) received intravenous contrast dye within 7 days of starting vancomycin or during therapy, or (3) required vasopressor support during therapy. Demographics, comorbid conditions, and treatment data were collected. The highest observed vancomycin trough value within 96 h of initiation of vancomycin therapy and the estimated vancomycin AUC were analyzed as measures of vancomycin exposure. The vancomycin AUC value from 0 to 24 h at steady state (in units of mg x h/L) for each patient was estimated by use of the maximum a posteriori probability Bayesian procedure in ADAPT II. Nephrotoxicity was defined as an increase in serum creatinine level of 0.5 mg/dL or 50%, whichever was greater, following initiation of vancomycin therapy. Logistic and Cox proportional hazards regression models identified the vancomycin pharmacodynamic index that best describes the relationship between vancomycin exposure and toxicity. RESULTS: During the study period, 166 patients met the inclusion criteria. Both initial vancomycin trough values and 0-24-h at steady state AUC values were associated with nephrotoxicity in the bivariate analyses. However, the vancomycin trough value, modeled as a continuous variable, was the only vancomycin exposure variable associated with nephrotoxicity in the multivariate analyses. CONCLUSIONS: The results indicate that a vancomycin exposure-toxicity response relationship exists. The vancomycin trough value is the pharmacodynamic index that best describes this association.

Essential helix interactions in the anion transporter domain of prestin revealed by evolutionary trace analysis.

Prestin, a member of the SLC26A family of anion transporters, is a polytopic membrane protein found in outer hair cells (OHCs) of the mammalian cochlea. Prestin is an essential component of the membrane-based motor that enhances electromotility of OHCs and contributes to frequency sensitivity and selectivity in mammalian hearing. Mammalian cells expressing prestin display a nonlinear capacitance (NLC), widely accepted as the electrical signature of electromotility. The associated charge movement requires intracellular anions reflecting the membership of prestin in the SLC26A family. We used the computational approach of evolutionary trace analysis to identify candidate functional (trace) residues in prestin for mutational studies. We created a panel of mutations at each trace residue and determined membrane expression and nonlinear capacitance associated with each mutant. We observe that several residue substitutions near the conserved sulfate transporter domain of prestin either greatly reduce or eliminate NLC, and the effect is dependent on the size of the substituted residue. These data suggest that packing of helices and interactions between residues surrounding the "sulfate transporter motif" is essential for normal prestin activity.

Fortuitous detection of papillary carcinoma of the thyroid with F-18 FDG positron emission tomography in a patient with non-Hodgkin lymphoma.

Use of F-18 fluorodeoxyglucose positron emission tomography (F-18 FDG PET) in patients with known thyroid cancer is well documented, but the role of this imaging modality in the initial workup of a thyroid nodule has not been defined. The incidental finding of a hypermetabolic focus in the thyroid on F-18 FDG PET in patients with a variety of primary malignancies is reported. Based on the authors' literature search, this is the first documented case of a thyroid cancer resulting from papillary carcinoma detected in a patient with a history of non-Hodgkin lymphoma.