Evaluation of Empiric Vancomycin for Fevers During High-dose Cytarabine Administration.

BACKGROUND: Cytarabine is a nucleoside analog used in chemotherapy regimens for the treatment of multiple hematologic malignancies. One of the known adverse effects of cytarabine, particularly in patients receiving high-dose cytarabine (HDAC), is drug-induced fever. Multiple studies have demonstrated an increased risk of viridans group streptococcal bacteremia in patients who have received HDAC. For this reason, our institution and several other institutions across the country routinely include vancomycin as empiric coverage for patients who develop fever during HDAC, due to concern for resistance to cephalosporin monotherapy. MATERIALS AND METHODS: Patient demographic, diagnosis, treatment, and outcome information was collected by electronic chart review for each HDAC infusion from 2007 to August 2018 at the University of Iowa Stead Family Children's Hospital. If fever was documented during or within 24 hours of HDAC, additional information was collected regarding patient outcome and diagnostic testing. RESULTS: Of 208 HDAC administrations documented, patients developed fevers during the course on 82 occasions (39.4%). A median of 3 blood cultures per febrile period were obtained from time of fever onset during HDAC administration through >24 hours afebrile. One blood culture was positive for an oral flora organism determined by the microbiology lab report to be a likely contaminant. There were no other positive blood cultures in non-neutropenic or neutropenic patients. CONCLUSION: Fever due to HDAC is relatively common but appears to frequently lack association with bacteremia during the time of HDAC administration. Broad-spectrum empiric antibiotic regimens including vancomycin may be unnecessary for these patients, particularly before they become neutropenic.

Prevalence of Helicobacter pylori infection in newly arrived refugees attending the Migrant Health Service, South Australia.

BACKGROUND: To determine the prevalence of Helicobacter pylori infection in the refugee population attending the Migrant Health Service, South Australia, identify demographic factors associated with infection and compare prevalence of infection in refugees with that of the nonrefugee population in Australia. MATERIALS AND METHODS: Cross-sectional study conducted between October 2010 and August 2013. Monoclonal stool antigen testing for H. pylori infection is performed as part of a comprehensive health assessment for newly arrived refugees. The sample population included 922 adults and children. Outcome measures were (i) prevalence of H. pylori infection (ii) association between demographic factors such as sex, ethnicity and age, and H. pylori infection. RESULTS: H. pylori infection was detected in 198 (21.5%) participants (95% CI 18.9%-24.3%). The odds of infection were lower in females OR 0.71 (95% CI 0.51-0.98) compared to males. Compared to Middle Eastern participants, the odds of infection were 1.75 (95% CI 1.17-2.62) times higher in African and 1.90 (95% CI 1.10-3.26) times higher in Burmese participants. Infection was not associated with age. DISCUSSION AND CONCLUSION: H. pylori infection is common among newly arrived refugees. The long latency of infection to development of complications and the availability of testing and relatively effective eradication regimens all add weight to a decision to screen in this population.

Age-related hearing loss in older adults with cognitive impairment.

BACKGROUND: Hearing loss can impair effective communication between caregivers and individuals with cognitive impairment. However, hearing loss is not often measured or addressed in care plans for these individuals. The aim of this study is to measure the prevalence of hearing loss and the utilization of hearing aids in a sample of individuals with cognitive impairment in a tertiary care memory clinic. METHODS: A retrospective review of 133 charts of individuals >50 years who underwent hearing assessment at a tertiary care memory clinic over a 12-month period (June 2014-June 2015) was undertaken. Using descriptive statistics, the prevalence of hearing loss was determined and associations with demographic variables, relevant medical history, cognitive status, and hearing aid utilization were investigated. RESULTS: Results indicate that hearing loss is highly prevalent among this sample of cognitively impaired older adults. Sixty percent of the sample had at least a mild hearing loss in the better hearing ear. Among variables examined, age, MMSE, and medical history of diabetes were strongly associated with hearing impairment. Hearing aid utilization increased in concordance with severity of hearing loss, from 9% to 54% of individuals with a mild or moderate/severe hearing loss, respectively. CONCLUSIONS: Hearing loss is highly prevalent among older adults with cognitive impairment. Despite high prevalence of hearing loss, hearing aid utilization remains low. Our study highlights the importance of hearing evaluation and rehabilitation as part of the cognitive assessment and care management plan in this vulnerable population.

Temporal changes in the prehospital management of trauma patients: 2014-2021.

INTRODUCTION: Aggressive prehospital interventions (PHI) in trauma may not improve outcomes compared to prioritizing rapid transport. The aim of this study was to quantify temporal changes in the frequency of PHI performed by EMS. METHODS: Retrospective chart review of adult patients transported by EMS to our trauma center from January 1, 2014 to 12/31/2021. PHI were recorded and annual changes in their frequency were assessed via year-by-year trend analysis and multivariate regression. RESULTS: Between the first and last year of the study period, the frequency of thoracostomy (6% vs. 9%, p â€‹= â€‹0.001), TXA administration (0.3% vs. 33%, p â€‹< â€‹0.001), and whole blood administration (0% vs. 20%, p â€‹< â€‹0.001) increased. Advanced airway procedures (21% vs. 12%, p â€‹< â€‹0.001) and IV fluid administration (57% vs. 36%, p â€‹< â€‹0.001) decreased. ED mortality decreased from 8% to 5% (p â€‹= â€‹0.001) over the study period. On multivariate regression, no PHI were independently associated with increased or decreased ED mortality. CONCLUSION: PHI have changed significantly over the past eight years. However, no PHI were independently associated with increased or decreased ED mortality.

PI3Kδ inhibition potentiates glucocorticoids in B-lymphoblastic leukemia by decreasing receptor phosphorylation and enhancing gene regulation.

Glucocorticoids, including dexamethasone and prednisone, are the cornerstone of B-lymphoblastic leukemia (B-ALL) therapy. Because response to glucocorticoids alone predicts overall outcomes for B-ALL, enhancing glucocorticoid potency is a route to improving outcomes. However, systematic toxicities prevent the use of higher dose and more potent glucocorticoids. We therefore took a functional genomic approach to identify targets to enhance glucocorticoid activity specifically in B-ALL cells. Here we show that inhibition of the lymphoid-restricted PI3Kδ, signaling through the RAS/MAPK pathway, enhances both prednisone and dexamethasone activity in almost all ex vivo B-ALL specimens tested. This potentiation is most synergistic at sub-saturating doses of glucocorticoids, approaching the EC50. Potentiation correlates with global enhancement of glucocorticoid-induced gene regulation, including regulation of effector genes that drive B-ALL cell death. Idelalisib reduces phosphorylation of the glucocorticoid receptor (GR) at MAPK1/ERK2 targets S203 and S226, and ablation of these phospho-acceptor sites enhances glucocorticoid potency. We further show that phosphorylation of S226 reduces the affinity of GR for DNA in vitro, which impairs DNA binding. We therefore propose that PI3Kδ inhibition improves glucocorticoid efficacy in B-ALL in part by decreasing GR phosphorylation, increasing DNA binding affinity, and enhancing downstream gene regulation. The overall enhancement of GR function suggests that idelalisib will provide benefit to most patients with B-ALL by improving outcomes for patients whose disease is less responsive to glucocorticoid-based therapy, including high-risk disease, and allowing less toxic glucocorticoid-sparing strategies for patients with standard-risk disease.

PI3Kδ Inhibition Potentiates Glucocorticoids in B-lymphoblastic Leukemia by Decreasing Receptor Phosphorylation and Enhancing Gene Regulation.

Glucocorticoids are the cornerstone of B-lymphoblastic leukemia (B-ALL) therapy. Because response to glucocorticoids alone predicts overall outcomes for B-ALL, enhancing glucocorticoid potency should improve treatment. We previously showed that inhibition of the lymphoid-restricted PI3Kδ with idelalisib enhances glucocorticoid activity in B-ALL cells. Here, we show that idelalisib enhances glucocorticoid potency in 90% of primary B-ALL specimens and is most pronounced at sub-saturating doses of glucocorticoids near the EC50. Potentiation is associated with enhanced regulation of all glucocorticoid-regulated genes, including genes that drive B-ALL cell death. Idelalisib reduces phosphorylation of the glucocorticoid receptor (GR) at PI3Kδ/MAPK1 (ERK2) targets S203 and S226. Ablation of these phospho-acceptor sites enhances sensitivity to glucocorticoids with ablation of S226 in particular reducing synergy. We also show that phosphorylation of S226 reduces the affinity of GR for DNA in vitro. We propose that PI3Kδ inhibition improves glucocorticoid efficacy in B-ALL in part by decreasing GR phosphorylation, increasing DNA binding affinity, and enhancing downstream gene regulation. This mechanism and the response of patient specimens suggest that idelalisib will benefit most patients with B-ALL, but particularly patients with less responsive, including high-risk, disease. This combination is also promising for the development of less toxic glucocorticoid-sparing therapies.

The indelible marks on dermatology: Impacts of COVID-19 on dermatology residency Match using the Texas STAR database.

With changes to interview format and away rotations, the COVID-19 pandemic has reshaped the residency application process. In this retrospective cohort study of data from the nationwide Texas Seeking Transparency in Applications to Residency (STAR) survey, we sought to understand how the pandemic has affected applicants in the 2021 dermatology Match. We compared applicants in the post-COVID-19 Match year (2021) with those in pre-COVID-19 Match years (2018-2020) regarding match rates, interview costs, residency geographic connections, and number of interviews attended. A total of 439 dermatology applicants who completed the Texas STAR survey were included. There was no difference in percentage of applicants with a geographic connection to their matched program (43.88% vs 47.20%). Compared with prior cycles, applicants in the 2021 Match had a higher percentage of interview offers (96% vs 90%, P < .0001), and more applicants attended 16 or more interviews (P = .0489). Applicants in the 2021 Match reported an average savings of $5,000 compared with prior cycles. Virtual interviews offer savings for applicants but may encourage interview hoarding. Though applicants did not perform away rotations, there was no increase in geographic connection for matched applicants. Stakeholders should consider these data when evaluating the pros and cons of virtual interviewing postpandemic.

Deacylcortivazol-like pyrazole regioisomers reveal a more accommodating expanded binding pocket for the glucocorticoid receptor.

Glucocorticoids (GCs) are widely used, potent anti-inflammatory and chemotherapeutic drugs. They work by binding to the glucocorticoid receptor (GR), a ligand-activated transcription factor, inducing translocation to the nucleus and regulation of genes that influence a variety of cellular activities. Despite being effective for a broad number of conditions, GC use is limited by severe side effects. To identify ligands that are more selective, we synthesized pairs of regioisomers in the pyrazole ring that probe the expanded binding pocket of GR opened by deacylcortivazol (DAC). Using an Ullmann-type reaction, a deacylcortivazol-like (DAC-like) backbone was modified with five pendant groups at the 1'- and 2'-positions of the pyrazole ring, yielding 9 ligands. Most of the compounds were cytotoxic to leukemia cells, and all required GR expression. Both aliphatic and other aromatic groups substituted at the 2'-position produced ligands with GC activity, with phenyl and 4-fluorophenyl substitutions exhibiting high cellular affinity for the receptor and >5× greater potency than dexamethasone, a commonly used strong GC. Surprisingly, phenyl substitution at the 1'-position produced a high-affinity ligand with ∼10× greater potency than dexamethasone, despite little apparent room in the expanded binding pocket to accommodate 1'-modifications. Other 1'-modifications, however, were markedly less potent. The potency of the 2'-substituted and 1'-substituted DAC-like compounds tracked linearly with cellular affinity but had different slopes, suggesting a different mode of interaction with GR. These data provide evidence that the expanded binding pocket opened by deacylcortivazol is more accommodating that expected, allowing development of new, and possibly selective, GCs by substitution within the pyrazole ring.

Antifungal resistance of Candida glabrata vaginal isolates and development of a quantitative reverse transcription-PCR-based azole susceptibility assay.

A multiplex quantitative reverse transcription-PCR assay was developed to detect azole resistance in Candida glabrata, an important opportunistic pathogen that develops resistance rapidly. Resistance was defined as a >or=3-fold increase in CDR1 expression by this assay, which proved to be 100% sensitive and 95% specific in comparison to the gold standard broth microdilution assay.

Appropriateness of children's nonurgent visits to selected Michigan emergency departments.

OBJECTIVES: To explore parental rationale and the appropriateness of children's visits to emergency departments (EDs) for nonurgent complaints. METHODS: At 13 Michigan EDs, interviews were conducted with parents of children aged 6 months to 18 years who were triaged by ED personnel as lowest acuity. Interviews explored chief complaint, reason for ED visit, insurance status, attempts to call for advice before coming to the ED, and usual primary care source. Investigators rated ED visit appropriateness as high, medium, or low based on characteristics of the complaint and parent care-seeking behaviors. RESULTS: Of 422 completed interviews, 51% involved parents of Medicaid enrollees, and 43% involved parents of privately insured enrollees. One third of children presented with injuries. Overall, 50% of visits were rated as high appropriateness. When injuries were excluded, 37% of visits were rated as high appropriateness. Thirty-eight percent of parents called for advice before coming to the ED; of those, 60% were told to go to the ED. The most common parent-reported reason for going to the ED was reassurance (41%), followed by thinking the situation was an emergency (33%). Medicaid patients who could name a primary care physician, rather than a clinic only, were more likely to have ED visits rated as high appropriateness (54% vs 38%, P < 0.05). CONCLUSIONS: Half of all nonurgent ED visits were rated as high appropriateness. Considering parental information sources, it would be incorrect to label all nonurgent ED visits as inappropriate. Questions remain as to whether primary care outpatient sites are an appropriate source of care for minor injuries.

Rapid detection of Atopobium vaginae and association with organisms implicated in bacterial vaginosis.

Atopobium vaginae, a fastidious, anaerobic, Gram-positive cocci-shaped bacterium that generates large quantities of lactic acid, is associated with bacterial vaginosis (BV). Published nucleic acid amplification tests for identifying A. vaginae are directed toward the 16S ribosomal DNA with suboptimal specificity and require isolation of the organism. Here, sequencing of an A. vaginae genomic library has led to the development of a highly specific and sensitive real-time PCR test for detection of A. vaginae directly from gynecological cervicovaginal swab samples. The real-time PCR did not cross-react with DNA extracted from other members of the Atopobium genus, species with closely related 16S ribosomal DNA, and a panel of 51 other human pathogens. The DNA extraction and PCR assembly were amenable to automation using Corbett Robotics X-tractor Gene and CAS-4200N liquid handling systems. The real-time PCR was used to analyze 96 cervicovaginal swab samples submitted to our clinical laboratory for detection of organisms associated with BV. Of those samples, 28 were positive for A. vaginae. Of the 28 positive samples, 23 were concomitant with Gardnerella vaginalis detection. These results suggest that further clinical study of the relationship of A. vaginae with G. vaginalis and the development of BV should be performed.

Childhood vaccine purchase costs in the public sector: past trends, future expectations.

OBJECTIVES: We examined recent public-sector trends in childhood vaccine costs and estimated future costs. METHODS: We used public-sector price data to calculate vaccine purchase cost per child for children aged 0 to 6 years from 1975 to 2001. We fit a linear regression model to historical data and then used it to project costs per child from 2002 to 2020, adjusted to 2001 US dollars. RESULTS: Controlling for inflation, the cost of vaccine purchase per child climbed from $10 in 1975 to $385 in 2001. The cost of vaccine purchase in the year 2020 following recommendation of 7 additional vaccines is estimated to be $1225 per child (95% confidence interval = $891, $1559). CONCLUSIONS: The cost per child for recommended vaccines at public-sector prices may triple over the next 2 decades. These projections have implications for vaccine financing at federal and state levels.