Factors Associated With the Discontinuation of Two Short-Course Tuberculosis Preventive Therapies in Programmatic Settings in the United States.

Background: The objective of this study was to investigate timing and risk factors for discontinuation of short-course tuberculosis preventive therapy (TPT) comparing directly observed 3-month isoniazid/rifapentine (3HP) vs self-administered 4-month rifampin (4R). Methods: This was a subanalysis of a 6-month health department cohort (2016-2017) of 993 latent tuberculosis infection (LTBI) patients initiating 3HP (20%) or 4R (80%). Time at risk of TPT discontinuation was compared across regimens. Risk factors were assessed using mixed-effects Cox models. Results: Short-course TPT discontinuation was higher with 4R (31% vs 14%; P < .0001), though discontinuation timing was similar. Latino ethnicity (hazard ratio [HR], 1.80; 95% CI, 1.20-2.90) and adverse events (HR, 4.30; 95% CI, 2.60-7.30) increased 3HP discontinuation risk. Social-behavioral factors such as substance misuse (HR, 12.00; 95% CI, 2.20-69.00) and congregate living (HR, 21.00; 95% CI, 1.20-360.00) increased 4R discontinuation risk. Conclusions: TPT discontinuation differed by regimen, with distinct risk factors. Addressing social determinants of health within TPT programs is critical to enhance completion rates and reduce TB disease risk in marginalized populations.

Hip and trunk kinematics during reaching on a mobile and stable seat.

Reaching movements are often used to assess selective trunk control in people with neurological conditions. Also, it is known that reaching performance after stroke is increased through training on a mobile seat compared to conventional physical therapy. However, the effect of a mobile seat on joint kinematics has not yet been investigated. This study aimed to quantify differences in the range of motion of the hip and trunk during reaching exercises on a mobile and stable sitting surface. Fifteen healthy participants performed reaching beyond arm's length on a mobile and a stable seat in four different directions: ipsilateral, anterior, contralateral, and contralateral diagonal. Biomechanical data were collected, including kinematics of the hip and trunk, and surface electromyography of the trunk muscles. The mobile sitting surface led to a higher range of motion in the trunk and the hip in the frontal and sagittal plane, but not in the rotational plane. Differences between reaching directions were found in all joint directions, except that of trunk flexion. Hence, movement patterns of the hip and trunk differ during reaching on different sitting surfaces and in different directions. A larger range of motion in the frontal or sagittal plane while training on the mobile seat provides added neuromuscular stimuli to the trunk muscles (= a higher demand on trunk muscles), which could result in more efficient training and therefore, increased trunk control after stroke. However, this has to be investigated in a future study with people after stroke.

The Effect on Muscle Activity of Reaching Beyond Arm's Length on a Mobile Seat: A Pilot Study for Trunk Control Training for People After Stroke.

Objective: This pilot study compared muscle activity during lateral reaching tasks between mobile and stable sitting using a novel therapy chair in people after stroke and healthy controls. Design: Observational pilot study. Setting: This study was conducted in a rehabilitation center for people after stroke and at the university's movement laboratory for healthy participants. Participants: A total of eleven people after stroke and fifteen healthy people (N=26) took part. Interventions: Lateral reaching exercises to the ipsilateral and contralateral sides were performed on a mobile and a stable seat. Main Outcome Measure: Muscular activity of the multifidus, erector spinae and external oblique was measured bilaterally. A within-subject linear mixed model was applied to analyze the effects of seat condition, task, muscle side, and group. Results: A seat condition effect was found for the multifidus and external oblique that was dependent on the muscle side and task. During ipsilateral reaching, the activity of the multifidi decreased for people after stroke on the mobile seat, while increasing for healthy participants. The erector spinae showed no condition effect. Decreased activity of the external oblique was found for both groups on the mobile seat. Conclusions: Mobile sitting influences muscular activity. However, these preliminary results should be further investigated in order to generate recommendations for rehabilitation.

The disparate impact of age-based COVID-19 vaccine prioritization by race/ethnicity in Denver, Colorado.

COVID-19 vaccines are an effective tool in preventing severe disease. Most states used an age-based prioritization for vaccine rollout. We examined the impact of a primarily age-based prioritization policy on reductions of severe disease in different racial and ethnic groups. We calculated age-specific rates of COVID-19 hospitalization and death by race/ethnicity in Denver, Colorado. To assess potentially averted hospitalizations and deaths by race/ethnicity, we then applied the first three phases of Colorado's primarily age-based vaccine rollout criteria to historical 2020 COVID-19 hospitalizations and deaths in Denver, Colorado. In the first 3 phases, 40% (1403/3473) of hospitalizations and 83% (503/604) of deaths occurred among those meeting age and long-term care facility criteria and could have been averted. Impacts varied by race/ethnicity with only 28% (440/1587) of hospitalizations and 74% (131/178) of deaths averted among Hispanic or Latino residents, compared to 57% (619/1094) of hospitalizations and 92% (252/274) of deaths among non-Hispanic White residents. We demonstrate using local data and policy that early age-based prioritization decisions disproportionately promoted reductions in severe disease among non-Hispanic White residents irrespective of COVID-19 risk in Denver, Colorado. These findings suggest that more equitable future vaccine prioritization policies, which lead with a goal of reducing health disparities through prioritizing susceptibility to adverse health outcomes rather than overall population-based cutoffs, are necessary. Our results have implications for future vaccination rollouts in limited vaccine resource conditions.

Surface electromyographic activity of trunk muscles during trunk control exercises for people after stroke; effect of a mobile and stable seat for rehabilitation.

The aim of this study was to explore differences in trunk muscle activity on a stable and mobile seat for people after stroke and healthy participants. Trunk control exercises are known to have a beneficial effect on trunk control, balance, and mobility after stroke. The effect of such exercises could be enhanced by the use of a mobile seat to provide further training stimuli. However, little research on the musculoskeletal effects of trunk training on mobile seats has been carried out. On a stable and a mobile seat, thirteen people after stroke and fifteen healthy participants performed two selective trunk control exercises, which were lateral flexion initiated by the pelvis and the thorax. The maximal surface electromyography relative to static sitting of the muscles multifidus, erector spinae, and obliquus externus was recorded bilaterally. The effects of group, seat condition, trunk control exercise, and muscle side were investigated employing within-subject linear-mixed-models. Compared to the stable seat, the maximal muscle activity of people after stroke on the mobile seat was higher during the thorax-initiated exercise and lower during the pelvis-initiated exercise. Healthy participants showed opposite results with higher muscle activity on the mobile seat during the pelvis-initiated exercise. For trunk control training on a mobile seat with high muscle activation people after stroke should perform trunk control exercises initiated by the thorax, for training with lower muscle activity people after stroke should initiate selective trunk movements by the pelvis. The results can support the planning of progressive trunk control rehabilitation programs.

Linezolid use for the treatment of multidrug-resistant tuberculosis, TB centers of excellence, United States, 2013-2018.

BACKGROUND: In 2019, the World Health Organization released guidelines reflecting major changes in multidrug-resistant tuberculosis (MDR-TB) management-prioritizing fluoroquinolones, bedaquiline, and linezolid (LZD) while de-emphasizing previously favored injectable agents. In some cases, linezolid use is associated with gastrointestinal intolerance, mitochondrial toxicity, and significant drug interactions. CDC's Division of Tuberculosis Elimination supports a network of regional TB Centers of Excellence, which provide medical consultation to healthcare providers. Consultations are documented in a medical consultation database (MCD) enabling evaluation of management questions and recommendations. We describe the scope of clinical inquiries and responses specific to linezolid use for MDR-TB in the US. RESEARCH QUESTION: What are the major themes of provider and patient challenges regarding the use of linezolid for the treatment of MDR-TB in the US? METHODS: We queried MCD consults categorized as "MDR/XDR-TB" from 1/1/2013 to 12/31/2018. Only linezolid-specific consultations were included; incomplete and duplicate entries were excluded as were those citing linezolid historically or theoretically. Subgroup characteristics were assessed (e.g., Center, year, provider type). A descriptive coding scheme was developed through inductive thematic analysis. RESULTS: In 2013-2018 of the 1889 consults regarding MDR/XDR-TB, 934 MDR-TB consults referenced linezolid; 137 met inclusion criteria, representing between 4 and 10% of MDR-TB consults annually. Four main themes emerged: adverse effects (71.5%); concerns about linezolid use due to co-morbidities or concurrent medication use (15.3%); dosing adjustments (8.8%); and monitoring and maintenance logistics (4.4%). INTERPRETATIONS: Linezolid consults consistently exceeded 4% of all consults annually over the 6-year period, suggesting a need for access to expert opinion for providers using linezolid to manage MDR-TB. While only a snapshot of MDR-TB in the US, this evaluation summarizes major provider concerns regarding particular adverse effects, and highlights a need for evidence-based guidance regarding linezolid dosing and toxicity management.

Higher Completion Rates With Self-administered Once-weekly Isoniazid-rifapentine Versus Daily Rifampin in Adults With Latent Tuberculosis.

BACKGROUND: Treatment of latent tuberculosis (LTBI) is important for tuberculosis (TB) prevention, and short course rifamycin-based therapies are preferred. Once-weekly isoniazid-rifapentine by self-administered therapy (3HP-SAT) has never been compared with 4 months of daily rifampin (4R). METHODS: Retrospective cohort study of adults ≥18 years of age initiating LTBI treatment with either 3HP-SAT or 4R in a United States (US)-based TB clinic between 11 April 2016 and 31 December 2018. We evaluated treatment completion through pharmacy fills and reviewed charts for reasons of noncompletion, including adverse events (AEs). The χ 2 test and a log-binomial multivariable model were used to compare treatment completion and AEs. RESULTS: Five hundred sixty individuals (42%) initiated 3HP-SAT and 773 (58%) initiated 4R. Median age was 38, 55% were female, and 89% were born outside of the US. Among those aged 18-49 years, treatment completion with 3HP-SAT was 79% compared to 68% with 4R (adjusted risk ratio [aRR], 1.17 [95% CI, 1.17-1.27]; P < .0001). Among individuals aged ≥50 years, treatment completion with 3HP-SAT was 87% compared to 64% with 4R (aRR, 1.35 [95% CI, 1.19-1.52]; P < .0001). Compared to 4R, there was no difference in risk of AEs in the 18-49 age group (aRR, 0.93 [95% CI, .58-1.48]; P = .75). Reduced risk of AEs was noted among patients aged ≥50 years who received 3HP-SAT (aRR, 0.37 [95% CI, .16-.85]; P = .02). CONCLUSIONS: 3HP-SAT was associated with higher LTBI treatment completion and lower rates of AEs compared to 4R in individuals aged 50 and older. Expanding 3HP-SAT as an option for patients with LTBI may enhance TB prevention strategies in the US.

Interferon-Gamma Release Assay Testing in Children Younger Than 2 Years in a US-Based Health System.

BACKGROUND: Use of interferon-gamma releasing assays (IGRAs) in children <2 years old may derive many of the same advantages, which have led to preference over tuberculin skin test (TST) in older children, but data are limited. Since 2011, we have tested children <2 years old with Quantiferon-TB Gold/Gold Plus (QFT)) in select clinical scenarios at Denver Health, a health system encompassing a TB clinic, refugee and immigrant screening and primary care. METHODS: We identified patients <2 years old tested with QFT between February, 2011 and August, 2019. The primary outcome measure was incident cases of TB among tested patients. Test results and in vitro characteristics were analyzed, as were demographic, epidemiologic and clinical outcomes. RESULTS: We analyzed 116 QFTs ordered in children age 7-23 months. Two were positive, 3 indeterminate, 3 failed/refused phlebotomy and the remainder (93%) were negative. Mitogen tube results were robust. Thirteen patients were TST-positive: 11 were QFT-negative, 1 QFT-positive and 1 failed phlebotomy. Eight patients received some form of TB medication, including 4 QFT-negative patients who were treated for active TB or latent TB infection based on positive TST or clinical findings. Among QFT-negative patients, including 6 TST-positive, not treated for active TB or latent TB infection, no TB disease has been identified over a median follow-up time of 2.96 years. CONCLUSIONS: IGRA use was not limited by barriers of phlebotomy, indeterminate result or gamma-interferon production. The risk of missing an infected but IGRA-negative patient can be reduced by treatment of select patients at higher risk. Current recommendations against IGRA use in children <2 years old could be amended to allow careful introduction, particularly among well-appearing BCG-vaccinated patients.

Clinical Characteristics of Active Tuberculosis Diagnosed After Starting Treatment for Latent Tuberculosis Infection.

Although rare, subclinical tuberculosis disease can be missed during evaluations for latent tuberculosis infection, and can manifest with symptoms during latent tuberculosis treatment. Among over 8000 patients treated for latent tuberculosis we found no evidence of acquired drug resistance, underscoring the safety of rifampin monotherapy for latent tuberculosis.

Diagnostic Tests for Latent Tuberculosis Infection.

Diagnosing latent tuberculosis (TB) infection (LTBI) is important globally for TB prevention. LTBI diagnosis requires a positive test for infection and negative evaluation for active disease. Current tests measure an immunologic response and include the tuberculin skin test (TST) and interferon-gamma release assays (IGRAs), T-SPOT.TB and QuantiFERON. The IGRAs are preferred in bacille Calmette-Guérin-vaccinated populations. The TST is still used when cost or logistical advantages over the IGRAs exist. Both TST and IGRAs have low positive predictive values. Tests that differentiate the TB spectrum and better predict future TB risk are needed.

Structural Basis of Nanobodies Targeting the Prototype Norovirus.

Human norovirus infections are a major disease burden. In this study, we analyzed three new norovirus-specific Nanobodies that interacted with the prototype human norovirus (i.e., genogroup I genotype 1 [GI.1]). We showed that the Nanobodies bound on the side (Nano-7 and Nano-62) and top (Nano-94) of the capsid-protruding (P) domain using X-ray crystallography. Nano-7 and Nano-62 bound at a similar region on the P domain, but the orientations of these two Nanobodies clashed with the shell (S) domain and neighboring P domains on intact particles. This finding suggested that the P domains on the particles should shift in order for Nano-7 and Nano-62 to bind to intact particles. Interestingly, both Nano-7 and Nano-94 were capable of blocking norovirus virus-like particles (VLPs) from binding to histo-blood group antigens (HBGAs), which are important cofactors for norovirus infection. Previously, we showed that the GI.1 HBGA pocket could be blocked with the soluble human milk oligosaccharide 2-fucosyllactose (2'FL). In the current study, we showed that a combined treatment of Nano-7 or Nano-94 with 2'FL enhanced the blocking potential with an additive (Nano-7) or synergistic (Nano-94) effect. We also found that GII Nanobodies with 2'FL also enhanced inhibition. The Nanobody inhibition likely occurred by different mechanisms, including particle aggregation or particle disassembly, whereas 2'FL blocked the HBGA binding site. Overall, these new data showed that the positive effect of the addition of 2'FL was not limited to a single mode of action of Nanobodies or to a single norovirus genogroup.IMPORTANCE The discovery of vulnerable regions on norovirus particles is instrumental in the development of effective inhibitors, particularly for GI noroviruses that are genetically diverse. Analysis of these GI.1-specific Nanobodies has shown that similar to GII norovirus particles, the GI particles have vulnerable regions. The only known cofactor region, the HBGA binding pocket, represents the main target for inhibition. With a combination treatment, i.e., the addition of Nano-7 or Nano-94 with 2'FL, the effect of inhibition was increased. Therefore, combination drug treatments might offer a better approach to combat norovirus infections, especially since the GI genotypes are highly diverse and are continually changing the capsid landscape, and few conserved epitopes have so far been identified.

Updates in the Treatment of Active and Latent Tuberculosis.

First-line therapy for active tuberculosis (TB) has remained unchanged for nearly 40 years. Isoniazid, rifampin, pyrazinamide, and ethambutol for the initial two-month phase followed by isoniazid and rifampin for 4 to 7 months is standard treatment for people at low risk for drug-resistant disease. Directly-observed therapy (DOT) remains the standard of care for pulmonary TB. Virtual treatment monitoring using digital technologies is becoming more common as a way to provide a more patient-centered approach to care. Attempts to shorten treatment duration have been unsuccessful based on recent clinical trials evaluating the role of fluoroquinolones. Treatment-shortening trials using higher doses of rifamycins are currently underway. Recently approved medications for TB treatment are recommended only for drug-resistant disease, but novel agents in varying stages of development are being evaluated. Rifamycin-based regimens for latent TB infection (LTBI) have been successful in preventing progression to TB disease. Once-weekly isoniazid and rifapentine for 12 weeks by DOT was shown to be safe and effective compared with 9 months of isoniazid. The same regimen was shown to have acceptable treatment completion when given self-administered. Newer studies are investigating even shorter LTBI treatment with durations of less than 2 months. Treatment of LTBI in people likely infected with multidrug resistant TB is very limited, but one observational study found that fluoroquinolones appear to be effective. The first randomized trials for treating LTBI in contacts to MDR-TB are currently enrolling.

Tuberculosis among individuals with community-acquired pneumonia presenting to emergency in Gaborone, Botswana.

Delays in diagnosing Tuberculosis (TB) are associated with increased transmission. TB may present as a clinical syndrome that mimics community-acquired pneumonia (CAP). The aim of this paper was to determine frequency of TB among patients with CAP at a referral hospital in Gaborone, Botswana. We performed a retrospective study of adults presenting with CAP from April 2010-October 2011 to the Emergency Department (ED); we matched this cohort to the National Botswana Tuberculosis Registry (NBTR) to identify individuals subsequently diagnosed with TB. We assessed demographics, time to TB diagnosis, clinical outcomes and performed logistic regressions to identify factors associated with TB diagnosis. We identified 1305 individuals presenting with CAP; TB was subsequently diagnosed in 68 (5.2%). The median time to TB diagnosis was 9.5 days. Forty percent were AFB sputum smear positive and 87% were identified as being HIV-positive. Subsequent diagnosis of TB is common among individuals with CAP at our ED, suggesting that TB may be present at the time of CAP presentation. Given the lack of distinguishing clinical factors between pulmonary TB and CAP, adults presenting with CAP should be evaluated for active TB in Botswana.

Better Completion of Pediatric Latent Tuberculosis Treatment Using 4 Months of Rifampin in a US-based Tuberculosis Clinic.

BACKGROUND: Children less than 5 years of age have the highest age-specific rate of progression from latent tuberculosis infection (LTBI) to active disease. Therefore, regimens for treatment of pediatric LTBI must be not only efficacious but practical enough to overcome the unique childhood barriers to regimen adherence. Since 2012, a 4-month regimen of daily rifampin (4R) has been the standard recommendation for pediatric LTBI at the Denver Metro Tuberculosis Clinic. METHODS: Using univariate and multivariate analyses, we compared treatment completion rates between 4R and 9-month isoniazid (9H) regimens for all pediatric patients treated for LTBI at the Denver Metro Tuberculosis Clinic between January 1, 2006, and December 31, 2015, and assessed the influence of clinical and demographic characteristics on successful completion of the 2 regimens. RESULTS: There were 395 children in the 4R cohort and 779 in the 9H cohort. Completion rates overall were significantly higher for 4R than 9H (83.5% vs. 68.8%, P < 0.001). Drug toxicity leading to treatment noncompletion was low in both groups (1.5% in 4R and 0.7% in 9H, P = 0.23), and no patient progressed to active tuberculosis in either cohort. The 9H cohort was more likely to fail treatment completion because of barriers potentially related to the longer duration of treatment such as relocation or loss to follow-up. CONCLUSIONS: Pediatric patients were significantly more likely to complete LTBI treatment using a 4R than with a 9-month isoniazid regimen. Better completion rates of 4R may increase efficacy of tuberculosis prevention and decrease demand on public health resources.

Preferential Use of Nitrofurantoin Over Fluoroquinolones for Acute Uncomplicated Cystitis and Outpatient Escherichia coli Resistance in an Integrated Healthcare System.

OBJECTIVES To evaluate changes in outpatient fluoroquinolone (FQ) and nitrofurantoin (NFT) use and resistance among E. coli isolates after a change in institutional guidance to use NFT over FQs for acute uncomplicated cystitis. DESIGN Retrospective preintervention-postintervention study. SETTING Urban, integrated healthcare system. PATIENTS Adult outpatients treated for acute cystitis. METHODS We compared 2 time periods: January 2003-June 2007 when FQs were recommended as first-line therapy, and July 2007-December 2012, when NFT was recommended. The main outcomes were changes in FQ and NFT use and FQ- and NFT-resistant E. coli by time-series analysis. RESULTS Overall, 5,714 adults treated for acute cystitis and 11,367 outpatient E. coli isolates were included in the analysis. After the change in prescribing guidance, there was an immediate 26% (95% CI, 20%-32%) decrease in FQ use (P<.001), and a nonsignificant 6% (95% CI, -2% to 15%) increase in NFT use (P=.12); these changes were sustained over the postintervention period. Oral cephalosporin use also increased during the postintervention period. There was a significant decrease in FQ-resistant E. coli of -0.4% per quarter (95% CI, -0.6% to -0.1%; P=.004) between the pre- and postintervention periods; however, a change in the trend of NFT-resistant E. coli was not observed. CONCLUSIONS In an integrated healthcare system, a change in institutional guidance for acute uncomplicated cystitis was associated with a reduction in FQ use, which may have contributed to a stabilization in FQ-resistant E. coli. Increased nitrofurantoin use was not associated with a change in NFT resistance. Infect Control Hosp Epidemiol 2017;38:461-468.

Effects of a Syndrome-Specific Antibiotic Stewardship Intervention for Inpatient Community-Acquired Pneumonia.

Background. Syndrome-specific interventions are a recommended approach to antibiotic stewardship, but additional data are needed to understand their potential impact. We implemented an intervention to improve the management of inpatient community-acquired pneumonia (CAP) and evaluated its effects on antibiotic and resource utilization. Methods. A stakeholder group developed and implemented a clinical practice guideline and order set for inpatient, non-intensive care unit CAP recommending a short course (5 days) of a fluoroquinolone-sparing antibiotic regimen in uncomplicated cases. Unless there was suspicion for complications or resistant pathogens, chest computed tomography (CT) and sputum cultures were discouraged. This was a retrospective preintervention postintervention study of patients hospitalized for CAP before (April 15, 2008-May 31, 2009) and after (July 1, 2011-July 31, 2012) implementation of the guideline. The primary comparison was the difference in duration of therapy during the baseline and intervention periods. Secondary outcomes included changes in use of levofloxacin, CT scans, and sputum culture. Results. One hundred sixty-six and 84 cases during the baseline and intervention periods, respectively, were included. From the baseline to intervention period, the median duration of therapy decreased from 10 to 7 days (P < .0001). Prescription of levofloxacin at discharge decreased from 60% to 27% of cases (P < .0001). Use of chest CT and sputum culture decreased from 47% to 32% of cases (P = .02) and 51% to 31% of cases (P = .03), respectively. The frequency of clinical failure between the 2 periods was similar. Conclusions. A syndrome-specific intervention for inpatient CAP was associated with shorter treatment durations and reductions in use of fluoroquinolones and low-yield diagnostic tests.

Mycobacterial Lung Disease Complicating HIV Infection.

Mycobacterial infections have caused enormous morbidity and mortality in people living with human immunodeficiency virus (HIV) infection. Of these, the most devastating has been tuberculosis (TB), the leading cause of death among HIV-positive persons globally. TB has killed more people living with HIV than any other infection. Diagnosis of latent TB infection (LTBI) is critical as treatment can prevent emergence of TB disease. Bacteriologic confirmation of TB disease should be sought whenever possible as well as drug susceptibility testing. When detected early, drug susceptible TB is curable. Similar to TB, nontuberculous mycobacteria (NTM) can also produce pulmonary and extrapulmonary infections including disseminated disease that can be fatal. Diagnosis through accurate identification of the pathogenic organism will greatly inform treatment. Depending on the NTM identified, treatment may not be curable. Ultimately, preventive strategies such as initiation of antiretroviral drugs and treatment of LTBI are interventions expected to have significant impacts on control of TB and NTM in the setting of HIV. This chapter will review the impact of pulmonary mycobacterial infections on HIV-positive individuals.