High variance in quantification of Mycobacterium tuberculosis at low bacterial loads and with differentially detectable mycobacteria.

We examined the correlation between three different methods of Mycobacterium tuberculosis quantification: time to positivity (TTP), log10 CFU, and an assay to detect differentially detectable M. tuberculosis (DD Mtb) from three different prospective studies. Participants with DD Mtb have significantly more variation in the CFU/TTP correlation than participants with no DD Mtb (P < 0.001). This may impact the design of early bactericidal activity studies that use TTP as the primary outcome.

Feasibility of a clinic-based, multicomponent hydroxyurea adherence intervention for adolescents and young adults with sickle cell disease.

Despite the effectiveness of hydroxyurea, adherence remains low for adolescents and young adults (AYA) living with sickle cell disease (SCD). This study evaluated the feasibility, acceptability, and initial efficacy of a clinic-based, multicomponent (e.g., storytelling, problem solving) intervention with 20 AYA living with SCD. Results found that adherence significantly improved from intervention to follow-up 1 [t(19) = -2.213, p = .039]. AYA also were generally satisfied with the intervention. These findings, although promising, should be replicated on a larger scale.

A bedaquiline, pyrazinamide, levofloxacin, linezolid, clofazimine second line regimen for tuberculosis displays similar early bactericidal activity as the standard rifampin based first line regimen.

BACKGROUND: In 2018 the World Health Organization (WHO) recommended a switch to an all oral bedaquiline based second line regimen for treatment of drug resistant (DR) tuberculosis (TB). How these new second line regimens fare in comparison to first line regimens for treatment of drug sensitive (DS) tuberculosis is not well known. METHODS: In this study, we contemporaneously enrolled subjects with DS (n = 31) and DR (n = 23) TB and assessed their response to therapy with first-line (rifampin, isoniazid, ethambutol, pyrazinamide) or second-line (bedaquiline, pyrazinamide, levofloxacin, linezolid, clofazimine) regimens, respectively. RESULTS: We found that the early bactericidal activity of first and second line regimens was similar during the first two weeks of therapy as determined by BACTEC MGIT, colony forming units (CFU), and a liquid limiting dilution (LD) assays capable of detecting differentially detectable/culturable Mtb (DD Mtb). Further, an identical percentage (77.8%) of subjects from the DS and DR cohorts converted to culture negative after two months of therapy. CONCLUSIONS: Despite presenting with more advanced disease at time of treatment, subjects with DR TB receiving an all oral bedaquiline based second line treatment regimen displayed a similar microbiological response to therapy as subjects with DS TB receiving a first-line treatment regimen.

Same-day testing with initiation of antiretroviral therapy or tuberculosis treatment versus standard care for persons presenting with tuberculosis symptoms at HIV diagnosis: A randomized open-label trial from Haiti.

BACKGROUND: Same-day HIV testing and antiretroviral therapy (ART) initiation is being widely implemented. However, the optimal timing of ART among patients with tuberculosis (TB) symptoms is unknown. We hypothesized that same-day treatment (TB treatment for those diagnosed with TB; ART for those not diagnosed with TB) would be superior to standard care in this population. METHODS AND FINDINGS: We conducted an open-label trial among adults with TB symptoms at initial HIV diagnosis at GHESKIO in Haiti; participants were recruited and randomized on the same day. Participants were randomized in a 1:1 ratio to same-day treatment (same-day TB testing with same-day TB treatment if TB diagnosed; same-day ART if TB not diagnosed) versus standard care (initiating TB treatment within 7 days and delaying ART to day 7 if TB not diagnosed). In both groups, ART was initiated 2 weeks after TB treatment. The primary outcome was retention in care with 48-week HIV-1 RNA <200 copies/mL, with intention to treat (ITT) analysis. From November 6, 2017 to January 16, 2020, 500 participants were randomized (250/group); the final study visit occurred on March 1, 2021. Baseline TB was diagnosed in 40 (16.0%) in the standard and 48 (19.2%) in the same-day group; all initiated TB treatment. In the standard group, 245 (98.0%) initiated ART at median of 9 days; 6 (2.4%) died, 15 (6.0%) missed the 48-week visit, and 229 (91.6%) attended the 48-week visit. Among all who were randomized, 220 (88.0%) received 48-week HIV-1 RNA testing; 168 had <200 copies/mL (among randomized: 67.2%; among tested: 76.4%). In the same-day group, 249 (99.6%) initiated ART at median of 0 days; 9 (3.6%) died, 23 (9.2%) missed the 48-week visit, and 218 (87.2%) attended the 48-week visit. Among all who were randomized, 211 (84.4%) received 48-week HIV-1 RNA; 152 had <200 copies/mL (among randomized: 60.8%; among tested: 72.0%). There was no difference between groups in the primary outcome (60.8% versus 67.2%; risk difference: -0.06; 95% CI [-0.15, 0.02]; p = 0.14). Two new grade 3 or 4 events were reported per group; none were judged to be related to the intervention. The main limitation of this study is that it was conducted at a single urban clinic, and the generalizability to other settings is uncertain. CONCLUSIONS: In patients with TB symptoms at HIV diagnosis, we found that same-day treatment was not associated with superior retention and viral suppression. In this study, a short delay in ART initiation did not appear to compromise outcomes. TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov NCT03154320.

Preventable harm because of outpatient medication errors among children with leukemia and lymphoma: A multisite longitudinal assessment.

BACKGROUND: There is little longitudinal information about the type and frequency of harm resulting from medication errors among outpatient children with cancer. We aimed to characterize rates and types of medication errors and harm to outpatient children with leukemia and lymphoma over 7 months of treatment. METHODS: We recruited children taking medications at home for leukemia or lymphoma from three pediatric cancer centers. Errors were identified by chart review, in-home medication review, observation of administration, and interviews. Physician reviewers confirmed error (Fleiss' κ = 0.95), harm (Fleiss' κ = 0.82), and suggested interventions. Generalized linear mixed models with random effects were used to account for clustering by site. RESULTS: Among 131 children taking 1669 medications with 367 home visits, 408 errors were identified, including 242 with potential for harm and 39 with harm (1.0 harm per 1000 patient-days [95% CI, 0.1-9.8]). Ten percent of children were injured by errors and 42% had errors with potential for harm. Twenty-six percent of caregivers reported that miscommunication led to missed doses or overdoses at home. Children on >13 medications had significantly more serious medication errors than those on fewer medications (77% vs 61%; p = .05). Physician reviewers judged that improved communication among caregivers and between caregivers and clinicians may have prevented the most harm (66%). CONCLUSIONS: In this longitudinal study, 10% children with leukemia or lymphoma experienced adverse drug events because of outpatient medication errors. Improvements addressing communication with and among caregivers should be codeveloped with families and based on human-factors engineering. PLAIN LANGUAGE SUMMARY: In this longitudinal study, medication errors in the clinic, pharmacy, or at home among children with leukemia or lymphoma over a 7-month period were common, and 10% suffered harm because of errors. Children on >13 medications had significantly more serious medication errors than those on fewer medications (77% vs 61%; p = .05). Physician reviewers judged that improved communication among caregivers and between caregivers and clinicians may have prevented the most harm (66%). Improvements addressing communication with and among caregivers should be codeveloped with families and based on human-factors engineering.

Professional stakeholders' perceptions of barriers to behavioral health care following pediatric traumatic brain injury.

OBJECTIVE: To examine professional stakeholders' perspectives of barriers to behavioral health care (BHC) follow-up and telepsychology after pediatric traumatic brain injury (TBI). METHODS: Twenty-nine professionals participated in a focus group (FG) or key informant interview (KII) between January and March 2020. Professionals answered questions about facilitators and barriers to BHC follow-up and telepsychology. Given widespread telepsychology implementation since COVID-19, a follow-up survey assessing telehealth perceptions since the pandemic was sent out in December 2020. Nineteen professionals completed the survey. RESULTS: Professionals identified individual (e.g., family factors, insurance coverage/finances, transportation/distance, availability, planning follow-up care) and system-level (e.g., lack of access to BHC providers) barriers to BHC post-injury. Possible solutions, like collaborative follow-up care, were also identified. Generally, clinical professionals have favorable impressions of telepsychology and utilized services as a delivery modality for clinical care. Though telepsychology could reduce barriers to care, professionals also expressed concerns (e.g., technology issues, security/safety) and challenges (e.g., funding, accessibility, training/licensure for clinicians) with implementing telepsychology. CONCLUSION: Barriers identified highlight the need for context-specific solutions to increase BHC access, with telepsychology generally recognized as a beneficial modality for BHC. Future work should continue to focus on understanding barriers to BHC and potential solutions after pediatric TBI.

Characterization of Differentially Detectable Mycobacterium tuberculosis in the Sputum of Subjects with Drug-Sensitive or Drug-Resistant Tuberculosis before and after Two Months of Therapy.

Standard methods for enumerating Mycobacterium tuberculosis in patient sputum can miss large populations of viable M. tuberculosis cells that are unable to grow either on solid medium or in liquid medium unless the medium has been extensively diluted. Because these bacteria can be detected in liquid medium after limiting dilution, they have been termed differentially culturable or differentially detectable M. tuberculosis (DD-Mtb). Treatment with isoniazid (H), rifampin (R), pyrazinamide (Z), and ethambutol (E) (HRZE) for 1 to 2 weeks has been shown to increase the representation of DD-Mtb in the sputum of drug-sensitive (DS) tuberculosis (TB) patients. However, little is known about DD-Mtb after longer periods of treatment with HRZE or in patients with drug-resistant (DR) TB who receive second-line therapies. Here, we measured the proportion of DD-Mtb cells in the sputum of 47 subjects, 29 with DS TB and 18 with DR TB, before initiation of treatment and at 2 weeks and 2 months thereafter. Prior to treatment, DD-Mtb cells represented the majority of M. tuberculosis cells in the sputum of 21% of subjects with DS TB, and this proportion rose to 65% after 2 weeks of treatment with first-line drugs. In subjects with DR TB, DD-Mtb cells were found in the sputum of 29% of subjects prior to treatment initiation, and this proportion remained steady at 31% after 2 weeks of treatment with second-line drugs. By 2 months, DD-Mtb cells were detected in the sputum of only 2/15 (13.3%) subjects with DS TB and in 0/15 of subjects with DR TB. One of the DS subjects whose sputum was positive for DD-Mtb at month 2 later experienced treatment failure.

Development and validation of a predictive model algorithm to identify anaphylaxis in adults with type 2 diabetes in U.S. administrative claims data.

PURPOSE: To use medical record adjudication and predictive modeling methods to develop and validate an algorithm to identify anaphylaxis among adults with type 2 diabetes (T2D) in administrative claims. METHODS: A conventional screening algorithm that prioritized sensitivity to identify potential anaphylaxis cases was developed and consisted of diagnosis codes for anaphylaxis or relevant signs and symptoms. This algorithm was applied to adults with T2D in the HealthCore Integrated Research Database (HIRD) from 2016 to 2018. Clinical experts adjudicated anaphylaxis case status from redacted medical records. We used confirmed case status as an outcome for predictive models developed using lasso regression with 10-fold cross-validation to identify predictors and estimate the probability of confirmed anaphylaxis. RESULTS: Clinical adjudicators reviewed medical records with sufficient information from 272 adults identified by the anaphylaxis screening algorithm, which had an estimated Positive Predictive Value (PPV) of 65% (95% confidence interval [CI]: 60%-71%). The predictive model algorithm had a c-statistic of 0.95. The model's probability threshold of 0.60 excluded 89% (84/94) of false positives identified by the screening algorithm, with a PPV of 94% (95% CI: 91%-98%). The model excluded very few true positives (15 of 178), and identified 92% (95% CI: 87%-96%) of the cases selected by the screening algorithm. CONCLUSIONS: Predictive modeling techniques yielded an accurate algorithm with high PPV and sensitivity for identifying anaphylaxis in administrative claims. This algorithm could be considered in future safety studies using similar claims data to reduce potential outcome misclassification.

A prospective multi-center quality improvement initiative (NINJA) indicates a reduction in nephrotoxic acute kidney injury in hospitalized children.

Nephrotoxic medication (NTMx) exposure is a common cause of acute kidney injury (AKI) in hospitalized children. The Nephrotoxic Injury Negated by Just-in time Action (NINJA) program decreased NTMx associated AKI (NTMx-AKI) by 62% at one center. To further test the program, we incorporated NINJA across nine centers with the goal of reducing NTMx exposure and, consequently, AKI rates across these centers. NINJA screens all non-critically ill hospitalized patients for high NTMx exposure (over three medications on the same day or an intravenous aminoglycoside over three consecutive days), and then recommends obtaining a daily serum creatinine level in exposed patients for the duration of, and two days after, exposure ending. Additionally, substitution of equally efficacious but less nephrotoxic medications for exposed patients starting the day of exposure was recommended when possible. The main outcome was AKI as defined by the Kidney Disease Improving Global Outcomes (KDIGO) serum creatinine criteria (increase of 50% or 0.3 mg/dl over baseline). The primary outcome measure was AKI episodes per 1000 patient-days. Improvement was defined by statistical process control methodology and confirmed by Autoregressive Integrated Moving Average (ARIMA) modeling. Eight consecutive bi-weekly measure rates in the same direction from the established baseline qualified as special cause change for special process control. We observed a significant and sustained 23.8% decrease in NTMx-AKI rates by statistical process control analysis and by ARIMA modeling; similar to those of the pilot single center. Thus, we have successfully applied the NINJA program to multiple pediatric institutions yielding decreased AKI rates.

Drosophila embryonic type II neuroblasts: origin, temporal patterning, and contribution to the adult central complex.

Drosophila neuroblasts are an excellent model for investigating how neuronal diversity is generated. Most brain neuroblasts generate a series of ganglion mother cells (GMCs) that each make two neurons (type I lineage), but 16 brain neuroblasts generate a series of intermediate neural progenitors (INPs) that each produce 4-6 GMCs and 8-12 neurons (type II lineage). Thus, type II lineages are similar to primate cortical lineages, and may serve as models for understanding cortical expansion. Yet the origin of type II neuroblasts remains mysterious: do they form in the embryo or larva? If they form in the embryo, do their progeny populate the adult central complex, as do the larval type II neuroblast progeny? Here, we present molecular and clonal data showing that all type II neuroblasts form in the embryo, produce INPs and express known temporal transcription factors. Embryonic type II neuroblasts and INPs undergo quiescence, and produce embryonic-born progeny that contribute to the adult central complex. Our results provide a foundation for investigating the development of the central complex, and tools for characterizing early-born neurons in central complex function.

Improved Outcomes With High-dose Isoniazid in Multidrug-resistant Tuberculosis Treatment in Haiti.

We report outcomes for a cohort of patients with multidrug-resistant tuberculosis who received high-dose isoniazid in Haiti. Patients who received high-dose isoniazid had a faster time to culture conversion and higher odds of successful outcome, despite high-level isoniazid resistance. This suggests high-dose isoniazid may have effectiveness even with phenotypic resistance.

High Burden of Non-communicable Diseases among a Young Slum Population in Haiti.

The objective of this study was to characterize the demographics and population health of four slum communities in Port-au-Prince, Haiti, including population density and the burden of communicable and non-communicable diseases. Four urban slums were surveyed using a population-representative design between July and October 2016. A multistage cluster area random sampling process was used to identify households and individuals for the survey. Household surveys included rosters of residents, household characteristics, adult and child deaths in the past year, child health, and healthcare access and utilization. Individual surveys of two randomly sampled adults from each household included sociodemographic data, maternal health, and adult health. Additionally, blood pressure, height, weight, and psychological distress were measured by study staff. Data were weighted for complex survey design and non-response. A total of 525 households and 894 individuals completed the survey (96% household and 90% individual response rate, respectively). The estimated population density was 58,000 persons/km2. Across slums, 55% of all residents were female, and 38% were adolescents and youth 10-24 years. Among adults, 58% were female with median age 29 years (22-38). The most common adult illnesses were severe psychological distress (24%), hypertension (20%), history of physical injury/trauma (10%), asthma (7%), history of cholera (4%), and history of tuberculosis (3%). Ten percent of adults had obesity (BMI > 30 kg/m2), and 7% currently smoked. The most common under-5 diseases during the last 3 months were respiratory and gastrointestinal illnesses (50% and 28%, respectively). One-third of households reported needing medical care for a child in the past year but not being able to access it, largely due to financial constraints. Unique features of these slums are a population structure dominated by adolescents and youth, a high proportion of females, and a high burden of non-communicable diseases including hypertension and psychological distress. Screening, diagnostic, and disease management interventions are urgently needed to protect and promote improved population health outcomes in these slum communities.

Factors associated with adolescent and caregiver reported problems in using asthma medications.

OBJECTIVES: The purpose of this study was to: (a) describe the types of medication problems/concerns youth with asthma and their caregivers reported and (b) examine the association between sociodemographic characteristics and youth and caregiver reported medication problems/concerns. METHODS: English- and Spanish-speaking youth ages 11-17 with persistent asthma were recruited at four pediatric clinics. Youth were interviewed and caregivers completed questionnaires about reported asthma medication concerns/problems. Multiple logistic regression was used to analyze the data. RESULTS: Three hundred and fifty-nine youth were recruited. Eighty percent of youth and 70% of caregivers reported one or more problems in using asthma medications. The most commonly reported problems by youth were: (a) hard to remember when to take the asthma medication (54%) and (b) hard to use asthma medication at school (34%). Younger children were significantly more likely to report difficulty in understanding their asthma medication's directions and difficulty reading the print on the medication's package. Caregivers' top-reported problem was that it is hard for their child to remember to take their asthma medications (49%). Caregivers without Medicaid were significantly more likely to express difficulty paying for their child's asthma medications. CONCLUSIONS: Difficulty remembering to take asthma medication was a significant problem for youth and their caregivers. Providers should work with youth and their caregivers to identify asthma medication problems and discuss strategies to address those problems.

Smart pumps improve medication safety but increase alert burden in neonatal care.

BACKGROUND: Smart pumps have been widely adopted but there is limited evidence to understand and support their use in pediatric populations. Our objective was to assess whether smart pumps are effective at reducing medication errors in the neonatal population and determine whether they are a source of alert burden and alert fatigue in an intensive care environment. METHODS: Using smart pump records, over 370,000 infusion starts for continuously infused medications used in neonates and infants hospitalized in a level IV NICU from 2014 to 2016 were evaluated. Attempts to exceed preset soft and hard maximum limits, percent variance from those limits, and pump alert frequency, patterns and salience were evaluated. RESULTS: Smart pumps prevented 160 attempts to exceed the hard maximum limit for doses that were as high as 7-29 times the maximum dose and resulted in the reprogramming or cancellation of 2093 infusions after soft maximum alerts. While the overall alert burden from smart pumps for continuous infusions was not high, alerts clustered around specific patients and medications, and a small portion (17%) of infusions generated the majority of alerts. Soft maximum alerts were often overridden (79%), consistent with low alert salience. CONCLUSIONS: Smart pumps have the ability to improve neonatal medication safety when compliance with dose error reducing software is high. Numerous attempts to administer high doses were intercepted by dosing alerts. Clustered alerts may generate a high alert burden and limit safety benefit by desensitizing providers to alerts. Future efforts should address ways to improve alert salience.

Evaluating the design and reporting of pragmatic trials in osteoarthritis research.

Objectives: Among the challenges in health research is translating interventions from controlled experimental settings to clinical and community settings where chronic disease is managed daily. Pragmatic trials offer a method for testing interventions in real-world settings but are seldom used in OA research. The aim of this study was to evaluate the literature on pragmatic trials in OA research up to August 2016 in order to identify strengths and weaknesses in the design and reporting of these trials. Methods: We used established guidelines to assess the degree to which 61 OA studies complied with pragmatic trial design and reporting. We assessed design according to the pragmatic-explanatory continuum indicator summary and reporting according to the pragmatic trials extension of the CONsolidated Standards of Reporting Trials guidelines. Results: None of the pragmatic trials met all 11 criteria evaluated and most of the trials met between 5 and 8 of the criteria. Criteria most often unmet pertained to practitioner expertise (by requiring specialists) and criteria most often met pertained to primary outcome analysis (by using intention-to-treat analysis). Conclusion: Our results suggest a lack of highly pragmatic trials in OA research. We identify this as a point of opportunity to improve research translation, since optimizing the design and reporting of pragmatic trials can facilitate implementation of evidence-based interventions for OA care.

Psychogenic pseudosyncope: Not always a diagnosis of exclusion.

BACKGROUND: Psychogenic pseudosyncope (PPS) frequently mimics syncope. The aim of this study was to assess the prevalence and clinical features of PPS and its relationship to vasovagal syncope (VVS). METHODS: We examined retrospectively the medical records of 1,401 consecutive patients referred to a syncope unit. We identified patients who had the final diagnosis of PPS. In these patients, we retrieved the initial diagnosis made during their first visit and the subsequent tests performed leading to the final diagnosis. RESULTS: Fourteen (1.0%) patients (mean age 35 ± 14; 11 females) were diagnosed as having PPS: seven had a diagnosis of PPS alone and seven had both VVS and PPS. High frequency of attacks (53 ± 35 attacks during the previous year), prolonged loss of consciousness (minutes to > 1 hour), and a history of psychiatric disorders characterized PPS patients. Tilt test reproduced a PPS attack in the presence of normal blood pressure and heart rate in seven patients (50%), and induced VVS in another three patients who had the final diagnosis of both PPS and VVS. In two patients, one or more events occurred during the clinic visits and were directly witnessed by the clinic personnel. CONCLUSIONS: We have shown that 1% of referrals to a syncope unit have the final diagnosis of PPS and that up to 50% of cases presented with a different initial diagnosis, namely VVS. Our findings suggest that causality between syncope and psychiatric disorders is likely bidirectional. The presence of a multidisciplinary team is important to address this often unrecognized relationship.

Targeted transgene integration overcomes variability of position effects in zebrafish.

Zebrafish transgenesis is increasingly popular owing to the optical transparency and external development of embryos, which provide a scalable vertebrate model for in vivo experimentation. The ability to express transgenes in a tightly controlled spatio-temporal pattern is an important prerequisite for exploitation of zebrafish in a wide range of biomedical applications. However, conventional transgenesis methods are plagued by position effects: the regulatory environment of genomic integration sites leads to variation of expression patterns of transgenes driven by engineered cis-regulatory modules. This limitation represents a bottleneck when studying the precise function of cis-regulatory modules and their subtle variants or when various effector proteins are to be expressed for labelling and manipulation of defined sets of cells. Here, we provide evidence for the efficient elimination of variability of position effects by developing a PhiC31 integrase-based targeting method. To detect targeted integration events, a simple phenotype scoring of colour change in the lens of larvae is used. We compared PhiC31-based integration and Tol2 transgenesis in the analysis of the activity of a novel conserved enhancer from the developmentally regulated neural-specific esrrga gene. Reporter expression was highly variable among independent lines generated with Tol2, whereas all lines generated with PhiC31 into a single integration site displayed nearly identical, enhancer-specific reporter expression in brain nuclei. Moreover, we demonstrate that a modified integrase system can also be used for the detection of enhancer activity in transient transgenesis. These results demonstrate the power of the PhiC31-based transgene integration for the annotation and fine analysis of transcriptional regulatory elements and it promises to be a generally desirable tool for a range of applications, which rely on highly reproducible patterns of transgene activity in zebrafish.

Measuring Harm in Health Care: Optimizing Adverse Event Review.

OBJECTIVE: The objective of this study was to identify modifiable factors that improve the reliability of ratings of severity of health care-associated harm in clinical practice improvement and research. METHODS: A diverse group of clinicians rated 8 types of adverse events: blood product, device or medical/surgical supply, fall, health care-associated infection, medication, perinatal, pressure ulcer, surgery. We used a generalizability theory framework to estimate the impact of number of raters, rater experience, and rater provider type on reliability. RESULTS: Pharmacists were slightly more precise and consistent in their ratings than either physicians or nurses. For example, to achieve high reliability of 0.83, 3 physicians could be replaced by 2 pharmacists without loss in precision of measurement. If only 1 rater was available for rating, ∼5% of the reviews for severe harm would have been incorrectly categorized. Reliability was greatly improved with 2 reviewers. CONCLUSIONS: We identified factors that influence the reliability of clinician reviews of health care-associated harm. Our novel use of generalizability analyses improved our understanding of how differences affect reliability. This approach was useful in optimizing resource utilization when selecting raters to assess harm and may have similar applications in other settings in health care.