Barriers to and Facilitators of Delabelling of Antimicrobial Allergies: A Qualitative Meta-synthesis.

Background: Patients who report penicillin allergies may receive alternative antibiotics. Such substitution contributes to antimicrobial resistance, lower treatment efficacy, increased frequency of adverse events, and increased costs. Approximately 90% of individuals who report a penicillin allergy can tolerate a penicillin. Objective: To identify the barriers to and facilitators of removal by health care workers of inaccurate antimicrobial allergies from patient records, known as delabelling. Data Sources: The MEDLINE database was searched from inception to December 29, 2020. Study Selection and Data Extraction: Qualitative studies evaluating health care professionals' perceptions of barriers to and/or facilitators of the act of delabelling a patient's antimicrobial allergies were included in the meta-synthesis. Data Synthesis: The Theoretical Domains Framework was used to code and group individual utterances from the included studies, which were mapped to the Behaviour Change Wheel and corresponding intervention function and policy categories. Results: Four studies met the inclusion criteria. Eight themes were identified as representing barriers to delabelling: delabelling skills, patient education skills, knowledge, electronic health records (EHRs), communication frameworks, time, fear about allergic reactions, and professional roles. Behaviour change interventions that may overcome these barriers include education, training, algorithms and toolkits, changes to EHRs, use of dedicated personnel, policies, incentivization of correct labelling, and an audit system. Conclusions: Eight themes were identified as barriers to delabelling of antimicrobial allergies. Future behaviour change interventions to address these barriers were proposed. Confidence in the findings of this study was judged to be moderate, according to the GRADE CERQual approach.

Contexte: Les patients qui signalent des allergies à la pénicilline peuvent recevoir d'autres antibiotiques. Une telle substitution contribue à la résistance aux antimicrobiens, à une moindre efficacité du traitement, à une fréquence accrue des événements indésirables et à une augmentation des coûts. Environ 90 % des personnes qui déclarent une allergie à la pénicilline peuvent la tolérer. Objectif: Identifier les obstacles à l'élimination par les travailleurs de la santé des allergies antimicrobiennes inexactes des dossiers des patients, ce que l'on appelle « le désétiquetage ¼, et les facteurs qui le favorisent. Sources des données: La base de données MEDLINE a été consultée depuis sa création jusqu'au 29 décembre 2020. Sélection de l'étude et extraction des données: Des études qualitatives évaluant les perceptions des professionnels de la santé quant aux obstacles à l'acte de désétiquetage des allergies aux antimicrobiens d'un patient et les facilitateurs de celui-ci ont été incluses dans la métasynthèse. Synthèse des données: Le cadre théorique des domaines a été utilisé pour coder et regrouper les énoncés individuels, qui ont ensuite été associés à la roue du changement de comportement ainsi qu'aux catégories de fonctions et de politiques d'intervention correspondantes. Résultats: Quatre études répondaient aux critères d'inclusion. Huit thèmes ont été identifiés comme représentant des obstacles au désétiquetage: les compétences en la matière, les compétences en matière d'éducation des patients, les connaissances, les dossiers de santé électroniques (DSE), les cadres de communication, le temps, la peur des réactions allergiques et les rôles professionnels. Les interventions visant le changement de comportement qui peuvent surmonter ces obstacles comprennent l'éducation, la formation, les algorithmes et les boîtes à outils de désétiquetage, la modification des DSE, le recours à du personnel dédié, des politiques, l'incitation à un étiquetage correct et un système d'audit. Conclusions: Huit thèmes ont été identifiés comme étant des obstacles au désétiquetage des allergies aux antimicrobiens. De futures interventions ciblant le changement de comportement pour les surmonter ont été proposées. La confiance dans les résultats de cette étude a été jugée modérée, selon l'approche GRADE CERQual.

Epidemiological and genomic investigation of chikungunya virus in Rio de Janeiro state, Brazil, between 2015 and 2018.

Since 2014, Brazil has experienced an unprecedented epidemic caused by chikungunya virus (CHIKV), with several waves of East-Central-South-African (ECSA) lineage transmission reported across the country. In 2018, Rio de Janeiro state, the third most populous state in Brazil, reported 41% of all chikungunya cases in the country. Here we use evolutionary and epidemiological analysis to estimate the timescale of CHIKV-ECSA-American lineage and its epidemiological patterns in Rio de Janeiro. We show that the CHIKV-ECSA outbreak in Rio de Janeiro derived from two distinct clades introduced from the Northeast region in mid-2015 (clade RJ1, n = 63/67 genomes from Rio de Janeiro) and mid-2017 (clade RJ2, n = 4/67). We detected evidence for positive selection in non-structural proteins linked with viral replication in the RJ1 clade (clade-defining: nsP4-A481D) and the RJ2 clade (nsP1-D531G). Finally, we estimate the CHIKV-ECSA's basic reproduction number (R0) to be between 1.2 to 1.6 and show that its instantaneous reproduction number (Rt) displays a strong seasonal pattern with peaks in transmission coinciding with periods of high Aedes aegypti transmission potential. Our results highlight the need for continued genomic and epidemiological surveillance of CHIKV in Brazil, particularly during periods of high ecological suitability, and show that selective pressures underline the emergence and evolution of the large urban CHIKV-ECSA outbreak in Rio de Janeiro.

Estimating dengue transmission intensity from serological data: A comparative analysis using mixture and catalytic models.

BACKGROUND: Dengue virus (DENV) infection is a global health concern of increasing magnitude. To target intervention strategies, accurate estimates of the force of infection (FOI) are necessary. Catalytic models have been widely used to estimate DENV FOI and rely on a binary classification of serostatus as seropositive or seronegative, according to pre-defined antibody thresholds. Previous work has demonstrated the use of thresholds can cause serostatus misclassification and biased estimates. In contrast, mixture models do not rely on thresholds and use the full distribution of antibody titres. To date, there has been limited application of mixture models to estimate DENV FOI. METHODS: We compare the application of mixture models and time-constant and time-varying catalytic models to simulated data and to serological data collected in Vietnam from 2004 to 2009 (N ≥ 2178) and Indonesia in 2014 (N = 3194). RESULTS: The simulation study showed larger mean FOI estimate bias from the time-constant and time-varying catalytic models (-0.007 (95% Confidence Interval (CI): -0.069, 0.029) and -0.006 (95% CI -0.095, 0.043)) than from the mixture model (0.001 (95% CI -0.036, 0.065)). Coverage of the true FOI was > 95% for estimates from both the time-varying catalytic and mixture model, however the latter had reduced uncertainty. When applied to real data from Vietnam, the mixture model frequently produced higher FOI and seroprevalence estimates than the catalytic models. CONCLUSIONS: Our results suggest mixture models represent valid, potentially less biased, alternatives to catalytic models, which could be particularly useful when estimating FOI from data with largely overlapping antibody titre distributions.

Effectively Conducting Oncology Clinical Trials During the COVID-19 Pandemic.

PURPOSE: Clinical trial enrollment has declined globally as a result of the coronavirus disease 2019 (COVID-19) pandemic. This underscores the importance of structured methods to continue critical medical research safely and efficiently. METHODS AND MATERIALS: We report the effect of a phased trial reopening strategy, remote research staffing, and telemedicine on cancer trial enrollment at one of the largest radiation oncology academic cancer centers. In phase 1, trials investigating definitive therapeutic benefit were opened, followed by trials not increasing patient exposure or pulmonary toxicity risk in phase 2. During phase 2.5, multicenter trials reopened and limited research staff were allowed on site. RESULTS: Despite initial enrollment declines during the early pandemic, the percentage of new patients enrolling in clinical trials from March to August 2020 was 8.8%, and represented a 10.5% relative increase from 2019. Monthly accrual enrollment from March to August 2019 ranged from 42 to 71, compared with enrollment during COVID-19 from 23 to 73 patients (P < .001). CONCLUSIONS: Through a phased approach to trial reopening and adaptive techniques, the division of radiation oncology maintained cancer trial accrual during the COVID-19 pandemic. The experience may help centers maintain accrual, preserve clinical trial integrity, and minimize risk to patients and staff.

System-wide Profiling of RNA-Binding Proteins Uncovers Key Regulators of Virus Infection.

The compendium of RNA-binding proteins (RBPs) has been greatly expanded by the development of RNA-interactome capture (RIC). However, it remained unknown if the complement of RBPs changes in response to environmental perturbations and whether these rearrangements are important. To answer these questions, we developed "comparative RIC" and applied it to cells challenged with an RNA virus called sindbis (SINV). Over 200 RBPs display differential interaction with RNA upon SINV infection. These alterations are mainly driven by the loss of cellular mRNAs and the emergence of viral RNA. RBPs stimulated by the infection redistribute to viral replication factories and regulate the capacity of the virus to infect. For example, ablation of XRN1 causes cells to be refractory to SINV, while GEMIN5 moonlights as a regulator of SINV gene expression. In summary, RNA availability controls RBP localization and function in SINV-infected cells.

A theory-informed assessment of the barriers and facilitators to nurse-driven antimicrobial stewardship.

BACKGROUND: Nurses represent an underused workforce for performing antimicrobial stewardship (AMS) activities. Before engaging nurses in these activities, barriers and facilitators to the targeted behavior change should be identified using a validated model. METHODS: This was a prospective, qualitative, descriptive study to determine the barriers and facilitators to the promotion of intravenous (IV) to oral (PO) antimicrobials by nurses. Semi-structured 1-on-1 interviews of nurses were conducted from January-February 2017. Interviews were analyzed for themes within the domains of the theoretical domains framework (TDF) by directed-content analysis. RESULTS: Evaluation of the 14 TDF domains revealed 9 modifiable barriers to nurse promotion of IV to PO step-down, including insufficient knowledge, lack of prescriber cooperation, lack of self-confidence, and low priority activity. Nine facilitators that could enhance nurse promotion of step-down were identified, including capability to assess patients for step-down, ability to communicate assessment results to the team, and preexistence of a variety of resources available for nurse education and training. Nurses perceived that increased step-down rates would increase nursing efficiency. CONCLUSIONS: Nurses have the potential to improve AMS through promotion of IV to PO step-down of antimicrobials. Themes pertaining to barriers and facilitators of nurses' participation in IV to PO step-down of antimicrobials were identified.

Evaluation of two multiplex real-time PCR screening capabilities for the detection of Bacillus anthracis, Francisella tularensis and Yersinia pestis in blood samples generated from murine infection models.

Two multiplex PCR screening capabilities (TaqMan Array Cards and FilmArray) were evaluated for their ability to detect Bacillus anthracis, Francisella tularensis and Yersinia pestis in blood samples obtained from respective murine infection models. Blood samples were obtained from infected mice at 24 h intervals after exposure. Multiplex PCR results were compared with standard blood culture and singleplex real-time PCR. Across all three models, 71 mice were tested in total, within which a subset of 43 samples was shown to contain an infecting agent by at least one of the detection technologies. Within this subset of positive samples, for each model studied, the detection rates of each technology were compared. The B. anthracis model blood culture (14 of 15 agent-containing samples tested) and FilmArray PCR (12 of 15) were shown to have equivalent detection rates, which were significantly higher (at the 95 % confidence level) than singleplex (five of 14) or Array Card (two of 14) PCRs. The F. tularensis model blood culture (12 of 12) was shown to have a significantly higher (at 95 % confidence level) detection rate than all PCR technologies, with FilmArray (seven of 11) and singleplex (seven of 12) PCRs shown to have significantly higher (at 95 % confidence level) detection rates than the Array Card PCR (two of 11). Within the Y. pestis model, there was no significant difference in detection rates between blood culture (10 of 16), singleplex PCR (14 of 16), Array Card PCR (10 of 16) and FilmArray PCR (10 of 13).

The potential of TaqMan Array Cards for detection of multiple biological agents by real-time PCR.

The TaqMan Array Card architecture, normally used for gene expression studies, was evaluated for its potential to detect multiple bacterial agents by real-time PCR. Ten PCR assays targeting five biological agents (Bacillus anthracis, Burkholderia mallei, Burkholderia pseudomallei, Francisella tularensis, and Yersinia pestis) were incorporated onto Array Cards. A comparison of PCR performance of each PCR in Array Card and singleplex format was conducted using DNA extracted from pure bacterial cultures. When 100 fg of agent DNA was added to Array Card channels the following levels of agent detection (where at least one agent PCR replicate returned a positive result) were observed: Y. pestis 100%, B. mallei & F. tularensis 93%; B. anthracis 71%; B. pseudomallei 43%. For B. mallei & pseudomallei detection the BPM2 PCR, which detects both species, outperformed PCR assays specific to each organism indicating identification of the respective species would not be reproducible at the 100 fg level. Near 100% levels of detection were observed when 100 fg of DNA was added to each PCR in singleplex format with singleplex PCRs also returning sporadic positives at the 10 fg per PCR level. Before evaluating the use of Array Cards for the testing of environmental and clinical sample types, with potential levels of background DNA and PCR inhibitors, users would therefore have to accept a 10-fold reduction in sensitivity of PCR assays on the Array Card format, in order to benefit for the capacity to test multiple samples for multiple agents. A two PCR per agent strategy would allow the testing of 7 samples for the presence of 11 biological agents or 3 samples for 23 biological agents per card (with negative control channels).

Further clinical and molecular delineation of the 15q24 microdeletion syndrome.

BACKGROUND: Chromosome 15q24 microdeletion syndrome is a rare genomic disorder characterised by intellectual disability, growth retardation, unusual facial morphology and other anomalies. To date, 20 patients have been reported; 18 have had detailed breakpoint analysis. AIM: To further delineate the features of the 15q24 microdeletion syndrome, the clinical and molecular characterisation of fifteen patients with deletions in the 15q24 region was performed, nearly doubling the number of reported patients. METHODS: Breakpoints were characterised using a custom, high-density array comparative hybridisation platform, and detailed phenotype information was collected for each patient. RESULTS: Nine distinct deletions with different breakpoints ranging in size from 266 kb to 3.75 Mb were identified. The majority of breakpoints lie within segmental duplication (SD) blocks. Low sequence identity and large intervals of unique sequence between SD blocks likely contribute to the rarity of 15q24 deletions, which occur 8-10 times less frequently than 1q21 or 15q13 microdeletions in our series. Two small, atypical deletions were identified within the region that help delineate the critical region for the core phenotype in the 15q24 microdeletion syndrome. CONCLUSION: The molecular characterisation of these patients suggests that the core cognitive features of the 15q24 microdeletion syndrome, including developmental delays and severe speech problems, are largely due to deletion of genes in a 1.1-Mb critical region. However, genes just distal to the critical region also play an important role in cognition and in the development of characteristic facial features associated with 15q24 deletions. Clearly, deletions in the 15q24 region are variable in size and extent. Knowledge of the breakpoints and size of deletion combined with the natural history and medical problems of our patients provide insights that will inform management guidelines. Based on common phenotypic features, all patients with 15q24 microdeletions should receive a thorough neurodevelopmental evaluation, physical, occupational and speech therapies, and regular audiologic and ophthalmologic screening.

Comparison of eight methods for the extraction of Bacillus atrophaeus spore DNA from eleven common interferents and a common swab.

Eight DNA extraction products or methods (Applied Biosystems PrepFiler Forensic DNA Extraction Kit; Bio-Rad Instagene Only, Bio-Rad Instagene & Spin Column Purification; EpiCentre MasterPure DNA & RNA Kit; FujiFilm QuickGene Mini80; Idaho Technologies 1-2-3 Q-Flow Kit; MoBio UltraClean Microbial DNA Isolation Kit; Sigma Extract-N-Amp Plant and Seed Kit) were adapted to facilitate extraction of DNA under BSL3 containment conditions. DNA was extracted from 12 common interferents or sample types, spiked with spores of Bacillus atropheaus. Resulting extracts were tested by real-time PCR. No one method was the best, in terms of DNA extraction, across all sample types. Statistical analysis indicated that the PrepFiler method was the best method from six dry powders (baking, biological washing, milk, plain flour, filler and talcum) and one solid (Underarm deodorant), the UltraClean method was the best from four liquids (aftershave, cola, nutrient broth, vinegar), and the MasterPure method was the best from the swab sample type. The best overall method, in terms of DNA extraction, across all sample types evaluated was the UltraClean method.

Development of beliefs about storybook reality.

The goal of this research was to assess children's beliefs about the reality status of storybook characters and events. In Experiment 1, 156 preschool age children heard realistic, fantastical, or religious stories, and their understanding of the reality status of the characters and events in the stories was assessed. Results revealed that 3-year-olds were more likely to judge characters as real than were 4- and 5-year-olds, but most children judged all characters as not real for all story types. Children of all ages who heard realistic stories made more claims that the events in the stories could happen in real life than did children who heard fantastical stories. Five-year-olds made significantly more claims that events in religious stories could happen in real life than did younger children. In Experiment 2, 136 4- and 5-year-olds heard similar stories. Results replicated those from Experiment 1, and also indicated a growing awareness of the basic nature of realistic fiction.

Brachydactylic multiple delta phalanges plus syndrome.

Delta phalanges are unusual, shortened bones of the hands and feet with abnormal epiphyses and diaphyses. Here, we report on a patient with a unique multiple congenital anomaly syndrome that includes brachydactyly consisting of multiple delta phalanges in several digits of the hands and feet. The patient, who was born to consanguineous parents, had several other congenital anomalies, including butterfly vertebrae, craniofacial dysmorphism, and coarctation of the aorta. We have called this distinctive condition "brachydactylic multiple delta phalanges plus syndrome." Although no other member of the family had obvious hand or foot anomalies, several siblings had other malformations. Possible modes of inheritance in this family include variable expression of a recessive or de novo dominant condition.

Factors influencing quality of life in patients with active tuberculosis.

BACKGROUND: With effective treatment strategies, the focus of tuberculosis (TB) management has shifted from the prevention of mortality to the avoidance of morbidity. As such, there should be an increased focus on quality of life (QoL) experienced by individuals being treated for TB. The objective of our study was to identify areas of QoL that are affected by active TB using focus groups and individual interviews. METHODS: English, Cantonese, and Punjabi-speaking subjects with active TB who were receiving treatment were eligible for recruitment into the study. Gender-based focus group sessions were conducted for the inner city participants but individual interviews were conducted for those who came to the main TB clinic or were hospitalized. Facilitators used open-ended questions and participants were asked to discuss their experiences of being diagnosed with tuberculosis, what impact it had on their lives, issues around adherence to anti-TB medications and information pertaining to their experience with side effects to these medications. All data were audio-recorded, transcribed verbatim, and analyzed using constant comparative analysis. RESULTS: 39 patients with active TB participated. The mean age was 46.2 years (SD 18.4) and 62% were male. Most were Canadian-born being either Caucasian or Aboriginal. Four themes emerged from the focus groups and interviews. The first describes issues related to the diagnosis of tuberculosis and sub-themes were identified as 'symptoms', 'health care provision', and 'emotional impact'. The second theme discusses TB medication factors and the sub-themes identified were 'adverse effects', 'ease of administration', and 'adherence'. The third theme describes social support and functioning issues for the individuals with TB. The fourth theme describes health behavior issues for the individuals with TB and the identified sub-themes were "behavior modification" and "TB knowledge." CONCLUSION: Despite the ability to cure TB, there remains a significant impact on QOL. Since much attention is spent on preventative or curative mechanisms, the impact of this condition on QoL is often not considered. Attention to the issues experienced by patients being treated for TB may optimize adherence and treatment success.

Once-daily cefazolin and probenecid for skin and soft tissue infections.

OBJECTIVE: To review the pharmacokinetic and clinical evidence for the use of once-daily cefazolin and probenecid in the treatment of skin and soft tissue infections (SSTI). DATA SOURCES: MEDLINE (1966-July 2003), EMBASE (1980-July 2003), and PubMed (1966-July 2003) databases for English language, human reports were searched. Search terms included cefazolin, probenecid, cellulitis, and soft tissue infections. STUDY SELECTION AND DATA EXTRACTION: Studies that described pharmacokinetic and clinical outcomes that evaluated the use of cefazolin in conjunction with probenecid for SSTI were included. All studies were evaluated independently by both authors. For pharmacokinetic studies, the effect of probenecid on the pharmacokinetics of cefazolin was evaluated. For clinical trials, efficacy and safety endpoints were evaluated. For efficacy endpoints, definition of cure was used as defined by each trial. DATA SYNTHESIS: In all 3 pharmacokinetic studies identified, the addition of probenecid to cefazolin therapy prolonged the half-life and increased serum concentrations of cefazolin. This process allowed serum concentrations to be above the minimal inhibitory concentrations (MIC) for the most likely skin pathogens (Staphylococcus aureus, beta-hemolytic streptococci) at the end of the dosing interval. In the first of 2 clinical trials, 7 (7%) of 96 patients receiving intravenous ceftriaxone 2 g and oral probenecid 1 g daily were reported to fail therapy compared with 8 (8%) of 98 patients receiving intravenous cefazolin 2 g and oral probenecid 1 g daily. In the second clinical trial, clinical success was reported in 51 (86%) of 59 patients receiving the same doses of cefazolin and probenecid as above compared with 55 (96%) of 57 patients receiving intravenous ceftriaxone 1 g and oral placebo daily. CONCLUSIONS: Limited pharmacokinetic and clinical data suggest that intravenous cefazolin 2 g and oral probenecid 1 g daily is an effective regimen in the treatment of SSTI.

Mycophenolate mofetil for solid organ transplantation: does the evidence support the need for clinical pharmacokinetic monitoring?

The need for clinical pharmacokinetic monitoring (CPM) of the immunosuppressant mycophenolate mofetil (MMF) has been debated. Using a previously developed algorithm, the authors reviewed the evidence to support or refute the utility of CPM of MMF. First, MMF has proven efficacy for prevention of organ rejection in renal and cardiac transplant populations. In addition, the pharmacologically active form of MMF, mycophenolic acid (MPA), can be measured readily in plasma, and relationships between the incidence of rejection and MPA predose concentrations and MPA area under the curve (AUC) have been reported. A lower limit of the therapeutic range (MPA predose concentrations >1.55 microg/mL, as measured by enzyme multiplied immunoassay technique [EMIT], or MPA AUC >30 or 40 microg. h/mL, as measured by high-performance liquid chromatography [HPLC]) has been suggested to prevent rejection in renal allograft patients. Similarly, in cardiac transplant patients, decreased incidences of organ rejection have been reported in patients with MPA concentrations >2 or 3 microg/mL (using EMIT) and total AUC values >42.8 microg. h/mL (using HPLC). However, the relationship between pharmacokinetic parameters and adverse events in renal and cardiac transplant patients remains unclear. Due to the nature of antirejection therapy, the pharmacologic response of MMF is not readily assessable, and therapy is life-long. MPA pharmacokinetics exhibit large inter- and intrapatient variability and may be altered in specific patient populations due to changes in protein binding, concomitant disease states, or interactions with concurrent immunosuppressants. Therefore, on the basis of current evidence, CPM can provide more information regarding efficacy of MMF than clinical judgment alone in select patient populations. However, further randomized, prospective trials are required to clarify unresolved issues. Specifically, an upper limit of the therapeutic range, above which the risk of side effects is increased, needs to be elucidated for MMF therapy. Other future directions for research include determining a practical limited sampling strategy for MPA AUC; clarifying the relationship between free MPA concentrations, efficacy, and toxicity; and defining the pharmacodynamic relationship between activity of inosine monophosphate dehydrogenase (the enzyme inhibited by MPA) and risk of rejection or adverse effects.

Valacyclovir versus acyclovir for HSV prophylaxisin neutropenic patients.

BACKGROUND: It is common practice to administer acyclovir as prophylaxis to patients with hematologic malignancies during neutropenia; however, effective therapy requires frequent dosing, which is difficult in this setting. Valacyclovir has greater oral bioavailability and requires less frequent dosing. OBJECTIVE: To evaluate the efficacy and safety of valacyclovir compared with acyclovir. METHODS: Patients who had been treated with chemotherapy or stem-cell transplantation were randomized to receive acyclovir 400 mg orally 3 times daily (n = 51), valacyclovir 500 mg orally twice daily (n = 48), or valacyclovir 250 mg orally twice daily (n = 52) during neutropenia. RESULTS: Clinical success, defined as the absence of an active herpes simplex virus (HSV) lesion or asymptomatic viral shedding, was similar between the 3 groups (acyclovir 96%, valacyclovir 500 mg 95%, valacyclovir 250 mg 100%). The overall rates of adverse events were similar in the 3 groups. CONCLUSIONS: Prophylactic treatment with valacyclovir is an effective and safe alternative to acyclovir for the prevention of HSV reactivation in patients with hematologic malignancies.